Delayed-enhanced cardiac MRI for differentiation of Fabry's disease from symmetric hypertrophic cardiomyopathy.

PubMed

De Cobelli, Francesco; Esposito, Antonio; Belloni, Elena; Pieroni, Maurizio; Perseghin, Gianluca; Chimenti, Cristina; Frustaci, Andrea; Del Maschio, Alessandro

2009-03-01

Fabry's disease may be difficult to differentiate from symmetric hypertrophic cardiomyopathy. Our aim was to compare the myocardial location and distribution patterns of delayed enhancement between patients with Fabry's disease who are affected by symmetric myocardial hypertrophy and patients with symmetric hypertrophic cardiomyopathy in order to identify a specific sign to best differentiate the two diseases. Patients with Fabry's disease-related hypertrophy showed left ventricular (LV) delayed enhancement with a typical and consistently found pattern characterized by the involvement of the inferolateral basal or mid basal segments and a mesocardial distribution that spared the subendocardium. This pattern seems to be specific to Fabry's disease; in fact, patients with symmetric hypertrophic cardiomyopathy had variable locations and distributions of delayed enhancement. These observations may contribute to identifying Fabry's disease as a specific cause of symmetric hypertrophy.

Hypertrophic Cardiomyopathy: Practical Steps for Preventing Sudden Death.

ERIC Educational Resources Information Center

Maron, Barry J.

2002-01-01

Hypertrophic cardiomyopathy (HCM) is a rare cause of death among athletes, with deaths occurring in young, apparently healthy people. Differentiating HCM from conditioning hypertrophy is challenging. Routine detection involves family history, physical examination, electrocardiography, and echocardiography. Keys to differential diagnosis include…

An abnormal Ca2+ response in mutant sarcomere protein–mediated familial hypertrophic cardiomyopathy

PubMed Central

Fatkin, Diane; McConnell, Bradley K.; Mudd, James O.; Semsarian, Christopher; Moskowitz, Ivan G.P.; Schoen, Frederick J.; Giewat, Michael; Seidman, Christine E.; Seidman, J.G.

2000-01-01

Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; αMHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated αMHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease. PMID:11104788

Hypertrophic Cardiomyopathy Associated with Mid-cavity Obstruction and High Left Intraventricular Pressure

PubMed Central

A. Bejiqi, Ramush; J. Retkoceri, Ragip; Sh. Bejiqi, Hana

2011-01-01

We report a case of a child, with a rare form of the idiopathic hypertrophic cardiomyopathy, associated with mid-cavity obstruction and high intraventricular peak pressure. Cardiomyopathy, diagnosed antenataly, was followed postnataly and, despite of a lot echocardiographic findings - the growing, development and clinical signs are minimal. PMID:23407799

The rare association of tetralogy of Fallot with hypertrophic cardiomyopathy. Report of 2 neonatal patients.

PubMed Central

Lewin, M B; Towbin, J A; Thapar, M K; Dreyer, W J; Feltes, T F

1997-01-01

Although tetralogy of Fallot is commonly associated with other congenital heart defects, it is rarely found in conjunction with hypertrophic cardiomyopathy. We describe the cases of 2 neonates with this rare condition, both of whom required surgical intervention during infancy. Because hypertrophic cardiomyopathy is frequently familial, and tetralogy of Fallot is commonly found in patients diagnosed with chromosomal anomalies, we speculate about a possible genetic cause for this association. PMID:9339511

Myectomy and LA-to-LV Conduit for Severe Calcific Mitral Stenosis and Hypertrophic Cardiomyopathy.

PubMed

Meghji, Zahara; Nguyen, Anita; Geske, Jeffrey B; Schaff, Hartzell V

2018-02-26

Severe calcific mitral valve stenosis can rarely occur concomitantly with obstructive hypertrophic cardiomyopathy. In these patients, surgical decalcification of the stenotic mitral valve followed by mitral valve replacement carries significant operative risk and may result in paravalvular leakage, atrioventricular groove disruption, and excessive bleeding. We report the first 2 cases of obstructive hypertrophic cardiomyopathy with severe calcific mitral valve stenosis successfully treated with concomitant transaortic septal myectomy and bypass of the stenotic mitral valve using a valved left atrium to left ventricular conduit. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

A New 4D Trajectory-Based Approach Unveils Abnormal LV Revolution Dynamics in Hypertrophic Cardiomyopathy

PubMed Central

Madeo, Andrea; Piras, Paolo; Re, Federica; Gabriele, Stefano; Nardinocchi, Paola; Teresi, Luciano; Torromeo, Concetta; Chialastri, Claudia; Schiariti, Michele; Giura, Geltrude; Evangelista, Antonietta; Dominici, Tania; Varano, Valerio; Zachara, Elisabetta; Puddu, Paolo Emilio

2015-01-01

The assessment of left ventricular shape changes during cardiac revolution may be a new step in clinical cardiology to ease early diagnosis and treatment. To quantify these changes, only point registration was adopted and neither Generalized Procrustes Analysis nor Principal Component Analysis were applied as we did previously to study a group of healthy subjects. Here, we extend to patients affected by hypertrophic cardiomyopathy the original approach and preliminarily include genotype positive/phenotype negative individuals to explore the potential that incumbent pathology might also be detected. Using 3D Speckle Tracking Echocardiography, we recorded left ventricular shape of 48 healthy subjects, 24 patients affected by hypertrophic cardiomyopathy and 3 genotype positive/phenotype negative individuals. We then applied Generalized Procrustes Analysis and Principal Component Analysis and inter-individual differences were cleaned by Parallel Transport performed on the tangent space, along the horizontal geodesic, between the per-subject consensuses and the grand mean. Endocardial and epicardial layers were evaluated separately, different from many ecocardiographic applications. Under a common Principal Component Analysis, we then evaluated left ventricle morphological changes (at both layers) explained by first Principal Component scores. Trajectories’ shape and orientation were investigated and contrasted. Logistic regression and Receiver Operating Characteristic curves were used to compare these morphometric indicators with traditional 3D Speckle Tracking Echocardiography global parameters. Geometric morphometrics indicators performed better than 3D Speckle Tracking Echocardiography global parameters in recognizing pathology both in systole and diastole. Genotype positive/phenotype negative individuals clustered with patients affected by hypertrophic cardiomyopathy during diastole, suggesting that incumbent pathology may indeed be foreseen by these methods

Association between ventricular filling patterns and the extent of late enhancement on magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

PubMed

De Zan, M; Carrascosa, P; Deviggiano, A; Capunay, C; Rodríguez-Granillo, G A

To explore the relationship between ventricular filling curves and the extent of late enhancement on cardiac magnetic resonance imaging (MRI) in patients with hypertrophic cardiomyopathy. We retrospectively included consecutive patients with suspected and/or confirmed hypertrophic cardiomyopathy and a control group of patients matched for age and sex who underwent cardiac MRI with evaluation of late enhancement. Among other determinations, we evaluated the following parameters on cine sequences: peak filling rate, time to the first peak filling rate, and filling rate normalized to the filling volume. Late enhancement was observed in 29 (73%) of the 40 patients with hypertrophic cardiomyopathy. The normalized peak filling rate was significantly lower in patients with late enhancement (4.9 ± 1.6 in those with hypertrophic cardiomyopathy positive for late enhancement vs. 5.8 ± 2.2 in those with hypertrophic cardiomyopathy negative for late enhancement vs. 6.3 ± 1.5 in controls, p = 0.008) and the time to peak filling was longer in patients with late enhancement (540.6 ± 89.7 ms vs. 505.5 ± 99.3 ms in those with hypertrophic cardiomyopathy negative for late enhancement vs. 486.9 ± 86.3 ms in controls, p = 0.02). When the population was stratified into three groups in function of the normalized peak filling rate, significant differences were observed among groups for age (p = 0.002), mean wall thickness (p = 0.036), and myocardial mass (p = 0.046) and atrial dimensions, whereas no significant differences with respect to late enhancement were seen. In patients with hypertrophic cardiomyopathy, we found a significant association between ventricular filling patterns and age, wall thicknesses, and atrial dimensions, but not with the extent of late enhancement. Copyright © 2016 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

Syncope in the young athlete: Assessment of prognosis in subjects with hypertrophic cardiomyopathy.

PubMed

Magalhães-Ribeiro, Carlos; Freitas, João

2016-01-01

Syncope is a common but concerning event in young athletes. Although mostly due to benign reflex causes, syncope may be arrhythmic and precede sudden cardiac death. Efforts must therefore be made to distinguish post-exertional syncope from syncope during exercise, which can be an ominous sign of a possible underlying heart disease, such as hypertrophic cardiomyopathy. Prevention requires cooperation between physician and athlete, in order to identify individuals at risk and to protect them from sudden death. Solving this diagnostic dilemma may lead to recommendations for athletes to be cleared to play or disqualified from competitive sports, and presents challenging and controversial decisions to the health care provider that can prove difficult to implement. Although exercise contributes to physical and psychological well-being, there are insufficient data to indicate whether an athlete with hypertrophic cardiomyopathy diagnosed after a syncopal episode can safely resume competitive physical activity. The purpose of this study was to review the literature on syncope in young athletes and its relationship to individuals with hypertrophic cardiomyopathy, in order to enable accurate assessment of prognosis and the possibility of resuming competitive sports. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Anaesthetic management of severe hypertrophic obstructive cardiomyopathy with bronchial asthma for emergency caesarean section.

PubMed

Rajesh, M C; Varma, Ravi; Lima, P; Ramdas, E K

2012-10-01

A 39-year-old primi and a known case of hypertrophic obstructive cardiomyopathy presented for emergency lower segment caesarean section. She was also an asthmatic with a recent exacerbation. She underwent uneventful lower segment caesarean section under general anaesthesia with lumbar epidural analgesia for postoperative pain relief. Anaesthetic agents and techniques were selected to suit the haemodynamic profile of severe hypertrophic obstructive cardiomyopathy in pregnancy. The case has been reported because of successful outcome in an emergency scenario with such high intraventricular gradients and omissions in the case so that it will be of benefit to readers who may happen to land up in similar situations.

Family communication in a population at risk for hypertrophic cardiomyopathy.

PubMed

Batte, Brittany; Sheldon, Jane P; Arscott, Patricia; Huismann, Darcy J; Salberg, Lisa; Day, Sharlene M; Yashar, Beverly M

2015-04-01

Encouraging family communication is an integral component of genetic counseling; therefore, we sought to identify factors impacting communication to family members at risk for Hypertrophic Cardiomyopathy (HCM). Participants (N = 383) completed an online survey assessing: 1) demographics (gender, genetic test results, HCM family history, and disease severity); 2) illness representations; 3) family functioning and cohesiveness; 4) coping styles; 5) comprehension of HCM autosomal dominant inheritance; and 6) communication of HCM risk information to at-risk relatives. Participants were a national sample of individuals with HCM, recruited through the Hypertrophic Cardiomyopathy Association. Data from 183 participants were analyzed using a logistic regression analysis, with family communication as a dichotomous dependent variable. We found that female gender and higher comprehension of autosomal dominant inheritance were significant predictors of participants' communication of HCM risk information to all their siblings and children. Our results suggest that utilizing interventions that promote patient comprehension (e.g., a teaching-focused model of genetic counseling) are important and may positively impact family communication within families with HCM.

Identification of novel biomarker candidates for hypertrophic cardiomyopathy and other cardiovascular diseases leading to heart failure.

PubMed

Rehulkova, H; Rehulka, P; Myslivcova Fucikova, A; Stulik, J; Pudil, R

2016-11-23

In-depth proteome discovery analysis represents new strategy in an effort to identify novel reliable specific protein markers for hypertrophic cardiomyopathy and other life threatening cardiovascular diseases. To systematically identify novel protein biomarkers of cardiovascular diseases with high mortality we employed an isobaric tag for relative and absolute quantitation (iTRAQ) proteome technology to make comparative analysis of plasma samples obtained from patients suffering from non-obstructive hypertrophic cardiomyopathy, stable dilated cardiomyopathy, aortic valve stenosis, chronic stable coronary artery disease and stable arterial hypertension. We found 128 plasma proteins whose abundances were uniquely regulated among the analyzed cardiovascular pathologies. 49 of them have not been described yet. Additionally, application of statistical exploratory analyses of the measured protein profiles indicated the relationship in pathophysiology of the examined cardiovascular pathologies.

Effect of Body Mass Index on Exercise Capacity in Patients With Hypertrophic Cardiomyopathy.

PubMed

Larsen, Carolyn M; Ball, Caroline A; Hebl, Virginia B; Ong, Kevin C; Siontis, Konstantinos C; Olson, Thomas P; Ackerman, Michael J; Ommen, Steve R; Allison, Thomas G; Geske, Jeffrey B

2018-01-01

The objective of this study was to evaluate the relation between body mass index (BMI), exercise capacity, and symptoms in patients with hypertrophic cardiomyopathy (HC) and to utilize results of cardiopulmonary exercise tests (CPX) and transthoracic echocardiograms to understand the mechanism(s) of reduced exercise capacity across body mass index groups. Over a 6-year period, 510 consecutive patients with HC seen at a tertiary referral center underwent (CPX) and a transthoracic echocardiogram. Increasing BMI was associated with decreased exercise capacity as assessed by peak VO 2 (ml/kg/min). However, the prevalence of cardiac impairment did not vary by BMI group. In conclusion, these findings suggest that in some patients with hypertrophic cardiomyopathy, cardiac impairment is not the primary cause of exercise limitation and weight loss may result in improved exercise capacity. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy: A Randomized Clinical Trial.

PubMed

Saberi, Sara; Wheeler, Matthew; Bragg-Gresham, Jennifer; Hornsby, Whitney; Agarwal, Prachi P; Attili, Anil; Concannon, Maryann; Dries, Annika M; Shmargad, Yael; Salisbury, Heidi; Kumar, Suwen; Herrera, Jonathan J; Myers, Jonathan; Helms, Adam S; Ashley, Euan A; Day, Sharlene M

2017-04-04

Formulating exercise recommendations for patients with hypertrophic cardiomyopathy is challenging because of concern about triggering ventricular arrhythmias and because a clinical benefit has not been previously established in this population. To determine whether moderate-intensity exercise training improves exercise capacity in adults with hypertrophic cardiomyopathy. A randomized clinical trial involving 136 patients with hypertrophic cardiomyopathy was conducted between April 2010 and October 2015 at 2 academic medical centers in the United States (University of Michigan Health System and Stanford University Medical Center). Date of last follow-up was November 2016. Participants were randomly assigned to 16 weeks of moderate-intensity exercise training (n = 67) or usual activity (n = 69). The primary outcome measure was change in peak oxygen consumption from baseline to 16 weeks. Among the 136 randomized participants (mean age, 50.4 [SD, 13.3] years; 42% women), 113 (83%) completed the study. At 16 weeks, the change in mean peak oxygen consumption was +1.35 (95% CI, 0.50 to 2.21) mL/kg/min among participants in the exercise training group and +0.08 (95% CI, -0.62 to 0.79) mL/kg/min among participants in the usual-activity group (between-group difference, 1.27 [95% CI, 0.17 to 2.37]; P = .02). There were no occurrences of sustained ventricular arrhythmia, sudden cardiac arrest, appropriate defibrillator shock, or death in either group. In this preliminary study involving patients with hypertrophic cardiomyopathy, moderate-intensity exercise compared with usual activity resulted in a statistically significant but small increase in exercise capacity at 16 weeks. Further research is needed to understand the clinical importance of this finding in patients with hypertrophic cardiomyopathy, as well as the long-term safety of exercise at moderate and higher levels of intensity. clinicaltrials.gov Identifier: NCT01127061.

[Hypertrophic cardiomyopathy: an intraoperative death case analysis and substantiation of the standards of perioperative anesthetic management in a non-cardiosurgery clinic].

PubMed

Fedosiuk, Roman N; Shchupachynska, Liliia O

2018-01-01

The article is based on the case analysis of a sudden and unexpected intraoperative death of a 51-year-old female patient with hypertrophic cardiomyopathy, who was undergoing a non-cardiac operation in a non-cardiosurgery clinic, from acute precipitation of left ventricular outflow tract obstruction provoked by surgery and anesthesia. It emphasizes the importance of raising non-cardiac anesthesiologists' awareness of the issue and having clear standards of pre-operative evaluation and perioperative management of patients with hypertrophic cardiomyopathy in order to avoid fatal medical errors. A literature review on the disease with an accent on anesthesia-related issues is also given, and four standards of perioperative anesthetic management of patients with hypertrophic cardiomyopathy presenting for non-cardiac surgery in general hospital settings are developed and offered.

Quantification of regional nonuniformity and paradoxical intramural mechanics in hypertrophic cardiomyopathy by high frame rate ultrasound myocardial strain mapping.

PubMed

Sengupta, Partho P; Mehta, Vimal; Arora, Ramesh; Mohan, Jagdish C; Khandheria, Bijoy K

2005-07-01

This study tested the hypothesis that linear mapping of regional myocardial strain comprehensively assesses variations in regional myocardial function in hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is characterized by disorganized myocardial architecture that results in spatial and temporal nonuniformity of regional function. Left ventricular deformation was quantified in 20 patients with hypertrophic cardiomyopathy and compared with 25 age- and sex-matched control subjects. Abnormalities in subendocardial strain ranged from reduced longitudinal shortening to paradoxical systolic lengthening and delayed regional longitudinal contractions that were often located in small subsegmental areas. These variations were underestimated significantly by arbitrary measurements compared with linear mapping, in which a region of interest was moved across the longitudinal length of left ventricle (difference of peak and least strain, 10.7% +/- 5.1% vs 17% +/- 5.5%; P < .001). Echocardiographic assessment of variations in regional strain requires careful mapping and may be inappropriately assessed if left ventricular segments are sampled at arbitrary focal locations.

Correlation of Electrocardiographic Changes with Cardiac Magnetic Resonance Findings in Patients with Hypertrophic Cardiomyopathy

PubMed Central

Paixão, Gabriela Miana de Mattos; Veronesi, Horácio Eduardo; da Silva, Halsted Alarcão Gomes Pereira; de Alencar Neto, José Nunes; Maldi, Carolina de Paulo; Aguiar Filho, Luciano de Figueiredo; Pinto, Ibrahim Masciarelli Francisco; de França, Francisco Faustino de Albuquerque Carneiro; Correia, Edileide de Barros

2018-01-01

Background Electrocardiogram is the initial test in the investigation of heart disease. Electrocardiographic changes in hypertrophic cardiomyopathy have no set pattern, and correlates poorly with echocardiographic findings. Cardiac magnetic resonance imaging has been gaining momentum for better assessment of hypertrophy, as well as the detection of myocardial fibrosis. Objectives To correlate the electrocardiographic changes with the location of hypertrophy in hypertrophic cardiomyopathy by cardiac magnetic resonance. Methods This descriptive cross-sectional study evaluated 68 patients with confirmed diagnosis of hypertrophic cardiomyopathy by cardiac magnetic resonance. The patients’ electrocardiogram was compared with the location of the greatest myocardial hypertrophy by cardiac magnetic resonance. Statistical significance level of 5% and 95% confidence interval were adopted. Results Of 68 patients, 69% had septal hypertrophy, 21% concentric and 10% apical hypertrophies. Concentric hypertrophy showed the greatest myocardial fibrosis mass (p < 0.001) and the greatest R wave size in D1 (p = 0.0280). The amplitudes of R waves in V5 and V6 (p = 0.0391, p = 0.0148) were higher in apical hypertrophy, with statistical significance. Apical hypertrophy was also associated with higher T wave negativity in D1, V5 and V6 (p < 0.001). Strain pattern was found in 100% of the patients with apical hypertrophy (p < 0.001). Conclusion The location of myocardial hypertrophy by cardiac magnetic resonance can be correlated with electrocardiographic changes, especially for apical hypertrophy. PMID:29538524

Left ventricular assist device implantation in a patient who had previously undergone apical myectomy for hypertrophic cardiomyopathy.

PubMed

Cho, Yang Hyun; Deo, Salil V; Topilsky, Yan; Grogan, Martha A; Park, Soon J

2012-03-01

Apical hypertrophy is a rare variant of hypertropic cardiomyopathy. These patients may present with end-stage congestive heart failure subsequent to long standing diastolic dysfunction. We report the technique for left ventricular assist device insertion in a patient with previous apical myectomy for hypertrophic cardiomyopathy. © 2012 Wiley Periodicals, Inc.

Myoadenylate deaminase deficiency, hypertrophic cardiomyopathy and gigantism syndrome.

PubMed

Skyllouriotis, M L; Marx, M; Bittner, R E; Skyllouriotis, P; Gross, M; Wimmer, M

1997-07-01

We report a 20-year-old man with gigantism syndrome, hypertrophic cardiomyopathy, muscle weakness, exercise intolerance, and severe psychomotor retardation since childhood. Histochemical and biochemical analysis of skeletal muscle biopsy revealed myoadenylate deaminase deficiency; molecular genetic analysis confirmed the diagnosis of primary (inherited) myoadenylate deaminase deficiency. Plasma, urine, and muscle carnitine concentrations were reduced. L-Carnitine treatment led to gradual improvement in exercise tolerance and cognitive performance; plasma and tissue carnitine levels returned to normal, and echocardiographic evidence of left ventricular hypertrophy disappeared. The combination of inherited myoadenylate deaminase deficiency, gigantism syndrome and carnitine deficiency has not previously been described.

The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy

PubMed Central

Spudich, James A.

2015-01-01

No matter how many times one explores the structure of the myosin molecule, there is always something new to discover. Here, I describe the myosin mesa, a structural feature of the motor domain that has the characteristics of a binding domain for another protein, possibly myosin-binding protein C (MyBP-C). Interestingly, many well-known hypertrophic cardiomyopathy (HCM) mutations lie along this surface and may affect the putative interactions proposed here. A potential unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy is discussed here. It involves increased power output of the cardiac muscle as a result of HCM mutations causing the release of inhibition by myosin binding protein C. PMID:25619247

Subaortic membrane mimicking hypertrophic cardiomyopathy.

PubMed

Anderson, Mark Joseph; Arruda-Olson, Adelaide; Gersh, Bernard; Geske, Jeffrey

2015-11-04

A 34-year-old man was referred for progressive angina and exertional dyspnoea refractory to medical therapy, with a presumptive diagnosis of hypertrophic cardiomyopathy (HCM). Transthoracic echocardiography (TTE) revealed asymmetric septal hypertrophy without systolic anterior motion of the mitral valve leaflet and with no dynamic left ventricular outflow tract (LVOT) obstruction. However, the LVOT velocity was elevated at rest as well as with provocation, without the characteristic late peaking obstruction seen in HCM. Focused TTE to evaluate for suspected fixed obstruction demonstrated a subaortic membrane 2.2 cm below the aortic valve. Coronary CT angiography confirmed the presence of the subaortic membrane and was negative for concomitant coronary artery disease. Surgical resection of the subaortic membrane and septal myectomy resulted in significant symptomatic relief and lower LVOT velocities on postoperative TTE. This case reminds the clinician to carefully evaluate for alternative causes of LVOT obstruction, especially subaortic membrane, as a cause of symptoms mimicking HCM. 2015 BMJ Publishing Group Ltd.

Subaortic membrane mimicking hypertrophic cardiomyopathy

PubMed Central

Anderson, Mark Joseph; Arruda-Olson, Adelaide; Gersh, Bernard; Geske, Jeffrey

2015-01-01

A 34-year-old man was referred for progressive angina and exertional dyspnoea refractory to medical therapy, with a presumptive diagnosis of hypertrophic cardiomyopathy (HCM). Transthoracic echocardiography (TTE) revealed asymmetric septal hypertrophy without systolic anterior motion of the mitral valve leaflet and with no dynamic left ventricular outflow tract (LVOT) obstruction. However, the LVOT velocity was elevated at rest as well as with provocation, without the characteristic late peaking obstruction seen in HCM. Focused TTE to evaluate for suspected fixed obstruction demonstrated a subaortic membrane 2.2 cm below the aortic valve. Coronary CT angiography confirmed the presence of the subaortic membrane and was negative for concomitant coronary artery disease. Surgical resection of the subaortic membrane and septal myectomy resulted in significant symptomatic relief and lower LVOT velocities on postoperative TTE. This case reminds the clinician to carefully evaluate for alternative causes of LVOT obstruction, especially subaortic membrane, as a cause of symptoms mimicking HCM. PMID:26538250

Left Atrial trajectory impairment in Hypertrophic Cardiomyopathy disclosed by Geometric Morphometrics and Parallel Transport

NASA Astrophysics Data System (ADS)

Piras, Paolo; Torromeo, Concetta; Re, Federica; Evangelista, Antonietta; Gabriele, Stefano; Esposito, Giuseppe; Nardinocchi, Paola; Teresi, Luciano; Madeo, Andrea; Chialastri, Claudia; Schiariti, Michele; Varano, Valerio; Uguccioni, Massimo; Puddu, Paolo E.

2016-10-01

The analysis of full Left Atrium (LA) deformation and whole LA deformational trajectory in time has been poorly investigated and, to the best of our knowledge, seldom discussed in patients with Hypertrophic Cardiomyopathy. Therefore, we considered 22 patients with Hypertrophic Cardiomyopathy (HCM) and 46 healthy subjects, investigated them by three-dimensional Speckle Tracking Echocardiography, and studied the derived landmark clouds via Geometric Morphometrics with Parallel Transport. Trajectory shape and trajectory size were different in Controls versus HCM and their classification powers had high AUC (Area Under the Receiving Operator Characteristic Curve) and accuracy. The two trajectories were much different at the transition between LA conduit and booster pump functions. Full shape and deformation analyses with trajectory analysis enabled a straightforward perception of pathophysiological consequences of HCM condition on LA functioning. It might be worthwhile to apply these techniques to look for novel pathophysiological approaches that may better define atrio-ventricular interaction.

Remission of recurrent gastrointestinal bleeding after septal reduction therapy in patients with hypertrophic obstructive cardiomyopathy-associated acquired von Willebrand syndrome.

PubMed

Blackshear, J L; Stark, M E; Agnew, R C; Moussa, I D; Safford, R E; Shapiro, B P; Waldo, O A; Chen, D

2015-02-01

Gastrointestinal hemorrhage is considered to be a severe complication of von Willebrand disease. The optimal therapy for acquired von Willebrand syndrome and severe gastrointestinal bleeding with hypertrophic cardiomyopathy is undefined. Seventy-seven patients (median age, 67 years; interquartile range [IQR], 56-75 years; 49% women) with hypertrophic cardiomyopathy underwent von Willebrand factor multimer testing and acquisition of bleeding history. Bleeding was detected in 27 (36%) (median age, 74 years; IQR 66-76 years; 74% women), 20 with gastrointestinal bleeding, including 11 women with transfusion dependence. In these 11 women, the median duration of transfusion dependency was 36 months (IQR 18-44 months), and the median number of transfusions required was 25 (IQR 20-38). Two patients had undergone bowel resection for bleeding, one of them twice. Seven patients showed angiodysplasia, and the remainder had no endoscopic lesion. Bleeding recurred after bowel surgery or endoscopic intervention and medical therapy for hypertrophic cardiomyopathy in 10 of 11 patients. Two patients had septal myectomy, and six patients underwent alcohol septal ablation. With the exception of one patient in whom a significant gradient persisted after septal ablation, after the periprocedural period, patients after septal reduction therapy remained free of recurrent bleeding and need for transfusions. Acquired von Willebrand syndrome is common in hypertrophic cardiomyopathy. Gastrointestinal bleeding often recurs after endoscopic therapy, but may be relieved by structural cardiac repair. © 2014 International Society on Thrombosis and Haemostasis.

Sex dimorphisms of crossbridge cycling kinetics in transgenic hypertrophic cardiomyopathy mice.

PubMed

Birch, Camille L; Behunin, Samantha M; Lopez-Pier, Marissa A; Danilo, Christiane; Lipovka, Yulia; Saripalli, Chandra; Granzier, Henk; Konhilas, John P

2016-07-01

Familial hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere and may lead to hypertrophic, dilated, restrictive, and/or arrhythmogenic cardiomyopathy, congestive heart failure, or sudden cardiac death. We hypothesized that hearts from transgenic HCM mice harboring a mutant myosin heavy chain increase the energetic cost of contraction in a sex-specific manner. To do this, we assessed Ca(2+) sensitivity of tension and crossbridge kinetics in demembranated cardiac trabeculas from male and female wild-type (WT) and HCM hearts at an early time point (2 mo of age). We found a significant effect of sex on Ca(2+) sensitivity such that male, but not female, HCM mice displayed a decrease in Ca(2+) sensitivity compared with WT counterparts. The HCM transgene and sex significantly impacted the rate of force redevelopment by a rapid release-restretch protocol and tension cost by the ATPase-tension relationship. In each of these measures, HCM male trabeculas displayed a gain-of-function when compared with WT counterparts. In addition, cardiac remodeling measured by echocardiography, histology, morphometry, and posttranslational modifications demonstrated sex- and HCM-specific effects. In conclusion, female and male HCM mice display sex dimorphic crossbridge kinetics accompanied by sex- and HCM-dependent cardiac remodeling at the morphometric, histological, and cellular level. Copyright © 2016 the American Physiological Society.

[Functional regulation of genome with peptide bioregulators by hypertrophic cardiomyopathy (by patients and relatives)].

PubMed

Dzhokhadze, T A; Buadze, T Zh; Gaĭozishvili, M N; Rogava, M A; Lazhava, T A

2013-12-01

In this paper, a comparative study of the functional genome indicators using lymphocyte cultures of patients with hypertrophic cardiomyopathy (HCM) and their first relatives. Studies conducted both in intact cultures and cultures exposed to the influence of peptide - bioregulators Epithalon, Vilon and Livagen. Last (Livagen) tested at separate and joint application with cobalt chloride salt. As indicated according to the results of the analysis, the cells of the individuals with HCM and their first relatives were characterized by higher frequency of spontaneous quantitative - structural disorders in comparison with the cells of healthy individuals. The findings suggest a different effect of bioregulators. The most effective protective action in relation normalization of functional parameters of the genome shows Epithalon for lowering the level of chromosomal instability in patients with hypertrophic cardiomyopathy and relatives of patients with HCM. On the basis of identified protective action Epithalon concludes prospects of its application in the development of preventive measures for individuals at increased risk of morbidity HCM.

Sahlgrenska Cardiomyopathy Project

ClinicalTrials.gov

2018-05-15

Dilated Cardiomyopathies; Hypertrophic Cardiomyopathy; Restrictive Cardiomyopathy; Arrhythmogenic Right Ventricular Cardiomyopathy; Myocarditis; Sarcoidosis With Myocarditis; Giant Cell Myocarditis; Amyloidosis; Heart (Manifestation)

Pressure-derived indices of left ventricular isovolumic relaxation in patients with hypertrophic cardiomyopathy.

PubMed Central

Thompson, D S; Wilmshurst, P; Juul, S M; Waldron, C B; Jenkins, B S; Coltart, D J; Webb-Peploe, M M

1983-01-01

High fidelity measurements of left ventricular pressure were made at increasing pacing rates in 21 patients with hypertrophic cardiomyopathy and a control group of 11 patients investigated for chest pain who proved to have normal hearts. In both groups the fall in pressure during isovolumic relaxation from the point of min dp/dt approximated closely to a monoexponential, and could be described by a time constant and asymptote. The time constant shortened and the asymptote increased as heart rate rose in both groups. The time constant was longer and min dp/dt less in the cardiomyopathy group than controls at all heart rates. In the cardiomyopathy patients min dp/dt, but not the time constant, was related to systolic pressure. During pacing, eight cardiomyopathy patients developed metabolic evidence of myocardial ischaemia, but indices of relaxation did not differ between these eight and the other 13 either at basal heart rate or the highest pacing rate. In 10 cardiomyopathy patients measurements were repeated at comparable pacing rates after propranolol (0.2 mg/kg). Left ventricular end-diastolic pressure and indices of contractility decreased after the drug, but the time constant did not change. Eight patients received verapamil (20 mg) after which there were substantial reductions in systolic pressure and contractility. Min dp/dt decreased in proportion to systolic pressure, but the time constant was unchanged. At the highest pacing rate before drug administration three patients had abnormal lactate extraction which was corrected by either propranolol (one patient) or verapamil (two patients). Despite abolition of metabolic evidence of ischaemia, relaxation did not improve. It is concluded that abnormal isovolumic relaxation is common in patients with hypertrophic cardiomyopathy, but its severity correlates poorly with other features of the disease. Abnormal relaxation is not the result of ischaemia, and pressure derived indices of relaxation do not improve after

The Portuguese Registry of Hypertrophic Cardiomyopathy: Overall results.

PubMed

Cardim, Nuno; Brito, Dulce; Rocha Lopes, Luís; Freitas, António; Araújo, Carla; Belo, Adriana; Gonçalves, Lino; Mimoso, Jorge; Olivotto, Iacopo; Elliott, Perry; Madeira, Hugo

2018-01-01

We report the results of the Portuguese Registry of Hypertrophic Cardiomyopathy, an initiative that reflects the current spectrum of cardiology centers throughout the territory of Portugal. A direct invitation to participate was sent to cardiology departments. Baseline and outcome data were collected. A total of 29 centers participated and 1042 patients were recruited. Four centers recruited 49% of the patients, of whom 59% were male, and mean age at diagnosis was 53±16 years. Hypertrophic cardiomyopathy (HCM) was identified as familial in 33%. The major reason for diagnosis was symptoms (53%). HCM was obstructive in 35% of cases and genetic testing was performed in 51%. Invasive septal reduction therapy was offered to 8% (23% of obstructive patients). Most patients (84%) had an estimated five-year risk of sudden death of <6%. Thirteen percent received an implantable cardioverter-defibrillator. After a median follow-up of 3.3 years (interquartile range [P25-P75] 1.3-6.5 years), 31% were asymptomatic. All-cause mortality was 1.19%/year and cardiovascular mortality 0.65%/year. The incidence of heart failure-related death was 0.25%/year, of sudden cardiac death 0.22%/year and of stroke-related death 0.04%/year. Heart failure-related death plus heart transplantation occurred in 0.27%/year and sudden cardiac death plus equivalents occurred in 0.53%/year. Contemporary HCM in Portugal is characterized by relatively advanced age at diagnosis, and a high proportion of invasive treatment of obstructive forms. Long-term mortality is low; heart failure is the most common cause of death followed by sudden cardiac death. However, the burden of morbidity remains considerable, emphasizing the need for disease-specific treatments that impact the natural history of the disease. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Identifying unmet clinical need in hypertrophic cardiomyopathy using national electronic health records.

PubMed

Pujades-Rodriguez, Mar; Guttmann, Oliver P; Gonzalez-Izquierdo, Arturo; Duyx, Bram; O'Mahony, Constantinos; Elliott, Perry; Hemingway, Harry

2018-01-01

To evaluate unmet clinical need in unselected hypertrophic cardiomyopathy (HCM) patients to determine the risk of a wide range of subsequent cardiovascular disease endpoints and safety endpoints relevant for trial design. Population based cohort (CALIBER, linked primary care, hospital and mortality records in England, period 1997-2010), all people diagnosed with HCM were identified and matched by age, sex and general practice with ten randomly selected people without HCM. Random-effects Poisson models were used to assess the associations between HCM and cardiovascular diseases and bleeding. Among 3,290,455 eligible people a diagnosis of hypertrophic cardiomyopathy was found in 4 per 10,000. Forty-one percent of the 1,160 individuals with hypertrophic cardiomyopathy were women and the median age was 57 years. The median follow-up was 4.0 years. Compared to general population controls, people with HCM had higher risk of ventricular arrhythmia (incidence rate ratio = 23.53, [95% confidence interval 12.67-43.72]), cardiac arrest or sudden cardiac death (6.33 [3.69-10.85]), heart failure (4.31, [3.30-5.62]), and atrial fibrillation (3.80 [3.04-4.75]). HCM was also associated with a higher incidence of myocardial infarction ([MI] 1.90 [1.27-2.84]) and coronary revascularisation (2.32 [1.46-3.69]).The absolute Kaplan-Meier risks at 3 years were 8.8% for the composite endpoint of cardiovascular death or heart failure, 8.4% for the composite of cardiovascular death, stroke or myocardial infarction, and 1.5% for major bleeding. Our study identified major unmet need in HCM and highlighted the importance of implementing improved cardiovascular prevention strategies to increase life-expectancy of the contemporary HCM population. They also show that national electronic health records provide an effective method for identifying outcomes and clinically relevant estimates of composite efficacy and safety endpoints essential for trial design in rare diseases.

Ehlers-Danlos Syndrome associated with cardiomyopathy hypertrophic obstructive*

PubMed Central

Pinto, Raimundo José Almeida de Oliveira; dos Santos, Adaílton Araújo; Azevedo, Mablo de Castro; Meira, Saulo Sacramento

2015-01-01

Ehlers-Danlos syndrome is a rare clinical condition caused by a genetic change that results in the formation of structurally or functionally altered collagen. The clinical manifestations are varied, being the most obvious skin hypermotility and increased joint flexibility, although other systems - such as cardiovascular, respiratory and neurological - may also be affected. This paper presents the report of a patient who sought medical attention with complaints of atypical chest pain. Clinical evaluation enabled hypothetical diagnosis of hypertrophic obstructive cardiomyopathy and Ehlers-Danlos syndrome. Initial electrocardiogram, echocardiogram and 24 hours holter allowed the confirmation of the first hypothesis. A skin biopsy performed later associated clinical data and confirmed the second hypothesis. PMID:26312722

Clinical Profile and Prognosis of Left Ventricular Apical Aneurysm in Hypertrophic Cardiomyopathy.

PubMed

Xiao, Yan; Wang, Lin-Ping; Yang, Yan-Kun; Tian, Tao; Yang, Kun-Qi; Sun, Xin; Jiang, Yong; Liu, Ya-Xin; Zhou, Xian-Liang; Li, Jian-Jun

2016-01-01

Hypertrophic cardiomyopathy with left ventricular apical aneurysm is a unique entity with diverse manifestations and varied prognoses among races. This study evaluated the prevalence, clinical characteristics and outcomes of apical aneurysm in Chinese patients with hypertrophic cardiomyopathy. Consecutive patients with apical aneurysm were recruited from 1,844 patients with HCM treated at our hospital from 2002-2013. Basic clinical data and follow-up data were collected and analyzed. Apical aneurysm was identified in 24 patients (1.3%) (mean age: 52 ± 14 years). We identified an hourglass-shaped (71%) or distally hypertrophic (29%) left ventricle and found mural thrombi and nonsustained and sustained ventricular tachycardia in 11 (46%), 4 (17%) and 9 (38%) patients, respectively. During follow-up (5.0 ± 3.4 years [range: 1-14 years]), following were the clinical adverse events experienced by 14 patients (58%) (annual rate: 11.7%): sudden cardiac death (n = 4), appropriate discharge of an implantable cardioverter-defibrillator (n = 4), progressive heart failure (n = 4) or heart failure-related death (n = 1) and stroke (n = 4). The 4 patients who underwent aneurysmectomy had no adverse events. Patients with SCD had a lower ejection fraction (P = 0.004) and a larger left ventricular end-diastolic diameter (P < 0.001) than nonoperated survivors. Apical aneurysm is not rare in patients with HCM and it confers an extremely poor prognosis. Early aggressive therapies should be considered for this entity and prophylactic aneurysmectomy may be an option. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Actinobacillus endocarditis associated with hypertrophic cardiomyopathy

PubMed Central

Jorge, Vanda Cristina; Araújo, Ana Carolina; Grilo, Ana; Noronha, Carla; Panarra, António; Riso, Nuno; Vaz Riscado, Manuel

2012-01-01

Infective endocarditis can be associated with complex clinical presentations, sometimes with a difficult multi-disciplinary management. Actinobacillus actinomycetemcomitans belongs to the Haemophilus species, Actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella species group, responsible for 5% to 10% of infective endocarditis in native heart valves. These organisms have slow fastidious growth pattern, often associated with negative cultures, and cause systemic embolism with abscess formation. The authors present the case of a 59-year-old man, admitted due to fever of unknown origin, with a personal history of obstructive hypertrophic cardiomyopathy and recent dental manipulation. The diagnosis of mitral valve’s endocarditis was established after a transoesophageal ecocardiography, with a late isolation of A actinomycetemcomitans in blood culture. Despite the institution of antibiotic therapy, the patient suffered from multiple episodes of septic embolism: skin, mucosae, cerebral abscesses, spondylodiscitis and uveitis. He was submitted to heart surgery with miectomy and replacement of the native mitral valve by a mechanical prosthesis, while on antibiotics. PMID:22891010

α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy

PubMed Central

Mogensen, Jens; Klausen, Ib C.; Pedersen, Anders K.; Egeblad, Henrik; Bross, Peter; Kruse, Torben A.; Gregersen, Niels; Hansen, Peter S.; Baandrup, Ulrik; Børglum, Anders D.

1999-01-01

We identified the α-cardiac actin gene (ACTC) as a novel disease gene in a pedigree suffering from familial hypertrophic cardiomyopathy (FHC). Linkage analyses excluded all the previously reported FHC loci as possible disease loci in the family studied, with lod scores varying between –2.5 and –6.0. Further linkage analyses of plausible candidate genes highly expressed in the adult human heart identified ACTC as the most likely disease gene, showing a maximal lod score of 3.6. Mutation analysis of ACTC revealed an Ala295Ser mutation in exon 5 close to 2 missense mutations recently described to cause the inherited form of idiopathic dilated cardiomyopathy (IDC). ACTC is the first sarcomeric gene described in which mutations are responsible for 2 different cardiomyopathies. We hypothesize that ACTC mutations affecting sarcomere contraction lead to FHC and that mutations affecting force transmission from the sarcomere to the surrounding syncytium lead to IDC. PMID:10330430

Ablation of hypertrophic septum using radiofrequency energy: an alternative for gradient reduction in patient with hypertrophic obstructive cardiomyopathy?

PubMed

Riedlbauchová, Lucie; Janoušek, Jan; Veselka, Josef

2013-06-01

Alcohol septal ablation and surgical myectomy represent accepted therapeutic options for treatment of symptomatic patients with hypertrophic obstructive cardiomyopathy. Long-term experience with radiofrequency ablation of arrhythmogenic substrates raised a question if this technique might be effective for left ventricular outflow tract (LVOT) gradient reduction. We report on a 63-year-old patient with recurrence of symptoms 1 year after alcohol septal ablation (ASA) leading originally to a significant reduction of both symptoms and gradient. Due to a new increase of gradient in the LVOT up to 200 mm Hg with corresponding worsening of symptoms and due to refusal of surgical myectomy by the patient, endocardial radiofrequency ablation of the septal hypertrophy (ERASH) was indicated. Radiofrequency ablation was performed in the LVOT using irrigated-tip ablation catheter; the target site was identified using intracardiac echocardiography and electroanatomical CARTO mapping. ERASH caused an immediate gradient reduction due to hypokinesis of the ablated septum. At 2-month follow-up exam, significant clinical improvement was observed, together with persistent gradient reduction assessed with Doppler echocardiography. Echocardiography and magnetic resonance revealed persistent septal hypokinesis and slight thinning of the ablated region. Septal ablation using radiofrequency energy may be a promising alternative or adjunct to the treatment of hypertrophic obstructive cardiomyopathy. Intracardiac echocardiography and electroanatomical CARTO mapping enable exact lesion placement and preservation of atrioventricular conduction.

Hypertrophic Cardiomyopathy in Liver Transplantation Patients.

PubMed

Pai, S-L; Aniskevich, S; Logvinov, I I; Matcha, G V; Palmer, W C; Blackshear, J L

2018-06-01

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder that presents with a hypertrophied nondilated left ventricle. In the absence of other known causes of cardiomyopathy, it is often associated with left ventricular outflow tract obstruction during systole, systolic anterior motion of the mitral valve, mitral regurgitation, and increased risk of sudden cardiac death. When HCM coexists with end-stage liver disease, it can be further complicated by cirrhosis-associated cardiovascular abnormalities, including hyperdynamic circulation, systolic and diastolic dysfunction, and electrophysiologic abnormalities. We retrospectively examined patient characteristics, comorbidities, preoperative echocardiogram results, sudden cardiac death risk prediction model score, and 1-year postoperative mortality of patients with HCM who underwent liver transplantation at our institution from January 1, 2000, through January 1, 2015. Of the 2,812 liver transplantations performed during the study period, we identified 15 patients with a preoperative diagnosis of HCM. When comparing the patients who did vs did not survive the first year after orthotopic liver transplantation, we identified significant differences in maximal left ventricular wall thickness (P = .004) and resting left ventricular outflow tract gradient (P = .004). Preoperative left atrium size (measured by echocardiography; P = .66) and the sudden cardiac death risk prediction model score (P = .32) were not significantly associated with 1-year survival. Preoperative left ventricular outflow tract gradient exceeding 60 mm Hg was strongly associated with death during the first year after transplant. These results suggest that the severity of HCM influences patient outcomes. Copyright © 2018 Elsevier Inc. All rights reserved.

A novel mutation of the beta myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy.

PubMed

Wang, Juan; Xu, Shi-Jie; Zhou, Hua; Wang, Li-Jie; Hu, Bo; Fang, Fang; Zhang, Xu-Min; Luo, Yi-Wei; He, Xiao-Yan; Zhuang, Shao-Wei; Li, Xin-Ming; Liu, Zhong-Ming; Hu, Da-Yi

2009-09-01

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder and shows high variability in genetic heterogeneity and phenotypic characteristics. The genetic etiology responsible for HCM in many individuals remains unclear. This instigation was sought to identify novel genetic determinants for familial hypertrophic cardiomyopathy. Six unrelated Chinese families with HCM were studied. For each of the 13 established HCM-susceptibility genes, 3 to 5 microsatellite markers were selected to perform genotyping and haplotype analysis. The linked genes were sequenced. Haplotype analyses on candidate genetic loci revealed cosegregation of the gene beta-myosin heavy chain (MYH7) with HCM in a single family. A novel double heterozygous missense mutation of Ala26Val plus Arg719Trp in MYH7 was subsequently identified by sequencing in this family and was associated with a severe phenotype of HCM. The novel double mutation of Ala26Val plus Arg719Trp in MYH7 identified in a Chinese family highlights the remarkable genetic heterogeneity of HCM, which provides important information for genetic counseling, accurate diagnosis, prognostic evaluation, and appropriate clinical management. Copyright 2009 Wiley Periodicals, Inc.

A new era in clinical genetic testing for hypertrophic cardiomyopathy.

PubMed

Wheeler, Matthew; Pavlovic, Aleksandra; DeGoma, Emil; Salisbury, Heidi; Brown, Colleen; Ashley, Euan A

2009-12-01

Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

Alcohol septal ablation in obstructive acromegalic hypertrophic cardiomyopathy - a first case report.

PubMed

Viveiros Monteiro, André; Fiarresga, António; Cacela, Duarte; de Sousa, Lídia; Ramos, Ruben; Galrinho, Ana; Branco, Luísa; Cruz Ferreira, Rui

2016-09-01

Acromegaly is a rare disease, mostly caused by a growth hormone (GH)-secreting benign pituitary tumor, with an increased production of GH and insulin-like growth factor 1 (IGF-1). Cardiovascular complications are common and are associated with cardiomyocyte apoptosis and concentric cardiac hypertrophy. Suppression of GH and IGF-1 appears to improve cardiac function only in the short term, with little or no decrease in left ventricular mass or improvement in cardiac function after prolonged treatment. Alcohol septal ablation (ASA) has emerged as a minimally invasive alternative to septal myectomy, with significant improvement in symptoms, gradients and left ventricular remodeling. In this report, we describe the case of a 73-year-old woman with acromegaly due to a pituitary adenoma diagnosed and treated surgically at the age of 38 but with recurrence and reoperation at the age of 50. She was referred to our cardiology department due to a three-month history of progressively worsening exercise-induced dyspnea and orthopnea under optimal medical therapy. Echocardiography and magnetic resonance imaging revealed severe basal hypertrophy of the interventricular septum (19 mm), dynamic left ventricular outflow tract obstruction with a gradient of 70 mmHg at rest and 120 mmHg with Valsalva maneuver, and systolic anterior movement (SAM). Genetic testing excluded the most frequent forms of familial hypertrophic cardiomyopathy. ASA was performed with injection of 2 cc of alcohol in the first septal branch of the left coronary artery, without complications. At one-year reassessment, significant clinical and echocardiographic improvement was noted, with disappearance of SAM. To our knowledge, there have been no previously reported cases of ASA in hypertrophic cardiomyopathy due to acromegaly. We report a case of successful ASA in acromegalic cardiomyopathy. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Hypertrophic Cardiomyopathy in Youth Athletes

PubMed Central

Fox, J. Christian; Lahham, Shadi; Maldonado, Graciela; Klaus, Suzi; Aish, Bassil; Sylwanowicz, Lauren V.; Yanuck, Justin; Wilson, Sean P.; Shieh, Mason; Anderson, Craig L.; English, Carter; Mayer, Ryan; Mohan, Uthara R.

2018-01-01

Objectives Hypertrophic cardiomyopathy (HCM) is a life-threatening genetic cardiovascular disease that often goes undetected in young athletes. Neither history nor physical examination are reliable to identify those at risk. The objective of this study is to determine whether minimally trained medical student volunteers can use ultrasound to screen for HCM. Methods This was a prospective enrollment of young athletes performed at 12 area high schools and three area colleges, between May 2012 and August 2013. All participants underwent point-of-care ultrasound performed screening for HCM by trained medical students and reviewed by a pediatric cardiologist. An interventricular septum to left ventricular posterior wall ratio greater than 1.25 was considered to be abnormal (positive screen). Results A total of 2332 participants were enrolled. There were 137 (5.8%) with a positive screening for HCM, of which 7 (5.1%) were confirmed to have HCM by a pediatric cardiologist. In a small cohort with positive screen for HCM, there was a 100% sensitivity (95% confidence interval, 59.04 to 100%) and 4.86% (95% confidence interval, 1.98 to 9.76%) positive predictive value of for having HCM. Conclusions Volunteer medical students, using point-of-care ultrasound, were able to effectively screen for HCM in young athletes. PMID:28258593

[Electrocardiographic differences between apical hypertrophic cardiomyopathy and apical non-ST segment myocardial infarction].

PubMed

Chillik, Iván; Gil Ramírez, Andreina; Ordóñez, Santiago; Tomás, Leandro; Parodi, Josefina; Costabel, Juan Pablo

2018-01-01

Apocal hypertrophic cardiomyopathy (AHCM) is a phenotypic variant within hypertrophic cardiomyopathies, in which ventricular repolarization alterations are present. These electrocardiographic disturbances can mimic an anterior infarction which triggers a series of studies and treatments that may be unnecessary. The aim of this study was to describe and compare electrocardiographic differences in a series of patients with AHCM and apical non-ST segment elevation myocardial infarction in patients (NSTEMI) with T-wave changes. We conducted an observational and retrospective study, including patients with diagnosed AHCM (N = 19) and apical NSTEMI (N = 19) with negative T waves in V1 and V6 lead of the EKG. Those with AHCM presented higher T-wave voltage (7 mV vs. 5 mV, p = 0.001) and peak voltage (29 mV vs. 17 mV, p = 0.003), higher R-waves (25 mV vs. 10 mV, p = 0.0001), and a maximum voltage of R and T sum (R + T) significantly higher (33 vs. 14, p = 0.00001). They also showed a greater T-wave asymmetry, with a TiTp / TpTf ratio > 1. At a cut-off value of 26.5 mV for the R + T variable, 68% sensitivity and 100% specificity were obtained to diagnose AHCM. This study shows the existence of major differences in electrocardiographic presentation of AHCM and apical NSTEMI.

Early detection of myocardial dysfunction using two-dimensional speckle tracking echocardiography in a young cat with hypertrophic cardiomyopathy

PubMed Central

Mochizuki, Yohei; Yoshimatsu, Hiroki; Niina, Ayaka; Teshima, Takahiro; Matsumoto, Hirotaka; Koyama, Hidekazu

2018-01-01

Case summary A 5-month-old intact female Scottish Fold cat was presented for cardiac evaluation. Careful auscultation detected a slight systolic murmur (Levine I/VI). The findings of electrocardiography, thoracic radiography, non-invasive blood pressure measurements and conventional echocardiographic studies were unremarkable. However, two-dimensional speckle tracking echocardiography revealed abnormalities in myocardial deformations, including decreased early-to-late diastolic strain rate ratios in longitudinal, radial and circumferential directions, and deteriorated segmental systolic longitudinal strain. At the follow-up examinations, the cat exhibited echocardiographic left ventricular hypertrophy and was diagnosed with hypertrophic cardiomyopathy using conventional echocardiography. Relevance and novel information This is the first report on the use of two-dimensional speckle tracking echocardiography for the early detection of myocardial dysfunction in a cat with hypertrophic cardiomyopathy; the myocardial dysfunction was detected before the development of hypertrophy. The findings from this case suggest that two-dimensional speckle tracking echocardiography can be useful for myocardial assessment when conventional echocardiographic and Doppler findings are ambiguous. PMID:29449957

Diagnosis of apical hypertrophic cardiomyopathy: T-wave inversion and relative but not absolute apical left ventricular hypertrophy☆

PubMed Central

Flett, Andrew S.; Maestrini, Viviana; Milliken, Don; Fontana, Mariana; Treibel, Thomas A.; Harb, Rami; Sado, Daniel M.; Quarta, Giovanni; Herrey, Anna; Sneddon, James; Elliott, Perry; McKenna, William; Moon, James C.

2015-01-01

Background Diagnosis of apical HCM utilizes conventional wall thickness criteria. The normal left ventricular wall thins towards the apex such that normal values are lower in the apical versus the basal segments. The impact of this on the diagnosis of apical hypertrophic cardiomyopathy has not been evaluated. Methods We performed a retrospective review of 2662 consecutive CMR referrals, of which 75 patients were identified in whom there was abnormal T-wave inversion on ECG and a clinical suspicion of hypertrophic cardiomyopathy. These were retrospectively analyzed for imaging features consistent with cardiomyopathy, specifically: relative apical hypertrophy, left atrial dilatation, scar, apical cavity obliteration or apical aneurysm. For comparison, the same evaluation was performed in 60 healthy volunteers and 50 hypertensive patients. Results Of the 75 patients, 48 met conventional HCM diagnostic criteria and went on to act as another comparator group. Twenty-seven did not meet criteria for HCM and of these 5 had no relative apical hypertrophy and were not analyzed further. The remaining 22 patients had relative apical thickening with an apical:basal wall thickness ratio > 1 and a higher prevalence of features consistent with a cardiomyopathy than in the control groups with 54% having 2 or more of the 4 features. No individual in the healthy volunteer group had more than one feature and no hypertension patient had more than 2. Conclusion A cohort of individuals exist with T wave inversion, relative apical hypertrophy and additional imaging features of HCM suggesting an apical HCM phenotype not captured by existing diagnostic criteria. PMID:25666123

Cardiac magnetic resonance in hypertrophic cardiomyopathy: current state of the art.

PubMed

Kwon, Deborah H; Desai, Milind Y

2010-01-01

Hypertrophic cardiomyopathy is a complex disorder with significant heterogeneity in clinical characteristics and natural history. Traditionally, the diagnosis has been based on clinical assessment and echocardiography; however, persistent challenges in its noninvasive evaluation remain. Hence, improved diagnostic techniques could lead to better risk stratification of patients, which would potentially identify patients likely to benefit from effective therapies. Recent studies have demonstrated the increasing utility of cardiac magnetic resonance in the management of this disease. With the increasing utilization of genetics, cardiac magnetic resonance is likely to play an even more important role in discerning the subtle morphologic differences seen in such patients with similar genotypic profiles.

Hypertrophic and dilated cardiomyopathy: four decades of basic research on muscle lead to potential therapeutic approaches to these devastating genetic diseases.

PubMed

Spudich, James A

2014-03-18

With the advent of technologies to obtain the complete sequence of the human genome in a cost-effective manner, this decade and those to come will see an exponential increase in our understanding of the underlying genetics that lead to human disease. And where we have a deep understanding of the biochemical and biophysical basis of the machineries and pathways involved in those genetic changes, there are great hopes for the development of modern therapeutics that specifically target the actual machinery and pathways altered by individual mutations. Prime examples of such a genetic disease are those classes of hypertrophic and dilated cardiomyopathy that result from single amino-acid substitutions in one of several of the proteins that make up the cardiac sarcomere or from the truncation of myosin binding protein C. Hypertrophic cardiomyopathy alone affects ∼1 in 500 individuals, and it is the leading cause of sudden cardiac death in young adults. Here I describe approaches to understand the molecular basis of the alterations in power output that result from these mutations. Small molecules binding to the mutant sarcomeric protein complex should be able to mitigate the effects of hypertrophic and dilated cardiomyopathy mutations at their sources, leading to possible new therapeutic approaches for these genetic diseases. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Living with hypertrophic cardiomyopathy and an implantable defibrillator.

PubMed

Magnusson, Peter; Jonsson, Jessica; Mörner, Stellan; Fredriksson, Lennart

2017-05-10

ICDs efficiently terminate life-threatening arrhythmias, but complications occur during long-term follow-up. Patients' own perspective is largely unknown. The aim of the study was to describe experiences of hypertrophic cardiomyopathy (HCM) patients with implantable defibrillators (ICDs). We analyzed 26 Swedish patient interviews using hermeneutics and latent content analysis. Patients (aged 27-76 years) were limited by HCM especially if it deteriorates into heart failure. The ICD implies safety, gratitude, and is accepted as a part of the body even when inappropriate ICD shocks are encountered. Nobody regretted the implant. Both the disease and the ICD affected professional life and leisure time activities, especially at younger ages. Family support was usually strong, but sometimes resulted in overprotection, whereas health care focused on medical issues. Despite limitations, patients adapted, accepted, and managed challenges. HCM patients with ICDs reported good spirit and hope even though they had to adapt and accept limitations over time.

Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial.

PubMed

Axelsson, Anna; Iversen, Kasper; Vejlstrup, Niels; Ho, Carolyn; Norsk, Jakob; Langhoff, Lasse; Ahtarovski, Kiril; Corell, Pernille; Havndrup, Ole; Jensen, Morten; Bundgaard, Henning

2015-02-01

No medical treatment has been reliably shown to halt or reverse disease progression in hypertrophic cardiomyopathy, but the results of several pilot studies have suggested beneficial effects of angiotensin II receptor blockers on left ventricular hypertrophy and fibrosis, which are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. In this single-centre, randomised, double-blind, placebo-controlled trial, adult patients (aged 18 years and older) with obstructive or non-obstructive hypertrophic cardiomyopathy were randomly assigned via computer-based system to losartan (100 mg per day) or placebo for 12 months. Patients and investigators were masked to assigned treatment. The primary endpoint was change in left ventricular mass as assessed by cardiac magnetic resonance imaging (CMR) or CT. Efficacy analyses were done in the modified intention-to-treat population (all patients with data available at the 12-month follow-up). The trial is registered with ClinicalTrials.gov, number NCT01447654. Between Dec 1, 2011, and May 1, 2013, 318 patients were screened. 133 patients (mean age 52 years [SD 13], 35% women) consented and were randomly assigned to placebo (n=69) or losartan (n=64). 124 (93%) patients completed the study and were included in the modified intention-to-treat analysis for the primary endpoint. After 12 months we noted no significant difference in the change in left ventricular mass between the placebo group and the losartan group (mean difference 1 g/m(2), 95% CI -3 to 6; p=0·60). A decrease in systolic blood pressure in the losartan group (from mean 127 mm Hg [SD 12] to 121 mm Hg [14]; p=0·0001) confirmed drug compliance; blood pressure did not decrease in the placebo group. Two (2%) patients, both in the placebo group, died from sudden cardiac death during follow-up. In the losartan group, one (1

Nonsurgical reduction of the interventricular septum in patients with hypertrophic cardiomyopathy.

PubMed

Shamim, Waqar; Yousufuddin, Mohammed; Wang, Duolao; Henein, Michael; Seggewiss, Hubert; Flather, Marcus; Coats, Andrew J S; Sigwart, Ulrich

2002-10-24

In patients with hypertrophic cardiomyopathy and obstruction of the left ventricular outflow tract, nonsurgical reduction of the septum is a treatment option when medical therapy has failed. We investigated the long-term effects of nonsurgical reduction of the septum on functional capacity and electrocardiographic and echocardiographic characteristics. Sixty-four consecutive patients with hypertrophic cardiomyopathy and a mean (+/-SD) age of 48.5+/-17.2 years underwent nonsurgical reduction of the septum by injection of ethanol into the septal perforator branch of the left anterior descending coronary artery. These patients were assessed by exercise testing, electrocardiography, and resting and dobutamine (stress-induced) echocardiography after a mean period of 3.0+/-1.3 years. At follow-up, patients had significant improvements in New York Heart Association class, peak oxygen consumption (from 18.4+/-5.8 to 30.0+/-4.4 ml per kilogram of body weight per minute, P<0.001), and left ventricular outflow tract gradients (resting gradient, from 64+/-36 to 16+/-15 mm Hg; P<0.001; stress-induced gradient, from 132+/-34 to 45+/-19 mm Hg; P<0.001). Procedure-related complications included right bundle-branch block in all patients, complete heart block in 31 patients (48 percent), and significant increases in QRS and corrected QT intervals. Seventeen patients (27 percent) required permanent pacing. R-wave amplitude was significantly decreased (from 32+/-8 to 17+/-7 mV, P<0.001). The dimensions of the left ventricular cavity increased, and the interventricular septal thickness was reduced. Nonsurgical septal reduction leads to sustained improvements in both subjective and objective measures of exercise capacity in association with a persistent reduction in resting and stress-induced left ventricular outflow tract gradients. It is also associated with a high incidence of procedure-related complete heart block, however, often requiring permanent pacing. Copyright 2002

Abnormal cardiac response to exercise in a murine model of familial hypertrophic cardiomyopathy.

PubMed

Nguyen, Lan; Chung, Jessica; Lam, Lien; Tsoutsman, Tatiana; Semsarian, Christopher

2007-07-10

Clinical outcome in familial hypertrophic cardiomyopathy (FHC) may be influenced by modifying factors such as exercise. Transgenic mice which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), develop all the characteristic phenotypic features of FHC. To study the modifying effect of exercise in early disease, mice underwent swimming exercise at an early age prior to the development of the FHC phenotype. In non-transgenic and cTnI-wt mice, swimming resulted in a significant increase in left ventricular wall thickness and contractility on echocardiography, consistent with a physiological hypertrophic response to exercise. In contrast, cTnI-G203S mice showed no increase in these parameters, indicating an abnormal response to exercise. The lack of a physiological response to exercise may indicate an important novel mechanistic insight into the role of exercise in triggering adverse events in FHC.

Cardiac Magnetic Resonance and Computed Tomography in Hypertrophic Cardiomyopathy: an Update

PubMed Central

de Oliveira, Diogo Costa Leandro; Assunção, Fernanda Boldrini; dos Santos, Alair Agusto Sarmet Moreira Damas; Nacif, Marcelo Souto

2016-01-01

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease and represents the main cause of sudden death in young patients. Cardiac magnetic resonance (CMR) and cardiac computed tomography (CCT) are noninvasive imaging methods with high sensitivity and specificity, useful for the establishment of diagnosis and prognosis of HCM, and for the screening of patients with subclinical phenotypes. The improvement of image analysis by CMR and CCT offers the potential to promote interventions aiming at stopping the natural course of the disease. This study aims to describe the role of RCM and CCT in the diagnosis and prognosis of HCM, and how these methods can be used in the management of these patients. PMID:27305111

The Metabolome in Finnish Carriers of the MYBPC3-Q1061X Mutation for Hypertrophic Cardiomyopathy.

PubMed

Jørgenrud, Benedicte; Jalanko, Mikko; Heliö, Tiina; Jääskeläinen, Pertti; Laine, Mika; Hilvo, Mika; Nieminen, Markku S; Laakso, Markku; Hyötyläinen, Tuulia; Orešič, Matej; Kuusisto, Johanna

2015-01-01

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters. 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation. Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.

Myocarditis caused by Feline Immunodeficiency Virus in Five Cats with Hypertrophic Cardiomyopathy.

PubMed

Rolim, V Machado; Casagrande, R Assis; Wouters, A Terezinha Barth; Driemeier, D; Pavarini, S Petinatti

2016-01-01

Viral infections have been implicated as the cause of cardiomyopathy in several mammalian species. This study describes hypertrophic cardiomyopathy (HCM) and myocarditis associated with feline immunodeficiency virus (FIV) infection in five cats aged between 1 and 4 years. Clinical manifestations included dyspnoea in four animals, one of which also exhibited restlessness. One animal showed only lethargy, anorexia and vomiting. Necropsy examination revealed marked cardiomegaly, marked left ventricular hypertrophy and pallor of the myocardium and epicardium in all animals. Microscopical and immunohistochemical examination showed multifocal infiltration of the myocardium with T lymphocytes and fewer macrophages, neutrophils and plasma cells. An intense immunoreaction for FIV antigen in the cytoplasm and nucleus of lymphocytes and the cytoplasm of some macrophages was observed via immunohistochemistry (IHC). IHC did not reveal the presence of antigen from feline calicivirus, coronavirus, feline leukaemia virus, feline parvovirus, Chlamydia spp. or Toxoplasma gondii. The results demonstrate the occurrence of FIV infection in inflammatory cells in the myocardium of five cats with myocarditis and HCM. Copyright © 2015 Elsevier Ltd. All rights reserved.

Electrocardiogram and Imaging: An Integrated Approach to Arrhythmogenic Cardiomyopathies.

PubMed

Savino, Ketty; Bagliani, Giuseppe; Crusco, Federico; Padeletti, Margherita; Lombardi, Massimo

2018-06-01

Cardiovascular imaging has radically changed the management of patients with arrhythmogenic cardiomyopathies. This article focuses on the role of echocardiography and MRI in the diagnosis of these structural diseases. Cardiomyopathies with hypertrophic pattern (hypertrophic cardiomyopathy, restrictive cardiomyopathies, amyloidosis, Anderson-Fabry disease, and sarcoidosis), cardiomyopathies with dilated pattern, inflammatory cardiac diseases, and right ventricular arrhythmogenic cardiomyopathy are analyzed. Finally, anatomic predictors of arrhythmias and sudden cardiac death are discussed. Each paragraph is attended by clinical cases that are discussed on the electrocardiogram, after integrated with the anatomic, functional, and hemodynamic modifications of cardiovascular imaging. Copyright © 2018 Elsevier Inc. All rights reserved.

Clinical long-term outcome of septal myectomy for obstructive hypertrophic cardiomyopathy in infants.

PubMed

Schleihauf, Julia; Cleuziou, Julie; Pabst von Ohain, Jelena; Meierhofer, Christian; Stern, Heiko; Shehu, Nerejda; Mkrtchyan, Naira; Kaltenecker, Emanuel; Kühn, Andreas; Nagdyman, Nicole; Hager, Alfred; Seidel, Heide; Lange, Rüdiger; Ewert, Peter; Wolf, Cordula M

2018-03-01

Surgical septal myectomy is performed to relieve left ventricular outflow tract narrowing in severe drug-refractory obstructive hypertrophic cardiomyopathy. The objective of this study was to assess the perioperative and long-term clinical outcome of this procedure performed during infancy. Clinical, transthoracic echocardiographic, electrocardiographic, 24-h Holter, cardiopulmonary exercise test and genetic data were extracted by medical record review. A subset of patients underwent additional prospective detailed clinical evaluation including cardiac magnetic resonance imaging with contrast. Surgery was performed in 23 paediatric patients between 1978 and 2015 at the German Heart Centre Munich. Twelve patients had undergone surgery during infancy (≤ 1 year) (Group A), 11 between 1 and 18 years of age (Group B). The underlying genetic diagnosis was Noonan syndrome spectrum and non-syndromic hypertrophic cardiomyopathy. As compared to Group B, patients in Group A showed more concomitant cardiac procedures and received more homologous transfusions. One perioperative death occurred in Group A, and none in Group B. Two patients in Group A but no patient in Group B required redo septal myectomy. The long-term clinical outcome was similar between the 2 groups. One patient in Group B required cardioverter-defibrillator/pacemaker implantation for higher degree atrioventricular block and none in Group A. There was no evidence of differences in myocardial fibrosis between groups on long-term follow-up magnetic resonance imaging. Surgical septal myectomy can be performed safely during infancy with favourable perioperative and long-term clinical outcome but with a trend towards a higher reoperation rate later in life. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Doppler echocardiographic evaluation of midventricular obstruction in cats with hypertrophic cardiomyopathy.

PubMed

MacLea, H B; Boon, J A; Bright, J M

2013-01-01

Hypertrophic cardiomyopathy (HCM) is heterogeneous in both people and cats, with variability in the distribution of hypertrophy, hemodynamic characteristics, and Doppler echocardiographic findings. To document the Doppler echocardiographic characteristics of midventricular obstruction in some cats with HCM. Eight cats with hypertrophic cardiomyopathy. Retrospective case series. The medical records of cats presenting to the cardiology service at Colorado State University between February 2009 and January 2012 were reviewed. All cats had a physical examination; Doppler systolic blood pressure measurement; and transthoracic two-dimensional (2D), M-mode, and Doppler echocardiography were performed. A more thorough evaluation of the echocardiographic images and measurements was performed. Cats included in this study had echocardiograms of adequate quality to confirm the diagnosis of midventricular obstruction by documentation of left midventricular concentric hypertrophy; a midventricular turbulent Doppler color flow pattern; and high velocity, late-peaking flow at the area of turbulence. Cats with evidence of systemic hypertension defined as a systolic Doppler blood pressure of greater than 170 mmHg were excluded. All 8 cats had left ventricular hypertrophy at the level of the papillary muscles; left, midventricular hypertrophy; and in 4/8 cats there was apical hypertrophy or basilar hypertrophy of the interventricular septum. Color flow Doppler revealed turbulent flow in 8/8 cats and spectral Doppler (continuous and pulsed wave) revealed increased flow velocities and late-peaking flow profiles at the level of the left midventricle. Two of 8 cats had a bifid midventricular flow profile in which there was a midsystolic decline in left ventricular velocities with elevated velocities extending into early diastole. The peak left ventricular outflow velocity in all 8 cats was normal. A variant of HCM characterized by hypertrophy at the level of the papillary muscles with

Does septal thickness influence outcome of myectomy for hypertrophic obstructive cardiomyopathy?

PubMed

Nguyen, Anita; Schaff, Hartzell V; Nishimura, Rick A; Dearani, Joseph A; Geske, Jeffrey B; Lahr, Brian D; Ommen, Steve R

2018-03-01

Patients with hypertrophic obstructive cardiomyopathy and basal septal thickness <18 mm are often considered unsuitable candidates for myectomy. Mitral valve (MV) replacement is frequently performed instead. We aimed to determine whether septal thickness affects outcomes and adequacy of myectomy. Clinical and echocardiographic data were reviewed for 1486 consecutive adult patients with hypertrophic obstructive cardiomyopathy who underwent transaortic septal myectomy from January 2005 through December 2014. Comparisons between patients, grouped by septal thickness (<18 mm, n = 369; 18-21 mm, n = 612 and >21 mm, n = 505), were performed with the Kruskal-Wallis and the Pearson χ2 tests and semiparametric analysis of covariance. Median group ages were 57, 57 and 54 years (P = 0.007); men comprised 50.4%, 56.7% and 62.0%, respectively (P = 0.003). Intrinsic MV disease was present in 5.9%, 5.2% and 4.6%, respectively (P = 0.80). All patients underwent transaortic septal myectomy. Additional mitral procedures were performed in 7.6%, 7.8% and 8.1%, respectively (P = 0.90). Reasons for MV surgery included intrinsic MV disease (66.7%), residual mitral regurgitation (30.8%) and residual gradient (2.6%). All groups had postoperative gradient relief (median reduction: 51, 54 and 50 mmHg; P = 0.11). Ventricular septal defect occurred in 4 patients (0.3%), and risk did not differ by group (P = 0.24). Adequate relief of left ventricular outflow tract obstruction can be achieved via transaortic septal myectomy without concomitant MV procedures when septal thickness is < 18 mm, and the risk of ventricular septal defect is minimal. Concomitant MV repair/replacement should be reserved for patients with intrinsic MV disease or inadequate relief of mitral regurgitation/left ventricular outflow tract obstruction following adequate extended septal myectomy. © The Author 2017. Published by Oxford University Press on behalf of the

A One Health Approach to Hypertrophic Cardiomyopathy

PubMed Central

Ueda, Yu; Stern, Joshua A.

2017-01-01

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease in humans and results in significant morbidity and mortality. Research over the past 25 years has contributed enormous insight into this inherited disease particularly in the areas of genetics, molecular mechanisms, and pathophysiology. Our understanding continues to be limited by the heterogeneity of clinical presentations with various genetic mutations associated with HCM. Transgenic mouse models have been utilized especially studying the genotypic and phenotypic interactions. However, mice possess intrinsic cardiac and hemodynamic differences compared to humans and have limitations preventing their direct translation. Other animal models of HCM have been studied or generated in part to overcome these limitations. HCM in cats shows strikingly similar molecular, histopathological, and genetic similarities to human HCM, and offers an important translational opportunity for the study of this disease. Recently, inherited left ventricular hypertrophy in rhesus macaques was identified and collaborative investigations have been conducted to begin to develop a non-human primate HCM model. These naturally-occurring large-animal models may aid in advancing our understanding of HCM and developing novel therapeutic approaches to this disease. This review will highlight the features of HCM in humans and the relevant available and developing animal models of this condition. PMID:28955182

Role of imaging in evaluation of sudden cardiac death risk in hypertrophic cardiomyopathy.

PubMed

Geske, Jeffrey B; Ommen, Steve R

2015-09-01

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and is associated with sudden cardiac death (SCD) - an uncommon but devastating clinical outcome. This review is designed to assess the role of imaging in established risk factor assessment and its role in emerging SCD risk stratification. Recent publications have highlighted the crucial role of imaging in HCM SCD risk stratification. Left ventricular hypertrophy assessment remains the key imaging determinant of risk. Data continue to emerge on the role of systolic dysfunction, apical aneurysms, left atrial enlargement and left ventricular outflow tract obstruction as markers of risk. Quantitative assessment of delayed myocardial enhancement and T1 mapping on cardiac MRI continue to evolve. Recent multicenter trials have allowed multivariate SCD risk assessment in large HCM cohorts. Given aggregate risk with presence of multiple risk factors, a single parameter should not be used in isolation to determine implantable cardiac defibrillator candidacy. Use of all available imaging data, including cardiac magnetic resonance tissue characterization, allows a comprehensive approach to SCD stratification and implantable cardiac defibrillator decision-making.

Alcohol septal ablation in obstructive hypertrophic cardiomyopathy: four years of experience at a reference center.

PubMed

Fiarresga, António; Cacela, Duarte; Galrinho, Ana; Ramos, Ruben; de Sousa, Lídia; Bernardes, Luís; Patrício, Lino; Cruz Ferreira, Rui

2014-01-01

We describe our center's initial experience with alcohol septal ablation (ASA) for the treatment of obstructive hypertrophic cardiomyopathy. The procedure, its indications, results and clinical outcomes will be addressed, as will its current position compared to surgical myectomy. To assess the results of ASA in all patients treated in the first four years of activity at our center. We retrospectively studied all consecutive and unselected patients treated by ASA between January 2009 and February 2013. In the first four years of experience 40 patients were treated in our center. In three patients (7.5%) the intervention was repeated. Procedural success was 84%. Minor complications occurred in 7.5%. Two patients received a permanent pacemaker for atrioventricular block (6% of those without previous pacemaker). The major complication rate was 5%. There were no in-hospital deaths; during clinical follow-up (22 ± 14 months) cardiovascular mortality was 2.5% and overall mortality was 5%. The results presented reflect the initial experience of our center with ASA. The success rate was high and in line with published results, but with room to improve with better patient selection. ASA was shown to be safe, with a low complication rate and no procedure-related mortality. Our experience confirms ASA as a percutaneous alternative to myectomy for the treatment of symptomatic patients with obstructive hypertrophic cardiomyopathy refractory to medical treatment. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Radiofrequency ablation of fast ventricular tachycardia causing an ICD storm in an infant with hypertrophic cardiomyopathy.

PubMed

Ergul, Yakup; Ozyilmaz, Isa; Bilici, Meki; Ozturk, Erkut; Haydin, Sertaç; Guzeltas, Alper

2018-04-01

An implantable cardioverter defibrillator (ICD) storm involves very frequent arrhythmia episodes and ICD shocks, and it is associated with poor short-term and long-term prognosis. Radiofrequency catheter ablation can be used as an effective rescue treatment for patients with an ICD storm. To our knowledge, this is the first report of an infant with hypertrophic cardiomyopathy presenting with an ICD storm and undergoing successful radiofrequency catheter ablation salvage treatment for the fast left posterior fascicular ventricular tachycardia. © 2017 Wiley Periodicals, Inc.

Flow-Induced Mitral Leaflet Motion in Hypertrophic Cardiomyopathy

NASA Astrophysics Data System (ADS)

Meschini, Valentina; Mittal, Rajat; Verzicco, Roberto

2017-11-01

Hypertrophic cardiomyopathy (HCM) is considered the cause of sudden cardiac death in developed countries. Clinically it is found to be related to the thickening of the intra-ventricular septum combined with elongated mitral leaflets. During systole the low pressure, induced by the abnormal velocities in the narrowed aortic channel, can attract one or both the mitral leaflets causing the aortic obstruction and sometimes instantaneous death. In this paper a fluid structure interaction model for the flow in the left ventricle with a native mitral valve is employed to investigate the physio-pathology of HCM. The problem is studied using direct numerical simulations of the Navier-Stokes equations with a two-way coupled structural solver based on interaction potential approach for the structure dynamics. Simulations are performed for two different degrees of hypertrophy, and two values of pumping efficiency. The leaflets dynamics and the ventricle deformation resulting from the echocardiography of patients affected by HCM are well captured by the simulations. Moreover, the procedures of leaflets plication and septum myectomy are simulated in order to get insights into the efficiency and reliability of such surgery.

Biventricular non-compaction hypertrophic cardiomyopathy in association with congenital complete heart block and type I mitochondrial complex deficiency.

PubMed

Dhar, Ranjana; Reardon, William; McMahon, Colin J

2015-06-01

We report a baby girl with an antenatal diagnosis of biventricular non-compaction and complete heart block detected at 22 weeks' gestation. Postnatal echocardiography confirmed severe biventricular non-compaction hypertrophic cardiomyopathy, multiple muscular ventricular septal defects, and mild-moderate pulmonary valve stenosis. Skeletal muscle biopsy confirmed complex 1 mitochondrial respiratory chain deficiency. An epicardial VVI pacemaker was implanted on day 3 of life and revised at 7 years of age. She remains stable at 8 years of age following pacing and medical treatment with carvedilol, aspirin, co-enzyme Q10, and carnitine. This represents the first report of biventricular non-compaction hypertrophic phenotype in association with congenital complete heart block and complex 1 mitochondrial respiratory chain deficiency in a child.

High left ventricular outflow tract gradient: Aortic stenosis, obstructive hypertrophic cardiomyopathy or both?

PubMed

Almeida, Inês; Caetano, Francisca; Trigo, Joana; Mota, Paula; Marques, António Leitão

2015-05-01

The authors report the case of a patient diagnosed with both hypertrophic cardiomyopathy and aortic stenosis. Due to clinical deterioration, additional investigation was performed, and a high left ventricular outflow tract gradient was identified. Correct identification of the condition causing the symptoms was challenging, and involved several imaging techniques, the contribution of transesophageal echocardiography being crucial. The final diagnosis of severe aortic stenosis led to successful valve replacement surgery. The presence of these two conditions in the same patient has been documented, although it is uncommon. This association poses particular diagnostic and therapeutic challenges, which are discussed in this paper. Copyright © 2015 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Assessment of left ventricular mass in hypertrophic cardiomyopathy by real-time three-dimensional echocardiography using single-beat capture image.

PubMed

Chang, Sung-A; Kim, Hyung-Kwan; Lee, Sang-Chol; Kim, Eun-Young; Hahm, Seung-Hee; Kwon, Oh Min; Park, Seung Woo; Choe, Yeon Hyeon; Oh, Jae K

2013-04-01

Left ventricular (LV) mass is an important prognostic indicator in hypertrophic cardiomyopathy. Although LV mass can be easily calculated using conventional echocardiography, it is based on geometric assumptions and has inherent limitations in asymmetric left ventricles. Real-time three-dimensional echocardiographic (RT3DE) imaging with single-beat capture provides an opportunity for the accurate estimation of LV mass. The aim of this study was to validate this new technique for LV mass measurement in patients with hypertrophic cardiomyopathy. Sixty-nine patients with adequate two-dimensional (2D) and three-dimensional echocardiographic image quality underwent cardiac magnetic resonance (CMR) imaging and echocardiography on the same day. Real-time three-dimensional echocardiographic images were acquired using an Acuson SC2000 system, and CMR-determined LV mass was considered the reference standard. Left ventricular mass was derived using the formula of the American Society of Echocardiography (M-mode mass), the 2D-based truncated ellipsoid method (2D mass), and the RT3DE technique (RT3DE mass). The mean time for RT3DE analysis was 5.85 ± 1.81 min. Intraclass correlation analysis showed a close relationship between RT3DE and CMR LV mass (r = 0.86, P < .0001). However, LV mass by the M-mode or 2D technique showed a smaller intraclass correlation coefficient compared with CMR-determined mass (r = 0.48, P = .01, and r = 0.71, P < .001, respectively). Bland-Altman analysis showed reasonable limits of agreement between LV mass by RT3DE imaging and by CMR, with a smaller positive bias (19.5 g [9.1%]) compared with that by the M-mode and 2D methods (-35.1 g [-20.2%] and 30.6 g [17.6%], respectively). RT3DE measurement of LV mass using the single-beat capture technique is practical and more accurate than 2D or M-mode LV mass in patients with hypertrophic cardiomyopathy. Copyright © 2013 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes.

PubMed

Francisco, Ana Rita G; Santos Gonçalves, Inês; Veiga, Fátima; Mendes Pedro, Mónica; Pinto, Fausto J; Brito, Dulce

2017-09-01

The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy. In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM

PubMed Central

Freeman, Lisa M.; Rush, John E.; Stern, Joshua A.; Huggins, Gordon S.; Maron, Martin S.

2017-01-01

Hypertrophic cardiomyopathy (HCM) is a common disease in pet cats, affecting 10-15% of the pet cat population. The similarity to human HCM, the rapid progression of disease, and the defined and readily determined endpoints of feline HCM make it an excellent natural model that is genotypically and phenotypically similar to human HCM. The Maine Coon and Ragdoll cats are particularly valuable models of HCM because of myosin binding protein-C mutations and even higher disease incidence compared to the overall feline population. The cat overcomes many of the limitations of rodent HCM models, and can provide enhanced translation of information from in vitro and induced small animal models to human clinical trials. Physicians and veterinarians working together in a collaborative and interdisciplinary approach can accelerate the discovery of more effective treatments for this and other cardiovascular diseases affecting human and veterinary patients. PMID:28868097

Amino-terminal domains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product

NASA Astrophysics Data System (ADS)

Rustgi, Anil K.; Dyson, Nicholas; Bernards, Rene

1991-08-01

THE proteins encoded by the myc gene family are involved in the control of cell proliferation and differentiation, and aberrant expression of myc proteins has been implicated in the genesis of a variety of neoplasms1. In the carboxyl terminus, myc proteins have two domains that encode a basic domain/helix-loop-helix and a leucine zipper motif, respectively. These motifs are involved both in DNA binding and in protein dimerization2-5. In addition, myc protein family members share several regions of highly conserved amino acids in their amino termini that are essential for transformation6,7. We report here that an N-terminal domain present in both the c-myc and N-myc proteins mediates binding to the retinoblastoma gene product, pRb. We show that the human papilloma virus E7 protein competes with c-myc for binding to pRb, indicating that these proteins share overlapping binding sites on pRb. Furthermore, a mutant Rb protein from a human tumour cell line that carried a 35-amino-acid deletion in its C terminus failed to bind to c-myc. Our results suggest that c-myc and pRb cooperate through direct binding to control cell proliferation.

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy

PubMed Central

Dossat, Amanda M.; Sanchez-Gonzalez, Marcos A.; Koutnik, Andrew P.; Leitner, Stefano; Ruiz, Edda L.; Griffin, Brittany; Rosenberg, Jens T.; Grant, Samuel C.; Fincham, Francis D.; Pinto, Jose R.; Kabbaj, Mohamed

2017-01-01

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3–4 mo) and aged adult (7–8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder–related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.—Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy. PMID

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

PubMed

Dossat, Amanda M; Sanchez-Gonzalez, Marcos A; Koutnik, Andrew P; Leitner, Stefano; Ruiz, Edda L; Griffin, Brittany; Rosenberg, Jens T; Grant, Samuel C; Fincham, Francis D; Pinto, Jose R; Kabbaj, Mohamed

2017-06-01

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3-4 mo) and aged adult (7-8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder-related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.-Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy. © FASEB.

Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

PubMed

Olivotto, Iacopo; Maron, Martin S; Autore, Camillo; Lesser, John R; Rega, Luigi; Casolo, Giancarlo; De Santis, Marcello; Quarta, Giovanni; Nistri, Stefano; Cecchi, Franco; Salton, Carol J; Udelson, James E; Manning, Warren J; Maron, Barry J

2008-08-12

Our aim was to assess the distribution and clinical significance of left ventricular (LV) mass in patients with hypertrophic cardiomyopathy (HCM). Hypertrophic cardiomyopathy is defined echocardiographically by unexplained left ventricular wall thickening. Left ventricular mass, quantifiable by modern cardiovascular magnetic resonance techniques, has not been systematically assessed in this disease. In 264 HCM patients (age 43 +/- 18 years; 75% men), LV mass by cardiovascular magnetic resonance was measured, indexed by body surface area, and compared with that in 606 healthy control subjects. The LV mass index in HCM patients significantly exceeded that of control subjects (104 +/- 40 g/m(2) vs. 61 +/- 10 g/m(2) in men and 89 +/- 33 g/m(2) vs. 47 +/- 7 g/m(2) in women; both p < 0.0001). However, values were within the normal range (< or = mean +2 SDs for control subjects) in 56 patients (21%), and only mildly increased (mean +2 to 3 SDs) in 18 (16%). The LV mass index showed a modest relationship to maximal LV thickness (r(2) = 0.38; p < 0.001), and was greater in men (104 +/- 40 g/m(2) vs. 89 +/- 33 g/m(2) in women; p < 0.001) and in patients with resting outflow obstruction (121 +/- 43 g/m(2) vs. 96 +/- 37 g/m(2) in nonobstructives; p < 0.001). During a 2.6 +/- 0.7-year follow-up, markedly increased LV mass index proved more sensitive in predicting outcome (100%, with 39% specificity), whereas maximal wall thickness >30 mm was more specific (90%, with 41% sensitivity). In distinction to prior perceptions, LV mass index was normal in about 20% of patients with definite HCM phenotype. Therefore, increased LV mass is not a requirement for establishing the clinical diagnosis of HCM. The LV mass correlated weakly with maximal wall thickness, and proved more sensitive in predicting outcome.

Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.

PubMed

Gómez, Juan; Lorca, Rebeca; Reguero, Julian R; Morís, César; Martín, María; Tranche, Salvador; Alonso, Belén; Iglesias, Sara; Alvarez, Victoria; Díaz-Molina, Beatriz; Avanzas, Pablo; Coto, Eliecer

2017-04-01

Recent exome sequencing studies identified filamin C ( FLNC ) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3 , TNNT2 , TNNI3 , ACTC1 , TNNC1 , MYL2 , MYL3 , TPM1 , and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported ( P =0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign. We provide a compelling evidence of the involvement of FLNC in the development of HCM. Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies. © 2017 American Heart Association, Inc.

Cardiovascular magnetic resonance imaging in hypertrophic cardiomyopathy: Current state of the art.

PubMed

Kamal, Muhammad Umar; Riaz, Irbaz Bin; Janardhanan, Rajesh

2016-01-01

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy with a prevalence of 1:500 (0.2%) in the general population. Sudden cardiac death (SCD) is the most feared presentation of HCM. Therefore, it is essential to identify individuals at high risk in order to prevent SCD. The absence of conventional risk factors does not nullify the risk of HCM related SCD. Although echocardiography is currently the most widely used imaging modality, cardiac magnetic resonance (CMR) allows detailed characterization of the HCM phenotype, which makes it possible to differentiate HCM from other causes of left ventricular hypertrophy. CMR has the potential to further refine risk stratification. Late gadolinium enhancement (LGE) on CMR is a high-risk feature and there is emerging data to suggest that the presence of LGE should be employed as a marker for major adverse outcomes such as SCD, arrhythmias, systolic and diastolic heart failure. Hence, LGE on CMR may be considered an additional risk factor for SCD in HCM patients and should be incorporated in decision-making for implant-able cardioverter defibrillator implantation to aid primary prevention. Novel markers such as the extent of myocardial fibrosis on CMR must be accounted for comprehensive risk stratifica-tion of HCM patients. The purpose of this review is to discuss the current status and emerging role of CMR in HCM.

Hypertrophic Cardiomyopathy: New Evidence Since the 2011 American Cardiology of Cardiology Foundation and American Heart Association Guideline.

PubMed

Fraiche, Ariane; Wang, Andrew

2016-07-01

Since publication of the 2011 American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy (HCM), more recent studies offer greater insights about this condition. With increased recognition of the role of sarcomere protein mutations and myocardial structural abnormalities in the pathophysiology of this disease, new evidence offers potential improvements for the management of patients with HCM. In this review of studies published since 2011, we highlight several studies that may impact diagnostic considerations, risk stratification, and treatment of symptoms in HCM.

Infective endocarditis in hypertrophic cardiomyopathy

PubMed Central

Dominguez, Fernando; Ramos, Antonio; Bouza, Emilio; Muñoz, Patricia; Valerio, Maricela C.; Fariñas, M. Carmen; de Berrazueta, José Ramón; Zarauza, Jesús; Pericás Pulido, Juan Manuel; Paré, Juan Carlos; de Alarcón, Arístides; Sousa, Dolores; Rodriguez Bailón, Isabel; Montejo-Baranda, Miguel; Noureddine, Mariam; García Vázquez, Elisa; Garcia-Pavia, Pablo

2016-01-01

Abstract Infective endocarditis (IE) complicating hypertrophic cardiomyopathy (HCM) is a poorly known entity. Although current guidelines do not recommend IE antibiotic prophylaxis (IEAP) in HCM, controversy remains. This study sought to describe the clinical course of a large series of IE HCM and to compare IE in HCM patients with IE patients with and without an indication for IEAP. Data from the GAMES IE registry involving 27 Spanish hospitals were analyzed. From January 2008 to December 2013, 2000 consecutive IE patients were prospectively included in the registry. Eleven IE HCM additional cases from before 2008 were also studied. Clinical, microbiological, and echocardiographic characteristics were analyzed in IE HCM patients (n = 34) and in IE HCM reported in literature (n = 84). Patients with nondevice IE (n = 1807) were classified into 3 groups: group 1, HCM with native-valve IE (n = 26); group 2, patients with IEAP indication (n = 696); group 3, patients with no IEAP indication (n = 1085). IE episode and 1-year follow-up data were gathered. One-year mortality in IE HCM was 42% in our study and 22% in the literature. IE was more frequent, although not exclusive, in obstructive HCM (59% and 74%, respectively). Group 1 exhibited more IE predisposing factors than groups 2 and 3 (62% vs 40% vs 50%, P < 0.01), and more previous dental procedures (23% vs 6% vs 8%, P < 0.01). Furthermore, Group 1 experienced a higher incidence of Streptococcus infections than Group 2 (39% vs 22%, P < 0.01) and similar to Group 3 (39% vs 30%, P = 0.34). Overall mortality was similar among groups (42% vs 36% vs 35%, P = 0.64). IE occurs in HCM patients with and without obstruction. Mortality of IE HCM is high but similar to patients with and without IEAP indication. Predisposing factors, previous dental procedures, and streptococcal infection are higher in IE HCM, suggesting that HCM patients could benefit from IEAP. PMID:27368014

Hypertrophic Cardiomyopathy from A to Z: Genetics, Pathophysiology, Imaging, and Management.

PubMed

Baxi, Ameya Jagdish; Restrepo, Carlos S; Vargas, Daniel; Marmol-Velez, Alejandro; Ocazionez, Daniel; Murillo, Horacio

2016-01-01

Hypertrophic cardiomyopathy (HCM) is a heterogeneous group of diseases related to sarcomere gene mutations exhibiting heterogeneous phenotypes with an autosomal dominant mendelian pattern of inheritance. The disorder is characterized by diverse phenotypic expressions and variable natural progression, which may range from dyspnea and/or syncope to sudden cardiac death. It is found across all racial groups and is associated with left ventricular hypertrophy in the absence of another systemic or cardiac disease. The management of HCM is based on a thorough understanding of the underlying morphology, pathophysiology, and clinical course. Imaging findings of HCM mirror the variable expressivity and penetrance heterogeneity, with the added advantage of diagnosis even in cases where a specific mutation may not yet be found. The diagnostic information obtained from imaging varies depending on the specific stage of HCM-phenotype manifestation, including the prehypertrophic, hypertrophic, and later stages of adverse remodeling into the burned-out phase of overt heart failure. However, subtle or obvious, these imaging findings become critical components in diagnosis, management, and follow-up of HCM patients. Although diagnosis of HCM traditionally relies on clinical assessment and transthoracic echocardiography, recent studies have demonstrated increased utility of multidetector computed tomography (CT) and particularly cardiac magnetic resonance (MR) imaging in diagnosis, phenotype differentiation, therapeutic planning, and prognostication. In this article, we provide an overview of the genetics, pathophysiology, and clinical manifestations of HCM, with the spectrum of imaging findings at MR imaging and CT and their contribution in diagnosis, risk stratification, and therapy. (©)RSNA, 2016.

Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal

PubMed Central

Kanatsu-Shinohara, Mito; Tanaka, Takashi; Ogonuki, Narumi; Ogura, Atsuo; Morimoto, Hiroko; Cheng, Pei Feng; Eisenman, Robert N.; Trumpp, Andreas; Shinohara, Takashi

2016-01-01

Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max, a Myc-binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1, whose deficiency impairs SSC self-renewal. Myc/Mycn-deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of active Akt1 or Pdpk1 (phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested that Myc-mediated glycolysis is an important factor that increases the frequency of SSC self-renewal division. PMID:28007786

High validity of cardiomyopathy diagnoses in western Sweden (1989–2009)

PubMed Central

Rosengren, Annika; Lindström, Sandra; Schaufelberger, Maria

2017-01-01

Abstract Aim Hospital discharges with a diagnosis of cardiomyopathy have more than doubled in Sweden since 1987. We validated the cardiomyopathy diagnoses over this time period to investigate that the increase was real and not a result of improved recognition of the diagnosis and better diagnostic methods. Methods and results Every fifth year from 1989 to 2009, records for all patients with a cardiomyopathy diagnosis were identified by searching the local registers in three hospitals in Västra Götaland, Sweden. The diagnoses were validated according to criteria defined by the European Society of Cardiology from 2008. The population comprised 611 cases with cardiomyopathy diagnoses [mean age 58.9 (SD 15.5) years, 68.2% male], divided into three major groups: dilated, hypertrophic, and other cardiomyopathies. Hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy were analysed as a group. Cardiomyopathies for which there were few cases, such as restrictive, arrhythmogenic right ventricular, left ventricular non‐compaction, takotsubo, and peripartum cardiomyopathies, were analysed together and defined as ‘other cardiomyopathies’. Relevant co‐morbidities were registered. The use of echocardiography was 99.7%, of which 94.6% was complete echocardiography reports. The accuracy rates of the diagnoses dilated cardiomyopathy, hypertrophic cardiomyopathy, and other cardiomyopathies were 85.5%, 87.5%, and 100%, respectively, with no differences between the three hospitals or years studied; nor did the prevalence of co‐morbidities differ. Conclusions The accuracy rate of the cardiomyopathy diagnoses from in‐hospital records from >600 patients in western Sweden during a 20 year period was 86.6%, with no significant trend over time, strengthening epidemiological findings that this is likely due to an actual increase in cardiomyopathy diagnoses rather than changes in coding practices. The use of echocardiography was high, and there was no

High validity of cardiomyopathy diagnoses in western Sweden (1989-2009).

PubMed

Basic, Carmen; Rosengren, Annika; Lindström, Sandra; Schaufelberger, Maria

2018-04-01

Hospital discharges with a diagnosis of cardiomyopathy have more than doubled in Sweden since 1987. We validated the cardiomyopathy diagnoses over this time period to investigate that the increase was real and not a result of improved recognition of the diagnosis and better diagnostic methods. Every fifth year from 1989 to 2009, records for all patients with a cardiomyopathy diagnosis were identified by searching the local registers in three hospitals in Västra Götaland, Sweden. The diagnoses were validated according to criteria defined by the European Society of Cardiology from 2008. The population comprised 611 cases with cardiomyopathy diagnoses [mean age 58.9 (SD 15.5) years, 68.2% male], divided into three major groups: dilated, hypertrophic, and other cardiomyopathies. Hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy were analysed as a group. Cardiomyopathies for which there were few cases, such as restrictive, arrhythmogenic right ventricular, left ventricular non-compaction, takotsubo, and peripartum cardiomyopathies, were analysed together and defined as 'other cardiomyopathies'. Relevant co-morbidities were registered. The use of echocardiography was 99.7%, of which 94.6% was complete echocardiography reports. The accuracy rates of the diagnoses dilated cardiomyopathy, hypertrophic cardiomyopathy, and other cardiomyopathies were 85.5%, 87.5%, and 100%, respectively, with no differences between the three hospitals or years studied; nor did the prevalence of co-morbidities differ. The accuracy rate of the cardiomyopathy diagnoses from in-hospital records from >600 patients in western Sweden during a 20 year period was 86.6%, with no significant trend over time, strengthening epidemiological findings that this is likely due to an actual increase in cardiomyopathy diagnoses rather than changes in coding practices. The use of echocardiography was high, and there was no significant difference in co-morbidities during the study period

Isolated papillary muscle hypertrophy: A gap in our knowledge of hypertrophic cardiomyopathy?

PubMed

Ferreira, Catarina; Delgado, Carlos; Vázquez, María; Trinidad, Carmen; Vilar, Manuel

2014-06-01

Increased thickness of left ventricular walls is the predominant characteristic and one of the diagnostic criteria of hypertrophic cardiomyopathy (HCM). This case illustrates an uncommon but important finding of isolated hypertrophy of the papillary muscles (PMs), observed in a young woman in whom an abnormal electrocardiogram was initially detected. During the investigation isolated PM hypertrophy was identified. The structural characteristics of the PMs have received scant attention in this setting and there is little information in the literature on this entity, whose real prevalence and clinical significance remain to be determined. The available information relates solitary PM hypertrophy with an early form or a different pattern of HCM. In this case PM hypertrophy was only detected due to the finding of an abnormal electrocardiogram, which prompted further diagnostic tests and a search for possible etiologies. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

[Mutation analysis of beta myosin heavy chain gene in hypertrophic cardiomyopathy families].

PubMed

Fan, Xin-ping; Yang, Zhong-wei; Feng, Xiu-li; Yang, Fu-hui; Xiao, Bai; Liang, Yan

2011-08-01

To detect the gene mutations of beta-myosin heavy chain gene (MYH7) in Chinese pedigrees with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype. Exons 3, 5, 7-9, 11-16 and 18-23 of the MYH7 gene were amplified with PCR in three Chinese pedigrees with HCM. The products were sequenced. Sequence alignment between the detected and the standard sequences was performed. A missense mutation of Thr441Met in exon 14 was identified in a pedigree, which was not detected in the controls. Several synonymous mutations of MYH7 gene were detected in the three pedigrees. The mutation of Thr441Met, located in the actin binding domain of the globular head, was first identified in Chinese. It probably caused HCM. HCM is a heterogeneous disease. Many factors are involved in the process of its occurrence and development.

Living with hypertrophic cardiomyopathy.

PubMed

Subasic, Kim

2013-12-01

The purpose of this study is to provide an insider's account of what it is like to live with hypertrophic cardiomyopathy (HCM), a genetic cardiovascular illness that carries the risk for sudden cardiac death. This study aims to reveal how HCM impacts the family and guides the decision whether or not to pursue genetic testing, how the physical limitations associated with HCM alter being-in-the-world, and how HCM alters social relationships. Fifteen adults with HCM were recruited for a longitudinal, phenomenological, qualitative study through purposive sampling and word of mouth. A total of 45 interviews were conducted by the researcher at a time and place designated by the participant between August 2011 and January 2012. The first interview with each participant was conducted in person. While efforts were made to conduct all interviews in person, a total of three interviews were conducted by telephone as requested by three participants due to scheduling conflicts. Through methods of interpretive phenomenology, three audio-recorded, semistructured interviews occurred over the course of 3 months. Detailed narratives were solicited and transcribed verbatim. Methodological and analytical documentation was supported with the identification of key phrases, similar experiences, themes, and documentation of the rationale for decisions throughout the research process. Participation in genetic testing carries a multitude of personal, familial, financial, and emotional implications. The results of a genetic test elicited an emotional response regardless of whether the results were negative, positive, or inconclusive. Living with a potentially life-threatening illness altered identity, disrupted social relationships, and generated chronic fear and uncertainty. A new normal was re-ordered or transformed by the demands and limitations posed by HCM, and by the person's concerns, priorities, and the meaning of the illness. Results from this study underscore the need for healthcare

N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy

PubMed Central

Wilder, Tanganyika; Ryba, David M.; Wieczorek, David F.; Wolska, Beata M.

2015-01-01

S-glutathionylation of cardiac myosin-binding protein C (cMyBP-C) induces Ca2+ sensitization and a slowing of cross-bridge kinetics as a result of increased oxidative signaling. Although there is evidence for a role of oxidative stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism is not well understood. We investigated whether oxidative myofilament modifications may be in part responsible for diastolic dysfunction in HCM. We administered N-acetylcysteine (NAC) for 30 days to 1-mo-old wild-type mice and to transgenic mice expressing a mutant tropomyosin (Tm-E180G) and nontransgenic littermates. Tm-E180G hearts demonstrate a phenotype similar to human HCM. After NAC administration, the morphology and diastolic function of Tm-E180G mice was not significantly different from controls, indicating that NAC had reversed baseline diastolic dysfunction and hypertrophy in our model. NAC administration also increased sarco(endo)plasmic reticulum Ca2+ ATPase protein expression, reduced extracellular signal-related kinase 1/2 phosphorylation, and normalized phosphorylation of phospholamban, as assessed by Western blot. Detergent-extracted fiber bundles from NAC-administered Tm-E180G mice showed nearly nontransgenic (NTG) myofilament Ca2+ sensitivity. Additionally, we found that NAC increased tension cost and rate of cross-bridge reattachment. Tm-E180G myofilaments were found to have a significant increase in S-glutathionylation of cMyBP-C, which was returned to NTG levels upon NAC administration. Taken together, our results indicate that oxidative myofilament modifications are an important mediator in diastolic function, and by relieving this modification we were able to reverse established diastolic dysfunction and hypertrophy in HCM. PMID:26432840

Risk and Causes of Death in Patients After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy.

PubMed

Veselka, Josef; Zemánek, David; Jahnlová, Denisa; Krejčí, Jan; Januška, Jaroslav; Dabrowski, Maciej; Bartel, Thomas; Tomašov, Pavol

2015-10-01

Because the final myocardial scar might be theoretically associated with an increased risk of sudden cardiac death, the long-term clinical course of patients who undergo alcohol septal ablation (ASA) is still a matter of debate. In this retrospective multicentre study, we report outcomes after ASA, including survival, analysis of causes of deaths, and association between time and cause of death. We enrolled 366 consecutive patients (58 ± 12 years, 54% women) who were treated using ASA and followed-up for 5.1 ± 4.5 years. The in-hospital and 30-day mortality were 0.5% and 0.8%, respectively; the ASA-related morbidity was < 20%. Overall, 52 patients died during 1867 patient-years, which means the all-cause mortality rate was 2.8% per year. The mortality rates of sudden death and sudden death with an appropriate implantable cardioverter-defibrillator (ICD) discharge were 0.4% and 1% per year, respectively. Patients with sudden death or appropriate ICD discharge experienced these mortality events at younger age than patients who died of other hypertrophic obstructive cardiomyopathy-related causes (60.8 years [range, 52-71.5 years] vs 72.4 years [range, 64.2-75.2 years]; P = 0.048). A total of 292 patients (80%) had an outflow gradient ≤ 30 mm Hg, and 327 patients (89%) were in New York Heart Association class ≤ II at the last clinical check-up. ASA had low procedure-related mortality, with subsequent 1% occurrence of sudden mortality events per year and 2.8% mortality rate per year in the long-term follow-up. Patients with sudden death or ICD discharge experienced the mortality events approximately 1 decade earlier than patients who died from other causes not related to hypertrophic cardiomyopathy. Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Intraoperative Two- and Three-Dimensional Transesophageal Echocardiography in Combined Myectomy-Mitral Operations for Hypertrophic Cardiomyopathy.

PubMed

Nampiaparampil, Robert G; Swistel, Daniel G; Schlame, Michael; Saric, Muhamed; Sherrid, Mark V

2018-03-01

Transesophageal echocardiography is essential in guiding the surgical approach for patients with obstructive hypertrophic cardiomyopathy. Septal hypertrophy, elongated mitral valve leaflets, and abnormalities of the subvalvular apparatus are prominent features, all of which may contribute to left ventricular outflow tract obstruction. Surgery aims to alleviate the obstruction via an extended myectomy, often with an intervention on the mitral valve and subvalvular apparatus. The goal of intraoperative echocardiography is to assess the anatomic pathology and pathophysiology in order to achieve a safe intraoperative course and a successful repair. This guide summarizes the systematic evaluation of these patients to determine the best surgical plan. Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal.

PubMed

Kanatsu-Shinohara, Mito; Tanaka, Takashi; Ogonuki, Narumi; Ogura, Atsuo; Morimoto, Hiroko; Cheng, Pei Feng; Eisenman, Robert N; Trumpp, Andreas; Shinohara, Takashi

2016-12-01

Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max, a Myc-binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1, whose deficiency impairs SSC self-renewal. Myc/Mycn-deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of active Akt1 or Pdpk1 (phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested that Myc-mediated glycolysis is an important factor that increases the frequency of SSC self-renewal division. © 2016 Kanatsu-Shinohara et al.; Published by Cold Spring Harbor Laboratory Press.

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin.

PubMed

Spudich, James A; Aksel, Tural; Bartholomew, Sadie R; Nag, Suman; Kawana, Masataka; Yu, Elizabeth Choe; Sarkar, Saswata S; Sung, Jongmin; Sommese, Ruth F; Sutton, Shirley; Cho, Carol; Adhikari, Arjun S; Taylor, Rebecca; Liu, Chao; Trivedi, Darshan; Ruppel, Kathleen M

2016-01-01

Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the fundamental force-generating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles. © 2016. Published by The Company of Biologists Ltd.

[Septal alcohol ablation in patients with hypertrophic cardiomyopathy].

PubMed

López-Aburto, Gustavo; Palacios-Rodríguez, Juan Manuel; Cantú-Ramírez, Samuel; Galván-García, Eduardo; Tolosa-Dzul, Gonzalo; Morán-Benavente, Armando; Ontiveros-Martínez, Raúl

2013-01-01

to know the clinical and hemodynamic course in septal obstructive hypertrophic cardiomyopathy (SOHC) after alcohol ablation. this was an observational, longitudinal study, including 21 patients with SOHC with functional class of the New York Heart Association (CF-NYHA) refractory to treatment and/or = 30 mm Hg gradient at rest or = 60 mm Hg provoked, or have systolic anterior motion or mitral incompetence (MI) > grade II by echocardiography. average age was 50 ± 16 years, males 38.1 %, females 61.9 %; symptoms: angina 42.9 %, dyspnea 85.7 %, syncope 23.8 %. Pre-ablation CF-NYHA was III and IV in 61.9 %; after a year follow-up all of them were class I-II. Pre-ablation, after and one year later, interventricle septum measures were 22.7 ± 4.9 and 20.7 ± 3.1 mm; left ventricular ejection fraction was 65.5 ± 7 %, 62.2 % ± 6.5 % and 68.7 ± 6.2 %; the output gradient of the left ventricle were 106.9 ± 29.9, 44.6 ± 24.3 and 22.0 ± 5.7 mm Hg. Pre-ablation MI grade-III and IV were 33.3 % and 47.6 %; after a year it was grade-0, 52.4 %, grade-I 28.6 %, grade-II, 19 %. There were no hospital mortality. the alcohol septal ablation in SOHC patients had a high success treatment with a low complication rate.

MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.

PubMed

Baruffini, Enrico; Dallabona, Cristina; Invernizzi, Federica; Yarham, John W; Melchionda, Laura; Blakely, Emma L; Lamantea, Eleonora; Donnini, Claudia; Santra, Saikat; Vijayaraghavan, Suresh; Roper, Helen P; Burlina, Alberto; Kopajtich, Robert; Walther, Anett; Strom, Tim M; Haack, Tobias B; Prokisch, Holger; Taylor, Robert W; Ferrero, Ileana; Zeviani, Massimo; Ghezzi, Daniele

2013-11-01

We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype. © 2013 The Authors. *Human Mutation published by Wiley Periodicals, Inc.

The Natural History of Nonobstructive Hypertrophic Cardiomyopathy.

PubMed

Hebl, Virginia B; Miranda, William R; Ong, Kevin C; Hodge, David O; Bos, J Martijn; Gentile, Federico; Klarich, Kyle W; Nishimura, Rick A; Ackerman, Michael J; Gersh, Bernard J; Ommen, Steve R; Geske, Jeffrey B

2016-03-01

To describe the survival of a large nonobstructive hypertrophic cardiomyopathy (NO-HCM) cohort and to identify risk factors for increased mortality in this population. Patients were identified from the Mayo Clinic HCM database from January 1, 1975, through November 30, 2006, for this retrospective observational study. Patients with resting or provocable left ventricular outflow tract gradients were excluded. Echocardiographic, clinical, and genetic data were compared between subgroups, and survival data were compared with expected population rates. A total of 706 patients with NO-HCM were identified. During median follow-up of 5 years (mean, 7 years), there were 208 deaths. Overall survival was no different than expected compared with age- and sex-matched white US population mortality rates (P=.77). Independent predictors of death were age at diagnosis, "burned out" HCM, and history of transient ischemic attack or stroke; use of an implantable cardioverter defibrillator (ICD) was inversely related to death. After exclusion of patients with an ICD, there was no difference in survival compared with age- and sex- matched individuals (P=.39); age, previous transient ischemic attack/stroke, and burned out HCM were predictors of death. In this cohort, patients with NO-HCM had similar survival rates as age- and sex-matched white US population mortality rates. Although use of an ICD was inversely related to death, no differences in overall survival were seen after those patients were excluded. Burned out HCM was independently associated with an increased risk of death, identifying a subset of patients who may benefit from more aggressive therapies. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

[Hypertrophic cardiomyopathy showing no 123I-BMIPP myocardial accumulation with type I CD36 deficiency].

PubMed

Watanabe, K; Miyajima, S; Kusano, Y; Tanabe, N; Hirokawa, Y

1997-07-01

A 57 years old male consulted our hospital in complaining chest oppression and short of breath. Familial and dilated phase hypertrophic cardiomyopathy (HCM) was detected by ECG, echocardiography, left ventriculography and left ventricular endomyocardial biopsy. 201T1 SPECT showed regional increased accumulation in the ventricular septum, however, no myocardial accumulation of 123I-beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) was observed. We analyzed CD36 in this patient, and found he had type 1 CD36 deficiency. Myocardial uptake of long-chain fatty acids occurs via a specific transporter, which is homologous with human CD36. We hypothesize that CD36 deficiency, especially type 1 CD36 deficiency, might be one factor of no myocardial 123I-BMIPP uptake.

MYC2 Orchestrates a Hierarchical Transcriptional Cascade That Regulates Jasmonate-Mediated Plant Immunity in Tomato.

PubMed

Du, Minmin; Zhao, Jiuhai; Tzeng, David T W; Liu, Yuanyuan; Deng, Lei; Yang, Tianxia; Zhai, Qingzhe; Wu, Fangming; Huang, Zhuo; Zhou, Ming; Wang, Qiaomei; Chen, Qian; Zhong, Silin; Li, Chang-Bao; Li, Chuanyou

2017-08-01

The hormone jasmonate (JA), which functions in plant immunity, regulates resistance to pathogen infection and insect attack through triggering genome-wide transcriptional reprogramming in plants. We show that the basic helix-loop-helix transcription factor (TF) MYC2 in tomato ( Solanum lycopersicum ) acts downstream of the JA receptor to orchestrate JA-mediated activation of both the wounding and pathogen responses. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq) assays, we identified 655 MYC2-targeted JA-responsive genes. These genes are highly enriched in Gene Ontology categories related to TFs and the early response to JA, indicating that MYC2 functions at a high hierarchical level to regulate JA-mediated gene transcription. We also identified a group of MYC2-targeted TFs (MTFs) that may directly regulate the JA-induced transcription of late defense genes. Our findings suggest that MYC2 and its downstream MTFs form a hierarchical transcriptional cascade during JA-mediated plant immunity that initiates and amplifies transcriptional output. As proof of concept, we showed that during plant resistance to the necrotrophic pathogen Botrytis cinerea , MYC2 and the MTF JA2-Like form a transcription module that preferentially regulates wounding-responsive genes, whereas MYC2 and the MTF ETHYLENE RESPONSE FACTOR.C3 form a transcription module that preferentially regulates pathogen-responsive genes. © 2017 American Society of Plant Biologists. All rights reserved.

Hypertrophic obstructive cardiomyopathy: the Mayo Clinic experience.

PubMed

Kotkar, Kunal D; Said, Sameh M; Dearani, Joseph A; Schaff, Hartzell V

2017-07-01

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease characterized by left ventricular hypertrophy in the absence of other etiologies. Clinical presentation may vary from asymptomatic to sudden cardiac death. Medical treatment is the first-line therapy for symptomatic patients. Extended left ventricular septal myectomy is the procedure of choice if medical treatment is unsuccessful or intolerable. More than 3,000 patients have had septal myectomy for HCM at the Mayo Clinic (MN, USA) from 1993 to 2016. Risk of hospital death after isolated septal myectomy for obstructive HCM is <1% and is similar to the risk of operation for elective mitral valve repair. Complications, such as complete heart block requiring permanent pacemaker, are uncommon (2%), although partial or complete left bundle branch block is a frequent finding on the postoperative ECG. Relief of left ventricular outflow tract (LVOT) obstruction with septal myectomy dramatically improves symptoms and exercise capacity in symptomatic patients with obstructive HCM. More than 90% of severely symptomatic patients have improvement by at least two functional classes, and reduction of outflow gradients by myectomy decreases or eliminates symptoms of dyspnea, angina and/or syncope. Basal obstruction with systolic anterior motion (SAM) is treated by transaortic myectomy. The transapical approach was applied in 115 patients with obstructive midventricular and apical variants of HCM between 1993 and 2012. All patients with midventricular obstruction had gradient relief and none developed an apical aneurysm or ventricular septal defect. Recurrent obstruction after satisfactory myectomy was rare. Septal myectomy effectively and definitively relieves LVOT obstruction and cardiac symptoms in patients with obstructive HCM. In experienced centers, early mortality for isolated septal myectomy is less than 1%, and overall results are excellent and continue to improve in the current era.

Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy.

PubMed

Topilsky, Yan; Pereira, Naveen L; Shah, Dipesh K; Boilson, Barry; Schirger, John A; Kushwaha, Sudhir S; Joyce, Lyle D; Park, Soon J

2011-05-01

Left ventricular assist device (LVAD) is being increasingly used in patients with end-stage dilated and ischemic cardiomyopathy. There have been no clinical trials addressing the use of LVAD therapy in patients with end-stage heart failure caused by restrictive (RCM) or hypertrophic cardiomyopathy (HCM). The purpose of this study was therefore to analyze the outcome of LVAD therapy in these patients. Eighty-three patients received continuous axial flow LVAD (Heart mate II, Thoratec, Pleasanton, CA) from February 2007 to May 2010 at our institution. We analyzed the baseline characteristics and surgical and long-term impact of LVAD therapy in 8 patients with RCM or HCM and compared their outcomes with the 75 patients with dilated and ischemic cardiomyopathy. Compared with patients with ischemic or dilated cardiomyopathy, patients with RCM and HCM have significantly smaller left ventricular end-diastolic dimensions (52.5±6 mm versus 68.6±8 mm; P<0.0001) and increased thickness of septal (16 [12, 19] mm versus 10[8.5, 11] mm, P=0.0003) and higher left ventricular ejection fraction (21 [20, 36]% versus 17 [15, 22]%; P=0.0009). We found no difference in early mortality (12.5% versus 9.3%, P=0.57) or length of hospital stay (11 [8, 45] days versus 18.5 [12.2, 27.7] days; P=0.51) between the 2 groups. The right atrial pressure was higher (18 [15, 20] mm Hg versus 12 [9, 15] mm Hg, P=0.03), and pump flow was lower (4.3 [3.8, 4.5] L versus 5.2 [4.7, 5.5] L, P=0.001) after LVAD implantation in patients with RCM and HCM. Central venous catheter related infections were more common in patients with RCM and HCM (87.5% versus 44.5%, P=0.006). There was no difference in the total number of blood units transfused. Median (min, max) follow-up duration after LVAD implantation was 166 [1, 1044] days. The 1-year actuarial survival rate was not different between the 2 groups (87.5% [95% confidence interval, 52.9% to 97.8%] versus 73.2 [95% confidence interval, 60% to 85%]; P=0.77). Our

Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene.

PubMed

Charron, P; Dubourg, O; Desnos, M; Bennaceur, M; Carrier, L; Camproux, A C; Isnard, R; Hagege, A; Langlard, J M; Bonne, G; Richard, P; Hainque, B; Bouhour, J B; Schwartz, K; Komajda, M

1998-06-09

Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (MYBPC3) gene. The aim of this study was to perform this type of analysis. We studied 76 genetically affected subjects from nine families with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) in the MYBPC3 gene. Detailed clinical, ECG, and echocardiographic parameters were analyzed. An intergene analysis was performed by comparing the MYBPC3 group to seven mutations in the beta-myosin heavy-chain gene (beta-MHC) group (n=52). There was no significant phenotypic difference among the different mutations in the MYBPC3 gene. However, in the MYBPC3 group compared with the beta-MHC group, (1) prognosis was significantly better (P<0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41+/-19 versus 35+/-17 years, P<0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low (41% versus 62%), maximal wall thicknesses lower (12+/-4 versus 16+/-7 mm, P<0.03), and abnormal T waves less frequent (9% versus 45%, P<0.02). These results are consistent with specific clinical features related to the MYBPC3 gene: onset of the disease appears delayed and the prognosis is better than that associated with the beta-MHC gene. These findings could be particularly important for the purpose of clinical management and genetic counseling in familial hypertrophic cardiomyopathy.

Contrast‐enhanced computed tomography with myocardial three‐dimensional printing can guide treatment in symptomatic hypertrophic obstructive cardiomyopathy

PubMed Central

Hamatani, Yasuhiro; Amaki, Makoto; Kanzaki, Hideaki; Yamashita, Kizuku; Nakashima, Yasuteru; Shibata, Atsushi; Okada, Atsushi; Takahama, Hiroyuki; Hasegawa, Takuya; Shimahara, Yusuke; Sugano, Yasuo; Fujita, Tomoyuki; Shiraishi, Isao; Yasuda, Satoshi; Kobayashi, Junjiro

2017-01-01

Abstract Both surgical myectomy and percutaneous transluminal septal myocardial ablation are effective treatments for drug‐refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). However, in some cases, it is not easy to elucidate the abnormal structure of left ventricular outflow obstruction to adopt these treatments. Here, we presented a young female patient with drug‐refractory symptomatic HOCM. In this case, contrast‐enhanced computed tomography enabled us to assess the suitability of percutaneous transluminal septal myocardial ablation. By creating three‐dimensional printed models using computed tomography data, we could also visualize intracardiac structure and simulate the surgical procedure. A multimodality assessment strategy is useful for evaluating patients complicated with drug‐refractory symptomatic HOCM. PMID:29154429

Successful catheter ablation of hemodynamically unstable monomorphic ventricular tachycardia in a patient with hypertrophic cardiomyopathy and apical aneurysm.

PubMed

Lim, Kiam-Khiang; Maron, Barry J; Knight, Bradley P

2009-04-01

Patients with hypertrophic cardiomyopathy (HCM) and left ventricular (LV) apical aneurysm represent a previously under-recognized but important subgroup within this heterogeneous disease spectrum. Apical aneurysms and the contiguous areas of myocardial fibrosis have been associated with monomorphic ventricular tachycardia (VT) and increased risk for adverse clinical events including sudden cardiac death, prioritizing the application of primary prevention implantable defibrillators. However, VT may be repetitive, thereby raising considerations for additional treatment strategies such as radiofrequency ablation. In this report, we describe such a patient with HCM and apical aneurysm in whom the mapping and ablation procedure was effective in identifying and abolishing the VT focus.

Associations Between Fibrocytes and Postcontrast Myocardial T1 Times in Hypertrophic Cardiomyopathy

PubMed Central

Fang, Lu; Beale, Anna; Ellims, Andris H.; Moore, Xiao‐lei; Ling, Liang‐han; Taylor, Andrew J.; Chin‐Dusting, Jaye; Dart, Anthony M.

2013-01-01

Background Fibrocytes are bone marrow‐derived mesenchymal progenitors that have been linked to various fibrotic disorders. This study was undertaken to investigate whether fibrocytes are increased in diffuse myocardial fibrosis in humans. Methods and Results Thirty‐seven patients with hypertrophic cardiomyopathy (HCM) and 20 healthy controls were recruited. Cardiac magnetic resonance imaging with postcontrast T1 mapping was performed to non‐invasively quantify diffuse myocardial fibrosis and these patients were classified into 2 groups (T1<470 ms or T1≥470 ms, as likely or unlikely to have diffuse fibrosis, respectively). Circulating fibrocytes (CD45+/CD34+/collagen I+) were measured by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were cultured for 13 days and fibrocytes were quantitated by flow cytometry (CD45+/collagen I+) and real‐time PCR (gene expression of matrix proteins). Plasma cytokines/chemokines mediating fibrocyte trafficking and differentiation were measured by multiplex assays. Circulating fibrocytes were decreased in HCM patients compared to controls. The proportion of fibrocytes derived from PBMCs was increased in patients with diffuse fibrosis compared with those without or controls (31.1±4.1% versus 18.9±3.9% and 10.9±2.0%, P<0.05 and P<0.001, respectively), and the proportion of fibrocytes was inversely correlated with T1 time (r=−0.37, P=0.03). Plasma levels of stromal cell‐derived factor‐1 were elevated in patients with diffuse fibrosis compared with those without or controls (5131±271 pg/mL versus 3893±356 pg/mL and 4172±185 pg/mL, respectively, both P<0.05). Conclusions HCM patients with diffuse fibrosis as assessed by postcontrast T1 mapping have elevated plasma SDF and an enhanced ability of PBMCs to differentiate into fibrocytes, suggesting that fibrocytes may contribute to the pathogenesis of myocardial fibrosis. PMID:24125844

MYC2 Orchestrates a Hierarchical Transcriptional Cascade That Regulates Jasmonate-Mediated Plant Immunity in Tomato[OPEN

PubMed Central

Liu, Yuanyuan; Deng, Lei; Wu, Fangming; Huang, Zhuo; Zhou, Ming; Chen, Qian; Zhong, Silin

2017-01-01

The hormone jasmonate (JA), which functions in plant immunity, regulates resistance to pathogen infection and insect attack through triggering genome-wide transcriptional reprogramming in plants. We show that the basic helix-loop-helix transcription factor (TF) MYC2 in tomato (Solanum lycopersicum) acts downstream of the JA receptor to orchestrate JA-mediated activation of both the wounding and pathogen responses. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq) assays, we identified 655 MYC2-targeted JA-responsive genes. These genes are highly enriched in Gene Ontology categories related to TFs and the early response to JA, indicating that MYC2 functions at a high hierarchical level to regulate JA-mediated gene transcription. We also identified a group of MYC2-targeted TFs (MTFs) that may directly regulate the JA-induced transcription of late defense genes. Our findings suggest that MYC2 and its downstream MTFs form a hierarchical transcriptional cascade during JA-mediated plant immunity that initiates and amplifies transcriptional output. As proof of concept, we showed that during plant resistance to the necrotrophic pathogen Botrytis cinerea, MYC2 and the MTF JA2-Like form a transcription module that preferentially regulates wounding-responsive genes, whereas MYC2 and the MTF ETHYLENE RESPONSE FACTOR.C3 form a transcription module that preferentially regulates pathogen-responsive genes. PMID:28733419

Hypertrophic Cardiomyopathy: A Vicious Cycle Triggered by Sarcomere Mutations and Secondary Disease Hits.

PubMed

Wijnker, Paul J M; Sequeira, Vasco; Kuster, Diederik W D; Velden, Jolanda van der

2018-04-11

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by left ventricular hypertrophy, diastolic dysfunction, and myocardial disarray. Disease onset occurs between 20 and 50 years of age, thus affecting patients in the prime of their life. HCM is caused by mutations in sarcomere proteins, the contractile building blocks of the heart. Despite increased knowledge of causal mutations, the exact path from genetic defect leading to cardiomyopathy is complex and involves additional disease hits. Recent Advances: Laboratory-based studies indicate that HCM development not only depends on the primary sarcomere impairment caused by the mutation but also on secondary disease-related alterations in the heart. Here we propose a vicious mutation-induced disease cycle, in which a mutation-induced energy depletion alters cellular metabolism with increased mitochondrial work, which triggers secondary disease modifiers that will worsen disease and ultimately lead to end-stage HCM. Evidence shows excessive cellular reactive oxygen species (ROS) in HCM patients and HCM animal models. Oxidative stress markers are increased in the heart (oxidized proteins, DNA, and lipids) and serum of HCM patients. In addition, increased mitochondrial ROS production and changes in endogenous antioxidants are reported in HCM. Mutant sarcomeric protein may drive excessive levels of cardiac ROS via changes in cardiac efficiency and metabolism, mitochondrial activation and/or dysfunction, impaired protein quality control, and microvascular dysfunction. Interventions restoring metabolism, mitochondrial function, and improved ROS balance may be promising therapeutic approaches. We discuss the effects of current HCM pharmacological therapies and potential future therapies to prevent and reverse HCM. Antioxid. Redox Signal. 00, 000-000.

Relation between thallium-201/iodine 123-BMIPP subtraction and fluorine 18 deoxyglucose polar maps in patients with hypertrophic cardiomyopathy.

PubMed

Ito, Y; Hasegawa, S; Yamaguchi, H; Yoshioka, J; Uehara, T; Nishimura, T

2000-01-01

Clinical studies have shown discrepancies in the distribution of thallium-201 and iodine 123-beta-methyl-iodophenylpentadecanoic acid (BMIPP) in patients with hypertrophic cardiomyopathy (HCM). Myocardial uptake of fluorine 18 deoxyglucose (FDG) is increased in the hypertrophic area in HCM. We examined whether the distribution of a Tl-201/BMIPP subtraction polar map correlates with that of an FDG polar map. We normalized to maximum count each Tl-201 and BMIPP bull's-eye polar map of 6 volunteers and obtained a standard Tl-201/BMIPP subtraction polar map by subtracting a normalized BMIPP bull's-eye polar map from a normalized Tl-201 bull's-eye polar map. The Tl-201/BMIPP subtraction polar map was then applied to 8 patients with HCM (mean age 65+/-12 years) to evaluate the discrepancy between Tl-201 and BMIPP distribution. We compared the Tl-201/BMIPP subtraction polar map with an FDG polar map. In patients with HCM, the Tl-201/BMIPP subtraction polar map showed a focal uptake pattern in the hypertrophic area similar to that of the FDG polar map. By quantitative analysis, the severity score of the Tl-201/BMIPP subtraction polar map was significantly correlated with the percent dose uptake of the FDG polar map. These results suggest that this new quantitative method may be an alternative to FDG positron emission tomography for the routine evaluation of HCM.

BIM is the primary mediator of MYC-induced apoptosis in multiple solid tissues.

PubMed

Muthalagu, Nathiya; Junttila, Melissa R; Wiese, Katrin E; Wolf, Elmar; Morton, Jennifer; Bauer, Barbara; Evan, Gerard I; Eilers, Martin; Murphy, Daniel J

2014-09-11

MYC is one of the most frequently overexpressed oncogenes in human cancer, and even modestly deregulated MYC can initiate ectopic proliferation in many postmitotic cell types in vivo. Sensitization of cells to apoptosis limits MYC's oncogenic potential. However, the mechanism through which MYC induces apoptosis is controversial. Some studies implicate p19ARF-mediated stabilization of p53, followed by induction of proapoptotic BH3 proteins NOXA and PUMA, whereas others argue for direct regulation of BH3 proteins, especially BIM. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used chemotherapeutic, doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

The L‐type Ca2+ channel facilitates abnormal metabolic activity in the cTnI‐G203S mouse model of hypertrophic cardiomyopathy

PubMed Central

Viola, Helena; Johnstone, Victoria; Cserne Szappanos, Henrietta; Richman, Tara; Tsoutsman, Tatiana; Filipovska, Aleksandra; Semsarian, Christopher

2016-01-01

Key points Genetic mutations in cardiac troponin I (cTnI) are associated with development of hypertrophic cardiomyopathy characterized by myocyte remodelling, disorganization of cytoskeletal proteins and altered energy metabolism.The L‐type Ca2+ channel is the main route for calcium influx and is crucial to cardiac excitation and contraction. The channel also regulates mitochondrial function in the heart by a functional communication between the channel and mitochondria via the cytoskeletal network.We find that L‐type Ca2+ channel kinetics are altered in cTnI‐G203S cardiac myocytes and that activation of the channel causes a significantly greater increase in mitochondrial membrane potential and metabolic activity in cTnI‐G203S cardiac myocytes.These responses occur as a result of impaired communication between the L‐type Ca2+ channel and cytoskeletal protein F‐actin, involving decreased movement of actin–myosin and block of the mitochondrial voltage‐dependent anion channel, resulting in a ‘hypermetabolic’ mitochondrial state.We propose that L‐type Ca2+ channel antagonists, such as diltiazem, might be effective in reducing the cardiomyopathy by normalizing mitochondrial metabolic activity. Abstract Genetic mutations in cardiac troponin I (cTnI) account for 5% of families with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is associated with disorganization of cytoskeletal proteins and altered energy metabolism. The L‐type Ca2+ channel (ICa‐L) plays an important role in regulating mitochondrial function. This involves a functional communication between the channel and mitochondria via the cytoskeletal network. We investigate the role of ICa‐L in regulating mitochondrial function in 25‐ to 30‐week‐old cardiomyopathic mice expressing the human disease‐causing mutation Gly203Ser in cTnI (cTnI‐G203S). The inactivation rate of ICa‐L is significantly faster in cTnI‐G203S myocytes [cTnI‐G203S: τ1 = 40.68 ± 3.22, n

Effect of amiodarone-induced hyperthyroidism on left ventricular outflow obstruction after septal myectomy for hypertrophic cardiomyopathy.

PubMed

Pokorney, Sean D; Stone, Neil J; Passman, Rod; Oyer, David; Rigolin, Vera H; Bonow, Robert O

2010-12-01

Patients with obstructive hypertrophic cardiomyopathy who undergo septal myectomy are at risk for developing postoperative atrial fibrillation. Amiodarone is effective in treating this arrhythmia but is associated with multiple adverse effects, often with delayed onset. A novel case is described of a patient who developed type 2 amiodarone-induced hyperthyroidism that presented as recurrence of outflow obstruction after septal myectomy. The patient's symptoms and echocardiographic findings of outflow obstruction resolved substantially with the treatment of the amiodarone-induced hyperthyroidism. Amiodarone-induced hyperthyroidism of delayed onset can be a subtle diagnosis, requiring a high index of suspicion. In conclusion, recognition of this diagnosis in patients with recurrence of outflow obstruction by symptoms and cardiac imaging after septal myectomy may avoid unnecessary repeat surgical intervention. Copyright © 2010 Elsevier Inc. All rights reserved.

Echocardiography and cardiac MRI in mutation-negative hypertrophic cardiomyopathy in an older patient: a case defining the need for ICD.

PubMed

Rodriguez, Fatima; Degnan, Kathleen O; Seidman, Christine E; Mangion, Judy R

2014-08-01

We report the case of a 67-year-old man with hypertrophic cardiomyopathy who presented for a second opinion about implantable cardio-defibrillator (ICD) placement after a witnessed syncopal episode. Despite his older age, being mutation-negative, and having a maximal septal thickness of 2.2 cm on echocardiography, he demonstrated rapid progression of myocardial fibrosis on cardiac MRI, correlating to ventricular tachyarrhythmias and syncope. We review the role of echocardiography and cardiac MRI in optimizing medical care for such patients who may not otherwise meet criteria for an ICD placement or further interventions. © 2014, Wiley Periodicals, Inc.

[Right ventricular hypertrophic cardiomyopathy in the fetus --may it be caused by chronic oral tocolysis with fenoterol?].

PubMed

Hamela-Olkowska, Anita; Szymkiewicz-Dangel, Joanna; Własienko, Paweł; Majewska, Urszula; Bokiniec, Renata

2012-02-01

The use of fenoterol in the treatment of preterm labor is associated with the risk of many complications in the mother and the fetus. We present a case of a multipara treated with oral fenoterol due to threatening preterm labor 14 weeks. At 35 weeks of gestation the fetus was diagnosed with hypertrophic cardiomyopathy with severe impairment of the right ventricle. The only factor that might have caused such a state of the fetal circulatory system was fenoterol, used from 21 weeks of gestation. After the withdrawal of the fenoterol the fetal right ventricular function improved gradually. However fetal cardiac hypertrophy persisted until the birth at 39 weeks of gestation. Concentric hypertrophy of the right ventricular wall and interventricular septum were confirmed in the newborn.

Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells

PubMed Central

Han, Lu; Li, Yang; Tchao, Jason; Kaplan, Aaron D.; Lin, Bo; Li, You; Mich-Basso, Jocelyn; Lis, Agnieszka; Hassan, Narmeen; London, Barry; Bett, Glenna C.L.; Tobita, Kimimasa; Rasmusson, Randall L.; Yang, Lei

2014-01-01

Aims Familial hypertrophic cardiomyopathy (HCM) is one the most common heart disorders, with gene mutations in the cardiac sarcomere. Studying HCM with patient-specific induced pluripotent stem-cell (iPSC)-derived cardiomyocytes (CMs) would benefit the understanding of HCM mechanism, as well as the development of personalized therapeutic strategies. Methods and results To investigate the molecular mechanism underlying the abnormal CM functions in HCM, we derived iPSCs from an HCM patient with a single missense mutation (Arginine442Glycine) in the MYH7 gene. CMs were next enriched from HCM and healthy iPSCs, followed with whole transcriptome sequencing and pathway enrichment analysis. A widespread increase of genes responsible for ‘Cell Proliferation’ was observed in HCM iPSC-CMs when compared with control iPSC-CMs. Additionally, HCM iPSC-CMs exhibited disorganized sarcomeres and electrophysiological irregularities. Furthermore, disease phenotypes of HCM iPSC-CMs were attenuated with pharmaceutical treatments. Conclusion Overall, this study explored the possible patient-specific and mutation-specific disease mechanism of HCM, and demonstrates the potential of using HCM iPSC-CMs for future development of therapeutic strategies. Additionally, the whole methodology established in this study could be utilized to study mechanisms of other human-inherited heart diseases. PMID:25209314

Eccentric apical hypertrophic cardiomyopathy unmasked by multimodality imaging: an uncommon but missed cause of out of hospital cardiac arrest

PubMed Central

Towe, Eric; Sharma, Saurabh; Geske, Jeffrey; Ackerman, Michael J

2015-01-01

A woman in her late 50s experienced a witnessed, sudden out of hospital cardiac arrest. Initial workup included coronary angiography, transthoracic echocardiogram and a CT scan of the chest to rule out pulmonary embolus. She was subsequently discharged home without an implantable cardioverter defibrillator (ICD) or a life vest. On follow-up at another facility, an ICD was placed and a Holter monitor showed no ventricular ectopy. Further transthoracic echocardiographic images were obtained, which were suggestive of apical hypertrophic cardiomyopathy. A limited transthoracic echocardiogram with contrast was performed, which did not elucidate the hypertrophy. However, eccentric left ventricular apical wall hypertrophy was visualised by a coronary CT scan. PMID:26153133

Long-Term Outcomes of Hypertrophic Cardiomyopathy Diagnosed During Childhood: Results from a National Population-Based Study.

PubMed

Alexander, Peta M A; Nugent, Alan W; Daubeney, Piers E F; Lee, Katherine J; Sleeper, Lynn A; Schuster, Tibor; Turner, Christian; Davis, Andrew M; Semsarian, Chris; Colan, Steven D; Robertson, Terry; Ramsay, James; Justo, Robert; Sholler, Gary F; King, Ingrid; Weintraub, Robert G

2018-02-28

Background -Late survival and symptomatic status of children with hypertrophic cardiomyopathy (HCM) have not been well defined. We examined long-term outcomes for pediatric HCM. Methods -The National Australian Childhood Cardiomyopathy Study is a longitudinal population-based cohort study of children (0-10 years) diagnosed with cardiomyopathy between 1987 and 1996. The primary study end-point was time to death or cardiac transplantation. Results -There were 80 patients with HCM with median age at diagnosis of 0.48 (Inter-quartile range [IQR] 0.1, 2.5) years. Freedom from death/transplantation (95% confidence interval [CI]) was 86 (77-92)% one year after presentation, 80 (69-87)% at 10 years and 78 (67-86)% at 20 years. From multivariable analyses, risk factors for death/transplantation included symmetric left ventricular hypertrophy at the time of diagnosis (hazard ratio [HR] 4.20 95%CI 1.60, 11.05 p=0.004), Noonan syndrome (HR 2.88, 95%CI 1.02, 8.08, p=0.045), higher posterior wall thickness z-score (HR 1.45, 95%CI 1.22, 1.73, p<0.001) and lower fractional shortening z-score (HR 0.84, 95%CI 0.74, 0.95, p=0.005) during follow-up. Nineteen (23%) subjects underwent left ventricular myectomy. At median 15.7 years' follow-up, 27 (42%) of 63 survivors were treated with beta-blocker and 13 (21%) had an implantable cardioverter-defibrillator. Conclusions -The highest risk of death or transplantation for children with HCM is within one year post-diagnosis, with low attrition rates thereafter. Many subjects receive medical, surgical or device therapy.

Computational Modeling of Blood Flow and Valve Dynamics in Hearts with Hypertrophic Cardiomyopathy

NASA Astrophysics Data System (ADS)

Zheng, Xudong; Mittal, Rajat; Abraham, Theodore; Pinheiro, Aurelio

2010-11-01

Hypertrophic Cardiomyopathy (HCM) is a cardiovascular disease manifested by the thickening of the ventricular wall and often leads to a partial obstruction to the blood flow out of the left ventricle. HCM is recognized as one of the most common causes of sudden cardiac death in athletes. In a heart with HCM, the hypertrophy usually narrows the blood flow pathway to the aorta and produces a low pressure zone between the mitral valve and the hypertrophy during systole. This low pressure can suck the mitral valve leaflet back and completely block the blood flow into the aorta. In the current study, a sharp interface immersed boundary method flow solver is employed to study the hemodynamics and valve dynamics inside a heart with HCM. The three-dimensional motion and configuration of the left ventricle including mitral valve leaflets and aortic valves are reconstructed based on echo-cardio data sets. The mechanisms of aortic obstruction associated with HCM are investigated. The long term objective of this study is to develop a computational tool to aid in the assessment and surgical management of HCM.

A Delta-Sarcoglycan Gene Polymorphism as a Risk Factor for Hypertrophic Cardiomyopathy

PubMed Central

Garrido-Garduño, Martín H.; Pérez-Martínez, Ramón A.; Ruiz, Victor M.; Herrera-Tepatlán, Esteban; Rodríguez-Cruz, Maricela; Jiménez-Vaca, Ana L.; Minauro-Sanmiguel, Fernando; Salamanca-Gómez, Fabio A.

2012-01-01

Background: The C allele of c.−94C>G polymorphism of the delta-sarcoglycan gene was associated as a risk factor for coronary spasm in Japanese patients with hypertrophic cardiomyopathy (HCM). Aim: We evaluated whether the c.−94C>G polymorphism can be a risk factor for HCM in Mexican patients. Methods: The polymorphism was genotyped and the risk was estimated in 35 HCM patients and 145 healthy unrelated individuals. Data of this polymorphism reported in Mexican Amerindian populations were included. Results: The C allele frequency in HCM patients was higher with an odds ratio (OR) of 2.37, and the risk for the CC genotype increased to 5.0. The analysis with Mexican Amerindian populations showed that the C allele frequency was significantly higher in HCM patients with an OR of 2.96 and for CC genotype the risk increased to 7.60. Conclusions: The C allele of the c.−94C>G polymorphism is a risk factor for HCM, which is increased by the Amerindian component and can play an important role in the etiology and progression of disease in Mexican patients. PMID:22524166

MYC association with cancer risk and a new model of MYC-mediated repression.

PubMed

Cole, Michael D

2014-07-01

MYC is one of the most frequently mutated and overexpressed genes in human cancer but the regulation of MYC expression and the ability of MYC protein to repress cellular genes (including itself) have remained mysterious. Recent genome-wide association studies show that many genetic polymorphisms associated with disease risk map to distal regulatory elements that regulate the MYC promoter through large chromatin loops. Cancer risk-associated single-nucleotide polymorphisms (SNPs) contain more potent enhancer activity, promoting higher MYC levels and a greater risk of disease. The MYC promoter is also subject to complex regulatory circuits and limits its own expression by a feedback loop. A model for MYC autoregulation is discussed which involves a signaling pathway between the PTEN (phosphatase and tensin homolog) tumor suppressor and repressive histone modifications laid down by the EZH2 methyltransferase. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Hypertrophic cardiomyopathy mutation in cardiac troponin T (R95H) attenuates length-dependent activation in guinea pig cardiac muscle fibers.

PubMed

Mickelson, Alexis V; Chandra, Murali

2017-12-01

The central region of cardiac troponin T (TnT) is important for modulating the dynamics of muscle length-mediated cross-bridge recruitment. Therefore, hypertrophic cardiomyopathy mutations in the central region may affect cross-bridge recruitment dynamics to alter myofilament Ca 2+ sensitivity and length-dependent activation of cardiac myofilaments. Given the importance of the central region of TnT for cardiac contractile dynamics, we studied if hypertrophic cardiomyopathy-linked mutation (TnT R94H )-induced effects on contractile function would be differently modulated by sarcomere length (SL). Recombinant wild-type TnT (TnT WT ) and the guinea pig analog of the human R94H mutation (TnT R95H ) were reconstituted into detergent-skinned cardiac muscle fibers from guinea pigs. Steady-state and dynamic contractile measurements were made at short and long SLs (1.9 and 2.3 µm, respectively). Our results demonstrated that TnT R95H increased pCa 50 (-log of free Ca 2+ concentration) to a greater extent at short SL; TnT R95H increased pCa 50 by 0.11 pCa units at short SL and 0.07 pCa units at long SL. The increase in pCa 50 associated with an increase in SL from 1.9 to 2.3 µm (ΔpCa 50 ) was attenuated nearly twofold in TnT R95H fibers; ΔpCa 50 was 0.09 pCa units for TnT WT fibers but only 0.05 pCa units for TnT R95H fibers. The SL dependency of rate constants of cross-bridge distortion dynamics and tension redevelopment was also blunted by TnT R95H Collectively, our observations on the SL dependency of pCa 50 and rate constants of cross-bridge distortion dynamics and tension redevelopment suggest that mechanisms underlying the length-dependent activation cardiac myofilaments are attenuated by TnT R95H NEW & NOTEWORTHY Mutant cardiac troponin T (TnT R95H ) differently affects myofilament Ca 2+ sensitivity at short and long sarcomere length, indicating that mechanisms underlying length-dependent activation are altered by TnT R95H TnT R95H enhances myofilament Ca 2

Analysis of selected genes associated with cardiomyopathy by next-generation sequencing.

PubMed

Szabadosova, Viktoria; Boronova, Iveta; Ferenc, Peter; Tothova, Iveta; Bernasovska, Jarmila; Zigova, Michaela; Kmec, Jan; Bernasovsky, Ivan

2018-02-01

As the leading cause of congestive heart failure, cardiomyopathy represents a heterogenous group of heart muscle disorders. Despite considerable progress being made in the genetic diagnosis of cardiomyopathy by detection of the mutations in the most prevalent cardiomyopathy genes, the cause remains unsolved in many patients. High-throughput mutation screening in the disease genes for cardiomyopathy is now possible because of using target enrichment followed by next-generation sequencing. The aim of the study was to analyze a panel of genes associated with dilated or hypertrophic cardiomyopathy based on previously published results in order to identify the subjects at risk. The method of next-generation sequencing by IlluminaHiSeq 2500 platform was used to detect sequence variants in 16 individuals diagnosed with dilated or hypertrophic cardiomyopathy. Detected variants were filtered and the functional impact of amino acid changes was predicted by computational programs. DNA samples of the 16 patients were analyzed by whole exome sequencing. We identified six nonsynonymous variants that were shown to be pathogenic in all used prediction softwares: rs3744998 (EPG5), rs11551768 (MGME1), rs148374985 (MURC), rs78461695 (PLEC), rs17158558 (RET) and rs2295190 (SYNE1). Two of the analyzed sequence variants had minor allele frequency (MAF)<0.01: rs148374985 (MURC), rs34580776 (MYBPC3). Our data support the potential role of the detected variants in pathogenesis of dilated or hypertrophic cardiomyopathy; however, the possibility that these variants might not be true disease-causing variants but are susceptibility alleles that require additional mutations or injury to cause the clinical phenotype of disease must be considered. © 2017 Wiley Periodicals, Inc.

Spectrum of Mutations in Hypertrophic Cardiomyopathy Genes Among Tunisian Patients.

PubMed

Jaafar, Nawel; Gómez, Juan; Kammoun, Ikram; Zairi, Ihsen; Amara, Wael Ben; Kachboura, Salem; Kraiem, Sondes; Hammami, Mohamed; Iglesias, Sara; Alonso, Belén; Coto, Eliecer

2016-11-01

Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disorder associated with heart failure and sudden death. Mutations in the cardiac sarcomere genes are found in approximately half of HCM patients and are more common among cases with a family history of the disease. Data about the mutational spectrum of the sarcomeric genes in HCM patients from Northern Africa are limited. The population of Tunisia is particularly interesting due to its Berber genetic background. As founder mutations have been reported in other disorders. We performed semiconductor chip (Ion Torrent PGM) next generation sequencing of the nine main sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1) as well as the recently identified as an HCM gene, FLNC, in 45 Tunisian HCM patients. We found sarcomere gene polymorphisms in 12 patients (27%), with MYBPC3 and MYH7 representing 83% (10/12) of the mutations. One patient was homozygous for a new MYL3 mutation and two were double MYBPC3 + MYH7 mutation carriers. Screening of the FLNC gene identified three new mutations, which points to FLNC mutations as an important cause of HCM among Tunisians. The mutational background of HCM in Tunisia is heterogeneous. Unlike other Mendelian disorders, there were no highly prevalent mutations that could explain most of the cases. Our study also suggested that FLNC mutations may play a role on the risk for HCM among Tunisians.

Increased Postnatal Cardiac Hyperplasia Precedes Cardiomyocyte Hypertrophy in a Model of Hypertrophic Cardiomyopathy

PubMed Central

Farrell, Emily T.; Grimes, Adrian C.; de Lange, Willem J.; Armstrong, Annie E.; Ralphe, J. Carter

2017-01-01

Rationale: Hypertrophic cardiomyopathy (HCM) occurs in ~0.5% of the population and is a leading cause of sudden cardiac death (SCD) in young adults. Cardiomyocyte hypertrophy has been the accepted mechanism for cardiac enlargement in HCM, but the early signaling responsible for initiating hypertrophy is poorly understood. Mutations in cardiac myosin binding protein C (MYBPC3) are among the most common HCM-causing mutations. Ablation of Mybpc3 in an HCM mouse model (cMyBP-C−/−) rapidly leads to cardiomegaly by postnatal day (PND) 9, though hearts are indistinguishable from wild-type (WT) at birth. This model provides a unique opportunity to explore early processes involved in the dramatic postnatal transition to hypertrophy. Methods and Results: We performed microarray analysis, echocardiography, qPCR, immunohistochemistry (IHC), and isolated cardiomyocyte measurements to characterize the perinatal cMyBP-C−/− phenotype before and after overt hypertrophy. cMyBP-C−/− hearts showed elevated cell cycling at PND1 that transitioned to hypertrophy by PND9. An expanded time course revealed that increased cardiomyocyte cycling was associated with elevated heart weight to body weight ratios prior to cellular hypertrophy, suggesting that cell cycling resulted in cardiomyocyte proliferation. Animals heterozygous for the cMyBP-C deletion trended in the direction of the homozygous null, yet did not show increased heart size by PND9. Conclusions: Results indicate that altered regulation of the cell cycling pathway and elevated proliferation precedes hypertrophy in the cMyBP-C−/− HCM model, and suggests that increased cardiomyocyte number contributes to increased heart size in cMyBP-C−/− mice. This pre-hypertrophic period may reflect a unique time during which the commitment to HCM is determined and disease severity is influenced. PMID:28659827

RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy.

PubMed

Kaufman, Beth D; Auerbach, Scott; Reddy, Sushma; Manlhiot, Cedric; Deng, Liyong; Prakash, Ashwin; Printz, Beth F; Gruber, Dorota; Papavassiliou, Dimitrios P; Hsu, Daphne T; Sehnert, Amy J; Chung, Wendy K; Mital, Seema

2007-12-01

Hypertrophic Cardiomyopathy (HCM) is a disease with variable rate of progression. Young age is an independent risk factor for poor outcome in HCM. The influence of renin-angiotensin-aldosterone (RAAS) genotype on the progression of HCM in children is unknown. Children with HCM (n = 65) were enrolled prospectively across two centers (2001-2005). All subjects were genotyped for five RAAS gene polymorphisms previously associated with LV hypertrophy (pro-LVH): AGT M235T, ACE DD, CMA-1903 A/G, AGTR1 1666 A/C and CYP11B2-344 C/T. Linear regression models, based on maximum likelihood estimates, were created to assess the independent effect of RAAS genotype on LV hypertrophy (LVH). Forty-six subjects were homozygous for <2 and 19 were homozygous for > or =2 pro-LVH RAAS polymorphisms. Mean age at presentation was 9.6 +/- 6 years. Forty children had follow-up echocardiograms after a median of 1.5 years. Indexed LV mass (LVMI) and LV mass z-scores were higher at presentation and follow-up in subjects with > or =2 pro-LVH genotypes compared to those with <2 (P < 0.05). Subjects with > or =2 pro-LVH genotypes also demonstrated a greater increase in septal thickness (IVST) and in LV outflow tract (LVOT) obstruction on follow-up (P < 0.05). On multivariate analysis, a higher number of pro-LVH genotypes was associated with a larger effect size (P < 0.05). Pro-LVH RAAS gene polymorphisms are associated with progressive septal hypertrophy and LVOT obstruction in children with HCM. Identification of RAAS modifier genes may help to risk-stratify patients with HCM.

Pilot study analyzing automated ECG screening of hypertrophic cardiomyopathy.

PubMed

Campbell, Matthew J; Zhou, Xuefu; Han, Chia; Abrishami, Hedayat; Webster, Gregory; Miyake, Christina Y; Sower, Christopher T; Anderson, Jeffrey B; Knilans, Timothy K; Czosek, Richard J

2017-06-01

Hypertrophic cardiomyopathy (HCM) is one of the leading causes of sudden cardiac death in athletes. However, preparticipation ECG screening has often been criticized for failing to meet cost-effectiveness thresholds, in part because of high false-positive rates and the cost of ECG screening itself. The purpose of this study was to assess the testing characteristics of an automated ECG algorithm designed to screen for HCM in a multi-institutional pediatric cohort. ECGs from patients with HCM aged 12 to 20 years from 3 pediatric institutions were screened for ECG criteria for HCM using a previously described automated computer algorithm developed specifically for HCM ECG screening. The results were compared to a known healthy pediatric cohort. The studies then were read by trained electrophysiologists using standard ECG criteria and compared to the results of automated screening. One hundred twenty-eight ECGs from unique patients with phenotypic HCM were obtained and compared with 256 studies from healthy control patients matched in 2:1 fashion. When presented with the ECGs, the non-voltage-based algorithm resulted in 81.2% sensitivity and 90.7% specificity. A trained electrophysiologist read the same data according to the Seattle Criteria, with 71% sensitivity with 95.7% specificity. The sensitivity of screening as well as the components of the ECG screening itself varied by institution. This pilot study demonstrates a potential for automated ECG screening algorithms to detect HCM with testing characteristics similar to that of a trained electrophysiologist. In addition, there appear to be differences in ECG characteristics between patient populations, which may account for the difficulties in universal screening. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Genetic advances in sarcomeric cardiomyopathies: state of the art

PubMed Central

Ho, Carolyn Y.; Charron, Philippe; Richard, Pascale; Girolami, Francesca; Van Spaendonck-Zwarts, Karin Y.; Pinto, Yigal

2015-01-01

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine. PMID:25634555

The Genetic and Molecular Bases for Hypertrophic Cardiomyopathy: The Role for Calcium Sensitization.

PubMed

Ren, Xianfeng; Hensley, Nadia; Brady, Mary Beth; Gao, Wei Dong

2018-02-01

Hypertrophic cardiomyopathy (HCM) affects millions of people around the world as one of the most common genetic heart disorders and leads to cardiac ischemia, heart failure, dysfunction of other organ systems, and increased risk for sudden unexpected cardiac deaths. HCM can be caused by single-point mutations, insertion or deletion mutations, or truncation of cardiac myofilament proteins. The molecular mechanism that leads to disease progression and presentation is still poorly understood, despite decades of investigations. However, recent research has made dramatic advances in the understanding of HCM disease development. Studies have shown that increased calcium sensitivity is a universal feature in HCM. At the molecular level, increased crossbridge force (or power) generation resulting in hypercontractility is the prominent feature. Thus, calcium sensitization/hypercontractility is emerging as the primary stimulus for HCM disease development and phenotypic expression. Cross-bridge inhibition has been shown to halt HCM presentation, and myofilament desensitization appears to reduce lethal arrhythmias in animal models of HCM. These advances in basic research will continue to deepen the knowledge of HCM pathogenesis and are beginning to revolutionize the management of HCM. Copyright © 2018 Elsevier Inc. All rights reserved.

Deletion of GSK-3β in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation

PubMed Central

Kerkela, Risto; Kockeritz, Lisa; MacAulay, Katrina; Zhou, Jibin; Doble, Bradley W.; Beahm, Cara; Greytak, Sarah; Woulfe, Kathleen; Trivedi, Chinmay M.; Woodgett, James R.; Epstein, Jonathan A.; Force, Thomas; Huggins, Gordon S.

2008-01-01

Based on extensive preclinical data, glycogen synthase kinase–3 (GSK-3) has been proposed to be a viable drug target for a wide variety of disease states, ranging from diabetes to bipolar disorder. Since these new drugs, which will be more powerful GSK-3 inhibitors than lithium, may potentially be given to women of childbearing potential, and since it has controversially been suggested that lithium therapy might be linked to congenital cardiac defects, we asked whether GSK-3 family members are required for normal heart development in mice. We report that terminal cardiomyocyte differentiation was substantially blunted in Gsk3b–/– embryoid bodies. While GSK-3α–deficient mice were born without a cardiac phenotype, no live-born Gsk3b–/– pups were recovered. The Gsk3b–/– embryos had a double outlet RV, ventricular septal defects, and hypertrophic myopathy, with near obliteration of the ventricular cavities. The hypertrophic myopathy was caused by cardiomyocyte hyperproliferation without hypertrophy and was associated with increased expression and nuclear localization of three regulators of proliferation — GATA4, cyclin D1, and c-Myc. These studies, which we believe are the first in mammals to examine the role of GSK-3α and GSK-3β in the heart using loss-of-function approaches, implicate GSK-3β as a central regulator of embryonic cardiomyocyte proliferation and differentiation, as well as of outflow tract development. Although controversy over the teratogenic effects of lithium remains, our studies suggest that caution should be exercised in the use of newer, more potent drugs targeting GSK-3 in women of childbearing age. PMID:18830417

[Left atrial function and left atrial appendage flow velocity in hypertrophic cardiomyopathy: comparison of patients with and without paroxysmal atrial fibrillation].

PubMed

Akasaka, K; Kawashima, E; Shiokoshi, T; Ishii, Y; Hasebe, N; Kikuchi, K

1998-07-01

The involvement of left atrial (LA) appendage flow velocity in reduced left atrial function was investigated in 24 patients with hypertrophic cardiomyopathy, who retained sinus rhythm at the examination. Patients were divided into 11 with a history of paroxysmal atrial fibrillation [PAf(+)] and 13 without such history [PAf(-)]. Transthoracic echocardiography was performed to evaluate LA fractional shortening (LA%FS) and mean velocity of circumferential LA fiber shortening (LAmVcf), as contractile functions of the left atrium at the phase of active atrial contraction. Transesophageal echocardiographic Doppler examination was performed in all patients to measure the LA appendage velocity. In all patients, significant positive correlations were observed between the LA appendage velocity and LA%FS (r = 0.50, p < 0.05) or LAmVcf (r = 0.82, p < 0.001). LAmVcf and LA appendage velocity in patients with paroxysmal fibrillation were significantly lower than in those without (0.84 +/- 0.15 vs 1.28 +/- 0.37 circ/sec, 44 +/- 12 vs 65 +/- 20 cm/sec, both p < 0.01), whereas LA diameter was greater in the former compared to the latter (45 +/- 5 vs 38 +/- 5 mm, p < 0.01). LAmVcf and LA appendage velocity were low in four patients with cerebral infarction or transient cerebral ischemic attack (LAmVcf < 1.0 circ/sec, LA appendage velocity < or = 40 cm/sec). Importantly, all these patients had a history of paroxysmal fibrillation. These results indicate that there is a close relationship between LA appendage velocity and LA contractile function in patients with hypertrophic cardiomyopathy with paroxysmal atrial fibrilation, and these patients have potential risk of cerebral infarction.

Women with hypertrophic cardiomyopathy have worse survival.

PubMed

Geske, Jeffrey B; Ong, Kevin C; Siontis, Konstantinos C; Hebl, Virginia B; Ackerman, Michael J; Hodge, David O; Miller, Virginia M; Nishimura, Rick A; Oh, Jae K; Schaff, Hartzell V; Gersh, Bernard J; Ommen, Steve R

2017-12-07

Sex differences in hypertrophic cardiomyopathy (HCM) remain unclear. We sought to characterize sex differences in a large HCM referral centre population. Three thousand six hundred and seventy-three adult patients with HCM underwent evaluation between January 1975 and September 2012 with 1661 (45.2%) female. Kaplan-Meier survival curves were assessed via log-rank test. Cox proportional hazard regression analyses evaluated the relation of sex with survival. At index visit, women were older (59 ± 16 vs. 52 ± 15 years, P < 0.0001) had more symptoms [New York Heart Association (NYHA) Class III-IV 45.0% vs. 35.3%, P < 0.0001], more obstructive physiology (77.4% vs. 71.8%, P = 0.0001), more mitral regurgitation (moderate or greater in 56.1% vs. 43.9%, P < 0.0001), higher E/e' ratio (n = 1649, 20.6 vs. 15.6, P < 0.0001), higher estimated pulmonary artery systolic pressure (n = 1783, 40.8 ± 15.4 vs. 34.8 ± 10.8 mmHg, P < 0.0001), worse cardiopulmonary exercise performance (n = 1267; percent VO2 predicted 62.8 ± 20% vs. 65.8 ± 19.2%, P = 0.007), and underwent more frequent alcohol septal ablation (4.9% vs. 3.0%, P = 0.004) but similar frequency of myectomy (28% vs. 30%, P = 0.24). Median follow-up was 10.9 (IQR 7.4-16.2) years. Kaplan-Meier analysis demonstrated lower survival in women compared with men (P < 0.0001). In multivariable modelling, female sex remained independently associated with mortality (HR 1.13 [1.03-1.22], P = 0.01) when adjusted for age, NYHA Class III-IV symptoms, and cardiovascular comorbidities. Women with HCM present at more advanced age, with more symptoms, worse cardiopulmonary exercise tolerance, and different haemodynamics than men. Sex is an important determinant in HCM management as women with HCM have worse survival. Women may require more aggressive diagnostic and therapeutic approaches. Published on behalf of the European Society of Cardiology. All

Hypertensive heart disease versus hypertrophic cardiomyopathy: multi-parametric cardiovascular magnetic resonance discriminators when end-diastolic wall thickness ≥ 15 mm.

PubMed

Rodrigues, Jonathan C L; Rohan, Stephen; Ghosh Dastidar, Amardeep; Harries, Iwan; Lawton, Christopher B; Ratcliffe, Laura E; Burchell, Amy E; Hart, Emma C; Hamilton, Mark C K; Paton, Julian F R; Nightingale, Angus K; Manghat, Nathan E

2017-03-01

European guidelines state left ventricular (LV) end-diastolic wall thickness (EDWT) ≥15mm suggests hypertrophic cardiomyopathy (HCM), but distinguishing from hypertensive heart disease (HHD) is challenging. We identify cardiovascular magnetic resonance (CMR) predictors of HHD over HCM when EDWT ≥15mm. 2481 consecutive clinical CMRs between 2014 and 2015 were reviewed. 464 segments from 29 HCM subjects with EDWT ≥15mm but without other cardiac abnormality, hypertension or renal impairment were analyzed. 432 segments from 27 HHD subjects with EDWT ≥15mm but without concomitant cardiac pathology were analyzed. Magnitude and location of maximal EDWT, presence of late gadolinium enhancement (LGE), LV asymmetry (>1.5-fold opposing segment) and systolic anterior motion of the mitral valve (SAM) were measured. Multivariate logistic regression was performed. Significance was defined as p<0.05. HHD and HCM cohorts were age-/gender-matched. HHD had significantly increased indexed LV mass (110±27g/m 2 vs. 91±31g/m 2 , p=0.016) but no difference in site or magnitude of maximal EDWT. Mid-wall LGE was significantly more prevalent in HCM. Elevated indexed LVM, mid-wall LGE and absence of SAM were significant multivariate predictors of HHD, but LV asymmetry was not. Increased indexed LV mass, absence of mid-wall LGE and absence of SAM are better CMR discriminators of HHD from HCM than EDWT ≥15mm. • Hypertrophic cardiomyopathy (HCM) is often diagnosed with end-diastolic wall thickness ≥15mm. • Hypertensive heart disease (HHD) can be difficult to distinguish from HCM. • Retrospective case-control study showed that location and magnitude of EDWT are poor discriminators. • Increased left ventricular mass and midwall fibrosis are independent predictors of HHD. • Cardiovascular magnetic resonance parameters facilitate a better discrimination between HHD and HCM.

Imaging and histology in the diagnosis of multiple papillary fibroelastomas in a patient with hypertrophic obstructive cardiomyopathy. Case report.

PubMed

Ionescu, Alin Alexandru; Radulescu, Bogdan; Herlea, Vlad; Miclea, Ioan; Parepa, Irinel; Bubenek, Serban; Popescu, Bogdan Alexandru; Ginghina, Carmen; Jurcut, Ruxandra

2017-11-29

Papillary fibroelastomas (PFEs) are one of the most frequent primary cardiac tumors and occur more often in patients with hypertrophic obstructive cardiomyopathy (HOCM). PFEs have been linked to an increased risk of neurological events. We report a case of a 59-year-old woman with HOCM in whom echocardiography (transthoracic and transesophageal, using 2D and 3D techniques) revealed multiple masses in various locations in the left cardiac chambers. Surgical excision of the cardiac tumors and aortic valve replacement was performed and the pathologic report confirmed the diagnosis of PFEs. Patient followup using ultrasonography is crucial since recurrence is a possibility. Current cardiac ultrasound techniques are essential for diagnosing and for guiding the management of these conditions.

Interaction of Adverse Disease Related Pathways in Hypertrophic Cardiomyopathy.

PubMed

Rowin, Ethan J; Maron, Martin S; Chan, Raymond H; Hausvater, Anais; Wang, Wendy; Rastegar, Hassan; Maron, Barry J

2017-12-15

Hypertrophic cardiomyopathy (HC) has been characterized as a generally progressive genetic heart disease, creating an ominous perspective for patients and managing cardiologists. We explored the HC disease burden and interaction of adverse clinical pathways to clarify patient expectations over long time periods in the contemporary therapeutic era. We studied 1,000 consecutive HC patients (52 ± 17 years) at Tufts Medical Center, followed 9.3 ± 8 years from diagnosis, employing a novel disease pathway model: 46% experienced a benign course free of adverse pathways, but 42% of patients progressed along 1 major pathway, most commonly refractory heart failure to New York Heart Association class III or IV requiring surgical myectomy (or alcohol ablation) or heart transplant; repetitive or permanent atrial fibrillation; and least commonly arrhythmic sudden death events. Eleven percent experienced 2 of these therapeutic end points at different times in their clinical course, most frequently the combination of advanced heart failure and atrial fibrillation, whereas only 1% incurred all 3 pathways. Freedom of progression from 1 to 2 disease pathways, or from 2 to 3 was 80% and 93% at 5 years, respectively. Annual HC-related mortality did not differ according to the number of pathways: 1 (0.8%), 2 (0.8%), or 3 (2.4%) (p = 0.56), and 93% of patients were in New York Heart Association classes I or II at follow-up. In conclusion, it is uncommon for HC patients to experience multiple adverse (but treatable) disease pathways, underscoring the principle that HC is not a uniformly progressive disease. These observations provide a measure of clarity and/or reassurance to patients regarding the true long-term disease burden of HC. Copyright © 2017 Elsevier Inc. All rights reserved.

J Waves for Predicting Cardiac Events in Hypertrophic Cardiomyopathy.

PubMed

Tsuda, Toyonobu; Hayashi, Kenshi; Konno, Tetsuo; Sakata, Kenji; Fujita, Takashi; Hodatsu, Akihiko; Nagata, Yoji; Teramoto, Ryota; Nomura, Akihiro; Tanaka, Yoshihiro; Furusho, Hiroshi; Takamura, Masayuki; Kawashiri, Masa-Aki; Fujino, Noboru; Yamagishi, Masakazu

2017-10-01

This study sought to investigate whether the presence of J waves was associated with cardiac events in patients with hypertrophic cardiomyopathy (HCM). It has been uncertain whether the presence of J waves predicts life-threatening cardiac events in patients with HCM. This study evaluated consecutive 338 patients with HCM (207 men; age 61 ± 17 years of age). A J-wave was defined as J-point elevation >0.1 mV in at least 2 contiguous inferior and/or lateral leads. Cardiac events were defined as sudden cardiac death, ventricular fibrillation or sustained ventricular tachycardia, or appropriate implantable cardiac defibrillator therapy. The study also investigated whether adding the J-wave in a conventional risk model improved a prediction of cardiac events. J waves were seen in 46 (13.6%) patients at registration. Cardiac events occurred in 31 patients (9.2%) during median follow-up of 4.9 years (interquartile range: 2.6 to 7.1 years). In a Cox proportional hazards model, the presence of J waves was significantly associated with cardiac events (adjusted hazard ratio: 4.01; 95% confidence interval [CI]: 1.78 to 9.05; p = 0.001). Compared with the conventional risk model, the model using J waves in addition to conventional risks better predicted cardiac events (net reclassification improvement, 0.55; 95% CI: 0.20 to 0.90; p = 0.002). The presence of J waves was significantly associated with cardiac events in HCM. Adding J waves to conventional cardiac risk factors improved prediction of cardiac events. Further confirmatory studies are needed before considering J-point elevation as a marker of risk for use in making management decisions regarding risk in patients with HCM. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Clinical Characteristics and Prognosis of End-stage Hypertrophic Cardiomyopathy.

PubMed

Xiao, Yan; Yang, Kun-Qi; Yang, Yan-Kun; Liu, Ya-Xin; Tian, Tao; Song, Lei; Jiang, Xiong-Jing; Zhou, Xian-Liang

2015-06-05

End-stage hypertrophic cardiomyopathy (HCM) is complicated by substantial adverse events. However, few studies have focused on electrocardiographic features and their prognostic values in HCM. This study aimed to evaluate the clinical manifestations and prognostic value of electrocardiography in patients with end-stage HCM. End-stage HCM patients were enrolled from a total of 1844 consecutive HCM patients from April 2002 to November 2013 at Fuwai Hospital. Clinical data, including medical history, electrocardiography, and echocardiography, were analyzed. Cox hazards regression analysis was used to assess the risk factors for cardiovascular mortality. End-stage HCM was identified in 99 (5.4%) patients, averaged at 52 ± 16 years old at entry. Atrial fibrillation was observed in 53 patients and mural thrombus in 19 patients. During 3.9 ± 3.0 years of follow-up, embolic stroke, refractory heart failure, and death or transplantation were observed in 20, 39, and 51 patients, respectively. The incidence of annual mortality was 13.2%. Multivariate Cox hazards regression analysis identified New York Heart Association Class (NYHA) III/IV at entry (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.05-3.80; P = 0.036), left bundle branch block (LBBB) (HR: 2.80; 95% CI: 1.47-5.31; P = 0.002), and an abnormal Q wave (HR: 2.21; 95% CI: 1.16-4.23; P = 0.016) as independent predictors of cardiovascular death, in accordance with all-cause death and heart failure-related death. LBBB and an abnormal Q wave are risk factors of cardiovascular mortality in end-stage HCM and provide new evidence for early intervention. Susceptibility of end-stage HCM patients to mural thrombus and embolic events warrants further attention.

Transactivation Domain of Human c-Myc Is Essential to Alleviate Poly(Q)-Mediated Neurotoxicity in Drosophila Disease Models.

PubMed

Raj, Kritika; Sarkar, Surajit

2017-05-01

Polyglutamine (poly(Q)) disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, represent a group of neurological disorders which arise due to an atypically expanded poly(Q) tract in the coding region of the affected gene. Pathogenesis of these disorders inside the cells begins with the assembly of these mutant proteins in the form of insoluble inclusion bodies (IBs), which progressively sequester several vital cellular transcription factors and other essential proteins, and finally leads to neuronal dysfunction and apoptosis. We have shown earlier that targeted upregulation of Drosophila myc (dmyc) dominantly suppresses the poly(Q) toxicity in Drosophila. The present study examines the ability of the human c-myc proto-oncogene and also identifies the specific c-Myc isoform which drives the mitigation of poly(Q)-mediated neurotoxicity, so that it could be further substantiated as a potential drug target. We report for the first time that similar to dmyc, tissue-specific induced expression of human c-myc also suppresses poly(Q)-mediated neurotoxicity by an analogous mechanism. Among the three isoforms of c-Myc, the rescue potential was maximally manifested by the full-length c-Myc2 protein, followed by c-Myc1, but not by c-MycS which lacks the transactivation domain. Our study suggests that strategies focussing on the transactivation domain of c-Myc could be a very useful approach to design novel drug molecules against poly(Q) disorders.

Myc-driven overgrowth requires unfolded protein response-mediated induction of autophagy and antioxidant responses in Drosophila melanogaster.

PubMed

Nagy, Péter; Varga, Agnes; Pircs, Karolina; Hegedűs, Krisztina; Juhász, Gábor

2013-01-01

Autophagy, a lysosomal self-degradation and recycling pathway, plays dual roles in tumorigenesis. Autophagy deficiency predisposes to cancer, at least in part, through accumulation of the selective autophagy cargo p62, leading to activation of antioxidant responses and tumor formation. While cell growth and autophagy are inversely regulated in most cells, elevated levels of autophagy are observed in many established tumors, presumably mediating survival of cancer cells. Still, the relationship of autophagy and oncogenic signaling is poorly characterized. Here we show that the evolutionarily conserved transcription factor Myc (dm), a proto-oncogene involved in cell growth and proliferation, is also a physiological regulator of autophagy in Drosophila melanogaster. Loss of Myc activity in null mutants or in somatic clones of cells inhibits autophagy. Forced expression of Myc results in cell-autonomous increases in cell growth, autophagy induction, and p62 (Ref2P)-mediated activation of Nrf2 (cnc), a transcription factor promoting antioxidant responses. Mechanistically, Myc overexpression increases unfolded protein response (UPR), which leads to PERK-dependent autophagy induction and may be responsible for p62 accumulation. Genetic or pharmacological inhibition of UPR, autophagy or p62/Nrf2 signaling prevents Myc-induced overgrowth, while these pathways are dispensable for proper growth of control cells. In addition, we show that the autophagy and antioxidant pathways are required in parallel for excess cell growth driven by Myc. Deregulated expression of Myc drives tumor progression in most human cancers, and UPR and autophagy have been implicated in the survival of Myc-dependent cancer cells. Our data obtained in a complete animal show that UPR, autophagy and p62/Nrf2 signaling are required for Myc-dependent cell growth. These novel results give additional support for finding future approaches to specifically inhibit the growth of cancer cells addicted to oncogenic

Genetic advances in sarcomeric cardiomyopathies: state of the art.

PubMed

Ho, Carolyn Y; Charron, Philippe; Richard, Pascale; Girolami, Francesca; Van Spaendonck-Zwarts, Karin Y; Pinto, Yigal

2015-04-01

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Relation of QRS duration to mortality in a community-based cohort with hypertrophic cardiomyopathy.

PubMed

Bongioanni, Sergio; Bianchi, Francesca; Migliardi, Alessandro; Gnavi, Roberto; Pron, Paolo Giay; Casetta, Marzia; Conte, Maria Rosa

2007-08-01

A prolonged QRS duration on the standard electrocardiogram is associated with an increased risk of cardiovascular death in cardiomyopathies of different origin. However, the relation between QRS duration and prognosis in hypertrophic cardiomyopathy (HC) remains undefined. We assessed the relation between QRS duration and cardiovascular death in 241 consecutive patients with HC. The study cohort was divided into 2 groups according to QRS duration: <120 and > or =120 ms. Of the 241 patients, 191 (79%) had a QRS duration <120 ms and 50 (21%) a QRS duration > or =120 ms. During a mean follow-up of 7.9 +/- 5.1 years, 35 patients died of cardiovascular causes related to HC. Of these 35 patients, 13 (6%) had a QRS duration <120 ms and 22 (43%) had a QRS duration > or =120 ms (p <0.01). Risk of cardiovascular death was significantly higher in patients with a QRS duration > or =120 ms than in those with a QRS duration <120 ms (relative risk 5.2, p <0.0001). At 8-year follow-up, cumulative risks of HC-related death were 7.1% in patients with a QRS duration <120 ms and 55% in those with a QRS duration > or =120 ms. Multivariate analysis confirmed that a QRS duration > or =120 ms was independently associated with an increased risk of cardiovascular death (hazard ratio 3.2, p = 0.007). New York Heart Association functional class III/IV was the only other clinical variable significantly and independently associated with an increased risk of cardiovascular death. In conclusion, in patients with HC, QRS duration on standard electrocardiogram is directly related to cardiovascular mortality, and a QRS duration > or =120 ms is a strong and independent predictor of prognosis.

Decreased coronary vasodilatory capacity in hypertrophic cardiomyopathy determined by split-dose thallium-dipyridamole myocardial scintigraphy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koga, Y.; Yamaguchi, R.; Ogata, M.

1990-05-01

Split-dose thallium-dipyridamole myocardial scintigraphy was performed in patients with nonobstructive hypertrophic cardiomyopathy (HC) who had angiographically normal coronary arteries. The dipyridamole-induced increases in thallium-201 uptake, calculated to evaluate coronary vasodilatory capacity, were significantly lower in 30 patients with HC than in 13 control subjects (177 +/- 58 vs 281 +/- 46%) and the reductions were observed in both the septal and lateral segments. The reductions of the septal segment in HC patients were significantly greater than those in 10 hypertensive patients with comparable degrees of septal hypertrophy. Of patients with HC, 16 had increases in thallium uptake well below themore » normal range. Compared with those having normal increases, these patients had significantly lower exercise duration (11 vs 15 minutes), with 33% having ST depression develop at a workload less than or equal to 80 watts. These data indicate that approximately one-half of patients with HC have impaired coronary vasodilatory capacity that could be an important pathophysiologic abnormality of HC resulting in the development of myocardial ischemia and the impairment of cardiac performance during exercise.« less

Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes

PubMed Central

Alamo, Lorenzo; Ware, James S; Pinto, Antonio; Gillilan, Richard E; Seidman, Jonathan G; Seidman, Christine E; Padrón, Raúl

2017-01-01

Cardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human β-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10−19; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis. DOI: http://dx.doi.org/10.7554/eLife.24634.001 PMID:28606303

Decreased exercise capacity and sleep-disordered breathing in patients with hypertrophic cardiomyopathy.

PubMed

Konecny, Tomas; Geske, Jeffrey B; Ludka, Ondrej; Orban, Marek; Brady, Peter A; Abudiab, Muaz M; Albuquerque, Felipe N; Placek, Alexander; Kara, Tomas; Sahakyan, Karine R; Gersh, Bernard J; Tajik, A Jamil; Allison, Thomas G; Ommen, Steve R; Somers, Virend K

2015-06-01

Mechanisms of decreased exercise capacity in patients with hypertrophic cardiomyopathy (HCM) are not well understood. Sleep-disordered breathing (SDB) is a highly prevalent but treatable disorder in patients with HCM. The role of comorbid SDB in the attenuated exercise capacity in HCM has not been studied previously. Overnight oximetry, cardiopulmonary exercise testing, and echocardiographic studies were performed in consecutive patients with HCM seen at the Mayo Clinic. SDB was considered present if the oxygen desaturation index (number of ≥ 4% desaturations/h) was ≥ 10. Peak oxygen consumption (VO2 peak) (the most reproducible and prognostic measure of cardiovascular fitness) was then correlated with the presence and severity of SDB. A total of 198 patients with HCM were studied (age, 53 ± 16 years; 122 men), of whom 32% met the criteria for the SDB diagnosis. Patients with SDB had decreased VO2 peak compared with those without SDB (16 mL O2/kg/min vs 21 mL O2/kg/min, P < .001). SDB remained significantly associated with VO2 peak after accounting for confounding clinical variables (P < .001) including age, sex, BMI, atrial fibrillation, and coronary artery disease. In patients with HCM, the presence of SDB is associated with decreased VO2 peak. SDB may represent an important and potentially modifiable contributor to impaired exercise tolerance in this unique population.

Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation.

PubMed

Wang, Jie; Wan, Ke; Sun, Jiayu; Li, Weihao; Liu, Hong; Han, Yuchi; Chen, Yucheng

2018-01-17

Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.

Cardiomyopathies in Noonan syndrome and the other RASopathies

PubMed Central

Gelb, Bruce D.; Roberts, Amy E.; Tartaglia, Marco

2015-01-01

Noonan syndrome and related disorders (Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with loose anagen hair, and other related traits) are autosomal dominant traits. Mutations causing these disorders alter proteins relevant for signaling through RAS. Thus, these traits are now collectively called the RASopathies. While the RASopathies have pleiomorphic features, this review will focus on the hypertrophic cardiomyopathy observed in varying percentages of all of these traits. In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy. The pathogeneses for the RASopathy-associated cardiomyopathies are being elucidated, principally using animal models, leading to genotype-specific insights into how signal transduction is perturbed. Based on those findings, small molecule therapies seem possible for RASopathy-associated cardiomyopathies. PMID:26380542

Differentiating hypertrophic cardiomyopathy from athlete's heart: An electrocardiographic and echocardiographic approach.

PubMed

Grazioli, Gonzalo; Usín, Domingo; Trucco, Emilce; Sanz, Maria; Montserrat, Silvia; Vidal, Bàrbara; Gutierrez, Josep; Canal, Ramon; Brugada, Josep; Mont, Lluis; Sitges, Marta

2016-01-01

Differential diagnosis of hypertrophic cardiomyopathy (HCM) vs athlete's heart is challenging in individuals with mild-moderate left-ventricular hypertrophy. This study aimed to assess ECG and echocardiographic parameters proposed for the differential diagnosis of HCM. The study included 75 men in three groups: control (n=30), "gray zone" athletes with interventricular septum (IVS) measuring 13-15mm (n=25) and HCM patients with IVS of 13-18mm (n=20). The most significant differences were found in relative septal thickness (RST), calculated as the ratio of 2 x IVS to left ventricle end-diastolic diameter (LV-EDD) (0.37, 0.51, 0.71, respectively; p<0.01) and in spatial QRS-T angle as visually estimated (9.8, 33.6, 66.2, respectively; p<0.01). The capacity for differential HCM diagnosis of each of the 5 criteria was assessed using the area under the curve (AUC), as follows: LV-EDD<54 (0.60), family history (0.61), T-wave inversion (TWI) (0.67), spatial QRS-T angle>45 (0.75) and RST>0.54 (0.92). Pearson correlation between spatial QRS-T angle>45 and TWI was 0.76 (p 0.01). The combination of spatial QRS-T angle>45 and RST>0.54 for diagnosis of HCM had an AUC of 0.79. The best diagnostic criteria for HCM was RST>0.54. The spatial QRS-T angle>45 did not add sensitivity if TWI was present. No additional improvement in differential diagnosis was obtained by combining parameters. Copyright © 2016 Elsevier Inc. All rights reserved.

Merits and pitfalls of genetic testing in a hypertrophic cardiomyopathy clinic.

PubMed

Arad, Michael; Monserrat, Lorenzo; Haron-Khun, Shiraz; Seidman, Jonathan G; Seidman, Christine E; Arbustini, Eloisa; Glikson, Michael; Freimark, Dov

2014-11-01

Hypertrophic cardiomyopathy (HCM) is a familial disease with autosomal dominant inheritance and age-dependent penetrance, caused primarily by mutations of sarcomere genes. Because the clinical variability of HCM is related to its genetic heterogeneity, genetic studies may improve the diagnosis and prognostic evaluation in HCM. To analyze the impact of genetic diagnosis on the clinical management of HCM. Genetic studies were performed for either research or clinical reasons. Once the disease-causing mutation was identified, the management plan was reevaluated. Family members were invited to receive genetic counseling and encouraged to be tested for the mutation. Ten mutations in sarcomere protein genes were identified in 9 probands: 2 novel and 8 previously described. Advanced heart failure or sudden death in a young person prompted the genetic study in 8 of the 9 families. Of 98 relatives available for genotyping, only 53 (54%) agreed to be tested. The compliance was higher in families with sudden death and lower in what appeared to be sporadic HCM or elderly-onset disease. Among the healthy we identified 9 carriers and 19 non-carriers. In 6 individuals the test result resolved an uncertainty about "possible HCM." In several cases the genetic result was also used for family planning and played a role in decisions on cardioverter-defibrillator implantation. Recurrence of a same mutation in different families created an opportunity to apply the information from the literature for risk stratification of individual patients. We suggest that the clinical context determines the indication for genetic testing and interpretation of the results.

Routine Papillary Muscle Realignment and Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy.

PubMed

Song, Howard K; Turner, Jason; Macfie, Rebekah; Kumar, Suwen; Mannello, Meghan J; Smith, Danielle; Bhamidipati, Castigliano; Raman, Jaishankar; Tibayan, Frederick; Heitner, Stephen B

2018-05-10

Septal myectomy has been the mainstay of the surgical treatment of obstructive hypertrophic cardiomyopathy (HCM), however recently there is growing appreciation for associated mitral valve abnormalities that contribute to left ventricular outflow tract (LVOT) obstruction. In this study, we describe our experience with combined papillary muscle realignment (PMR) and septal myectomy for the treatment of obstructive HCM. We identified 44 patients undergoing surgery for obstructive HCM whose anatomy was amenable to combined PMR and septal myectomy at our institution over a 20-month period. All patients underwent resting and stress echocardiography pre- and postoperatively. Demographic, clinical, and imaging data were prospectively collected in a cardiac surgery database. Patient age ranged broadly, with mean age of 54 years (range 18-76). Preoperatively, 70% of patients were NYHA Class III or IV, the mean stress LVOT gradient was 144 mmHg, and severe mitral regurgitation (MR) with stress was seen in 81% . Additional procedures included division of myocardial bands (50%) and chordae (43%) and resection of accessory papillary muscles (25%). Following the procedure, mean resting and stress gradients were reduced to normal (12 and 27 mmHg, respectively, p < 0.0001). No patient had severe MR and only 3 (6.8%) had moderate MR (p < 0.0001).Mean length of stay was 6 days and there were no mortalities. Septal myectomy combined with PMR is a safe, highly effective, and reproducible procedure that reliably relieves LVOT obstruction and corrects MR without the need for mitral valve repair or replacement. Copyright © 2018. Published by Elsevier Inc.

A Novel Missense Mutation p.Gly162Glu of the Gene MYL2 Involved in Hypertrophic Cardiomyopathy: A Pedigree Analysis of a Proband.

PubMed

Renaudin, Pauline; Janin, Alexandre; Millat, Gilles; Chevalier, Philippe

2018-04-01

Hypertrophic cardiomyopathy (HCM), a common and clinically heterogeneous disease characterized by unexplained ventricular myocardial hypertrophy, is mostly caused by mutations in sarcomeric genes. Identifying the genetic cause is important for management, therapy, and genetic counseling. A molecular diagnosis was performed on a 51-year-old woman diagnosed with HCM using a next-generation sequencing workflow based on a panel designed for sequencing the most prevalent cardiomyopathy-causing genes. Segregation analysis was performed on the woman's family. A novel myosin regulatory light chain (MYL2) missense variant, NM_000432.3:c485G>A, p.Gly162Glu, was identified and firstly considered as a putative pathogenic mutation. Among the 27 family members tested, 16 were carriers for the MYL2-p.Gly162Glu mutation, of whom 12 with the phenotype were positive. None of the 11 family members without mutation had cardiomyopathy. Genetic analysis combined with a segregation study allowed us to classify this novel MYL2 variation, p.Gly162Glu, as a novel pathogenic mutation leading to a familial form of HCM. Due to absence of fast in vitro approaches to evaluate the functional impact of missense variants on HCM-causing genes, segregation studies remain, when possible, the easiest approach to evaluate the putative pathogenicity of novel gene variants, more particularly missense ones.

Down-regulation of microRNA-451a facilitates the activation and proliferation of CD4+ T cells by targeting Myc in patients with dilated cardiomyopathy.

PubMed

Zeng, Zhipeng; Wang, Ke; Li, Yuanyuan; Xia, Ni; Nie, Shaofang; Lv, Bingjie; Zhang, Min; Tu, Xin; Li, Qianqian; Tang, Tingting; Cheng, Xiang

2017-04-07

CD4 + T cells are abnormally activated in patients with dilated cardiomyopathy (DCM) and might be associated with the immunopathogenesis of the disease. However, the underlying mechanisms of CD4 + T cell activation remain largely undefined. Our aim was to investigate whether the dysregulation of microRNAs (miRNAs) was associated with CD4 + T cell activation in DCM. CD4 + T cells from DCM patients showed increased expression levels of CD25 and CD69 and enhanced proliferation in response to anti-CD3/28, indicating an activated state. miRNA profiling analysis of magnetically sorted CD4 + T cells revealed a distinct pattern of miRNA expression in CD4 + T cells from DCM patients compared with controls. The level of miRNA-451a (miR-451a) was significantly decreased in the CD4 + T cells of DCM patients compared with that of the controls. The transfection of T cells with an miR-451a mimic inhibited their activation and proliferation, whereas an miR-451a inhibitor produced the opposite effects. Myc was directly inhibited by miR-451a via interaction with its 3'-UTR, thus identifying it as an miR-451a target in T cells. The knockdown of Myc suppressed the activation and proliferation of T cells, and the expression of Myc was significantly up-regulated at the mRNA level in CD4 + T cells from patients with DCM. A strong inverse correlation was observed between the Myc mRNA expression and miR-451a transcription level. Our data suggest that the down-regulation of miR-451a contributes to the activation and proliferation of CD4 + T cells by targeting the transcription factor Myc in DCM patients and may contribute to the immunopathogenesis of DCM. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

[Usefullness of Beta-blocker for Hemodynamic Changes Induced by Uterotonic Drug in a Patient with Hypertrophic Obstructive Cardiomyopathy Undergoing Elective Cesarean Section].

PubMed

Tsukano, Yuri; Sugita, Michiko; Ikuta, Yoshihiro; Yamamoto, Tatsuo

2015-06-01

Combined spinal-epidural anesthesia (CSEA) was given to a 27-year-old woman with hypertrophic obstructive cardiomyopathy (HOCM) for a selective cesarean section. After the injection of uterotonic drug via uterine muscle and a vein after delivery, the patient developed dyspnea, tachycardia, ST-change on elecrocardiogram and hypotension. It is important in HOCM patients to control heart rate and left ventricular contractile force. We started to infuse beta-blocker (landiolol, 10 μg x kg(-1) x min(-1)) and improved these symptoms of the patient. This case demonstrates that CSEA is safe for HOCM patients and beta-blocker is effective to improve hemodynamic changes induced by uterotonic drug in these patients.

A Murine Hypertrophic Cardiomyopathy Model: The DBA/2J Strain.

PubMed

Zhao, Wenyuan; Zhao, Tieqiang; Chen, Yuanjian; Zhao, Fengbo; Gu, Qingqing; Williams, Robert W; Bhattacharya, Syamal K; Lu, Lu; Sun, Yao

2015-01-01

Familial hypertrophic cardiomyopathy (HCM) is attributed to mutations in genes that encode for the sarcomere proteins, especially Mybpc3 and Myh7. Genotype-phenotype correlation studies show significant variability in HCM phenotypes among affected individuals with identical causal mutations. Morphological changes and clinical expression of HCM are the result of interactions with modifier genes. With the exceptions of angiotensin converting enzyme, these modifiers have not been identified. Although mouse models have been used to investigate the genetics of many complex diseases, natural murine models for HCM are still lacking. In this study we show that the DBA/2J (D2) strain of mouse has sequence variants in Mybpc3 and Myh7, relative to widely used C57BL/6J (B6) reference strain and the key features of human HCM. Four-month-old of male D2 mice exhibit hallmarks of HCM including increased heart weight and cardiomyocyte size relative to B6 mice, as well as elevated markers for cardiac hypertrophy including β-myosin heavy chain (MHC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and skeletal muscle alpha actin (α1-actin). Furthermore, cardiac interstitial fibrosis, another feature of HCM, is also evident in the D2 strain, and is accompanied by up-regulation of type I collagen and α-smooth muscle actin (SMA)-markers of fibrosis. Of great interest, blood pressure and cardiac function are within the normal range in the D2 strain, demonstrating that cardiac hypertrophy and fibrosis are not secondary to hypertension, myocardial infarction, or heart failure. Because D2 and B6 strains have been used to generate a large family of recombinant inbred strains, the BXD cohort, the D2 model can be effectively exploited for in-depth genetic analysis of HCM susceptibility and modifier screens.

Acute Effects of Nasal CPAP in Patients With Hypertrophic Cardiomyopathy.

PubMed

Nerbass, Flávia B; Salemi, Vera M C; Pedrosa, Rodrigo P; Portilho, Natanael de P; Ferreira-Filho, Julio C A; Moriya, Henrique T; Antunes, Murillo O; Arteaga-Fernández, Edmundo; Drager, Luciano F; Lorenzi-Filho, Geraldo

2016-11-01

Hypertrophic cardiomyopathy (HCM) is a common genetic disease that may cause left ventricular outflow tract (LVOT) obstruction, heart failure, and sudden death. Recent studies have shown a high prevalence of OSA among patients with HCM. Because the hemodynamics in patients with LVOT obstruction are unstable and depend on the loading conditions of the heart, we evaluated the acute effects of CPAP on hemodynamics and cardiac performance in patients with HCM. We studied 26 stable patients with HCM divided into nonobstructive HCM (n = 12) and obstructive HCM (n = 14) groups (LVOT gradient pressure lower or higher than 30 mm Hg, respectively). Patients in the supine position while awake were continuously monitored with beat-to-beat BP measurements and electrocardiography. Two-dimensional echocardiography was performed at rest (baseline) and after 20 min of nasal CPAP at 1.5 cm H 2 O and 10 cm H 2 O, which was applied in a random order interposed by 10 min without CPAP. BP, cardiac output, stroke volume, heart rate, left ventricular ejection fraction, and LVOT gradient did not change during the study period in either group. CPAP at 10 cm H 2 O decreased right atrial size and right ventricular relaxation in all patients. It also decreased left atrial volume significantly and decreased right ventricular outflow acceleration time, suggesting an increase in pulmonary artery pressure in patients with obstructive HCM. The acute application of CPAP is apparently safe in patients with HCM, because CPAP does not lead to hemodynamic compromise. Long-term studies in patients with HCM and sleep apnea and nocturnal CPAP are warranted. ClinicalTrials.gov; No. NCT01631006; URL: www.clinicaltrials.gov. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Pulmonary hypertension is associated with worse survival in hypertrophic cardiomyopathy.

PubMed

Ong, Kevin C; Geske, Jeffrey B; Hebl, Virginia B; Nishimura, Rick A; Schaff, Hartzell V; Ackerman, Michael J; Klarich, Kyle W; Siontis, Konstantinos C; Coutinho, Thais; Dearani, Joseph A; Ommen, Steve R; Gersh, Bernard J

2016-06-01

Pulmonary hypertension (PH) is associated with increased mortality in various forms of left-sided heart disease. However, the implications of PH in hypertrophic cardiomyopathy (HCM) have not been elucidated. The objective of this study was to determine the prevalence and prognostic implications of PH in HCM. The study cohort consisted of 1570 (54 ± 15 years; 53% male) adults with HCM followed for a median of 3.3 years. PH [pulmonary artery systolic pressure (PASP) >36 mmHg] was identified in 38% of patients who were older (57 ± 15 vs. 52 ± 15 years, P < 0.0001), more likely to be female (59 vs. 40%, P < 0.0001), and were characterized by a higher prevalence of New York Heart Association (NYHA) class 3 or 4 symptoms (61 vs. 45%, P < 0.0001) and atrial fibrillation (29 vs. 15%, P < 0.0001) vs. those without PH. Only 12% had moderate or severe PH (PASP >50 mmHg). In multivariate Cox regression analyses adjusted for age, sex, NYHA class 3 or 4 symptoms, and atrial fibrillation, PASP was an independent predictor of all-cause mortality in patients with non-obstructive HCM (HR 1.59 per 10 mmHg PASP increase, 95% CI 1.28-1.96, P < 0.0001) and in those with obstructive physiology who did not undergo septal reduction therapy (SRT) (HR 1.15 per 10 mmHg PASP, 95% CI 1.01-1.31, P = 0.035). However, PH was not predictive of outcomes in patients with obstructive HCM who underwent SRT. Over one-third of adults evaluated in our referral HCM clinic demonstrated concomitant PH, and this was associated with increased mortality except in those with obstructive HCM who underwent SRT. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

QT prolongation and sudden cardiac death risk in hypertrophic cardiomyopathy.

PubMed

Patel, Salma I; Ackerman, Michael J; Shamoun, Fadi E; Geske, Jeffrey B; Ommen, Steve R; Love, William T; Cha, Stephen S; Bos, Johan M; Lester, Steven J

2018-03-07

Risk assessment for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) remains complex. The goal of this study was to assess electrocardiogram (ECG)-derived risk factors on SCD in a large HCM population Methods: Retrospective review of adults with HCM evaluated at Mayo Clinic, Rochester, MN from 1 December 2002 to 31 December 2012 was performed. Data inclusive of ECG and 24-hour ambulatory Holter monitor were assessed. SCD events were documented by ventricular fibrillation (VF) noted on implantable cardioverter defibrillator (ICD), or appropriate VT or VF-terminating ICD shock. Overall, 1615 patients (mean age 53.7 ± 15.2 years; 943 males, 58.4%) were assessed, with mean follow-up 2.46 years and 110 SCD events. Via logistic regression (n = 820), the odds of SCD increased with increasing number of conventional risk factors. With one risk factor the OR was 4.88 (p < .0001; CI 2.22-10.74), two risk factors the OR was 6.922 (p < .0001; CI 2.94-16.28) and three or more risk factors, the OR was 13.997 (p < .0001; CI 5.649-34.68). Adding QTc > 450 to this logistic regression model had OR 1.722 (p = .04, CI 1.01-2.937) to predict SCD. QTc ≥ 450 was a significant predictor for death (HR 1.88, p = .021, CI 1.10-3.20). There was no correlation between sinus bradycardia, sinus tachycardia, first degree AV block, atrial fibrillation, left bundle branch block, right bundle branch block, premature atrial complexes, premature ventricular complexes, supraventricular tachycardia, PR interval, QRS interval and SCD. Prolonged QTc was a risk factor for SCD and death even when controlling for typical risk factors.

Decreased Exercise Capacity and Sleep-Disordered Breathing in Patients With Hypertrophic Cardiomyopathy

PubMed Central

Konecny, Tomas; Geske, Jeffrey B.; Ludka, Ondrej; Orban, Marek; Brady, Peter A.; Abudiab, Muaz M.; Albuquerque, Felipe N.; Placek, Alexander; Kara, Tomas; Sahakyan, Karine R.; Gersh, Bernard J.; Tajik, A. Jamil; Allison, Thomas G.; Ommen, Steve R.

2015-01-01

BACKGROUND: Mechanisms of decreased exercise capacity in patients with hypertrophic cardiomyopathy (HCM) are not well understood. Sleep-disordered breathing (SDB) is a highly prevalent but treatable disorder in patients with HCM. The role of comorbid SDB in the attenuated exercise capacity in HCM has not been studied previously. METHODS: Overnight oximetry, cardiopulmonary exercise testing, and echocardiographic studies were performed in consecutive patients with HCM seen at the Mayo Clinic. SDB was considered present if the oxygen desaturation index (number of ≥ 4% desaturations/h) was ≥ 10. Peak oxygen consumption (V.o2peak) (the most reproducible and prognostic measure of cardiovascular fitness) was then correlated with the presence and severity of SDB. RESULTS: A total of 198 patients with HCM were studied (age, 53 ± 16 years; 122 men), of whom 32% met the criteria for the SDB diagnosis. Patients with SDB had decreased V.o2peak compared with those without SDB (16 mL O2/kg/min vs 21 mL O2/kg/min, P < .001). SDB remained significantly associated with V.o2peak after accounting for confounding clinical variables (P < .001) including age, sex, BMI, atrial fibrillation, and coronary artery disease. CONCLUSIONS: In patients with HCM, the presence of SDB is associated with decreased V.o2peak. SDB may represent an important and potentially modifiable contributor to impaired exercise tolerance in this unique population. PMID:25633371

[Myocardial regional thickness in patients with and without cardiomyopathy assessed by cardiac magnetic resonance].

PubMed

de Zan, Macarena; Carrascosa, Patricia; Deviggiano, Alejandro; Capuñay, Carlos; Rodríguez-Granillo, Gastón A

To explore regional differences in myocardial wall thickness (WT) among the most prevalent cardiomyopathies and in individuals without structural heart disease using cardiac magnetic resonance. Patients older than 18 years referred to cardiac magnetic resonance during the period between January 2014 and September 2014, with a diagnosis of hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy, ischemic cardiomyopathy, and myocarditis were retrospectively selected from our database. One hundred twenty patients patients were included. The control group had an average WT of 5.9±1.1mm, with a WT index of 2.9±0.8. Significantly lower mean WT in the apical segments were identified in both the control group (basal 6.7±1.3 vs. mid 6.0±1.3 vs. apical 4.6±1.0mm, P<.0001) and in all evaluated cardiomyopathies (hypertrophic cardiomyopathy: basal 10.5±2.4 vs. mid 10.8±2.7 vs. apical 7.3±3.3mm, P<.0001; idiopathic dilated cardiomyopathy: basal 7.7±1.7 vs. mid 7.6±1.3 vs. apical 5.4±1.3mm, P<.0001; ischemic cardiomyopathy: basal 7.4±1.7 vs. mid 7.5±1.9 vs. apical 5.5±1.8mm, P<.0001; myocarditis: basal 7.1±1.5 vs. mid 6.4±1.1 vs. apical 5.1±0.8, P<.0001). Significant gender differences were also evident regarding the mean WT both in the control group (male 6.5±2.1 vs. female 5.2±1.7mm, P<.0001), as in hypertrophic cardiomyopathy (10.5±5.3 vs. 8.5±5.7mm, P<.0001) and myocarditis (6.6±2.0 vs. 5.2±1.6mm, P<.0001). We found a relatively high prevalence of segments commonly deemed thinned among patients without structural heart disease. We also observed a marked asymmetry and longitudinal gradient in wall thickness both in controls and in the various cardiomyopathies evaluated. Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

Contemporary Natural History and Management of Nonobstructive Hypertrophic Cardiomyopathy.

PubMed

Maron, Martin S; Rowin, Ethan J; Olivotto, Iacopo; Casey, Susan A; Arretini, Anna; Tomberli, Benedetta; Garberich, Ross F; Link, Mark S; Chan, Raymond H M; Lesser, John R; Maron, Barry J

2016-03-29

Left ventricular outflow tract gradients are absent in an important proportion of patients with hypertrophic cardiomyopathy (HCM). However, the natural course of this important patient subgroup remains largely unresolved. The authors systematically employed exercise (stress) echocardiography to define those patients without obstruction to left ventricular outflow at rest and/or under physiological exercise and to examine their natural history and clinical course to create a more robust understanding of this complex disease. We prospectively studied 573 consecutive HCM patients in 3 centers (44 ± 17 years; 66% male) with New York Heart Association functional class I/II symptoms at study entry, including 249 in whom left ventricular outflow tract obstruction was absent both at rest and following physiological exercise (<30 mm Hg; nonobstructive HCM) and retrospectively assembled clinical follow-up data. Over a median follow-up of 6.5 years, 225 of 249 nonobstructive patients (90%) remained in classes I/II, whereas 24 (10%) developed progressive heart failure to New York Heart Association functional classes III/IV. Nonobstructive HCM patients were less likely to experience advanced limiting class III/IV symptoms than the 324 patients with outflow obstruction (1.6%/year vs. 7.4%/year rest obstruction vs. 3.2%/year provocable obstruction; p < 0.001). However, 7 nonobstructive patients (2.8%) did require heart transplantation for progression to end stage versus none of the obstructive patients. HCM-related mortality among nonobstructive patients was low (n = 8; 0.5%/year), with 5- and 10-year survival rates of 99% and 97%, respectively, which is not different from expected all-cause mortality in an age- and sex-matched U.S. population (p = 0.15). HCM patients with nonobstructive disease appear to experience a relatively benign clinical course, associated with a low risk for advanced heart failure symptoms, other disease complications, and HCM-related mortality, and

Right ventricular mechanics in hypertrophic cardiomyopathy using feature tracking

PubMed Central

Badran, Hala Mahfouz; Soliman, Mahmood; Hassan, Hesham; Abdelfatah, Raed; Saadan, Haythem; Yacoub, Magdi

2013-01-01

Objectives: Right ventricular (RV) mechanics in hypertrophic cardiomyopathy (HCM) are poorly understood. We investigate global and regional deformation of the RV in HCM and its relationship to LV phenotype, using 2D strain vector velocity imaging (VVI). Methods: 100 HCM patients (42% females, 41 ± 19 years) and 30 control patients were studied using VVI. Longitudinal peak systolic strain (ϵsys), strain rate (SR), time to peak (ϵ) (TTP), displacement of RV free wall (RVFW) and septal wall were analyzed. Similar parameters were quantified in LV septal, lateral, anterior and inferior segments. Intra-V-delay was defined as SD of TTP. Inter-V-delay was estimated from TTP difference between the most delayed LV segment & RVFW. Results: ϵsys and SR of both RV & LV, showed loss of base to apex gradient and significant decline in HCM (p < 0.001). Deformation variables estimated from RVFW were strongly correlated with each other (r = 0.93, p < 0.0001). Both were directly related to LV ϵsys, SRsys, SRe, ejection fraction (EF)%, RVFW displacement (P < 0.001) and inversely related to age, positive family history (p < 0.004, 0.005), RV wall thickness, maximum wall thickness (MWT), intra-V-delay, LA volume (P < 0.0001), LVOT gradient (p < 0.02, 0.005) respectively. ROC curves were constructed to explore the cut-off point that discriminates RV dysfunction. Global and RVFW ϵsys: − 19.5% shows 77, 70% sensitivity & 97% specificity, SRsys: − 1.3s− 1 shows 82, 70% sensitivity & 30% specificity. Multivariate analyses revealed that RVFW displacement (β = − 0.9, p < 0.0001) and global LV SRsys (β = 5.9, p < 0.0001) are independent predictors of global RV deformation. Conclusions: Impairment of RV deformation is evident in HCM using feature tracking. It is independently influenced by LV mechanics and correlated to the severity of LV phenotype. RVFW deformation analysis and global RV assessment are comparable. PMID:24689019

The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Xiaochuan; Suphamungmee, Worawit; Janco, Miro

2012-08-03

Highlights: Black-Right-Pointing-Pointer Well-known tropomyosin mutants, D175N and E180G are linked to cardiomyopathies. Black-Right-Pointing-Pointer The structural mechanics of D175N and E180G tropomyosins have been investigated. Black-Right-Pointing-Pointer D175N and E180G mutations increase both local and global tropomyosin flexibility. Black-Right-Pointing-Pointer In muscle, this increased flexibility will enhance myosin interactions on actin. Black-Right-Pointing-Pointer Extra myosin interaction can alter cardiac Ca{sup 2+}-switching, leading to dysfunction. -- Abstract: Point mutations targeting muscle thin filament proteins are the cause of a number of cardiomyopathies. In many cases, biological effects of the mutations are well-documented, whereas their structural and mechanical impact on filament assembly and regulatory function ismore » lacking. In order to elucidate molecular defects leading to cardiac dysfunction, we have examined the structural mechanics of two tropomyosin mutants, E180G and D175N, which are associated with hypertrophic cardiomyopathy (HCM). Tropomyosin is an {alpha}-helical coiled-coil dimer which polymerizes end-to-end to create an elongated superhelix that wraps around F-actin filaments of muscle and non-muscle cells, thus modulating the binding of other actin-binding proteins. Here, we study how flexibility changes in the E180G and D175N mutants might affect tropomyosin binding and regulatory motion on F-actin. Electron microscopy and Molecular Dynamics simulations show that E180G and D175N mutations cause an increase in bending flexibility of tropomyosin both locally and globally. This excess flexibility is likely to increase accessibility of the myosin-binding sites on F-actin, thus destabilizing the low-Ca{sup 2+} relaxed-state of cardiac muscle. The resulting imbalance in the on-off switching mechanism of the mutants will shift the regulatory equilibrium towards Ca{sup 2+}-activation of cardiac muscle, as is observed in

Regional difference of microcirculation in patients with asymmetric hypertrophic cardiomyopathy: transthoracic Doppler coronary flow velocity reserve analysis.

PubMed

Tesic, Milorad; Djordjevic-Dikic, Ana; Beleslin, Branko; Trifunovic, Danijela; Giga, Vojislav; Marinkovic, Jelena; Petrovic, Olga; Petrovic, Milan; Stepanovic, Jelena; Dobric, Milan; Vukcevic, Vladan; Stankovic, Goran; Seferovic, Petar; Ostojic, Miodrag; Vujisic-Tesic, Bosiljka

2013-07-01

To evaluate, by noninvasive coronary flow velocity reserve (CFVR), whether patients with asymmetric hypertrophic cardiomyopathy (HC), with or without left ventricular outflow tract obstruction, demonstrate significant regional differences of CFVR. We evaluated 61 patients with HC (27 men; mean age 49 ± 16 years), including 20 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 41 patients without obstruction (HCM). The control group included 20 age- and sex-matched subjects. Transthoracic Doppler echocardiography CFVR of the left anterior descending coronary artery (LAD) and the posterior descending coronary artery (PD) were performed, including calculation of relative CFVR as the ratio between CFVR LAD and CFVR PD. Compared with the controls, all the patients with HC had lower CFVR LAD (2.12 ± 0.53 vs 3.34 ± 0.67; P < .001) and CFVR PD (2.29 ± 0.49 vs 3.21 ± 0.65; P < .001). CFVR LAD in HOCM group in comparison with the HCM group was significantly lower (1.93 ± 0.42 vs 2.22 ± 0.55; P = .047), due to higher basal diastolic coronary flow velocities (0.40 ± 0.09 vs 0.33 ± 0.07 m/sec; P = .002), with similar hyperemic diastolic flow velocities (0.71 ± 0.16 vs 0.76 ± 0.19 m/sec; P = .330), respectively. There was no significant difference in CFVR PD between patients with HOCM and those with HCM (2.33 ± 0.46 vs 2.27 ± 0.50; P = .636), respectively. Relative CFVR was lower in the HOCM group compared with the HCM group (0.84 ± 0.16 vs 0.98 ± 0.14; P = .001). By multivariable regression analysis, left ventricular outflow tract gradient was the independent predictor of CFVR LAD (B = -0.24; P = .008) and relative CFVR (B = -0.34; P = .016). CFVR LAD and relative CFVR were significantly lower in patients with HOCM compared with patients with HCM. Regional differences of CFVR are present only in patients with significant left ventricular outflow tract obstruction, which suggests that obstruction per se, by increasing wall stress in basal conditions

Domain-specific c-Myc ubiquitylation controls c-Myc transcriptional and apoptotic activity

PubMed Central

Zhang, Qin; Spears, Erick; Boone, David N.; Li, Zhaoliang; Gregory, Mark A.; Hann, Stephen R.

2013-01-01

The oncogenic transcription factor c-Myc causes transformation and tumorigenesis, but it can also induce apoptotic cell death. Although tumor suppressors are necessary for c-Myc to induce apoptosis, the pathways and mechanisms are unclear. To further understand how c-Myc switches from an oncogenic protein to an apoptotic protein, we examined the mechanism of p53-independent c-Myc–induced apoptosis. We show that the tumor suppressor protein ARF mediates this switch by inhibiting ubiquitylation of the c-Myc transcriptional domain (TD). Whereas TD ubiquitylation is critical for c-Myc canonical transcriptional activity and transformation, inhibition of ubiquitylation leads to the induction of the noncanonical c-Myc target gene, Egr1, which is essential for efficient c-Myc–induced p53-independent apoptosis. ARF inhibits the interaction of c-Myc with the E3 ubiquitin ligase Skp2. Overexpression of Skp2, which occurs in many human tumors, inhibits the recruitment of ARF to the Egr1 promoter, leading to inhibition of c-Myc–induced apoptosis. Therapeutic strategies could be developed to activate this intrinsic apoptotic activity of c-Myc to inhibit tumorigenesis. PMID:23277542

Clinical and Mechanistic Insights into the Genetics of Cardiomyopathy

PubMed Central

Burke, Michael A.; Cook, Stuart A.; Seidman, Jonathan G.; Seidman, Christine E.

2018-01-01

Over the last quarter-century, there has been tremendous progress in genetics research that has defined molecular causes for cardiomyopathies. More than a thousand mutations have been identified in many genes with varying ontologies, therein indicating the diverse molecules and pathways that cause hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathies. Translation of this research to the clinic via genetic testing can precisely group affected patients according to molecular etiology, and identify individuals without evidence of disease who are at high risk for developing cardiomyopathy. These advances provide insights into the earliest manifestations of cardiomyopathy and help to define the molecular pathophysiological basis for cardiac remodeling. Although these efforts remain incomplete, new genomic technologies and analytic strategies provide unparalleled opportunities to fully explore the genetic architecture of cardiomyopathies. Such data hold the promise that mutation-specific pathophysiology will uncover novel therapeutic targets, and herald the beginning of precision therapy for cardiomyopathy patients. PMID:28007147

Physical activity and other health behaviors in adults with hypertrophic cardiomyopathy.

PubMed

Reineck, Elizabeth; Rolston, Brice; Bragg-Gresham, Jennifer L; Salberg, Lisa; Baty, Linda; Kumar, Suwen; Wheeler, Matthew T; Ashley, Euan; Saberi, Sara; Day, Sharlene M

2013-04-01

The clinical expression of hypertrophic cardiomyopathy (HC) is undoubtedly influenced by modifying genetic and environmental factors. Lifestyle practices such as tobacco and alcohol use, poor nutritional intake, and physical inactivity are strongly associated with adverse cardiovascular outcomes and increased mortality in the general population. Before addressing the direct effect of such modifiable factors on the natural history of HC, it is critical to define their prevalence in this population. A voluntary survey, drawing questions in part from the 2007 to 2008 National Health and Nutrition Examination Survey (NHANES), was posted on the HC Association website and administered to patients with HC at the University of Michigan. Propensity score matching to NHANES participants was used. Dichotomous and continuous health behaviors were analyzed using logistic and linear regression, respectively, and adjusted for body mass index and propensity score quintile. Compared to the matched NHANES participants, the patients with HC reported significantly less alcohol and tobacco use but also less time engaged in physical activity at work and for leisure. Time spent participating in vigorous or moderate activity was a strong predictor of self-reported exercise capacity. The body mass index was greater in the HC cohort than in the NHANES cohort. Exercise restrictions negatively affected emotional well-being in most surveyed subjects. In conclusion, patients with HC are less active than the general United States population. The well-established relation of inactivity, obesity, and cardiovascular mortality might be exaggerated in patients with HC. More data are needed on exercise in those with HC to strike a balance between acute risks and the long-term health benefits of exercise. Copyright © 2013 Elsevier Inc. All rights reserved.

Factors Influencing the Phenotypic Expression of Hypertrophic Cardiomyopathy in Genetic Carriers.

PubMed

Pérez-Sánchez, Inmaculada; Romero-Puche, Antonio José; García-Molina Sáez, Esperanza; Sabater-Molina, María; López-Ayala, José María; Muñoz-Esparza, Carmen; López-Cuenca, David; de la Morena, Gonzalo; Castro-García, Francisco José; Gimeno-Blanes, Juan Ramón

2018-03-01

Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM. We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied. The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables. Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif.

PubMed

Thomas, L R; Foshage, A M; Weissmiller, A M; Popay, T M; Grieb, B C; Qualls, S J; Ng, V; Carboneau, B; Lorey, S; Eischen, C M; Tansey, W P

2016-07-07

The MYC family of oncogenes encodes a set of three related transcription factors that are overexpressed in many human tumors and contribute to the cancer-related deaths of more than 70,000 Americans every year. MYC proteins drive tumorigenesis by interacting with co-factors that enable them to regulate the expression of thousands of genes linked to cell growth, proliferation, metabolism and genome stability. One effective way to identify critical co-factors required for MYC function has been to focus on sequence motifs within MYC that are conserved throughout evolution, on the assumption that their conservation is driven by protein-protein interactions that are vital for MYC activity. In addition to their DNA-binding domains, MYC proteins carry five regions of high sequence conservation known as Myc boxes (Mb). To date, four of the Mb motifs (MbI, MbII, MbIIIa and MbIIIb) have had a molecular function assigned to them, but the precise role of the remaining Mb, MbIV, and the reason for its preservation in vertebrate Myc proteins, is unknown. Here, we show that MbIV is required for the association of MYC with the abundant transcriptional coregulator host cell factor-1 (HCF-1). We show that the invariant core of MbIV resembles the tetrapeptide HCF-binding motif (HBM) found in many HCF-interaction partners, and demonstrate that MYC interacts with HCF-1 in a manner indistinguishable from the prototypical HBM-containing protein VP16. Finally, we show that rationalized point mutations in MYC that disrupt interaction with HCF-1 attenuate the ability of MYC to drive tumorigenesis in mice. Together, these data expose a molecular function for MbIV and indicate that HCF-1 is an important co-factor for MYC.

Results of surgical septal myectomy for obstructive hypertrophic cardiomyopathy: the Tufts experience

PubMed Central

Boll, Griffin; Rowin, Ethan J.; Dolan, Noreen; Carroll, Catherine; Udelson, James E.; Wang, Wendy; Carpino, Philip; Maron, Barry J.; Maron, Martin S.; Chen, Frederick Y.

2017-01-01

Background For over 50 years, surgical septal myectomy has been the preferred treatment for drug-refractory heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM). Over this time in the United States, the majority of myectomy operations have been performed in a small number of select referral centers. Methods We have taken the opportunity to report results from the relatively new Tufts HCM Center and surgical program, incorporated 13 years ago, during which 507 myectomies (52±14 years of age; 56% male) were performed by one cardiothoracic surgeon, Dr. Hassan Rastegar. Results Resting left ventricular (LV) outflow gradients were reduced from 56±42 mmHg preoperatively to 1.2±6.8 mmHg on most recent echocardiogram 2.0±2.5 years after surgery, and 94% of patients showed clinical improvement to NYHA functional class I or II. The first 200 myectomies were performed without mortality or major complications. Among all patients, 30-day mortality rate was 0.8%. Over follow-up of 3.2±2.8 years, 11 patients died (four due to HCM causes) with long-term survival after myectomy of 94% at 5 years (95% CI: 89–96%) and 91% at 10 years (95% CI: 84–95%), which did not differ from the age- and gender-matched general U.S. population (log-rank P=0.9). Conclusions This experience demonstrates that, with the appropriate support, new HCM surgical programs can provide patients successful relief of outflow obstruction, extended longevity and restored of quality of life. PMID:28944176

Single-Coil Defibrillator Leads Yield Satisfactory Defibrillation Safety Margin in Hypertrophic Cardiomyopathy.

PubMed

Okamura, Hideo; Friedman, Paul A; Inoue, Yuko; Noda, Takashi; Aiba, Takeshi; Yasuda, Satoshi; Ogawa, Hisao; Kamakura, Shiro; Kusano, Kengo; Espinosa, Raul E

2016-09-23

Single-coil defibrillator leads have gained favor because of their potential ease of extraction. However, a high defibrillation threshold remains a concern in patients with hypertrophic cardiomyopathy (HCM), and in many cases, dual-coil leads have been used for this patient group. There is little data on using single-coil leads for HCM patients. We evaluated 20 patients with HCM who received an implantable cardioverter-defibrillator (ICD) on the left side in combination with a dual-coil lead. Two sets of defibrillation tests were performed in each patient, one with the superior vena cava (SVC) coil "on" and one with the SVC coil "off". ICDs were programmed to deliver 25 joules (J) for the first attempt followed by maximum energy (35 J or 40 J). Shock impedance and shock pulse width at 25 J in each setting as well as the results of the shock were analyzed. All 25-J shocks in both settings successfully terminated ventricular fibrillation. However, shock impedance and pulse width increased substantially with the SVC coil programmed "off" compared with "on" (66.4±6.1 ohm and 14.0±1.3 ms "off" vs. 41.9±5.0 ohm and 9.3±0.8 ms "on", P<0.0001 respectively). Biphasic 25-J shocks with the SVC coil 'off' successfully terminated ventricular fibrillation in HCM patients, indicating a satisfactory safety margin for 35-J devices. Single-coil leads appear appropriate for left-sided implantation in this patient group. (Circ J 2016; 80: 2199-2203).

Loss of MYC and E-box3 binding contributes to defective MYC-mediated transcriptional suppression of human MC-let-7a-1~let-7d in glioblastoma

PubMed Central

Wang, Zifeng; Lin, Sheng; Zhang, Ji; Xu, Zhenhua; Xiang, Yu; Yao, Hong; Ge, Lei; Xie, Dan; Kung, Hsiang-fu; Lu, Gang; Poon, Wai Sang; Liu, Quentin; Lin, Marie Chia-mi

2016-01-01

Previously, we reported that MYC oncoprotein down-regulates the transcription of human MC-let-7a-1~let-7d microRNA cluster in hepatocarcinoma (HCC). Surprisingly, in silico analysis indicated that let-7 miRNA expression levels are not reduced in glioblastoma (GBM). Here we investigated the molecular basis of this differential expression. Using human GBM U87 and U251 cells, we first demonstrated that forced over-expression of MYC indeed could not down-regulate the expression of human MC-let-7a-1~let-7d microRNA cluster in GBM. Furthermore, analysis of MC-let-7a-1~let-7d promoter in GBM indicated that MYC failed to inhibit the promoter activity. Pearson's correlation and Linear Regression analysis using the expression data from GSE55092 (HCC) and GSE4290 (GBM) demonstrated a converse relationship of MC-let-7a-1~let-7d and MYC only in HCC but not in GBM. To understand the underlying mechanisms, we examined whether MYC could bind to the non-canonical E-box 3 located in the promoter of MC-let-7a-1~let-7d. Results from both chromatin immune-precipitation (ChIP) and super-shift assays clearly demonstrated the loss of MYC and E-box 3 binding in GBM, suggesting for the first time that a defective MYC and E-box3 binding in GBM is responsible for the differential MYC mediated transcriptional inhibition of MC-let-7a-1~let-7d and potentially other tumor suppressors. MYC and let-7 are key oncoprotein and tumor suppressor, respectively. Understanding the molecular mechanisms of their regulations will provide new insight and have important implications in the therapeutics of GBM as well as other cancers. PMID:27409345

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

DOE PAGES

Yuan, Chen-Ching; Muthu, Priya; Kazmierczak, Katarzyna; ...

2015-06-29

Myosin light chain kinase (MLCK)-dependent phosphorylation of the regulatory light chain (RLC) of cardiac myosin is known to play a beneficial role in heart disease, but the idea of a phosphorylation-mediated reversal of a hypertrophic cardiomyopathy (HCM) phenotype is novel. Our previous studies on transgenic (Tg) HCM-RLC mice revealed that the D166V (Aspartate166 →Valine) mutation-induced changes in heart morphology and function coincided with largely reduced RLC phosphorylation in situ. In this paper, we hypothesized that the introduction of a constitutively phosphorylated Serine15 (S15D) into the hearts of D166V mice would prevent the development of a deleterious HCM phenotype. In supportmore » of this notion, MLCK-induced phosphorylation of D166V-mutated hearts was found to rescue some of their abnormal contractile properties. Tg-S15D-D166V mice were generated with the human cardiac RLC-S15D-D166V construct substituted for mouse cardiac RLC and were subjected to functional, structural, and morphological assessments. The results were compared with Tg-WT and Tg-D166V mice expressing the human ventricular RLC-WT or its D166V mutant, respectively. Echocardiography and invasive hemodynamic studies demonstrated significant improvements of intact heart function in S15D-D166V mice compared with D166V, with the systolic and diastolic indices reaching those monitored in WT mice. A largely reduced maximal tension and abnormally high myofilament Ca 2+ sensitivity observed in D166V-mutated hearts were reversed in S15D-D166V mice. Low-angle X-ray diffraction study revealed that altered myofilament structures present in HCM-D166V mice were mitigated in S15D-D166V rescue mice. Finally, our collective results suggest that expression of pseudophosphorylated RLC in the hearts of HCM mice is sufficient to prevent the development of the pathological HCM phenotype.« less

Clinical, Radiographic, and Microbiologic Features of Infective Endocarditis in Patients With Hypertrophic Cardiomyopathy.

PubMed

Sims, Jason R; Anavekar, Nandan S; Bhatia, Subir; O'Horo, John C; Geske, Jeffrey B; Chandrasekaran, Krishnaswamy; Wilson, Walter R; Baddour, Larry M; Gersh, Bernard J; DeSimone, Daniel C

2018-02-15

Infective endocarditis (IE) is an infection of the inner lining of the heart with high morbidity and mortality despite medical and surgical advancements in recent decades. Hypertrophic cardiomyopathy (HC) is one of several medical conditions that have been linked to an increased risk of IE, but there is a paucity of data on this association. We therefore sought to define the clinical phenotype of IE in patients with HC at a single tertiary care center. A retrospective cohort of 30 adult patients with HC diagnosed with IE between January 1, 2006 and December 31, 2016 at Mayo Clinic Rochester were identified. Similar rates of aortic (n = 14) and mitral (n = 16) valve involvement by IE were noted (47% vs 53%). This finding persisted even in patients with left-ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. Symptomatic embolic complications occurred in 10 cases (33%). Surgical intervention was performed in 11 cases (37%). One-year mortality was remarkably low at 7%. In conclusion, in the largest single-center cohort of IE complicating HC, there were similar rates of both mitral and aortic valve involvement regardless of the presence of left ventricular outflow tract obstruction, which is contrary to a long-standing tenet regarding the association of HC and IE. Moreover, no "high risk" IE subset was identified based on HC-related parameters. Copyright © 2017 Elsevier Inc. All rights reserved.

Speckle tracking echocardiography to assess regional ventricular function in patients with apical hypertrophic cardiomyopathy.

PubMed

Saccheri, María Cristina; Cianciulli, Tomás Francisco; Morita, Luis Alberto; Méndez, Ricardo José; Beck, Martín Alejandro; Guerra, Juan Enrique; Cozzarin, Alberto; Puente, Luciana Jimena; Balletti, Lorena Romina; Lax, Jorge Alberto

2017-04-26

To explore regional systolic strain of midwall and endocardial segments using speckle tracking echocardiography in patients with apical hypertrophic cardiomyopathy (HCM). We prospectively assessed 20 patients (mean age 53 ± 16 years, range: 18-81 years, 10 were male), with apical HCM. We measured global longitudinal peak systolic strain (GLPSS) in the midwall and endocardium of the left ventricle. The diastolic thickness of the 4 apical segments was 16.25 ± 2.75 mm. All patients had a normal global systolic function with a fractional shortening of 50% ± 8%. In spite of supernormal left ventricular (LV) systolic function, midwall GLPSS was decreased in all patients, more in the apical (-7.3% ± -8.8%) than in basal segments (-15.5% ± -6.93%), while endocardial GLPPS was significantly greater and reached normal values (apical: -22.8% ± -7.8%, basal: -17.9% ± -7.5%). This study shows that two-dimensional strain was decreased mainly confined to the mesocardium, while endocardium myocardial deformation was preserved in HCM and allowed to identify subclinical LV dysfunction. This transmural heterogeneity in systolic strain had not been previously described in HCM and could be explained by the distribution of myofibrillar disarray in deep myocardial areas. The clinical application of this novel finding may help further understanding of the pathophysiology of HCM.

Hypertrophic Cardiomyopathy in Youth Athletes: Successful Screening With Point-of-Care Ultrasound by Medical Students.

PubMed

Fox, J Christian; Lahham, Shadi; Maldonado, Graciela; Klaus, Suzi; Aish, Bassil; Sylwanowicz, Lauren V; Yanuck, Justin; Wilson, Sean P; Shieh, Mason; Anderson, Craig L; English, Carter; Mayer, Ryan; Mohan, Uthara R

2017-06-01

Hypertrophic cardiomyopathy (HCM) is a life-threatening genetic cardiovascular disease that often goes undetected in young athletes. Neither history nor physical examination are reliable to identify those at risk. The objective of this study is to determine whether minimally trained medical student volunteers can use ultrasound to screen for HCM. This was a prospective enrollment of young athletes performed at 12 area high schools and three area colleges, between May 2012 and August 2013. All participants underwent point-of-care ultrasound performed screening for HCM by trained medical students and reviewed by a pediatric cardiologist. An interventricular septum to left ventricular posterior wall ratio greater than 1.25 was considered to be abnormal (positive screen). A total of 2332 participants were enrolled. There were 137 (5.8%) with a positive screening for HCM, of which 7 (5.1%) were confirmed to have HCM by a pediatric cardiologist. In a small cohort with positive screen for HCM, there was a 100% sensitivity (95% confidence interval, 59.04 to 100%) and 4.86% (95% confidence interval, 1.98 to 9.76%) positive predictive value of for having HCM. Volunteer medical students, using point-of-care ultrasound, were able to effectively screen for HCM in young athletes. © 2017 by the American Institute of Ultrasound in Medicine.

Prevalence and Impact of Coexistent Bicuspid Aortic Valve in Hypertrophic Cardiomyopathy.

PubMed

Padang, Ratnasari; Gersh, Bernard J; Ommen, Steve R; Geske, Jeffrey B

2018-01-01

The association between bicuspid aortic valve (BAV) and hypertrophic cardiomyopathy (HCM) has been reported but its true prevalence is unknown. This study investigated the prevalence and clinical impact of coexistent BAV in a large referral HCM population. Retrospective analysis of 3765 echocardiograms between 2004 and 2014 in 2640 consecutive patients with HCM was performed to assess for BAV. Patients with coexistent conditions were studied. Twenty-three patients (0.9%) were identified with coexisting BAV and HCM. Mean age was 52±16years, 18 males (78%), 16 with NYHA functional class I/II at initial evaluation (70%). A family history of HCM was present in five patients (22%); none had a family history of BAV or aortopathy. Maximal left ventricular wall thickness was 24±6mm; the majority had either reverse curve or sigmoid septal morphology. Moderate or greater aortic valve dysfunction was present in seven patients (30%), BAV-related aortopathy in 18 patients (78%) and dynamic left ventricular outflow tract (LVOT) obstruction in nine patients (39%). Three patients had combined LVOT obstruction and aortic stenosis. Median time from diagnosis of BAV or HCM to last follow-up was 11±12.5years. At last follow-up, 22% had undergone BAV-related surgeries, 30% had septal reduction therapy (SRT), and 17% had combined SRT and BAV-related surgeries. Overall survival was 95% at 10 years. This study reported a 0.9% prevalence of BAV among HCM population, similar to the general population. Aortopathy and LVOT obstruction were common, necessitating cardiac interventions in over one-third of cases. Long-term survival appeared favourable. Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Physical activity in hypertrophic cardiomyopathy: prevalence of inactivity and perceived barriers

PubMed Central

Sweeting, Joanna; Ingles, Jodie; Timperio, Anna; Patterson, Jillian; Ball, Kylie; Semsarian, Christopher

2016-01-01

Objectives This study aimed to determine the prevalence of physical inactivity and perceived barriers to physical activity among individuals with hypertrophic cardiomyopathy (HCM), and to determine potential demographic, clinical and health-related factors influencing likelihood of meeting physical activity guidelines. Methods This was a cross-sectional study of consecutive patients (n=198) with HCM attending a specialist HCM centre from July 2014 to November 2015. The primary outcome measure was physical activity (minutes per day), as measured by self-report (International Physical Activity Questionnaire (IPAQ)) and objective means (ActiGraph accelerometer). For both, participants were classified as meeting guidelines if they did at least 150 min per week of physical activity. Quality of life (Short Form-36 V.2, SF-36v2), barriers to exercise and clinical–demographic data were also collected. Results In total, 54.8% of participants did not meet physical activity recommendations based on IPAQ, and 12.7% did not meet guidelines based on accelerometer data. The most commonly identified barriers to exercise were ‘pain interferes with my exercise’ (33%) and ‘I have an injury/disability that stops me’ (29%). Independent factors associated with meeting guidelines included older age (OR 0.66, 95% CI 0.51 to 0.85, p=0.002), higher education level (OR 2.31, 95% CI 1.08 to 4.93, p=0.03), better physical quality of life (OR 1.05, 95% CI 1.0 to 1.09, p=0.05) and more reported barriers (OR 0.71, 95% CI 0.56 to 0.91, p=0.01). Conclusions More than half of the patients with HCM did not meet minimum physical activity recommendations. Several barriers to exercise among individuals with HCM exist, and provide the basis for targeted interventions to promote physical activity and improve overall health in patients with HCM. PMID:27547438

MYC Mediates mRNA Cap Methylation of Canonical Wnt/β-catenin Signaling Transcripts by Recruiting CDK7 and RNA Methyltransferase

PubMed Central

Posternak, Valeriya; Ung, Matthew H.; Cheng, Chao; Cole, Michael D.

2016-01-01

MYC is a pleiotropic transcription factor that activates and represses a wide range of target genes and is frequently deregulated in human tumors. While much is known about the role of MYC in transcriptional activation and repression, MYC can also regulate mRNA cap methylation through a mechanism that has remained poorly understood. Here it is reported that MYC enhances mRNA cap methylation of transcripts globally, specifically increasing mRNA cap methylation of genes involved in Wnt/β-catenin signaling. Elevated mRNA cap methylation of Wnt signaling transcripts in response to MYC leads to augmented translational capacity, elevated protein levels, and enhanced Wnt signaling activity. Mechanistic evidence indicates that MYC promotes recruitment of RNA methyltransferase (RNMT) to Wnt signaling gene promoters by enhancing phosphorylation of serine 5 on the RNA Polymerase II Carboxy-Terminal Domain, mediated in part through an interaction between the TIP60 acetyltransferase complex and TFIIH. Implications MYC enhances mRNA cap methylation above and beyond transcriptional induction. PMID:27899423

Intraoperative Diagnosis of Anderson-Fabry Disease in Patients With Obstructive Hypertrophic Cardiomyopathy Undergoing Surgical Myectomy.

PubMed

Cecchi, Franco; Iascone, Maria; Maurizi, Niccolò; Pezzoli, Laura; Binaco, Irene; Biagini, Elena; Fibbi, Maria Laura; Olivotto, Iacopo; Pieruzzi, Federico; Fruntelata, Ana; Dorobantu, Lucian; Rapezzi, Claudio; Ferrazzi, Paolo

2017-10-01

Diagnostic screening for Anderson-Fabry cardiomyopathy (AFC) is performed in the presence of specific clinical red flags in patients with hypertrophic cardiomyopathy (HCM) older than 25 years. However, left ventricular outflow tract obstruction (LVOTO) has been traditionally considered an exclusion criteria for AFC. To examine a series of patients diagnosed with HCM and severe basal LVOTO undergoing myectomy in whom the diagnosis of AFC was suspected by the cardiac surgeon intraoperatively and confirmed by histological and genetic examinations. This retrospective analysis of patients undergoing surgical septal reduction strategies was conducted in 3 European tertiary referral centers for HCM from July 2013 to December 2016. Patients with a clinical diagnosis of obstructive HCM referred for surgical management of LVOTO were observed for at least 18 months after the procedure (mean [SD] follow-up, 33 [14] months). Etiology of patients with HCM who underwent surgical myectomy. From 2013, 235 consecutive patients with a clinical diagnosis of HCM underwent septal myectomy. The cardiac surgeon suspected a storage disease in 3 patients (1.3%) while inspecting their heart samples extracted from myectomy. The mean (SD) age at diagnosis for these 3 patients was 42 (4) years; all were male. None of the 3 patients presented with extracardiac features suggestive of AFC. All patients showed asymmetrical left ventricular hypertrophy, with maximal left ventricular thickness in the basal septum (19-31 mm), severe basal LVOTO (70-120 mm Hg), and left atrial dilatation (44-57 mm). Only 1 patient presented with late gadolinium enhancement on cardiovascular magnetic resonance at the right ventricle insertion site. The mean (SD) age at surgical procedure was 63 (5) years. On tactile sensation, the surgeon felt a spongy consistency of the surgical samples, different from the usual stony-elastic consistency typical of classic HCM, and this prompted histological examinations. Histology

SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

PubMed Central

Zhou, Xiaorong; Comerford, Sarah A.; York, Brian; O’Donnell, Kathryn A.

2017-01-01

Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver. PMID:28273073

Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene.

PubMed

Ripoll-Vera, Tomás; Gámez, José María; Govea, Nancy; Gómez, Yolanda; Núñez, Juana; Socías, Lorenzo; Escandell, Ángela; Rosell, Jorge

2016-02-01

Mutations in the troponin T gene (TTNT2) have been associated in small studies with the development of hypertrophic cardiomyopathy characterized by a high risk of sudden death and mild hypertrophy. We describe the clinical course of patients carrying mutations in this gene. We analyzed the clinical characteristics and prognosis of patients with mutations in the TNNT2 gene who were seen in an inherited cardiac disease unit. Of 180 families with genetically studied cardiomyopathies, 21 families (11.7%) were identified as having mutations in TNNT2: 10 families had Arg92Gln, 5 had Arg286His, 3 had Arg278Cys, 1 had Arg92Trp, 1 had Arg94His, and 1 had Ile221Thr. Thirty-three additional genetic carriers were identified through family assessment. The study included 54 genetic carriers: 56% were male, and the mean average age was 41 ± 17 years. There were 33 cases of hypertrophic cardiomyopathy, 9 of dilated cardiomyopathy, and 1 of noncompaction cardiomyopathy, and maximal myocardial thickness was 18.5 ± 6mm. Ventricular dysfunction was present in 30% of individuals and a history of sudden death in 62%. During follow-up, 4 patients died and 14 (33%) received a defibrillator (8 probands, 6 relatives). Mean survival was 54 years. Carriers of Arg92Gln had early disease development, high penetrance, a high risk of sudden death, a high rate of defibrillator implantation, and a high frequency of mixed phenotype. Mutations in the TNNT2 gene were more common in this series than in previous studies. The clinical and prognostic profiles depended on the mutation present. Carriers of the Arg92Gln mutation developed hypertrophic or dilated cardiomyopathy and had a significantly worse prognosis than those with other mutations in TNNT2 or other sarcomeric genes. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Atrial Fibrillation in Hypertrophic Cardiomyopathy: Is the Extent of Septal Hypertrophy Important?

PubMed

Park, Kyoung-Min; Im, Sung Il; Kim, Eun Kyoung; Lee, Sang-Chol; Park, Seung-Jung; Kim, June Soo; On, Young Keun

2016-01-01

Hypertrophic cardiomyopathy (HCM) is a cardiac disease associated with a high incidence of atrial fibrillation (AF). Recent studies have suggested that interventricular septum thickness may influence the risk stratification of patients with AF. We evaluated the effects of septal hypertrophy on morbidity and mortality in patients with HCM. Patients were followed for a median of 6.1 years and were divided into two groups according to the extent of septal hypertrophy. A total of 1,360 HCM patients were enrolled: 482 (33%) apical or apicoseptal, 415 (28%) asymmetric septal, 388 (27%) basal septal, 38 (2.6%) concentric, and 37 (2.5%) diffuse and mixed type. Ninety-two all-cause deaths and 21 cardiac deaths occurred. The total event rates were significantly higher for patients with HCM with more extensive septal hypertrophy (group A) compared to those with HCM ± focal septal hypertrophy (group B), regardless of type (p<0.001). Arrhythmias occurred in 502 patients, with a significantly higher incidence in group A than in group B (p<0.001). Among patients with arrhythmias, the incidence of AF was significantly higher in group A than group B (p<0.001). In univariate Cox analysis, a greater extent of septal hypertrophy (p<0.001), E/E´ ratio (p = 0.011), and mitral regurgitation grade (p = 0.003) were significantly associated with developing AF. In multivariate Cox analyses, a greater extent of septal hypertrophy [odds ratio (OR) 5.44 (2.29-12.92), p<0.001] in patients with HCM was significantly associated with developing AF. In conclusion, a greater extent of septal hypertrophy is an independent predictor of progression to AF in patients with HCM.

[The Val606Met mutation of human beta myosin heavy chain in a Chinese familial hypertrophic cardiomyopathy family].

PubMed

Yuan, Jian-song; Qiao, Shu-bin; Wang, Shu-xia; Teng, Si-yong; You, Shi-jie; Yang, Wei-xian; Gao, Run-lin; Chen, Ji-lin; Yang, Yue-jin

2008-04-01

To explore the disease-causing gene mutation in Chinese families with hypertrophic cardiomyopathy (HCM) and to analyze the correlation between the genotype and phenotype. Samples of peripheral blood were collected from three Chinese families with HCM (at least two HCM patients existed/family). The exons in the functional regions of the beta myosin heavy chain gene (MYH7) were amplified with PCR and the products were sequenced. A Val606Met missen mutation was identified in the exon 16 of MYH7 gene in a Chinese family and this mutation was identified in all HCM patients (n = 4) and there was also a 15-years-old young mutation carrier who was not HCM patient now (penetrance of 80%). This mutation was not identified in other healthy family members in this family, in other 2 Chinese familiar HCM families and in 120 non-HCM control patients. The Val606Met missen mutation is closely associated with familiar HCM in a Chinese family which is associated with clinical phenotype with a penetrance of 80%.

Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice.

PubMed

Gedicke-Hornung, Christina; Behrens-Gawlik, Verena; Reischmann, Silke; Geertz, Birgit; Stimpel, Doreen; Weinberger, Florian; Schlossarek, Saskia; Précigout, Guillaume; Braren, Ingke; Eschenhagen, Thomas; Mearini, Giulia; Lorain, Stéphanie; Voit, Thomas; Dreyfus, Patrick A; Garcia, Luis; Carrier, Lucie

2013-07-01

Exon skipping mediated by antisense oligoribonucleotides (AON) is a promising therapeutic approach for genetic disorders, but has not yet been evaluated for cardiac diseases. We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM). KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs. We identified an alternative variant (Var-4) deleted of exons 5-6 in wild-type and KI mice. To enhance its expression and suppress aberrant mRNAs we designed AON-5 and AON-6 that mask splicing enhancer motifs in exons 5 and 6. AONs were inserted into modified U7 small nuclear RNA and packaged in adeno-associated virus (AAV-U7-AON-5+6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5+6 increased Var-4 mRNA/protein levels and reduced aberrant mRNAs. Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy. Although the therapeutic effect was transient and therefore requires optimization to be maintained over an extended period, this proof-of-concept study paves the way towards a causal therapy of HCM. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)

PubMed Central

Messer, Andrew E.; Chan, Jasmine; Daley, Alex; Copeland, O'Neal; Marston, Steven B.; Connolly, David J.

2017-01-01

Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model. PMID:28642712

A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas

PubMed Central

Lwin, Tint; Zhao, Xiaohong; Cheng, Fengdong; Zhang, Xinwei; Huang, Andy; Shah, Bijal; Zhang, Yizhuo; Moscinski, Lynn C.; Choi, Yong Sung; Kozikowski, Alan P.; Bradner, James E.; Dalton, William S.; Sotomayor, Eduardo; Tao, Jianguo

2013-01-01

A dynamic interaction occurs between the lymphoma cell and its microenvironment, with each profoundly influencing the behavior of the other. Here, using a clonogenic coculture growth system and a xenograft mouse model, we demonstrated that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymphoma stromal cells confers drug resistance, clonogenicity, and induction of histone deacetylase 6 (HDAC6). Furthermore, stroma triggered a c-Myc/miR-548m feed-forward loop, linking sustained c-Myc activation, miR-548m downregulation, and subsequent HDAC6 upregulation and stroma-mediated cell survival and lymphoma progression in lymphoma cell lines, primary MCL and other B cell lymphoma cell lines. Treatment with an HDAC6-selective inhibitor alone or in synergy with a c-Myc inhibitor enhanced cell death, abolished cell adhesion–mediated drug resistance, and suppressed clonogenicity and lymphoma growth ex vivo and in vivo. Together, these data suggest that the lymphoma-stroma interaction in the lymphoma microenvironment directly impacts the biology of lymphoma through genetic and epigenetic regulation, with HDAC6 and c-Myc as potential therapeutic targets. PMID:24216476

Effects of verapamil on left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy: pressure-volume analysis with a nonimaging scintillation probe.

PubMed

Bonow, R O; Ostrow, H G; Rosing, D R; Cannon, R O; Lipson, L C; Maron, B J; Kent, K M; Bacharach, S L; Green, M V

1983-11-01

To investigate the effects of verapamil on left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy, we studied 14 patients at catheterization with a nonimaging scintillation probe before and after serial intravenous infusions of low-, medium-, and high-dose verapamil (total dose 0.17 to 0.72 mg/kg). Percent change in radionuclide stroke counts after verapamil correlated well with percent change in thermodilution stroke volume (r = .87), and changes in diastolic and systolic counts were used to assess relative changes in left ventricular volumes after verapamil. Verapamil produced dose-related increases in end-diastolic counts (19 +/- 9% increase; p less than .001), end-systolic counts (91 +/- 54% increase; p less than .001), and stroke counts (7 +/- 10% increase; p less than .02). This was associated with a decrease in ejection fraction (83 +/- 8% control, 73 +/- 10% verapamil; p less than .001) and, in the 10 patients with left ventricular outflow tract gradients, a reduction in gradient (62 +/- 27 mm Hg control, 32 +/- 35 mm Hg verapamil; p less than .01). The end-systolic pressure-volume relation was shifted downward and rightward in all patients, suggesting a negative inotropic effect. In 10 patients, left ventricular pressure-volume loops were constructed with simultaneous micromanometer pressure recordings and the radionuclide time-activity curve. In five patients, verapamil shifted the diastolic pressure-volume curve downward and rightward, demonstrating improved pressure-volume relations despite the negative inotropic effect, and also increased the peak rate of rapid diastolic filling. In the other five patients, the diastolic pressure-volume relation was unaltered by verapamil, and increased end-diastolic volumes occurred at higher end-diastolic pressures; in these patients, the peak rate of left ventricular diastolic filling was not changed by verapamil. The negative inotropic effects of intravenous verapamil are

Plasma cardiac troponin I concentration and cardiac death in cats with hypertrophic cardiomyopathy.

PubMed

Borgeat, K; Sherwood, K; Payne, J R; Luis Fuentes, V; Connolly, D J

2014-01-01

The use of cardiac biomarkers to assist in the diagnosis of occult and symptomatic hypertrophic cardiomyopathy (HCM) in cats has been established. There is limited data describing their prognostic utility in cats with HCM. Circulating concentrations of N-terminal B-type natriuretic peptide (NTproBNP) and cardiac troponin I (cTnI) predict cardiac death in cats with HCM. Forty-one cats diagnosed with HCM at a veterinary teaching hospital, between February 2010 and May 2011. Prospective investigational study. Plasma samples were collected from cats diagnosed with HCM and concentrations of NTproBNP and cTnI were analyzed at a commercial laboratory. Echocardiographic measurements from the day of blood sampling were recorded. Long-term outcome data were obtained. Associations with time to cardiac death were analyzed using Cox proportional hazards models. When controlling for the presence/absence of heart failure and echocardiographic measures of left atrial size and function, cTnI > 0.7 ng/mL was independently associated with time to cardiac death. In univariable analysis, NTproBNP > 250 pmol/L was associated with cardiac death (P = .023), but this did not remain significant (P = .951) when controlling for the effect of clinical signs or left atrial size/function. Plasma concentration of cTnI (cutoff >0.7 ng/mL) is a predictor of cardiac death in cats with HCM that is independent of the presence of heart failure or left atrial dilatation. Copyright © 2014 by the American College of Veterinary Internal Medicine.

Implantable Cardioverter-defibrillator Therapy for Hypertrophic Cardiomyopathy: Usefulness in Primary and Secondary Prevention.

PubMed

Sarrias, Axel; Galve, Enrique; Sabaté, Xavier; Moya, Àngel; Anguera, Ignacio; Núñez, Elaine; Villuendas, Roger; Alcalde, Óscar; García-Dorado, David

2015-06-01

Hypertrophic cardiomyopathy is a frequent cause of sudden death. Clinical practice guidelines indicate defibrillator implantation for primary prevention in patients with 1 or more risk factors and for secondary prevention in patients with a history of aborted sudden death or sustained ventricular arrhythmias. The aim of the present study was to analyze the follow-up of patients who received an implantable defibrillator following the current guidelines in nonreferral centers for this disease. This retrospective observational study included all patients who underwent defibrillator implantation between January 1996 and December 2012 in 3 centers in the province of Barcelona. The study included 69 patients (mean age [standard deviation], 44.8 [17] years; 79.3% men), 48 in primary prevention and 21 in secondary prevention. The mean number of risk factors per patient was 1.8 in the primary prevention group and 0.5 in the secondary prevention group (P=.029). The median follow-up duration was 40.5 months. The appropriate therapy rate was 32.7/100 patient-years in secondary prevention and 1.7/100 patient-years in primary prevention (P<.001). Overall mortality was 10.1%. Implant-related complications were experienced by 8.7% of patients, and 13% had inappropriate defibrillator discharges. In patients with a defibrillator for primary prevention, the appropriate therapy rate is extremely low, indicating the low predictive power of the current risk stratification criteria. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

c-myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3

PubMed Central

Sutherland, Kate D; Vaillant, François; Alexander, Warren S; Wintermantel, Tim M; Forrest, Natasha C; Holroyd, Sheridan L; McManus, Edward J; Schutz, Gunther; Watson, Christine J; Chodosh, Lewis A; Lindeman, Geoffrey J; Visvader, Jane E

2006-01-01

Suppressor of cytokine signalling (SOCS) proteins are critical attenuators of cytokine-mediated signalling in diverse tissues. To determine the importance of Socs3 in mammary development, we generated mice in which Socs3 was deleted in mammary epithelial cells. No overt phenotype was evident during pregnancy and lactation, indicating that Socs3 is not a key physiological regulator of prolactin signalling. However, Socs3-deficient mammary glands exhibited a profound increase in epithelial apoptosis and tissue remodelling, resulting in precocious involution. This phenotype was accompanied by augmented Stat3 activation and a marked increase in the level of c-myc. Moreover, induction of c-myc before weaning using an inducible transgenic model recapitulated the Socs3 phenotype, and elevated expression of likely c-myc target genes, E2F-1, Bax and p53, was observed. Our data establish Socs3 as a critical attenuator of pro-apoptotic pathways that act in the developing mammary gland and provide evidence that c-myc regulates apoptosis during involution. PMID:17139252

Distinguishing hypertrophic cardiomyopathy from athlete's heart physiological remodelling: clinical significance, diagnostic strategies and implications for preparticipation screening.

PubMed

Maron, B J

2009-09-01

Sudden cardiac death in young competitive athletes is an important public health problem, although a relatively low-event-rate phenomenon. The single most common cardiovascular cause of these unexpected catastrophes is hypertrophic cardiomyopathy (HCM), accounting for about one-third of cases. Since the phenotypic expression of HCM is variable, and not uncommonly includes patients with mild and localised left ventricular hypertrophy, the differential diagnosis with physiological remodelling of athlete's heart not uncommonly arises. This review discusses those non-invasive strategies that are useful in distinguishing the benign consequences of systematic athletic training from pathological left ventricular hypertrophy with the potential for sudden cardiac death. Preparticipation screening in healthy general athlete populations may raise the suspicion of HCM, and ultimately lead to definitive diagnosis. However, recently controversy has arisen regarding the most effective and practical strategy for the screening of athletes. European investigators have promoted routine 12-lead ECGs as part of a national mandatory programme distinct from the customary practice in the US which is limited to history and physical examinations. Consensus criteria and recommendations for eligibility and disqualification of athletes with HCM (and other cardiovascular abnormalities) have proved useful to the practising community.

[Pro731Ser mutation in the β-myosin heavy chain and hypertrophic cardiomyopathy in a Chinese pedigree].

PubMed

Zhao, Xintao; Wu, Yajie; Chen, Yi; Feng, Xinxing; Song, Ying; Wang, Yilu; Zou, Yubao; Wang, Jizheng; Shao, Yibing; Hui, Rutai; Song, Lei; Wang, Xu

2014-07-01

To identify the casual mutation of a Chinese pedigree with hypertrophic cardiomyopathy (HCM), and to analyze the genotype-phenotype relationship. The coding exons of 26 reported disease genes were sequenced by targeted resequencing in the proband and the identified mutation were detected with bi-directional Sanger sequencing in all family members and 307 healthy controls. The genotype-phenotype correlation was analyzed in the family. A missense mutation (c.2191C > T, p. Pro731Ser) in the 20th exon of MYH7 gene was identified. This mutation was absent in 307 healthy controls and predicted to be pathogenic by PolyPhen-HCM. Totally 13 family members carried this mutation, including 10 patients with HCM and 3 asymptomatic mutation carriers. The proband manifested severe congestive heart failure and 8 patients expressed various clinical manifestations of heart failure, including dyspnea, palpitations, chest pain, amaurosis or syncope. Five patients were diagnosed as HCM at the age of 16 or younger. One family member suffered sudden cardiac death. The Pro731Ser of MYH7 gene mutation is a causal and malignant mutation linked with familiar HCM.

Targets for therapy in sarcomeric cardiomyopathies

PubMed Central

Tardiff, Jil C.; Carrier, Lucie; Bers, Donald M.; Poggesi, Corrado; Ferrantini, Cecilia; Coppini, Raffaele; Maier, Lars S.; Ashrafian, Houman; Huke, Sabine; van der Velden, Jolanda

2015-01-01

To date, no compounds or interventions exist that treat or prevent sarcomeric cardiomyopathies. Established therapies currently improve the outcome, but novel therapies may be able to more fundamentally affect the disease process and course. Investigations of the pathomechanisms are generating molecular insights that can be useful for the design of novel specific drugs suitable for clinical use. As perturbations in the heart are stage-specific, proper timing of drug treatment is essential to prevent initiation and progression of cardiac disease in mutation carrier individuals. In this review, we emphasize potential novel therapies which may prevent, delay, or even reverse hypertrophic cardiomyopathy caused by sarcomeric gene mutations. These include corrections of genetic defects, altered sarcomere function, perturbations in intracellular ion homeostasis, and impaired myocardial energetics. PMID:25634554

Comparison of left atrial size and function in hypertrophic cardiomyopathy and in Fabry disease with left ventricular hypertrophy.

PubMed

Saccheri, María Cristina; Cianciulli, Tomás Francisco; Challapa Licidio, Wilde; Lax, Jorge A; Beck, Martín A; Morita, Luis A; Gagliardi, Juan A

2018-05-01

Fabry disease (FD) and hypertrophic cardiomyopathy (HCM) are two diseases with a different pathophysiology, both cause left ventricular hypertrophy (LVH) and myocardial fibrosis. Although remodeling and systolic dysfunction of the left atrium (LA) are associated with atrial fibrillation and stroke in HCM, changes in the size and function of the LA have not been well studied in FD with LVH. The following groups were studied prospectively, and their respective findings compared: 19 patients with non-obstructive HCM (Group I), 20 patients with a diagnosis of Fabry cardiomyopathy (Group II), and 20 normal subjects matched for sex and age (Group III). Left ventricular mass index was measured using Devereux' formula, left atrial volume with Simpson's biplane method and left atrial mechanical function, including strain and strain rate, was measured using the speckle tracking technique. Strain and strain rate of the reservoir were measured during the three phases: reservoir (SR S), passive conduit (SR E) and atrial contraction (SR A). Patients with HCM had a larger left atrial volume than patients with FD (48.16 ± 14.3 mL/m 2 vs 38.9 ± 14.9 mL/m 2 respectively, P < .001), but in both disorders there was a severe decrease in left atrial function: reservoir strain in the apical four-chamber view: 17.47% in HCM vs 22.5% in FD, P = .24), strain rate in the apical chamber view: SR A: -0.80/seconds in HCM vs -1.04/seconds in FD (P = .88), SR S: 0.69/seconds in HCM vs 0.93 in FD (P = .12), SR E: -0.80 seconds in HCM vs -0.97/seconds in FD (P = .18). In this echocardiographic study we used speckle tracking to assess left atrial mechanical function and showed that FD is associated to an atrial cardiomyopathy, affecting the three phasic functions of the LA. Although in patients with HCM left atrial volume is larger than in patients with FD, both disorders exhibit severe decrease in left atrial function. These findings should be considered, given the potentially

Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation

PubMed Central

Marin, Talita M.; Keith, Kimberly; Davies, Benjamin; Conner, David A.; Guha, Prajna; Kalaitzidis, Demetrios; Wu, Xue; Lauriol, Jessica; Wang, Bo; Bauer, Michael; Bronson, Roderick; Franchini, Kleber G.; Neel, Benjamin G.; Kontaridis, Maria I.

2011-01-01

LEOPARD syndrome (LS) is an autosomal dominant “RASopathy” that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11Y279C/+ (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients. PMID:21339643

Subcutaneous Implantable Cardioverter Defibrillator in Patients With Hypertrophic Cardiomyopathy: An Initial Experience.

PubMed

Weinstock, Jonathan; Bader, Yousef H; Maron, Martin S; Rowin, Ethan J; Link, Mark S

2016-02-12

The subcutaneous implantable cardioverter defibrillator (S-ICD) has been developed to avert risks associated with transvenous defibrillator leads. The technology is attractive for younger patients, such as those with hypertrophic cardiomyopathy (HCM). However, there are limited data on S-ICD use in HCM. HCM patients identified at risk for sudden death were considered for S-ICD implantation. Patients were screened for potential oversensing by surface electrocardiography (ECG). At implant, defibrillation threshold (DFT) testing was performed at 65, 50, and 35 joules (J). Twenty-seven patients were considered for S-ICD implantation, and after screening, 23 (85%) remained eligible. The presence of a bundle branch block was associated with screening failure, whereas elevated body mass index (BMI) showed a trend toward association. One patient passed screening at rest, but failed with an ECG obtained after exercise. At implant, the S-ICD terminated ventricular fibrillation (VF) with a 65J shock in all 15 implanted patients and a 50J shock was successful in 12 of 15. A 35J shock terminated VF in 10 of 12 patients. DFT failure at 50 J was associated with a higher BMI. There were no appropriate shocks after a median follow-up of 17.5 (3-35) months, and 1 patient received an inappropriate shock attributable to a temporary reduction in QRS amplitude while bending forward, resulting in oversensing, despite successful screening. In a high-risk HCM cohort without a pacing indication referred for consideration of an ICD, the majority were eligible for S-ICD. The S-ICD is effective at recognizing and terminating VF at implant with a wide safety margin. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Magnesium status and the effect of magnesium supplementation in feline hypertrophic cardiomyopathy.

PubMed

Freeman, L M; Brown, D J; Smith, F W; Rush, J E

1997-07-01

Magnesium deficiency has been associated with the development of cardiovascular disease in several species. Cats may be predisposed to alterations in magnesium status because of recent changes in the composition of commercial feline diets. The purposes of this study were 1) to examine the dietary history of cats with hypertrophic cardiomyopathy (HCM), 2) to study magnesium status of cats with HCM compared to normal cats, and 3) to determine the effects of magnesium supplementation in cats with HCM. In part 1 of the study, diets of 65 cats with HCM were examined retrospectively. Forty of the 45 cats for which diets could be determined (89%) ate a diet designed to be magnesium-restricted and/or to produce an acidic urine. In part 2 of the study, 10 cats with HCM were compared to 10 healthy control cats for serum creatinine and magnesium; urine creatinine and magnesium, urine specific gravity and pH, and fractional excretion of magnesium. Urine creatinine and specific gravity were higher in control cats than in cats with HCM. No other differences were found between the 2 groups. In part 3, cats with HCM were supplemented with either 210 mg magnesium chloride (n = 15) or 210 mg lactose (n = 15) for 12 wk. No differences between the 2 groups were found for changes in either magnesium status or echocardiographic parameters. However, the 30 cats with HCM, as a group, did show significant improvements in measures of cardiac hypertrophy over the 12-week period. This was likely the result of treatment with other medications, rather than the magnesium supplementation. The results of this study suggest that cats with HCM are likely to be fed magnesium-restricted diets, but that they do not appear to have altered magnesium status compared to healthy controls.

Calmodulin-mediated activation of Akt regulates survival of c-Myc-overexpressing mouse mammary carcinoma cells.

PubMed

Deb, Tushar B; Coticchia, Christine M; Dickson, Robert B

2004-09-10

c-Myc-overexpressing mammary epithelial cells are proapoptotic; their survival is strongly promoted by epidermal growth factor (EGF). We now demonstrate that EGF-induced Akt activation and survival in transgenic mouse mammary tumor virus-c-Myc mouse mammary carcinoma cells are both calcium/calmodulin-dependent. Akt activation is abolished by the phospholipase C-gamma inhibitor U-73122, by the intracellular calcium chelator BAPTA-AM, and by the specific calmodulin antagonist W-7. These results implicate calcium/calmodulin in the activation of Akt in these cells. In addition, Akt activation by serum and insulin is also inhibited by W-7. EGF-induced and calcium/calmodulin-mediated Akt activation occurs in both tumorigenic and non-tumorigenic mouse and human mammary epithelial cells, independent of their overexpression of c-Myc. These results imply that calcium/calmodulin may be a common regulator of Akt activation, irrespective of upstream receptor activator, mammalian species, and transformation status in mammary epithelial cells. However, only c-Myc-overexpressing mouse mammary carcinoma cells (but not normal mouse mammary epithelial cells) undergo apoptosis in the presence of the calmodulin antagonist W-7, indicating the vital selective role of calmodulin for survival of these cells. Calcium/calmodulin-regulated Akt activation is mediated directly by neither calmodulin kinases nor phosphatidylinositol 3-kinase (PI-3 kinase). Pharmacological inhibitors of calmodulin kinase kinase and calmodulin kinases II and III do not inhibit EGF-induced Akt activation, and calmodulin antagonist W-7 does not inhibit phosphotyrosine-associated PI-3 kinase activation. Akt is, however, co-immunoprecipitated with calmodulin in an EGF-dependent manner, which is inhibited by calmodulin antagonist W-7. We conclude that calmodulin may serve a vital regulatory function to direct the localization of Akt to the plasma membrane for its activation by PI-3 kinase.

Functional effects of losartan in hypertrophic cardiomyopathy-a randomised clinical trial.

PubMed

Axelsson, Anna; Iversen, Kasper; Vejlstrup, Niels; Ho, Carolyn Y; Havndrup, Ole; Kofoed, Klaus F; Norsk, Jakob; Jensen, Morten; Bundgaard, Henning

2016-02-15

There is a lack of disease-modifying treatments in hypertrophic cardiomyopathy (HCM). The aim of this randomised, placebo-controlled study was to assess if losartan could improve or ameliorate deterioration of cardiac function and exercise capacity. Echocardiography, exercise test and MRI or CT were performed at baseline and after 12 months in 133 patients (52±13 years, 35% female) randomly allocated to losartan (100 mg/day) or placebo. Losartan had no effect on systolic function compared with placebo (mean difference for left ventricular ejection fraction (LVEF) 0% (95% CI -3% to 4%), p=0.84 or global longitudinal strain 0.7% (95% CI -0.2% to 1.6%), p=0.13). Neither Doppler measures of diastolic function, left atrial volume (mean difference 2 mL/m(2) (95% CI -4 to 8 mL/m(2)) p=0.53) nor exercise capacity (mean difference -0.3 metabolic equivalents (METS) (95% CI -1.0 to 0.3 METS), p=0.28) differed between the treatment groups. At follow-up, there was further progression of disease, with the most prominent impairment being an increase in left atrial volume of 6 mL/m(2) (95% CI 3 to 9 mL/m(2), p<0.0001) in both groups combined. LVEF decreased (mean change -2%, (95% CI -3% to -1%), p=0.037) and 4% of patients had end-stage HCM with a LVEF of less than 50% at the end of the study. Treatment with losartan had no effect on cardiac function or exercise capacity compared with placebo. Losartan fail to improve myocardial performance and failed to alter the progression of the disease. These findings do not support the use of angiotensin II receptor blockers as disease modifiers in adult patients with overt HCM. NCT01447654-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Mutation of Arg723Gly in beta-myosin heavy chain gene in five Chinese families with hypertrophic cardiomyopathy.

PubMed

Yang, Jun-hua; Zheng, Dong-dong; Dong, Ning-zheng; Yang, Xiang-jun; Song, Jian-ping; Jiang, Ting-bo; Cheng, Xu-jie; Li, Hong-xia; Zhou, Bing-yuan; Zhao, Cai-ming; Jiang, Wen-ping

2006-11-05

Hypertrophic cardiomyopathy (HCM) is a form of cardiomyopathy with an autosomal dominant inherited disease, which is caused by mutations in at least one of the sarcomeric protein genes. Mutations in the beta-myosin heavy chain (beta-MHC) are the most common cause of HCM. This study was to reveal the disease-causing gene mutations in Chinese population with HCM, and to analyze the correlation between the genotype and phenotype. The exons 3 to 26 of MYH7 were amplified by PCR, and the PCR products were sequenced in five non-kin HCM patients. A 17-year-old patient was detected to be an Arg723Gly mutation carrier. Then his family was gene-screened, and the correlation between genotype and phenotype was analyzed. The mutation of Arg723Gly in a Chinese family with HCM was detected for the first time. With a C-G transversion in nucleotide 13,619 of the MYH7 gene, located at the essential light chain interacting region in S1, the replacement of arginine by glycine took place at amino acid residue 723. A two-dimensional echocardiogram showed moderate asymmetrical septal hypertrophy with left atria enlargement. There was no obstruction in the left ventricular outflow tract. In his family, a total of 13 individuals were diagnosed HCM and 5 of them were dead of congestive heart failure at a mean age of 66-year-old. Eight living members were all detected to carry the mutation, in which 3 developed progressive heart failure. Moreover, the heart function of the people evidently deteriorates when their age are older than 50. The mutation and the disease show co-separated. The Arg723Gly mutation is a malignant type. In Chinese the mutation has the similar characters to the former report but has low degree malignant.

LeMYC2 acts as a negative regulator of blue light mediated photomorphogenic growth, and promotes the growth of adult tomato plants

PubMed Central

2014-01-01

Background Arabidopsis ZBF1/MYC2bHLH transcription factor is a repressor of photomorphogenesis, and acts as a point of cross talk in light, abscisic acid (ABA) and jasmonic acid (JA) signaling pathways. MYC2 also functions as a positive regulator of lateral root development and flowering time under long day conditions. However, the function of MYC2 in growth and development remains unknown in crop plants. Results Here, we report the functional analyses of LeMYC2 in tomato (Lycopersicon esculentum). The amino acid sequence of LeMYC2 showed extensive homology with Arabidopsis MYC2, containing the conserved bHLH domain. To study the function of LeMYC2 in tomato, overexpression and RNA interference (RNAi) LeMYC2 tomato transgenic plants were generated. Examination of seedling morphology, physiological responses and light regulated gene expression has revealed that LeMYC2 works as a negative regulator of blue light mediated photomorphogenesis. Furthermore, LeMYC2 specifically binds to the G-box of LeRBCS-3A promoter. Overexpression of LeMYC2 has led to increased root length with more number of lateral roots. The tomato plants overexpressing LeMYC2 have reduced internode distance with more branches, and display the opposite morphology to RNAi transgenic lines. Furthermore, this study shows that LeMYC2 promotes ABA and JA responsiveness. Conclusions Collectively, this study highlights that working in light, ABA and JA signaling pathways LeMYC2 works as an important regulator for growth and development in tomato plants. PMID:24483714

NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes.

PubMed

Ceyhan-Birsoy, Ozge; Miatkowski, Maya M; Hynes, Elizabeth; Funke, Birgit H; Mason-Suares, Heather

2018-04-25

RASopathies include a group of syndromes caused by pathogenic germline variants in RAS-MAPK pathway genes and typically present with facial dysmorphology, cardiovascular disease, and musculoskeletal anomalies. Recently, variants in RASopathy-associated genes have been reported in individuals with apparently nonsyndromic cardiomyopathy, suggesting that subtle features may be overlooked. To determine the utility and burden of adding RASopathy-associated genes to cardiomyopathy panels, we tested 11 RASopathy-associated genes by next-generation sequencing (NGS), including NGS-based copy number variant assessment, in 1,111 individuals referred for genetic testing for hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Disease-causing variants were identified in 0.6% (four of 692) of individuals with HCM, including three missense variants in the PTPN11, SOS1, and BRAF genes. Overall, 36 variants of uncertain significance (VUSs) were identified, averaging ∼3VUSs/100 cases. This study demonstrates that adding a subset of the RASopathy-associated genes to cardiomyopathy panels will increase clinical diagnoses without significantly increasing the number of VUSs/case. © 2018 Wiley Periodicals, Inc.

Acromegaly-induced cardiomyopathy with dobutamine-induced outflow tract obstruction.

PubMed

Abdelsalam, Mahmoud A; Nippoldt, Todd B; Geske, Jeffrey B

2016-03-09

A 50-year-old man with a history of acromegaly was referred for preoperative cardiac evaluation preceding trans-sphenoidal resection of a pituitary macroadenoma. Dobutamine stress echocardiography was negative for myocardial ischaemia. Resting left ventricular (LV) LV ejection fraction (LVEF) was 64% and there was hypertrophy of ventricular septum (18 mm) without resting LV outflow tract obstruction. With 40 µg/kg/min of dobutamine, the LVEF became hyperdynamic at 80%, and there was a maximal instantaneous LV outflow tract gradient of 77 mm Hg. There was no delayed myocardial enhancement on cardiac MRI and the pattern of hypertrophy was concentric. Acromegaly-induced cardiomyopathy can mimic hypertrophic cardiomyopathy in the setting of dobutamine provocation. Because cardiomyopathy is an important cause of mortality in acromegaly, diagnosis and appropriate management are critical to improve survival. 2016 BMJ Publishing Group Ltd.

Kinetics of a single cross-bridge in familial hypertrophic cardiomyopathy heart muscle measured by reverse Kretschmann fluorescence

PubMed Central

Mettikolla, Prasad; Calander, Nils; Luchowski, Rafal; Gryczynski, Ignacy; Gryczynski, Zygmunt; Borejdo, Julian

2010-01-01

Familial hypertrophic cardiomyopathy (FHC) is a serious heart disease that often leads to a sudden cardiac death of young athletes. It is believed that the alteration of the kinetics of interaction between actin and myosin causes FHC by making the heart to pump blood inefficiently. We set out to check this hypothesis ex vivo. During contraction of heart muscle, a myosin cross-bridge imparts periodic force impulses to actin. The impulses are analyzed by fluorescence correlation spectroscopy (FCS) of fluorescently labeled actin. To minimize observation volume and background fluorescence, we carry out FCS measurements in surface plasmon coupled emission mode in a reverse Kretschmann configuration. Fluorescence is a result of near-field coupling of fluorophores excited in the vicinity of the metal-coated surface of a coverslip with the surface plasmons propagating in the metal. Surface plasmons decouple on opposite sides of the metal film and emit in a directional manner as far-field p-polarized radiation. We show that the rate of changes of orientation is significantly faster in contracting cardiac myofibrils of transgenic mice than wild type. These results are consistent with the fact that mutated heart muscle myosin translates actin faster in in vitro motility assays. PMID:20210485

THE INVOLVEMENT OF HUMAN MONOGENIC CARDIOMYOPATHY GENES IN EXPERIMENTAL POLYGENIC CARDIAC HYPERTROPHY.

PubMed

Prestes, Priscilla R; Marques, Francine Z; Lopez-Campos, Guillermo; Lewandowski, Paul; Delbridge, Lea M D; Charchar, Fadi J; Harrap, Stephen B

2018-05-18

Hypertrophic cardiomyopathy thickens heart muscles reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole-genome of 13-week old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at five ages (2-days old, 4-, 13-, 33- and 50-weeks old) compared to human idiopathic dilated data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-days old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in non-coding regions of HHR and NHR. We found 29 genes differentially expressed in at least one age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.

High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort

PubMed Central

2012-01-01

Background Hypertrophic Cardiomyopathy (HCM) is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine. Methodology In this report, we evaluated High Resolution Melting (HRM) robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associated sarcomere genes, as well as 24 genes with lower reported HCM-phenotype association. We analyzed 80 Portuguese individuals with clinical phenotype of HCM allowing simultaneously a better characterization of this disease in the Portuguese population. Results HRM technology allowed us to identify 60 mutated alleles in 72 HCM patients: 49 missense mutations, 3 nonsense mutations, one 1-bp deletion, one 5-bp deletion, one in frame 3-bp deletion, one insertion/deletion, 3 splice mutations, one 5'UTR mutation in MYH7, MYBPC3, TNNT2, TNNI3, CSRP3, MYH6 and MYL2 genes. Significantly 22 are novel gene mutations. Conclusions HRM was proven to be a technique with high sensitivity and a low false positive ratio allowing a rapid, innovative and low cost genotyping of HCM. In a short return, HRM as a gene scanning technique could be a cost-effective gene-based diagnosis for an accurate HCM genetic diagnosis and hopefully providing new insights into genotype/phenotype correlations. PMID:22429680

Slowed atrial and atrioventricular conduction and depressed HRV in a murine model of hypertrophic cardiomyopathy.

PubMed

Lim, Wei-Wen; Baumert, Mathias; Neo, Melissa; Kuklik, Pawel; Ganesan, Anand N; Lau, Dennis H; Tsoutsman, Tatiana; Semsarian, Christopher; Sanders, Prashanthan; Saint, David A

2016-01-01

Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac disorder with diverse clinical outcomes including sudden death, heart failure, and stroke. Depressed heart rate variability (HRV), a measure of cardiac autonomic regulation, has been shown to predict mortality in patients with cardiovascular disease. Cardiac autonomic remodelling in animal models of HCM are not well characterised. This study analysed Gly203Ser cardiac troponin-I transgenic (TG) male mice previously demonstrated to develop hallmarks of HCM by age 21 weeks. 33 mice aged 30 and 50 weeks underwent continuous electrocardiogram (ECG) recording for 30 min under anaesthesia. TG mice demonstrated prolonged P-wave duration (P < 0.001) and PR intervals (P < 0.001) compared to controls. Additionally, TG mice demonstrated depressed standard deviation of RR intervals (SDRR; P < 0.01), coefficient of variation of RR intervals (CVRR; P < 0.001) and standard deviation of heart rate (SDHR; P < 0.001) compared to controls. Additionally, total power was significantly reduced in TG mice (P < 0.05). No significant age-related difference in either strain was observed in ECG or HRV parameters. Mice with HCM developed slowed atrial and atrioventricular conduction and depressed HRV. These changes were conserved with increasing age. This finding may be indicative of atrial and ventricular hypertrophy or dysfunction, and perhaps an indication of worse clinical outcome in heart failure progression in HCM patients. © 2015 Wiley Publishing Asia Pty Ltd.

Early induction of c-Myc is associated with neuronal cell death.

PubMed

Lee, Hyun-Pil; Kudo, Wataru; Zhu, Xiongwei; Smith, Mark A; Lee, Hyoung-gon

2011-11-14

Neuronal cell cycle activation has been implicated in neurodegenerative diseases such as Alzheimer's disease, while the initiating mechanism of cell cycle activation remains to be determined. Interestingly, our previous studies have shown that cell cycle activation by c-Myc (Myc) leads to neuronal cell death which suggests Myc might be a key regulator of cell cycle re-entry mediated neuronal cell death. However, the pattern of Myc expression in the process of neuronal cell death has not been addressed. To this end, we examined Myc induction by the neurotoxic agents camptothecin and amyloid-β peptide in a differentiated SH-SY5Y neuronal cell culture model. Myc expression was found to be significantly increased following either treatment and importantly, the induction of Myc preceded neuronal cell death suggesting it is an early event of neuronal cell death. Since ectopic expression of Myc in neurons causes the cell cycle activation and neurodegeneration in vivo, the current data suggest that induction of Myc by neurotoxic agents or other disease factors might be a key mediator in cell cycle activation and consequent cell death that is a feature of neurodegenerative diseases. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

MYC and metabolism on the path to cancer

PubMed Central

Hsieh, Annie L.; Walton, Zandra E.; Altman, Brian J.; Stine, Zachary E.; Dang, Chi V.

2015-01-01

The MYC proto-oncogene is frequently deregulated in human cancers, activating genetic programs that orchestrate biological processes to promote growth and proliferation. Altered metabolism characterized by heightened nutrients uptake, enhanced glycolysis and glutaminolysis and elevated fatty acid and nucleotide synthesis is the hallmark of MYC-driven cancer. Recent evidence strongly suggests that Myc-dependent metabolic reprogramming is critical for tumorigenesis, which could be attenuated by targeting specific metabolic pathways using small drug-like molecules. Understanding the complexity of MYC-mediated metabolic re-wiring in cancers as well as how MYC cooperates with other metabolic drivers such as mammalian target of rapamycin (mTOR) will provide translational opportunities for cancer therapy. PMID:26277543

CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy.

PubMed

Mosqueira, Diogo; Mannhardt, Ingra; Bhagwan, Jamie R; Lis-Slimak, Katarzyna; Katili, Puspita; Scott, Elizabeth; Hassan, Mustafa; Prondzynski, Maksymilian; Harmer, Stephen C; Tinker, Andrew; Smith, James G W; Carrier, Lucie; Williams, Philip M; Gaffney, Daniel; Eschenhagen, Thomas; Hansen, Arne; Denning, Chris

2018-05-08

Sarcomeric gene mutations frequently underlie hypertrophic cardiomyopathy (HCM), a prevalent and complex condition leading to left ventricle thickening and heart dysfunction. We evaluated isogenic genome-edited human pluripotent stem cell-cardiomyocytes (hPSC-CM) for their validity to model, and add clarity to, HCM. CRISPR/Cas9 editing produced 11 variants of the HCM-causing mutation c.C9123T-MYH7 [(p.R453C-β-myosin heavy chain (MHC)] in 3 independent hPSC lines. Isogenic sets were differentiated to hPSC-CMs for high-throughput, non-subjective molecular and functional assessment using 12 approaches in 2D monolayers and/or 3D engineered heart tissues. Although immature, edited hPSC-CMs exhibited the main hallmarks of HCM (hypertrophy, multi-nucleation, hypertrophic marker expression, sarcomeric disarray). Functional evaluation supported the energy depletion model due to higher metabolic respiration activity, accompanied by abnormalities in calcium handling, arrhythmias, and contraction force. Partial phenotypic rescue was achieved with ranolazine but not omecamtiv mecarbil, while RNAseq highlighted potentially novel molecular targets. Our holistic and comprehensive approach showed that energy depletion affected core cardiomyocyte functionality. The engineered R453C-βMHC-mutation triggered compensatory responses in hPSC-CMs, causing increased ATP production and αMHC to energy-efficient βMHC switching. We showed that pharmacological rescue of arrhythmias was possible, while MHY7: MYH6 and mutant: wild-type MYH7 ratios may be diagnostic, and previously undescribed lncRNAs and gene modifiers are suggestive of new mechanisms.

Phenotypic expression in hypertrophic cardiomyopathy and late gadolinium enhancement on cardiac magnetic resonance.

PubMed

Caetano, Francisca; Botelho, Ana; Trigo, Joana; Silva, Joana; Almeida, Inês; Venâncio, Margarida; Pais, João; Sanches, Conceição; Leitão Marques, António

2014-05-01

The prognostic value of late gadolinium enhancement (LGE) for risk stratification of hypertrophic cardiomyopathy (HCM) patients is the subject of disagreement. We set out to examine the association between clinical and morphological variables, risk factors for sudden cardiac death and LGE in HCM patients. From a population of 78 patients with HCM, we studied 53 who underwent cardiac magnetic resonance. They were divided into two groups according to the presence or absence of LGE. Ventricular arrhythmias and morbidity and mortality during follow-up were analyzed. Patients with LGE were younger at the time of diagnosis (p=0.046) and more often had a family history of sudden death (p=0.008) and known coronary artery disease (p=0.086). On echocardiography they had greater maximum wall thickness (p=0.007) and left atrial area (p=0.037) and volume (p=0.035), and more often presented a restrictive pattern of diastolic dysfunction (p=0.011) with a higher E/É ratio (p=0.003) and left ventricular systolic dysfunction (p=0.038). Cardiac magnetic resonance supported the association between LGE and previous echocardiographic findings: greater left atrial area (p=0.029) and maximum wall thickness (p<0.001) and lower left ventricular ejection fraction (p=0.056). Patients with LGE more often had an implantable cardioverter-defibrillator (ICD) (p=0.015). At follow-up, no differences were found in the frequency of ventricular arrhythmias, appropriate ICD therapies or mortality. The presence of LGE emerges as a risk marker, associated with the classical predictors of sudden cardiac death in this population. However, larger studies are required to confirm its independent association with clinical events. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Insights Into Hypertrophic Cardiomyopathy Evaluation Through Follow-up of a Founder Pathogenic Variant.

PubMed

Lorca, Rebeca; Gómez, Juan; Martín, María; Cabanillas, Rubén; Calvo, Juan; León, Víctor; Pascual, Isaac; Morís, César; Coto, Eliecer; R Reguero, José Julián

2018-04-06

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. The current challenge relies on the accurate classification of the pathogenicity of the variants. Transthoracic echocardiography (TTE) is recommended at initial evaluation and cardiac magnetic resonance (CMR) imaging should also be considered. We aimed to reappraise the penetrance and clinical expression of the MYBPC3 p.G263* variant. Three hundred and eighty-four HCM probands and a control cohort of 450 individuals were studied for the main sarcomere genes by next-generation sequencing. All MYBPC3 p.G263* carriers were identified and family screening was performed. Clinical information was recorded retrospectively before 2015 and prospectively thereafter. Extra effort was invested in performing CMR in all carriers, despite TTE results. Thirteen HCM probands and none of the controls were carriers of the MYBPC3 p.G263* pathogenic variant (according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology). A total of 39 carriers were identified with family screening. Most patients with HCM were asymptomatic at the time of diagnosis and showed late-onset disease. Despite having a relatively benign course in the young, late HCM-related complications could occur. Penetrance was around 70% when evaluated by TTE and was 87.2% with TTE plus CMR. Penetrance was age-dependent, reaching 100% in carriers older than 55 years. MYBPC3 p.G263* shares with most truncating pathogenic variants in this gene a late onset, relatively benign clinical course in the young, and high penetrance. Cardiac magnetic resonance could be a useful tool to evaluate carriers despite TTE results. Copyright © 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy.

PubMed

Sherrid, Mark V; Barac, Ivan; McKenna, William J; Elliott, Perry M; Dickie, Shaughan; Chojnowska, Lidia; Casey, Susan; Maron, Barry J

2005-04-19

In this study we assessed the long-term efficacy and safety of disopyramide for patients with obstructive hypertrophic cardiomyopathy (HCM). It has been reported that disopyramide may reduce left ventricular outflow gradient and improve symptoms in patients with HCM. However, long-term efficacy and safety of disopyramide has not been shown in a large cohort. Clinical and echocardiographic data were evaluated in 118 obstructive HCM patients treated with disopyramide at 4 HCM treatment centers. Mortality in the disopyramide-treated patients was compared with 373 obstructive HCM patients not treated with disopyramide. Patients were followed with disopyramide for 3.1 +/- 2.6 years; dose 432 +/- 181 mg/day (97% also received beta-blockers). Seventy-eight patients (66%) were maintained with disopyramide without the necessity for major non-pharmacologic intervention with surgical myectomy, alcohol ablation, or pacing; outflow gradient at rest decreased from 75 +/- 33 to 40 +/- 32 mm Hg (p < 0.0001) and mean New York Heart Association functional class from 2.3 +/- 0.7 to 1.7 +/- 0.6 (p < 0.0001). Forty other patients (34%) could not be satisfactorily managed with disopyramide and required major invasive interventions because of inadequate symptom and gradient control or vagolytic side effects. All-cause annual cardiac death rate between disopyramide and non-disopyramide-treated patients did not differ significantly, 1.4% versus 2.6%/year (p = 0.07). There was also no difference in sudden death rate, 1.0%/year versus 1.8%/year (p = 0.08). Two-thirds of obstructed HCM patients treated with disopyramide could be managed medically with amelioration of symptoms and about 50% reduction in subaortic gradient over >/=3 years. Disopyramide therapy does not appear to be proarrhythmic in HCM and should be considered before proceeding to surgical myectomy or alternate strategies.

Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.

PubMed

Sequeira, Vasco; Wijnker, Paul J M; Nijenkamp, Louise L A M; Kuster, Diederik W D; Najafi, Aref; Witjas-Paalberends, E Rosalie; Regan, Jessica A; Boontje, Nicky; Ten Cate, Folkert J; Germans, Tjeerd; Carrier, Lucie; Sadayappan, Sakthivel; van Slegtenhorst, Marjon A; Zaremba, Ruud; Foster, D Brian; Murphy, Anne M; Poggesi, Corrado; Dos Remedios, Cris; Stienen, Ger J M; Ho, Carolyn Y; Michels, Michelle; van der Velden, Jolanda

2013-05-24

High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.

Familial hypertrophic cardiomyopathy: functional effects of myosin mutation R723G in cardiomyocytes.

PubMed

Kraft, Theresia; Witjas-Paalberends, E Rosalie; Boontje, Nicky M; Tripathi, Snigdha; Brandis, Almuth; Montag, Judith; Hodgkinson, Julie L; Francino, Antonio; Navarro-Lopez, Francisco; Brenner, Bernhard; Stienen, Ger J M; van der Velden, Jolanda

2013-04-01

Familial Hypertrophic Cardiomyopathy (FHC) is frequently caused by mutations in the β-cardiac myosin heavy chain (β-MyHC). To identify changes in sarcomeric function triggered by such mutations, distinguishing mutation effects from other functional alterations of the myocardium is essential. We previously identified a direct effect of mutation R723G (MyHC723) on myosin function in slow Musculus soleus fibers. Here we investigate contractile features of left ventricular cardiomyocytes of FHC-patients with the same MyHC723-mutation and compare these to the soleus data. In mechanically isolated, triton-permeabilized MyHC723-cardiomyocytes, maximum force was significantly lower but calcium-sensitivity was unchanged compared to donor. Conversely, MyHC723-soleus fibers showed significantly higher maximum force and reduced calcium-sensitivity compared to controls. Protein phosphorylation, a potential myocardium specific modifying mechanism, might account for differences compared to soleus fibers. Analysis revealed reduced phosphorylation of troponin I and T, myosin-binding-protein C, and myosin-light-chain 2 in MyHC723-myocardium compared to donor. Saturation of protein-kinaseA phospho-sites led to comparable, i.e., reduced MyHC723-calcium-sensitivity in cardiomyocytes as in M. soleus fibers, while maximum force remained reduced. Myofibrillar disarray and lower density of myofibrils, however, largely account for reduced maximum force in MyHC723-cardiomyocytes. The changes seen when phosphorylation of sarcomeric proteins in myocardium of affected patients is matched to control tissue suggest that the R723G mutation causes reduced Ca(++)-sensitivity in both cardiomyocytes and M. soleus fibers. In MyHC723-myocardium, however, hypophosphorylation can compensate for the reduced calcium-sensitivity, while maximum force generation, lowered by myofibrillar deficiency and disarray, remains impaired, and may only be compensated by hypertrophy. Copyright © 2013 Elsevier Ltd. All

Changes in left atrial deformation in hypertrophic cardiomyopathy: Evaluation by vector velocity imaging

PubMed Central

Badran, Hala Mahfouz; Soltan, Ghada; Hassan, Hesham; Nazmy, Ahmed; Faheem, Naglaa; Saadan, Haythem; Yacoub, Magdi H.

2012-01-01

Abstract: Objectives: Hypertrophic cardiomyopathy (HCM) represents a generalized myopathic process affecting both ventricular and atrial myocardium. We assessed the global and regional left atrial (LA) function and its relation to left ventricular (LV) mechanics and clinical status in patients with HCM using Vector Velocity Imaging (VVI). Methods: VVI of the LA and LV was acquired from apical four- and two-chamber views of 108 HCM patients (age 40 ± 19years, 56.5% men) and 33 healthy subjects, all had normal LV systolic function. The LA subendocardium was traced to obtain atrial volumes, ejection fraction, velocities, and strain (ϵ)/strain rate (SR) measurements. Results: Left atrial reservoir (ϵsys,SRsys) and conduit (early diastolic SRe) function were significantly reduced in HCM compared to controls (P < .0001). Left atrial deformation directly correlated to LVϵsys, SRsys and negatively correlated to age, NYHA class, left ventricular outflow tract (LVOT) gradient, left ventricular mass index (LVMI), LA volume index and severity of mitral regurge (P < 0.001). Receiver operating characterist was constructed to explore the cutoff value of LA deformation in differentiation of LA dysfunction; ϵsys < 40% was 75% sensitive, 50% specific, SRsys < 1.7s− 1 was 70% sensitive, 61% specific, SRe> − 1.8s− 1 was 81% sensitive and 30% specific, SRa> − 1.5s− 1 was 73% sensitive and 40% specific. By multivariate analysis global LVϵsys and LV septal thickness are independent predictors for LAϵsys, while end systolic diameter is the only independent predictor for SRsys, P < .001. Conclusion: Left atrial reservoir and conduit function as measured by VVI were significantly impaired while contractile function was preserved among HCM patients. Left atrial deformation was greatly influenced by LV mechanics and correlated to severity of phenotype. PMID:24688992

Is treatment of feline hypertrophic cardiomyopathy based in science or faith? A survey of cardiologists and a literature search.

PubMed

Rishniw, Mark; Pion, Paul D

2011-07-01

Feline hypertrophic cardiomyopathy (HCM) is the most common cardiac disease of cats. Treatment of HCM is usually directed at controlling signs of congestive heart failure (CHF), preventing occurrence or recurrence of systemic thromboembolism or delaying/preventing/reversing progression of subclinical disease. Despite the laudable goals of therapy, however, little objective evidence supporting therapeutic decisions has been published. We, therefore, hypothesized that cardiologists base their treatment strategies on information other than published clinically relevant science. To gain insight into therapeutic decisions that cardiologists and clinicians with an interest in cardiology (n=99) make for cats with HCM, and on what information they base these decisions, we presented participants with, and asked them to select therapy for, 12 hypothetical scenarios of HCM (± CHF). Responses and justifications for treatment choices were compiled and compared with the results of a comprehensive literature search for published information about treatment of feline HCM. Evaluation of the therapeutic strategies chosen for these hypothetical cases of HCM suggests that cardiologists or clinicians with a strong interest in cardiology often prescribe treatments knowing that little documented evidence supports their decisions. Copyright © 2011 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation.

PubMed

Nilsson, Jonas A; Keller, Ulrich B; Baudino, Troy A; Yang, Chunying; Norton, Sara; Old, Jennifer A; Nilsson, Lisa M; Neale, Geoffrey; Kramer, Debora L; Porter, Carl W; Cleveland, John L

2005-05-01

Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.

X-linked cardiomyopathy is heterogeneous

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilson, M.J.; Sillence, D.O.; Mulley, J.C.

Two major loci of X-linked cardiomyopathy have been mapped by linkage analysis. The gene for X-linked dilated cardiomyopathy (XLCM) is mapped to the dystrophin locus at Xp21, while Barth syndrome has been localised to distal Xq28. XLCM usually presents in juvenile males with no skeletal disease but decreased dystrophin in cardiac muscle. Barth syndrome most often presents in infants and is characterized by skeletal myopathy, short stature and neutropenia in association with cardiomyopathy of variable severity. Prior to carrier or prenatal diagnosis in a family, delineation of the cardiomyopathy locus involved is essential. We report the linkage mapping of amore » large kindred in which several male infants have died with hypertrophic cardiomyopathy. There is a family history of unexplained death of infant males less than 6 months old over 4 generations. Features of Barth syndrome such as short stature, skeletal myopathy and neutropenia have not been observed. Genotyping at 10 marker loci in Xq28 has revealed significant pairwise lod scores with the cardiomyopathy phenotype at DXS52 (Z=2.21 at {theta}=0.0), at markers p26 and p39 near DXS15 (Z=2.30 at {theta}=0.0) and at F8C (Z=2.24 at {theta}=0.0). A recombinant detected with DXS296 defines the proximal limit to the localization. No recombinants were detected at any of the loci distal to DXS296. The most distal marker in Xq28, DXS1108, is within 500 kb of the telomere. As the gene in this family is localized to Xq28, it is possible that this disorder is an allelic variant at the Barth syndrome locus.« less

Blunted Myocardial Oxygenation Response During Vasodilator Stress in Patients With Hypertrophic Cardiomyopathy

PubMed Central

Karamitsos, Theodoros D.; Dass, Sairia; Suttie, Joseph; Sever, Emily; Birks, Jacqueline; Holloway, Cameron J.; Robson, Matthew D.; Jerosch-Herold, Michael; Watkins, Hugh; Neubauer, Stefan

2013-01-01

Objectives This study sought to assess myocardial perfusion and tissue oxygenation during vasodilator stress in patients with overt hypertrophic cardiomyopathy (HCM), as well as in HCM mutation carriers without left ventricular (LV) hypertrophy, and to compare findings to those in athletes with comparable hypertrophy and normal controls. Background Myocardial perfusion under vasodilator stress is impaired in patients with HCM. Whether this is associated with impaired myocardial oxygenation and tissue ischemia is unknown. Furthermore, it is not known whether perfusion and oxygenation are impaired in HCM mutation carriers without left ventricular hypertrophy (LVH). Methods A total of 27 patients with overt HCM, 10 HCM mutation carriers without LVH, 11 athletes, and 20 healthy controls underwent cardiovascular magnetic resonance (CMR) scanning at 3-T. Myocardial function, perfusion (perfusion reserve index [MPRI]), and oxygenation (blood-oxygen level dependent signal intensity [SI] change) under adenosine stress were assessed. Results MPRI was significantly reduced in HCM (1.3 ± 0.1) compared to controls (1.8 ± 0.1, p < 0.001) and athletes (2.0 ± 0.1, p < 0.001), but remained normal in HCM mutation carriers without LVH (1.7 ± 0.1; p = 0.61 vs. controls, p = 0.02 vs. overt HCM). Oxygenation response was attenuated in overt HCM (SI change 6.9 ± 1.4%) compared to controls (18.9 ± 1.4%, p < 0.0001) and athletes (18.7 ± 2.0%, p < 0.001). Interestingly, HCM mutation carriers without LVH also showed an impaired oxygenation response to adenosine (10.4 ± 2.0%; p = 0.001 vs. controls, p = 0.16 vs. overt HCM, p = 0.003 vs. athletes). Conclusions In overt HCM, both perfusion and oxygenation are impaired during vasodilator stress. However, in HCM mutation carriers without LVH, only oxygenation is impaired. In athletes, stress perfusion and oxygenation are normal. CMR assessment of myocardial oxygenation has the potential to become a novel risk factor in HCM. PMID:23498131

Characteristic systolic waveform of left ventricular longitudinal strain rate in patients with hypertrophic cardiomyopathy.

PubMed

Okada, Kazunori; Kaga, Sanae; Mikami, Taisei; Masauzi, Nobuo; Abe, Ayumu; Nakabachi, Masahiro; Yokoyama, Shinobu; Nishino, Hisao; Ichikawa, Ayako; Nishida, Mutsumi; Murai, Daisuke; Hayashi, Taichi; Shimizu, Chikara; Iwano, Hiroyuki; Yamada, Satoshi; Tsutsui, Hiroyuki

2017-05-01

We analyzed the waveform of systolic strain and strain-rate curves to find a characteristic left ventricular (LV) myocardial contraction pattern in patients with hypertrophic cardiomyopathy (HCM), and evaluated the utility of these parameters for the differentiation of HCM and LV hypertrophy secondary to hypertension (HT). From global strain and strain-rate curves in the longitudinal and circumferential directions, the time from mitral valve closure to the peak strains (T-LS and T-CS, respectively) and the peak systolic strain rates (T-LSSR and T-CSSR, respectively) were measured in 34 patients with HCM, 30 patients with HT, and 25 control subjects. The systolic strain-rate waveform was classified into 3 patterns ("V", "W", and "√" pattern). In the HCM group, T-LS was prolonged, but T-LSSR was shortened; consequently, T-LSSR/T-LS ratio was distinctly lower than in the HT and control groups. The "√" pattern of longitudinal strain-rate waveform was more frequently seen in the HCM group (74 %) than in the control (4 %) and HT (20 %) groups. Similar but less distinct results were obtained in the circumferential direction. To differentiate HCM from HT, the sensitivity and specificity of the T-LSSR/T-LS ratio <0.34 and the "√"-shaped longitudinal strain-rate waveform were 85 and 63 %, and 74 and 80 %, respectively. In conclusion, in patients with HCM, a reduced T-LSSR/T-LS ratio and a characteristic "√"-shaped waveform of LV systolic strain rate was seen, especially in the longitudinal direction. The timing and waveform analyses of systolic strain rate may be useful to distinguish between HCM and HT.

Clinical Spectrum and Management of Heart Failure in Hypertrophic Cardiomyopathy.

PubMed

Maron, Barry J; Rowin, Ethan J; Udelson, James E; Maron, Martin S

2018-05-01

Heart failure (HF), characterized by excessive exertional dyspnea, is a common complication within the broad clinical spectrum of hypertrophic cardiomyopathy (HCM). HF has become an increasingly prominent management issue with the reduction in sudden deaths due to use of implantable defibrillators in this disease. Exertional dyspnea ranges in severity from mild to severe (New York Heart Association functional classes II to IV) and not uncommonly becomes refractory to medical management, leading to progressive disability, but largely in the absence of pulmonary congestion and volume overload requiring hospitalization. HCM-related HF is most commonly due to dynamic mechanical impedance to left ventricular outflow produced by mitral valve systolic anterior motion, leading to high intracavity pressures. Surgical septal myectomy with low operative mortality (<1%) produces HF reversal and symptom relief in 90% to 95% of patients, while also conveying a survival benefit. Exercise echocardiography has assumed an important role in the evaluation of patients with HCM, i.e., by identifying candidates for septal reduction therapy with refractory HF when outflow gradients are present only with physiological exercise, distinguishing highly symptomatic nonobstructive patients as heart transplant candidates, and predicting future development of progressive HF. Notably, mortality directly attributable to HF has become exceedingly uncommon in HCM (<0.5%/year) in contrast with HF in non-HCM diseases (by 20-fold). In conclusion, HF in HCM is associated with diverse and complex pathophysiology, but a substantially more favorable prognosis than conventional non-HCM HF, and highly amenable to effective treatment options in the vast majority of patients. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants

PubMed Central

Kraker, Jessica; Viswanathan, Shiv Kumar; Knöll, Ralph; Sadayappan, Sakthivel

2016-01-01

The South Asian population, numbered at 1.8 billion, is estimated to comprise around 20% of the global population and 1% of the American population, and has one of the highest rates of cardiovascular disease. While South Asians show increased classical risk factors for developing heart failure, the role of population-specific genetic risk factors has not yet been examined for this group. Hypertrophic cardiomyopathy (HCM) is one of the major cardiac genetic disorders among South Asians, leading to contractile dysfunction, heart failure, and sudden cardiac death. This disease displays autosomal dominant inheritance, and it is associated with a large number of variants in both sarcomeric and non-sarcomeric proteins. The South Asians, a population with large ethnic diversity, potentially carries region-specific polymorphisms. There is high variability in disease penetrance and phenotypic expression of variants associated with HCM. Thus, extensive studies are required to decipher pathogenicity and the physiological mechanisms of these variants, as well as the contribution of modifier genes and environmental factors to disease phenotypes. Conducting genotype-phenotype correlation studies will lead to improved understanding of HCM and, consequently, improved treatment options for this high-risk population. The objective of this review is to report the history of cardiovascular disease and HCM in South Asians, present previously published pathogenic variants, and introduce current efforts to study HCM using induced pluripotent stem cell-derived cardiomyocytes, next-generation sequencing, and gene editing technologies. The authors ultimately hope that this review will stimulate further research, drive novel discoveries, and contribute to the development of personalized medicine with the aim of expanding therapeutic strategies for HCM. PMID:27840609

Evaluation of a motion artifacts removal approach on breath-hold cine-magnetic resonance images of hypertrophic cardiomyopathy subjects

NASA Astrophysics Data System (ADS)

Betancur, Julián.; Simon, Antoine; Schnell, Frédéric; Donal, Erwan; Hernández, Alfredo; Garreau, Mireille

2013-11-01

The acquisition of ECG-gated cine magnetic resonance images of the heart is routinely performed in apnea in order to suppress the motion artifacts caused by breathing. However, many factors including the 2D nature of the acquisition and the use of di erent beats to acquire the multiple-view cine images, cause this kind of artifacts to appear. This paper presents the qualitative evaluation of a method aiming to remove motion artifacts in multipleview cine images acquired on patients with hypertrophic cardiomyopathy diagnosis. The approach uses iconic registration to reduce for in-plane artifacts in long-axis-view image stacks and in-plane and out-of-plane motion artifacts in sort-axis-view image stack. Four similarity measures were evaluated: the normalized correlation, the normalized mutual information, the sum of absolute voxel di erences and the Slomka metric proposed by Slomka et al. The qualitative evaluation assessed the misalignment of di erent anatomical structures of the left ventricle as follows: the misalignment of the interventricular septum and the lateral wall for short-axis-view acquisitions and the misalignment between the short-axis-view image and long-axis-view images. Results showed the correction using the normalized correlation as the most appropriated with an 80% of success.

The R403Q Myosin Mutation Implicated in Familial Hypertrophic Cardiomyopathy Causes Disorder at the Actomyosin Interface

PubMed Central

Volkmann, Niels; Lui, HongJun; Hazelwood, Larnele; Trybus, Kathleen M.; Lowey, Susan; Hanein, Dorit

2007-01-01

Background Mutations in virtually all of the proteins comprising the cardiac muscle sarcomere have been implicated in causing Familial Hypertrophic Cardiomyopathy (FHC). Mutations in the β-myosin heavy chain (MHC) remain among the most common causes of FHC, with the widely studied R403Q mutation resulting in an especially severe clinical prognosis. In vitro functional studies of cardiac myosin containing the R403Q mutation have revealed significant changes in enzymatic and mechanical properties compared to wild-type myosin. It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype. Principal Findings Here we examine the structural consequences of the R403Q mutation in a recombinant smooth muscle myosin subfragment (S1), whose kinetic features have much in common with slow β-MHC. We obtained three-dimensional reconstructions of wild-type and R403Q smooth muscle S1 bound to actin filaments in the presence (ADP) and absence (apo) of nucleotide by electron cryomicroscopy and image analysis. We observed that the mutant S1 was attached to actin at highly variable angles compared to wild-type reconstructions, suggesting a severe disruption of the actin-myosin interaction at the interface. Significance These results provide structural evidence that disarray at the molecular level may be linked to the histopathological myocyte disarray characteristic of the diseased state. PMID:17987111

Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function.

PubMed

Sommese, Ruth F; Sung, Jongmin; Nag, Suman; Sutton, Shirley; Deacon, John C; Choe, Elizabeth; Leinwand, Leslie A; Ruppel, Kathleen; Spudich, James A

2013-07-30

Cardiovascular disorders are the leading cause of morbidity and mortality in the developed world, and hypertrophic cardiomyopathy (HCM) is among the most frequently occurring inherited cardiac disorders. HCM is caused by mutations in the genes encoding the fundamental force-generating machinery of the cardiac muscle, including β-cardiac myosin. Here, we present a biomechanical analysis of the HCM-causing mutation, R453C, in the context of human β-cardiac myosin. We found that this mutation causes a ∼30% decrease in the maximum ATPase of the human β-cardiac subfragment 1, the motor domain of myosin, and a similar percent decrease in the in vitro velocity. The major change in the R453C human β-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type, with no appreciable change in the stroke size, as observed with a dual-beam optical trap. These results predict that the overall force of the ensemble of myosin molecules in the muscle should be higher in the R453C mutant compared with wild type. Loaded in vitro motility assay confirms that the net force in the ensemble is indeed increased. Overall, this study suggests that the R453C mutation should result in a hypercontractile state in the heart muscle.

c-Myc Alters Substrate Utilization and O-GlcNAc Protein Posttranslational Modifications without Altering Cardiac Function during Early Aortic Constriction

PubMed Central

Ledee, Dolena; Smith, Lincoln; Bruce, Margaret; Kajimoto, Masaki; Isern, Nancy; Portman, Michael A.; Olson, Aaron K.

2015-01-01

Hypertrophic stimuli cause transcription of the proto-oncogene c-Myc (Myc). Prior work showed that myocardial knockout of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we assessed the interplay between Myc, substrate oxidation and cardiac function during early pressure overload hypertrophy. Mice with cardiac specific, inducible Myc knockout (MycKO-TAC) and non-transgenic littermates (Cont-TAC) were subjected to transverse aortic constriction (TAC; n = 7/group). Additional groups underwent sham surgery (Cont-Sham and MycKO-Sham, n = 5 per group). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. In sham hearts, Myc knockout did not affect cardiac function or substrate preferences for the citric acid cycle. However, Myc knockout altered fractional contributions during TAC. The unlabeled fractional contribution increased in MycKO-TAC versus Cont-TAC, whereas ketone and free fatty acid fractional contributions decreased. Additionally, protein posttranslational modifications by O-GlcNAc were significantly greater in Cont-TAC versus both Cont-Sham and MycKO-TAC. In conclusion, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy, which may regulate Myc-induced metabolic changes. PMID:26266538

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors.

PubMed

Jung, L A; Gebhardt, A; Koelmel, W; Ade, C P; Walz, S; Kuper, J; von Eyss, B; Letschert, S; Redel, C; d'Artista, L; Biankin, A; Zender, L; Sauer, M; Wolf, E; Evan, G; Kisker, C; Eilers, M

2017-04-06

MYC genes have both essential roles during normal development and exert oncogenic functions during tumorigenesis. Expression of a dominant-negative allele of MYC, termed OmoMYC, can induce rapid tumor regression in mouse models with little toxicity for normal tissues. How OmoMYC discriminates between physiological and oncogenic functions of MYC is unclear. We have solved the crystal structure of OmoMYC and show that it forms a stable homodimer and as such recognizes DNA in the same manner as the MYC/MAX heterodimer. OmoMYC attenuates both MYC-dependent activation and repression by competing with MYC/MAX for binding to chromatin, effectively lowering MYC/MAX occupancy at its cognate binding sites. OmoMYC causes the largest decreases in promoter occupancy and changes in expression on genes that are invaded by oncogenic MYC levels. A signature of OmoMYC-regulated genes defines subgroups with high MYC levels in multiple tumor entities and identifies novel targets for the eradication of MYC-driven tumors.

Investigation into the use of plasma NT-proBNP concentration to screen for feline hypertrophic cardiomyopathy.

PubMed

Hsu, Adonia; Kittleson, Mark D; Paling, Anna

2009-05-01

To evaluate the utility of feline NT-proBNP plasma concentration [NT-proBNP] as a screening tool for cats with subclinical hypertrophic cardiomyopathy (HCM). Forty adult Maine Coon or Maine Coon crossbred cats from the feline HCM research colony at the University of California, Davis were studied. All cats had previously been genotyped as heterozygous or negative for the A31P myosin binding protein C (MYBPC) mutation. Echocardiograms were performed to assess the severity of HCM in each cat. Blood samples were collected for evaluation of [NT-proBNP]. In these cats with severe HCM, [NT-proBNP] was significantly elevated (P<0.0001) when compared to all other groups of cats and an [NT-proBNP]>44pmol/L accurately predicted the presence of severe HCM. However, [NT-proBNP] was not increased in cats with moderate or equivocal HCM when compared to normal cats. Cats heterozygous for the MYBPC mutation had a significantly elevated [NT-proBNP] when compared to cats without the A31P mutation (P=0.028). Measurement of [NT-proBNP] has a high sensitivity and specificity as a means of detecting severe HCM in cats, but it is not sensitive for the identification of moderate HCM as judged by the evaluation of Maine Coon and Maine Coon cross cats in our colony. Consequently, we conclude that this test cannot be used to screen cats for the presence of mild to moderate HCM.

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

PubMed Central

Vakrou, Styliani; Foster, D. Brian; Sorensen, Lars; Guan, Yufan; Woldemichael, Kirubel; Pineda-Reyes, Roberto; Liu, Ting; Tardiff, Jill C.; Leinwand, Leslie A.; Abraham, Theodore P.; O’Rourke, Brian

2018-01-01

Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation–bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti–TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM. PMID:29563334

Ineffective and prolonged apical contraction is associated with chest pain and ischaemia in apical hypertrophic cardiomyopathy.

PubMed

Stephenson, Edward; Monney, Pierre; Pugliese, Francesca; Malcolmson, James; Petersen, Steffen E; Knight, Charles; Mills, Peter; Wragg, Andrew; O'Mahony, Constantinos; Sekhri, Neha; Mohiddin, Saidi A

2018-01-15

To investigate the hypothesis that persistence of apical contraction into diastole is linked to reduced myocardial perfusion and chest pain. Apical hypertrophic cardiomyopathy (HCM) is defined by left ventricular (LV) hypertrophy predominantly of the apex. Hyperdynamic contractility resulting in obliteration of the apical cavity is often present. Apical HCM can lead to drug-refractory chest pain. We retrospectively studied 126 subjects; 76 with apical HCM and 50 controls (31 with asymmetrical septal hypertrophy (ASH) and 19 with non-cardiac chest pain and culprit free angiograms and structurally normal hearts). Perfusion cardiac magnetic resonance imaging (CMR) scans were assessed for myocardial perfusion reserve index (MPRi), late gadolinium enhancement (LGE), LV volumes (muscle and cavity) and regional contractile persistence (apex, mid and basal LV). In apical HCM, apical MPRi was lower than in normal and ASH controls (p<0.05). In apical HCM, duration of contractile persistence was associated with lower MPRi (p<0.01) and chest pain (p<0.05). In multivariate regression, contractile persistence was independently associated with chest pain (p<0.01) and reduced MPRi (p<0.001). In apical HCM, regional contractile persistence is associated with impaired myocardial perfusion and chest pain. As apical myocardium makes limited contributions to stroke volume, apical contractility is also largely ineffective. Interventions to reduce apical contraction and/or muscle mass are potential therapies for improving symptoms without reducing cardiac output. Copyright © 2017 Elsevier B.V. All rights reserved.

Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy.

PubMed

Mahmoudabady, Maryam; Mathieu, Myrielle; Touihri, Karim; Hadad, Ielham; Da Costa, Agnes Mendes; Naeije, Robert; Mc Entee, Kathleen

2009-10-09

Insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGFbeta) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy. Echocardiographic recordings and myocardial sampling for measurements of gene expressions of IGF-1, its receptor (IGF-1R), TGFbeta and of cyclins A, B, D1, D2, D3 and E, were obtained in 8 dogs with a healed myocardial infarction, 8 dogs after 7 weeks of overpacing and in 7 healthy control dogs. Ischemic cardiomyopathy was characterized by moderate left ventricular systolic dysfunction and eccentric hypertrophy, with increased expressions of IGF-1, IGF-1R and cyclins B, D1, D3 and E. Tachycardiomyopathy was characterized by severe left ventricular systolic dysfunction and dilation with no identifiable hypertrophic response. In the latter model, only IGF-1 was overexpressed while IGF-1R, cyclins B, D1, D3 and E stayed unchanged as compared to controls. The expressions of TGFbeta, cyclins A and D2 were comparable in the 3 groups. The expression of IGF-1R was correlated with the thickness of the interventricular septum, in systole and diastole, and to cyclins B, D1, D3 and E expression. These results agree with the notion that IGF-1/IGF-1R and cyclins are involved in the hypertrophic response observed in cardiomyopathies.

Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy

PubMed Central

Mahmoudabady, Maryam; Mathieu, Myrielle; Touihri, Karim; Hadad, Ielham; Da Costa, Agnes Mendes; Naeije, Robert; Mc Entee, Kathleen

2009-01-01

Background Insulin-like growth factor-1 (IGF-1), transforming growth factor β (TGFβ) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy. Methods Echocardiographic recordings and myocardial sampling for measurements of gene expressions of IGF-1, its receptor (IGF-1R), TGFβ and of cyclins A, B, D1, D2, D3 and E, were obtained in 8 dogs with a healed myocardial infarction, 8 dogs after 7 weeks of overpacing and in 7 healthy control dogs. Results Ischemic cardiomyopathy was characterized by moderate left ventricular systolic dysfunction and eccentric hypertrophy, with increased expressions of IGF-1, IGF-1R and cyclins B, D1, D3 and E. Tachycardiomyopathy was characterized by severe left ventricular systolic dysfunction and dilation with no identifiable hypertrophic response. In the latter model, only IGF-1 was overexpressed while IGF-1R, cyclins B, D1, D3 and E stayed unchanged as compared to controls. The expressions of TGFβ, cyclins A and D2 were comparable in the 3 groups. The expression of IGF-1R was correlated with the thickness of the interventricular septum, in systole and diastole, and to cyclins B, D1, D3 and E expression. Conclusion These results agree with the notion that IGF-1/IGF-1R and cyclins are involved in the hypertrophic response observed in cardiomyopathies. PMID:19818143

MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis.

PubMed

Hsu, Ying-Han R; Yogasundaram, Haran; Parajuli, Nirmal; Valtuille, Lucas; Sergi, Consolato; Oudit, Gavin Y

2016-01-01

Heart failure remains an important clinical burden, and mitochondrial dysfunction plays a key role in its pathogenesis. The heart has a high metabolic demand, and mitochondrial function is a key determinant of myocardial performance. In mitochondrial disorders, hypertrophic remodeling is the early pattern of cardiomyopathy with progression to dilated cardiomyopathy, conduction defects and ventricular pre-excitation occurring in a significant proportion of patients. Cardiac dysfunction occurs in approximately a third of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, a stereotypical example of a mitochondrial disorder leading to a cardiomyopathy. We performed unique comparative ultrastructural and gene expression in a MELAS heart compared with non-failing controls. Our results showed a remarkable increase in mitochondrial inclusions and increased abnormal mitochondria in MELAS cardiomyopathy coupled with variable sarcomere thickening, heterogeneous distribution of affected cardiomyocytes and a greater elevation in the expression of disease markers. Investigation and management of patients with mitochondrial cardiomyopathy should follow the well-described contemporary heart failure clinical practice guidelines and include an important role of medical and device therapies. Directed metabolic therapy is lacking, but current research strategies are dedicated toward improving mitochondrial function in patients with mitochondrial disorders.

Animal Models of Congenital Cardiomyopathies Associated With Mutations in Z-Line Proteins.

PubMed

Bang, Marie-Louise

2017-01-01

The cardiac Z-line at the boundary between sarcomeres is a multiprotein complex connecting the contractile apparatus with the cytoskeleton and the extracellular matrix. The Z-line is important for efficient force generation and transmission as well as the maintenance of structural stability and integrity. Furthermore, it is a nodal point for intracellular signaling, in particular mechanosensing and mechanotransduction. Mutations in various genes encoding Z-line proteins have been associated with different cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, and left ventricular noncompaction, and mutations even within the same gene can cause widely different pathologies. Animal models have contributed to a great advancement in the understanding of the physiological function of Z-line proteins and the pathways leading from mutations in Z-line proteins to cardiomyopathy, although genotype-phenotype prediction remains a great challenge. This review presents an overview of the currently available animal models for Z-line and Z-line associated proteins involved in human cardiomyopathies with special emphasis on knock-in and transgenic mouse models recapitulating the clinical phenotypes of human cardiomyopathy patients carrying mutations in Z-line proteins. Pros and cons of mouse models will be discussed and a future outlook will be given. J. Cell. Physiol. 232: 38-52, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Elevation of c-MYC Disrupts HLA Class II-mediated Immune Recognition of Human B-cell Tumors1

PubMed Central

God, Jason M.; Cameron, Christine; Figueroa, Janette; Amria, Shereen; Hossain, Azim; Kempkes, Bettina; Bornkamm, Georg W.; Stuart, Robert K.; Blum, Janice S.; Haque, Azizul

2014-01-01

Elevated levels of the transcription factor c-myc are strongly associated with various cancers, and in particular B-cell lymphomas. While many of c-MYC’s functions have been elucidated, its effect on the presentation of antigen (Ag) through the HLA class II pathway has not previously been reported. This is an issue of considerable importance, given the low immunogenicity of many c-MYC-positive tumors. We report here that increased c-MYC expression has a negative effect on the ability of B-cell lymphomas to functionally present Ags/peptides to CD4+ T cells. This defect was associated with alterations in the expression of distinct co-factors as well as interactions of antigenic peptides with class II molecules required for the presentation of class II-peptide complexes and T cell engagement. Using early passage Burkitt’s lymphoma (BL) tumors and transformed cells, we show that compared to B-lymphoblasts, BL cells express decreased levels of the class II editor HLA-DM, lysosomal thiol-reductase GILT, and a 47kDa enolase-like protein. Functional Ag presentation was partially restored in BL cells treated with a c-MYC inhibitor, demonstrating the impact of this oncogene on Ag recognition. This restoration of HLA class II-mediated Ag presentation in early passage BL tumors/cells was linked to enhanced HLA-DM expression and a concurrent decrease in HLA-DO in BL cells. Taken together, these results reveal c-MYC exerts suppressive effects at several critical checkpoints in Ag presentation which contribute to the immunoevasive properties of BL tumors. PMID:25595783

Tripeptidyl Peptidase II Is Required for c-MYC-Induced Centriole Overduplication and a Novel Therapeutic Target in c-MYC-Associated Neoplasms.

PubMed

Duensing, Stefan; Darr, Sebastian; Cuevas, Rolando; Melquiot, Nadja; Brickner, Anthony G; Duensing, Anette; Münger, Karl

2010-09-01

Centrosome aberrations are frequently detected in c-MYC-associated human malignancies. Here, we show that c-MYC-induced centrosome and centriole overduplication critically depend on the protease tripeptidyl peptidase II (TPPII). We found that TPPII localizes to centrosomes and that overexpression of TPPII, similar to c-MYC, can disrupt centriole duplication control and cause centriole multiplication, a process during which maternal centrioles nucleate the formation of more than a single daughter centriole. We report that inactivation of TPPII using chemical inhibitors or siRNA-mediated protein knockdown effectively reduced c-MYC-induced centriole overduplication. Remarkably, the potent and selective TPPII inhibitor butabindide not only potently suppressed centriole aberrations but also caused significant cell death and growth suppression in aggressive human Burkitt lymphoma cells with c-MYC overexpression. Taken together, these results highlight the role of TPPII in c-MYC-induced centriole overduplication and encourage further studies to explore TPPII as a novel antineoplastic drug target.

Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse.

PubMed

Cupesi, Mihaela; Yoshioka, Jun; Gannon, Joseph; Kudinova, Anastacia; Stewart, Colin L; Lammerding, Jan

2010-06-01

Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna(-/-) mice develop severe muscular dystrophy and dilated cardiomyopathy and die by 8 weeks of age, heterozygous Lmna(+/-) mice have a much milder phenotype, with changes in ventricular function and morphology only becoming apparent at 1 year of age. Here, we studied 8- to 20-week-old Lmna(+/-) mice and wild-type littermates in a pressure overload model to examine whether increased mechanical load can accelerate or exacerbate myocardial dysfunction in the heterozygotes. While overall survival was similar between genotypes, Lmna(+/-) animals had a significantly attenuated hypertrophic response to pressure overload as evidenced by reduced ventricular mass and myocyte size. Analysis of pressure overload-induced transcriptional changes suggested that the reduced hypertrophy in the Lmna(+/-) mice was accompanied by impaired activation of the mechanosensitive gene Egr-1. In conclusion, our findings provide further support for a critical role of lamins A and C in regulating the cellular response to mechanical stress in cardiomyocytes and demonstrate that haploinsufficiency of lamins A and C alone is sufficient to alter hypertrophic responses and cardiac function in the face of pressure overload in the heart. (c) 2009 Elsevier Ltd. All rights reserved.

Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse

PubMed Central

Cupesi, Mihaela; Yoshioka, Jun; Gannon, Joseph; Kudinova, Anastacia; Stewart, Colin L.; Lammerding, Jan

2009-01-01

Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna−/− mice develop severe muscular dystrophy and dilated cardiomyopathy and die by 8 weeks of age, heterozygous Lmna+/− mice have a much milder phenotype, with changes in ventricular function and morphology only becoming apparent at one year of age. Here, we studied 8 to 20 week old Lmna+/− mice and wild-type littermates in a pressure overload model to examine whether increased mechanical load can accelerate or exacerbate myocardial dysfunction in the heterozygotes. While overall survival was similar between genotypes, Lmna+/− animals had a significantly attenuated hypertrophic response to pressure overload as evidenced by reduced ventricular mass and myocyte size. Analysis of pressure-overload induced transcriptional changes suggested that the reduced hypertrophy in the Lmna+/− mice was accompanied by impaired activation of the mechanosensitive gene Egr-1. In conclusion, our findings provide further support for a critical role of lamins A and C in regulating the cellular response to mechanical stress in cardiomyocytes and demonstrate that haploinsufficiency of lamins A and C alone is sufficient to alter hypertrophic responses and cardiac function in the face of pressure overload in the heart. PMID:19913544

Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes.

PubMed

Sabbagh, Yves; Carpenter, Thomas O; Demay, Marie B

2005-07-05

Rickets is seen in association with vitamin D deficiency and in several genetic disorders associated with abnormal mineral ion homeostasis. Studies in vitamin D receptor (VDR)-null mice have demonstrated that expansion of the late hypertrophic chondrocyte layer, characteristic of rickets, is secondary to impaired apoptosis of these cells. The observation that normalization of mineral ion homeostasis in the VDR-null mice prevents rachitic changes suggests that rickets is secondary to hypocalcemia, hypophosphatemia, or hyperparathyroidism, rather than impaired VDR action. To determine which of these abnormalities is responsible for impaired chondrocyte apoptosis and subsequent rachitic changes, two additional models were examined: diet-induced hypophosphatemia/hypercalcemia and hypophosphatemia secondary to mutations in the Phex gene. The former model is associated with suppressed parathyroid hormone levels as a consequence of hypercalcemia. The latter model demonstrates normal calcium and parathyroid hormone levels, but 1,25-dihydroxyvitamin D levels that are inappropriately low for the degree of hypophosphatemia. Our studies demonstrate that normal phosphorus levels are required for growth plate maturation and implicate a critical role for phosphate-regulated apoptosis of hypertrophic chondrocytes via activation of the caspase-9-mediated mitochondrial pathway.

Plasma level of big endothelin-1 predicts the prognosis in patients with hypertrophic cardiomyopathy.

PubMed

Wang, Yilu; Tang, Yida; Zou, Yubao; Wang, Dong; Zhu, Ling; Tian, Tao; Wang, Jizheng; Bao, Jingru; Hui, Rutai; Kang, Lianming; Song, Lei; Wang, Ji

2017-09-15

Cardiac remodeling is one of major pathological process in hypertrophic cardiomyopathy (HCM). Endothelin-1 has been linked to cardiac remodeling. Big endothelin-1 is the precursor of endothelin-1. A total of 245 patients with HCM were enrolled from 1999 to 2011 and partitioned to low, middle and high level groups according to their plasma big endothelin-1 levels. At baseline, significant associations were found between high level of big endothelin-1 and left atrium size, heart function and atrial fibrillation. Big endothelin-1 was positively correlated with N-terminal B-type natriuretic peptide (r=0.291, p<0.001) and late gadolinium enhancement (LGE) on magnetic resonance imaging (r=0.222, p=0.016). During a follow-up of 3 (range, 2-5) years, big endothelin-1 level was positively associated with the risks of all-cause mortality, cardiovascular death and progression to NYHA class 3 or 4 (p=0.020, 0.044 and 0.032, respectively). The rate of above events in the highest tertile were 18.1%, 15.7%, 24.2%, respectively. After adjusting for multiple factors related to survival and cardiac function, the significance remained in the association of big endothelin-1 with the risk of all-cause mortality (hazard ratio (HR)=4.94, 95% confidence interval (CI) 1.07-22.88; p=0.041) and progression to NYHA class 3 or 4 (HR=4.10, 95%CI 1.32-12.75, p=0.015). Our study showed that high level of plasma big endothelin-1 predicted prognosis for patients with HCM and it can be added to the marker panel in stratifying HCM patients for giving treatment priority to those at high risk. Copyright © 2017. Published by Elsevier B.V.

Left ventricular aneurysms in hypertrophic cardiomyopathy with midventricular obstruction: A systematic review of literature.

PubMed

Elsheshtawy, Moustafa O; Mahmoud, Ahmed N; Abdelghany, Mahmoud; Suen, Ida H; Sadiq, Adnan; Shani, Jacob

2018-05-22

Hypertrophic cardiomyopathy (HCM) with or without left ventricular apical aneurysm (LVA) had been studied in the past. Midventricular obstruction associated with HCM and LVA is a unique entity that has not been distinguished previously as a separate phenotypic disease in HCM patients. A systematic review of Pubmed and Google Scholar was conducted from inception until September 2017 for all observational studies conducted on HCM with midventricular obstruction and LVA. A total of 94 patients from 39 studies were included in our analysis. The mean age of the patients was 58.05 ± 11.76 years with 59.6% being males. The most common electrocardiographic finding was T wave inversion occurring in 13.8% of the cases followed by ST elevation (9.5%). Maximal left ventricle (LV) wall thickness was reported 18.89 ± 5.19 mm on transthoracic echocardiography and paradoxical Jet flow was detected in 29.8% of patients. Beta-blockers (58.5%) were the most common drug therapy at baseline and amiodarone (10.6%) was the most common antiarrhythmic used for ventricular tachycardia (VT). The most common complication, ventricular tachycardia, occurred in 39.3% of cases and the incidence of all-cause mortality was 13.8 % over 16 ± 20.1 months follow-up. Implantable cardioverter defibrillator was used in 37.2% of patients with 25.7% of patients with ICD received appropriate shock therapy. HCM with LVA and midventricular obstruction is a unique entity that appears to be associated with high incidence of morbidity and mortality. Thus, early diagnosis and therapeutic intervention is recommended for management of this condition. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Platelet Function Analyzer 100 and Brain Natriuretic Peptide as Biomarkers in Obstructive Hypertrophic Cardiomyopathy.

PubMed

Blackshear, Joseph L; Safford, Robert E; Thomas, Colleen S; Bos, J Martijn; Ackerman, Michael J; Geske, Jeffrey B; Ommen, Steve R; Shapiro, Brian P; Johns, Gretchen S

2018-03-15

To test dual blood biomarkers compared with electrocardiogram (ECG) for hypertrophic cardiomyopathy (HC) screening, we performed 3 analyses and cut-point assessments. First, we measured platelet function analyzer (PFA)-100 (n = 99) and normalized B-type natriuretic peptide (BNP) or NT-proBNP (BNP/upper limit of normal [ULN], n = 92) in 64 patients with HC and 29 normal controls (NCs). Second, from the regression equation between PFA and gradient (r = 0.77), we derived estimated PFA in a population of 189 patients with functional class I HC in whom measured BNP/ULN and ECG were available, and calculated single and dual biomarker sensitivity and specificity compared with ECG. Finally, we compared BNP/ULN in class I patients based on mutation and familial history status. In 42 patients with obstructive HC versus NCs, there was a slight overlap of PFA and BNP/ULN, but for the product of PFA × BNP/ULN, there was near-complete separation of values. Among patients with class I obstructive HC, estimated PFA × BNP/ULN had a sensitivity of 93% and a specificity of 100%; in latent and nonobstructive HC, sensitivity dropped to 61% and 72%; for ECG in obstructive, latent, and nonobstructive HC, sensitivity was 71%, 34%, and 67%. Functional class I patients with positive (n = 28) and negative (n = 36) sarcomere mutations and a positive (n = 71) or a negative (n = 109) family history had significant elevations of BNP/ULN versus NC, with no between-group differences. In conclusion, PFA and BNP were highly associated with obstructive HC and could potentially be used for screening; BNP was not uniquely elevated in patients with familial versus nonfamilial or mutation-positive versus mutation-negative HC. Copyright © 2017 Elsevier Inc. All rights reserved.

Co-occurrence of hypertrophic cardiomyopathy and myeloproliferative disorder in a neonate with Noonan syndrome carrying Thr73Ile mutation in PTPN11.

PubMed

Yagasaki, Hideaki; Nakane, Takaya; Hasebe, Youhei; Watanabe, Atsushi; Kise, Hiroaki; Toda, Takako; Koizumi, Keiichi; Hoshiai, Minako; Sugita, Kanji

2015-12-01

Most cases of Noonan syndrome (NS) result from mutations in one of the RAS-MAPK signaling genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 (MAP2K1), and CBL. Cardiovascular diseases of varying severity, such as pulmonary stenosis and hypertrophic cardiomyopathy (HCM), are common in NS patients. RAF1 mutations are most frequent in NS with HCM, while PTPN11 mutations are also well known. Thr73Ile is a gain-of-function mutation of PTPN11, which has been highly associated with juvenile myelomonocytic leukemia and NS/myeloproliferative disease (MPD), but has not previously been reported in HCM. Here, we report a Japanese female infant with NS carrying the PTPN11 T73I mutation with NS/MPD, complete atrio-ventricular septal defect, and rapidly progressive HCM. No other HCM-related mutations were detected in PTPN11, RAF1, KRAS, BRAF, and SHOC2. This patient provides additional information regarding the genotype-phenotype correlation for PTPN11 T73I mutation in NS. © 2015 Wiley Periodicals, Inc.

Screening Mutations of MYBPC3 in 114 Unrelated Patients with Hypertrophic Cardiomyopathy by Targeted Capture and Next-generation Sequencing.

PubMed

Liu, Xuxia; Jiang, Tengyong; Piao, Chunmei; Li, Xiaoyan; Guo, Jun; Zheng, Shuai; Zhang, Xiaoping; Cai, Tao; Du, Jie

2015-06-19

Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death. Mutations in the MYBPC3 gene represent the cause of HCM in ~35% of patients with HCM. However, genetic testing in clinic setting has been limited due to the cost and relatively time-consuming by Sanger sequencing. Here, we developed a HCM Molecular Diagnostic Kit enabling ultra-low-cost targeted gene resequencing in a large cohort and investigated the mutation spectrum of MYBPC3. In a cohort of 114 patients with HCM, a total of 20 different mutations (8 novel and 12 known mutations) of MYBPC3 were identified from 25 patients (21.9%). We demonstrated that the power of targeted resequencing in a cohort of HCM patients, and found that MYBPC3 is a common HCM-causing gene in Chinese patients. Phenotype-genotype analyses showed that the patients with double mutations (n = 2) or premature termination codon mutations (n = 12) showed more severe manifestations, compared with patients with missense mutations (n = 11). Particularly, we identified a recurrent truncation mutation (p.Y842X) in four unrelated cases (4/25, 16%), who showed severe phenotypes, and suggest that the p.Y842X is a frequent mutation in Chinese HCM patients with severe phenotypes.

β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

PubMed

Blankenburg, Robert; Hackert, Katarzyna; Wurster, Sebastian; Deenen, René; Seidman, J G; Seidman, Christine E; Lohse, Martin J; Schmitt, Joachim P

2014-07-07

Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family. To characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice. Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling. The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations. © 2014 American Heart Association, Inc.

Prevalence of hypertrophic cardiomyopathy on an electrocardiogram-based pre-participation screening programme in a young male South-East Asian population: results from the Singapore Armed Forces Electrocardiogram and Echocardiogram screening protocol.

PubMed

Ng, Choon Ta; Chee, Tek Siong; Ling, Lee Fong; Lee, Yian Ping; Ching, Chi Keong; Chua, Terrance S J; Cheok, Christopher; Ong, Hean Yee

2011-06-01

Hypertrophic cardiomyopathy is a leading cause of sudden cardiac death (SCD) in young people in the USA. Pre-participation screening for athletes might reduce the incidence of SCD. In Singapore, military service is compulsory for all young able-bodied male citizens. The Singapore Armed Forces Electrocardiogram and Echocardiogram (SAFE) pre-participation screening protocol based on the Italian programme was introduced. This study evaluates the prevalence of hypertrophic cardiomyopathy (HCM) in a young male South-East Asian population. From October 2008 to May 2009, all male military conscripts underwent pre-participation screening. For all conscripts whose electrocardiogram (ECG) findings fulfilled any of these pre-specified criteria (Group A), direct referral for a transthoracic echocardiogram was mandatory. Conscripts with ECG findings other than pre-specified criteria (e.g. T-wave inversions, repolarization abnormalities) were referred for secondary screening by cardiologists (Group B), which could include echocardiography. Out of 18 476 subjects screened during the study period, 988 (5.3%) subjects were fast tracked for echocardiogram (Group A). Of them, there were three (0.3%) cases with severe abnormalities; there was one case each of HCM, bicuspid aortic valve with significant aortic valve regurgitation, and atrial septal defect with right ventricular systolic dysfunction. The patient with HCM had left axis deviation on ECG. None of the 215 patients who underwent echocardiography following cardiology consult (Group B) had HCM. The prevalence of HCM in our young male population (mean age 19.5, range 16-27) using an ECG-based screening protocol was 0.005%; this appeared lower than published data from other geographical cohorts. Possible explanations include a later age of phenotypic manifestation in our population, limitations of the ECG criteria for screening, or a truly lower prevalence of HCM. More population-based longitudinal studies would be needed to

Long-term outcomes of septal reduction for obstructive hypertrophic cardiomyopathy.

PubMed

Sedehi, Daniel; Finocchiaro, Gherardo; Tibayan, Yen; Chi, Jeffrey; Pavlovic, Aleksandra; Kim, Young M; Tibayan, Frederick A; Reitz, Bruce A; Robbins, Robert C; Woo, Joseph; Ha, Richard; Lee, David P; Ashley, Euan A

2015-07-01

Surgical myectomy and alcohol septal ablation (ASA) aim to decrease left ventricular outflow tract (LVOT) gradient in hypertrophic cardiomyopathy (HCM). Outcome of myectomy beyond 10 years has rarely been described. We describe 20 years of follow-up of surgical myectomy and 5 years of follow-up for ASA performed for obstructive HCM. We studied 171 patients who underwent myectomy for symptomatic LVOT obstruction between 1972 and 2006. In addition, we studied 52 patients who underwent ASA for the same indication and who declined surgery. Follow-up of New York Heart Association (NYHA) functional class, echocardiographic data, and vital status were obtained from patient records. Mortality rates were compared with expected mortality rates of age- and sex-matched populations. Surgical myectomy improved NYHA class (2.74±0.65 to 1.54±0.74, p<0.001), reduced resting gradient (67.4±43.4mmHg to 11.2±16.4mmHg, p<0.001), and inducible LVOT gradient (98.1±34.7mmHg to 33.6±34.9mmHg, p<0.001). Similarly, ASA improved functional class (2.99±0.35 to 1.5±0.74, p<0.001), resting gradient (67.1±26.9mmHg to 23.9±29.4mmHg, p<0.001) and provoked gradient (104.4±34.9mmHg to 35.5±38.6mmHg, p<0.001). Survival after myectomy at 5, 10, 15, and 20 years of follow-up was 92.9%, 81.1%, 68.9%, and 47.5%, respectively. Of note, long-term survival after myectomy was lower than for the general population [standardized mortality ratio (SMR)=1.40, p<0.005], but still compared favorably with historical data from non-operated HCM patients. Survival after ASA at 2 and 5 years was 97.8% and 94.7%, respectively. Short-term (5 year) survival after ASA (SMR=0.61, p=0.48) was comparable to that of the general population. Long-term follow-up of septal reduction strategies in obstructive HCM reveals that surgical myectomy and ASA are effective for symptom relief and LVOT gradient reduction and are associated with favorable survival. While overall prognosis for the community HCM population is similar

Expression of a mutation causing hypertrophic cardiomyopathy disrupts sarcomere assembly in adult feline cardiac myocytes.

PubMed

Marian, A J; Yu, Q T; Mann, D L; Graham, F L; Roberts, R

1995-07-01

Mutations in the beta-myosin heavy chain (beta MyHC) induce hypertrophic cardiomyopathy (HCM), cardiac hypertrophy, and sarcomere disarray, with the latter being the characteristic hallmark. Thus, we sought to determine whether expression of mutant beta MyHC in adult feline cardiac myocytes, a species known to develop HCM with a phenotype identical to that in humans, induces sarcomere disarray. A full-length beta MyHC cDNA was cloned from a human heart cDNA library, and an HCM-causing mutation (Arg403Gln) was induced in the beta MyHC cDNA by site-directed mutagenesis using polymerase chain reaction (PCR). The normal and mutant beta MyHC cDNAs were cloned into p delta E1spIB shuttle vector, downstream from a cytomegalovirus (CMV) promoter. Replication-deficient recombinant adenoviral constructs (Ad5/CMV/beta MyHC-N and Ad5/CMV/beta MyHC-403) were generated through homologous recombination of p delta E1spIB/CMV/beta MyHC-N or Ad5/CMV/beta MyHC-403 and pBHG10 after cotransfection in 293 host cells. Infection of COS-1 cells with the beta MyHC construct resulted in the expression of a full-length myosin protein. Efficiency of infection of isolated adult cardiac myocytes was > 95%. Expression of the beta MyHC constructs into mRNA at 48 hours after infection of feline cardiac myocytes was confirmed by reverse transcription-PCR. The net total protein and beta-myosin synthesis were determined by using the amount of incorporation of [3H]phenylalanine into total protein and beta-myosin, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of left ventricular twist mechanics in cardiomyopathies, dance of the helices

PubMed Central

Kauer, Floris; Geleijnse, Marcel Leonard; van Dalen, Bastiaan Martijn

2015-01-01

Left ventricular twist is an essential part of left ventricular function. Nevertheless, knowledge is limited in “the cardiology community” as it comes to twist mechanics. Fortunately the development of speckle tracking echocardiography, allowing accurate, reproducible and rapid bedside assessment of left ventricular twist, has boosted the interest in this important mechanical aspect of left ventricular deformation. Although the fundamental physiological role of left ventricular twist is undisputable, the clinical relevance of assessment of left ventricular twist in cardiomyopathies still needs to be established. The fact remains; analysis of left ventricular twist mechanics has already provided substantial pathophysiological understanding on a comprehensive variety of cardiomyopathies. It has become clear that increased left ventricular twist in for example hypertrophic cardiomyopathy may be an early sign of subendocardial (microvascular) dysfunction. Furthermore, decreased left ventricular twist may be caused by left ventricular dilatation or an extensive myocardial scar. Finally, the detection of left ventricular rigid body rotation in noncompaction cardiomyopathy may provide an indispensible method to objectively confirm this difficult diagnosis. All this endorses the value of left ventricular twist in the field of cardiomyopathies and may further encourage the implementation of left ventricular twist parameters in the “diagnostic toolbox” for cardiomyopathies. PMID:26322187

Effect of Hypertrophic Cardiomyopathy-Linked Troponin C Mutations on the Response of Reconstituted Thin Filaments to Calcium upon Troponin I Phosphorylation†

PubMed Central

Albury, Acchia N. J.; Swindle, Nicholas; Swartz, Darl R.; Tikunova, Svetlana B.

2012-01-01

The objective of this work was to investigate the effect of hypertrophic cardiomyopathy-linked A8V and E134D mutations in cardiac troponin C (cTnC) on the response of reconstituted thin filaments to calcium upon phosphorylation of cardiac troponin I (cTnI) by protein kinase A. The phosphorylation of cTnI at protein kinase A sites was mimicked by S22D/S23D mutation in cTnI. Our results demonstrate that the A8V and E134D mutations had no effect on the extent of calcium desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. However, the A8V mutation enhanced the effect of cTnI pseudo-phosphorylation on the rate of calcium dissociation from reconstituted thin filaments and on calcium dependence of actomyosin ATPase. Consequently, while the A8V mutation still led to a slower rate of calcium dissociation from reconstituted thin filaments upon pseudo-phosphorylation of cTnI, the ability of the A8V mutation to decrease the rate of calcium dissociation was diminished. In addition, the ability of the A8V mutation to sensitize actomyosin ATPase to calcium was diminished after cTnI was replaced by the phosphorylation mimetic of cTnI. Consistent with the hypothesis that the E134D mutation is benign, it exerted minor to no effect on the rate of calcium dissociation from reconstituted thin filaments, and on calcium sensitivity of actomyosin ATPase, regardless of cTnI phosphorylation status. In conclusion, our study enhances understanding of how cardiomyopathy-linked cTnC mutations affect the response of reconstituted thin filaments to calcium upon cTnI phosphorylation. PMID:22489623

Exome Sequencing Identifies Mitochondrial Alanyl-tRNA Synthetase Mutations in Infantile Mitochondrial Cardiomyopathy

PubMed Central

Götz, Alexandra; Tyynismaa, Henna; Euro, Liliya; Ellonen, Pekka; Hyötyläinen, Tuulia; Ojala, Tiina; Hämäläinen, Riikka H.; Tommiska, Johanna; Raivio, Taneli; Oresic, Matej; Karikoski, Riitta; Tammela, Outi; Simola, Kalle O.J.; Paetau, Anders; Tyni, Tiina; Suomalainen, Anu

2011-01-01

Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure. PMID:21549344

Obesity and its association to phenotype and clinical course in hypertrophic cardiomyopathy.

PubMed

Olivotto, Iacopo; Maron, Barry J; Tomberli, Benedetta; Appelbaum, Evan; Salton, Carol; Haas, Tammy S; Gibson, C Michael; Nistri, Stefano; Servettini, Eleonora; Chan, Raymond H; Udelson, James E; Lesser, John R; Cecchi, Franco; Manning, Warren J; Maron, Martin S

2013-07-30

This study sought to assess the impact of body mass index (BMI) on cardiac phenotypic and clinical course in a multicenter hypertrophic cardiomyopathy (HCM) cohort. It is unresolved whether clinical variables promoting left ventricular (LV) hypertrophy in the general population, such as obesity, may influence cardiac phenotypic and clinical course in patients with HCM. In 275 adult HCM patients (age 48 ± 14 years; 70% male), we assessed the relation of BMI to LV mass, determined by cardiovascular magnetic resonance (CMR) and heart failure progression. At multivariate analysis, BMI proved independently associated with the magnitude of hypertrophy: pre-obese and obese HCM patients (BMI 25 to 30 kg/m(2) and >30 kg/m(2), respectively) showed a 65% and 310% increased likelihood of an LV mass in the highest quartile (>120 g/m(2)), compared with normal weight patients (BMI <25 kg/m(2); hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 0.73 to 3.74, p = 0.22 and 3.1; 95% CI: 1.42 to 6.86, p = 0.004, respectively). Other features associated with LV mass >120 g/m(2) were LV outflow obstruction (HR: 4.9; 95% CI: 2.4 to 9.8; p < 0.001), systemic hypertension (HR: 2.2; 95% CI: 1.1 to 4.5; p = 0.026), and male sex (HR: 2.1; 95% CI: 0.9 to 4.7; p = 0.083). During a median follow-up of 3.7 years (interquartile range: 2.5 to 5.3), obese patients showed an HR of 3.6 (95% CI: 1.2 to 10.7, p = 0.02) for developing New York Heart Association (NYHA) functional class III to IV symptoms compared to nonobese patients, independent of outflow obstruction. Noticeably, the proportion of patients in NYHA functional class III at the end of follow-up was 13% among obese patients, compared with 6% among those of normal weight (p = 0.03). In HCM patients, extrinsic factors such as obesity are independently associated with increase in LV mass and may dictate progression of heart failure symptoms. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights

Sequential treatment with aurora B inhibitors enhances cisplatin-mediated apoptosis via c-Myc.

PubMed

Ma, Yaxi; Cao, Handi; Lou, Siyue; Shao, Xuejing; Lv, Wen; Qi, Xiaotian; Liu, Yujia; Ying, Meidan; He, Qiaojun; Yang, Xiaochun

2015-04-01

Platinum compound such as cisplatin is the first-line chemotherapy of choice in most patients with ovarian carcinoma. However, patients with inherent or acquired cisplatin resistance often experience relapse. Therefore, novel therapies are urgently required to treat drug-resistant ovarian carcinoma. Here, we showed that compared to the non-functional traditional simultaneous treatment, sequential combination of Aurora B inhibitors followed by cisplatin synergistically enhanced apoptotic response in cisplatin-resistant OVCAR-8 cells. This effect was accompanied by the induction of polyploidy in a c-Myc-dependent manner, as c-Myc knockdown reduced the efficacy of the combination by suppressing the expression of Aurora B and impairing cellular response to Aurora B inhibitor, as indicated by the decreased polyploidy and hyperphosphorylation of histone H1. In c-Myc-deficient SKOV3 cells, c-Myc overexpression restored Aurora B expression, induced polyploidy after inhibition of Aurora B, and sensitized cells to this combination therapy. Thus, our report reveals for the first time that sequential treatment of Aurora B inhibitors and cisplatin is essential to inhibit ovarian carcinoma by inducing polyploidy and downregulating c-Myc and that c-Myc is identified as a predictive biomarker to select cells responsive to chemotherapeutical combinations targeting Aurora B. Collectively, these studies provide novel approaches to overcoming cisplatin chemotherapy resistance in ovarian cancer. Pretreatment of Aurora B inhibitors augment apoptotic effects of cisplatin. The synergy of Aurora B inhibitor with cisplatin is dependent on c-Myc expression. c-Myc-dependent induction of polyploidy sensitizes cells to cisplatin.

Vortical features for myocardial rotation assessment in hypertrophic cardiomyopathy using cardiac tagged magnetic resonance.

PubMed

Sanz-Estébanez, Santiago; Cordero-Grande, Lucilio; Sevilla, Teresa; Revilla-Orodea, Ana; de Luis-García, Rodrigo; Martín-Fernández, Marcos; Alberola-López, Carlos

2018-07-01

Left ventricular rotational motion is a feature of normal and diseased cardiac function. However, classical torsion and twist measures rely on the definition of a rotational axis which may not exist. This paper reviews global and local rotation descriptors of myocardial motion and introduces new curl-based (vortical) features built from tensorial magnitudes, intended to provide better comprehension about fibrotic tissue characteristics mechanical properties. Fifty-six cardiomyopathy patients and twenty-two healthy volunteers have been studied using tagged magnetic resonance by means of harmonic phase analysis. Rotation descriptors are built, with no assumption about a regular geometrical model, from different approaches. The extracted vortical features have been tested by means of a sequential cardiomyopathy classification procedure; they have proven useful for the regional characterization of the left ventricular function by showing great separability not only between pathologic and healthy patients but also, and specifically, between heterogeneous phenotypes within cardiomyopathies. Copyright © 2018 Elsevier B.V. All rights reserved.

ENDEAVOUR: Phase 3 Multicenter Study of Revusiran (ALN-TTRSC) in Patients With Transthyretin (TTR) Mediated Familial Amyloidotic Cardiomyopathy (FAC)

ClinicalTrials.gov

2017-12-08

Transthyretin (TTR) Mediated Familial Amyloidotic Cardiomyopathy (FAC); Amyloidosis, Hereditary; Amyloid Neuropathies, Familial; Amyloid Neuropathies; Amyloidosis, Hereditary, Transthyretin-Related; Familial Transthyretin Cardiac Amyloidosis

Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1

PubMed Central

Sussman, Mark A.; Welch, Sara; Walker, Angela; Klevitsky, Raisa; Hewett, Timothy E.; Price, Robert L.; Schaefer, Erik; Yager, Karen

2000-01-01

The ras family of small GTP-binding proteins exerts powerful effects upon cell structure and function. One member of this family, rac, induces actin cytoskeletal reorganization in nonmuscle cells and hypertrophic changes in cultured cardiomyocytes. To examine the effect of rac1 activation upon cardiac structure and function, transgenic mice were created that express constitutively activated rac1 specifically in the myocardium. Transgenic rac1 protein was expressed at levels comparable to endogenous rac levels, with activation of the rac1 signaling pathway resulting in two distinct cardiomyopathic phenotypes: a lethal dilated phenotype associated with neonatal activation of the transgene and a transient cardiac hypertrophy seen among juvenile mice that resolved with age. Neither phenotype showed myofibril disarray and hypertrophic hearts were hypercontractilein working heart analyses. The rac1 target p21-activated kinase translocated from a cytosolic to a cytoskeletal distribution, suggesting that rac1 activation was inducing focal adhesion reorganization. Corroborating results showed altered localizations of src in dilated cardiomyopathy and paxillin in both cardiomyopathic phenotypes. This study, the first examination of rac1-mediated cardiac effects in vivo, demonstrates that dilation and hypertrophy can share a common molecular origin and presents evidence that both timing and concurrent signaling from multiple pathways can influence cardiac remodeling. PMID:10749567

Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy.

PubMed

Ismail, Tevfik F; Jabbour, Andrew; Gulati, Ankur; Mallorie, Amy; Raza, Sadaf; Cowling, Thomas E; Das, Bibek; Khwaja, Jahanzaib; Alpendurada, Francisco D; Wage, Ricardo; Roughton, Michael; McKenna, William J; Moon, James C; Varnava, Amanda; Shakespeare, Carl; Cowie, Martin R; Cook, Stuart A; Elliott, Perry; O'Hanlon, Rory; Pennell, Dudley J; Prasad, Sanjay K

2014-12-01

Myocardial fibrosis identified by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM) is associated with adverse cardiovascular events, but its value as an independent risk factor for sudden cardiac death (SCD) is unknown. We investigated the role of LGE-CMR in the risk stratification of HCM. We conducted a prospective cohort study in a tertiary referral centre. Consecutive patients with HCM (n=711, median age 56.3 years, IQR 46.7-66.6; 70.0% male) underwent LGE-CMR and were followed for a median 3.5 years. The primary end point was SCD or aborted SCD. Overall, 471 patients (66.2%) had myocardial fibrosis (median 5.9% of left ventricular mass, IQR: 2.2-13.3). Twenty-two (3.1%) reached the primary end point. The extent but not the presence of fibrosis was a significant univariable predictor of the primary end point (HR per 5% LGE: 1.24, 95% CI 1.06 to 1.45; p=0.007 and HR for LGE: 2.69, 95% CI 0.91 to 7.97; p=0.073, respectively). However, on multivariable analysis, only LV-EF remained statistically significant (HR: 0.92, 95% CI 0.89 to 0.95; p<0.001). For the secondary outcome of cardiovascular mortality/aborted SCD, the presence and the amount of fibrosis were significant predictors on univariable but not multivariable analysis after adjusting for LV-EF and non-sustained ventricular tachycardia. The amount of myocardial fibrosis was a strong univariable predictor of SCD risk. However, this effect was not maintained after adjusting for LV-EF. Further work is required to elucidate the interrelationship between fibrosis and traditional predictors of outcome in HCM. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Familial hypertrophic cardiomyopathy: functional variance among individual cardiomyocytes as a trigger of FHC-phenotype development

PubMed Central

Brenner, Bernhard; Seebohm, Benjamin; Tripathi, Snigdha; Montag, Judith; Kraft, Theresia

2014-01-01

Familial hypertrophic cardiomyopathy (FHC) is the most frequent inherited cardiac disease. It has been related to numerous mutations in many sarcomeric and even some non-sarcomeric proteins. So far, however, no common mechanism has been identified by which the many different mutations in different sarcomeric and non-sarcomeric proteins trigger development of the FHC phenotype. Here we show for different MYH7 mutations variance in force pCa-relations from normal to highly abnormal as a feature common to all mutations we studied, while direct functional effects of the different FHC-mutations, e.g., on force generation, ATPase or calcium sensitivity of the contractile system, can be quite different. The functional variation among individual M. soleus fibers of FHC-patients is accompanied by large variation in mutant vs. wildtype β-MyHC-mRNA. Preliminary results show a similar variation in mutant vs. wildtype β-MyHC-mRNA among individual cardiomyocytes. We discuss our previously proposed concept as to how different mutations in the β-MyHC and possibly other sarcomeric and non-sarcomeric proteins may initiate an FHC-phenotype by functional variation among individual cardiomyocytes that results in structural distortions within the myocardium, leading to cellular and myofibrillar disarray. In addition, distortions can activate stretch-sensitive signaling in cardiomyocytes and non-myocyte cells which is known to induce cardiac remodeling with interstitial fibrosis and hypertrophy. Such a mechanism will have major implications for therapeutic strategies to prevent FHC-development, e.g., by reducing functional imbalances among individual cardiomyocytes or by inhibition of their triggering of signaling paths initiating remodeling. Targeting increased or decreased contractile function would require selective targeting of mutant or wildtype protein to reduce functional imbalances. PMID:25346696

Sin3b interacts with Myc and decreases Myc levels.

PubMed

Garcia-Sanz, Pablo; Quintanilla, Andrea; Lafita, M Carmen; Moreno-Bueno, Gema; García-Gutierrez, Lucia; Tabor, Vedrana; Varela, Ignacio; Shiio, Yuzuru; Larsson, Lars-Gunnar; Portillo, Francisco; Leon, Javier

2014-08-08

Myc expression is deregulated in many human cancers. A yeast two-hybrid screen has revealed that the transcriptional repressor Sin3b interacts with Myc protein. Endogenous Myc and Sin3b co-localize and interact in the nuclei of human and rat cells, as assessed by co-immunoprecipitation, immunofluorescence, and proximity ligation assay. The interaction is Max-independent. A conserved Myc region (amino acids 186-203) is required for the interaction with Sin3 proteins. Histone deacetylase 1 is recruited to Myc-Sin3b complexes, and its deacetylase activity is required for the effects of Sin3b on Myc. Myc and Sin3a/b co-occupied many sites on the chromatin of human leukemia cells, although the presence of Sin3 was not associated with gene down-regulation. In leukemia cells and fibroblasts, Sin3b silencing led to Myc up-regulation, whereas Sin3b overexpression induced Myc deacetylation and degradation. An analysis of Sin3b expression in breast tumors revealed an association between low Sin3b expression and disease progression. The data suggest that Sin3b decreases Myc protein levels upon Myc deacetylation. As Sin3b is also required for transcriptional repression by Mxd-Max complexes, our results suggest that, at least in some cell types, Sin3b limits Myc activity through two complementary activities: Mxd-dependent gene repression and reduction of Myc levels. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Resetting cancer stem cell regulatory nodes upon MYC inhibition.

PubMed

Galardi, Silvia; Savino, Mauro; Scagnoli, Fiorella; Pellegatta, Serena; Pisati, Federica; Zambelli, Federico; Illi, Barbara; Annibali, Daniela; Beji, Sara; Orecchini, Elisa; Alberelli, Maria Adele; Apicella, Clara; Fontanella, Rosaria Anna; Michienzi, Alessandro; Finocchiaro, Gaetano; Farace, Maria Giulia; Pavesi, Giulio; Ciafrè, Silvia Anna; Nasi, Sergio

2016-12-01

MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc-a MYC-derived polypeptide interfering with MYC activity-taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells. © 2016 The Authors.

Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature.

PubMed

Mazurova, Stella; Magner, Martin; Kucerova-Vidrova, Vendula; Vondrackova, Alzbeta; Stranecky, Viktor; Pristoupilova, Anna; Zamecnik, Josef; Hansikova, Hana; Zeman, Jiri; Tesarova, Marketa; Honzik, Tomas

2017-07-01

Cardiomyopathy is a common manifestation in neonates and infants with mitochondrial disorders. In this study, we report two cases manifesting with fatal mitochondrial hypertrophic cardiomyopathy, which include the third known patient with thymidine kinase 2 deficiency and the ninth patient with alanyl-tRNA synthetase 2 deficiency. The girl with thymidine kinase 2 deficiency had hypertrophic cardiomyopathy together with regression of gross motor development at the age of 13 months. Neurological symptoms and cardiac involvement progressed into severe myopathy, psychomotor arrest, and cardiorespiratory failure at the age of 22 months. The imaging methods and autoptic studies proved that she suffered from unique findings of leucoencephalopathy, severe, mainly cerebellar neuronal degeneration, and hepatic steatosis. The girl with alanyl-tRNA synthetase 2 deficiency presented with cardiac failure and underlying hypertrophic cardiomyopathy within 12 hours of life and subsequently died at 9 weeks of age. Muscle biopsy analyses demonstrated respiratory chain complex I and IV deficiencies, and histological evaluation revealed massive mitochondrial accumulation and cytochrome c oxidase-negative fibres in both cases. Exome sequencing in the first case revealed compound heterozygozity for one novel c.209T>C and one previously published c.416C>T mutation in the TK2 gene, whereas in the second case homozygozity for the previously described mutation c.1774C>T in the AARS2 gene was determined. The thymidine kinase 2 mutations resulted in severe mitochondrial DNA depletion (to 12% of controls) in the muscle. We present, for the first time, severe leucoencephalopathy and hepatic steatosis in a patient with thymidine kinase 2 deficiency and the finding of a ragged red fibre-like image in the muscle biopsy in a patient with alanyl-tRNA synthetase 2 deficiency.

The Cardiomyopathy Registry of the EURObservational Research Programme of the European Society of Cardiology: baseline data and contemporary management of adult patients with cardiomyopathies.

PubMed

Charron, Philippe; Elliott, Perry M; Gimeno, Juan R; Caforio, Alida L P; Kaski, Juan Pablo; Tavazzi, Luigi; Tendera, Michal; Maupain, Carole; Laroche, Cécile; Rubis, Pawel; Jurcut, Ruxandra; Calò, Leonardo; Heliö, Tiina M; Sinagra, Gianfranco; Zdravkovic, Marija; Kavoliuniene, Aušra; Felix, Stephan B; Grzybowski, Jacek; Losi, Maria-Angela; Asselbergs, Folkert W; García-Pinilla, José Manuel; Salazar-Mendiguchia, Joel; Mizia-Stec, Katarzyna; Maggioni, Aldo P

2018-05-21

The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe.

Ribosomal proteins L5 and L11 co-operatively inactivate c-Myc via RNA-induced silencing complex.

PubMed

Liao, J-M; Zhou, X; Gatignol, A; Lu, H

2014-10-09

Oncogene MYC is highly expressed in many human cancers and functions as a global regulator of ribosome biogenesis. Previously, we reported that ribosomal protein (RP) L11 binds to c-Myc and inhibits its transcriptional activity in response to ribosomal stress. Here, we show that RPL5, co-operatively with RPL11, guides the RNA-induced silencing complex (RISC) to c-Myc mRNA and mediates the degradation of the mRNA, consequently leading to inhibition of c-Myc activity. Knocking down of RPL5 induced c-Myc expression at both mRNA and protein levels, whereas overexpression of RPL5 suppressed c-Myc expression and activity. Immunoprecipitation revealed that RPL5 binds to 3'UTR of c-Myc mRNA and two subunits of RISC, TRBP (HIV-1 TAR RNA-binding protein) and Ago2, mediating the targeting of c-Myc mRNA by miRNAs. Interestingly, RPL5 and RPL11 co-resided on c-Myc mRNA and suppressed c-Myc expression co-operatively. These findings uncover a mechanism by which these two RPs can co-operatively suppress c-Myc expression, allowing a tightly controlled ribosome biogenesis in cells.

The novel mitochondrial 16S rRNA 2336T>C mutation is associated with hypertrophic cardiomyopathy

PubMed Central

Liu, Zhong; Song, Yanrui; Li, Dan; He, Xiangyu; Li, Shishi; Wu, Bifeng; Wang, Wei; Gu, Shulian; Zhu, Xiaoyu; Wang, Xuexiang; Zhou, Qiyin; Dai, Yu; Yan, Qingfeng

2014-01-01

Background Hypertrophic cardiomyopathy (HCM) is a primary disorder characterised by asymmetric thickening of septum and left ventricular wall, with a prevalence of 0.2% in the general population. Objective To describe a novel mitochondrial DNA mutation and its association with the pathogenesis of HCM. Methods and results All maternal members of a Chinese family with maternally transmitted HCM exhibited variable severity and age at onset, and were implanted permanent pacemakers due to complete atrioventricular block (AVB). Nuclear gene screening (MYH7, MYBPC3, TNNT2 and TNNI3) was performed, and no potential pathogenic mutation was identified. Mitochondrial DNA sequencing analysis identified a novel homoplasmic 16S rRNA 2336T>C mutation. This mutation was exclusively present in maternal members and absent in non-maternal members. Conservation index by comparison to 16 other vertebrates was 94.1%. This mutation disturbs the 2336U-A2438 base pair in the stem–loop structure of 16S rRNA domain III, which is involved in the assembly of mitochondrial ribosome. Oxygen consumption rate of the lymphoblastoid cells carrying 2336T>C mutation had decreased by 37% compared with controls. A reduction in mitochondrial ATP synthesis and an increase in reactive oxidative species production were also observed. Electron microscopic analysis indicated elongated mitochondria and abnormal mitochondrial cristae shape in mutant cells. Conclusions It is suggested that the 2336T>C mutation is one of pathogenic mutations of HCM. This is the first report of mitochondrial 16S rRNA 2336T>C mutation and an association with maternally inherited HCM combined with AVB. Our findings provide a new insight into the pathogenesis of HCM. PMID:24367055

Diltiazem Treatment for Preclinical Hypertrophic Cardiomyopathy Mutation Carriers: A Pilot Randomized Trial to Modify Disease Expression

PubMed Central

Ho, Carolyn Y.; Lakdawala, Neal K.; Cirino, Allison L.; Lipshultz, Steven E.; Sparks, Elizabeth; Abbasi, Siddique A.; Kwong, Raymond Y.; Antman, Elliott M.; Semsarian, Christopher; González, Arantxa; López, Begoña; Diez, Javier; Orav, E. John; Colan, Steven D.; Seidman, Christine E.

2014-01-01

Background Hypertrophic cardiomyopathy (HCM) is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate alterations in intracellular calcium handling before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. Objectives To assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk HCM mutation carriers. Methods In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean age 15.8 years) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. Results Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular end diastolic diameter improved towards normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. −0.5; P<0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group, but increased in controls (−0.02 vs. +0.15; P=0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, two in each treatment group. Conclusions Preclinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. PMID:25543971

The prognostic value of standardized reference values for speckle-tracking global longitudinal strain in hypertrophic cardiomyopathy.

PubMed

Hartlage, Gregory R; Kim, Jonathan H; Strickland, Patrick T; Cheng, Alan C; Ghasemzadeh, Nima; Pernetz, Maria A; Clements, Stephen D; Williams, B Robinson

2015-03-01

Speckle-tracking left ventricular global longitudinal strain (GLS) assessment may provide substantial prognostic information for hypertrophic cardiomyopathy (HCM) patients. Reference values for GLS have been recently published. We aimed to evaluate the prognostic value of standardized reference values for GLS in HCM patients. An analysis of HCM clinic patients who underwent GLS was performed. GLS was defined as normal (more negative or equal to -16%) and abnormal (less negative than -16%) based on recently published reference values. Patients were followed for a composite of events including heart failure hospitalization, sustained ventricular arrhythmia, and all-cause death. The power of GLS to predict outcomes was assessed relative to traditional clinical and echocardiographic variables present in HCM. 79 HCM patients were followed for a median of 22 months (interquartile range 9-30 months) after imaging. During follow-up, 15 patients (19%) met the primary outcome. Abnormal GLS was the only echocardiographic variable independently predictive of the primary outcome [multivariate Hazard ratio 5.05 (95% confidence interval 1.09-23.4, p = 0.038)]. When combined with traditional clinical variables, abnormal GLS remained independently predictive of the primary outcome [multivariate Hazard ratio 5.31 (95 % confidence interval 1.18-24, p = 0.030)]. In a model including the strongest clinical and echocardiographic predictors of the primary outcome, abnormal GLS demonstrated significant incremental benefit for risk stratification [net reclassification improvement 0.75 (95 % confidence interval 0.21-1.23, p < 0.0001)]. Abnormal GLS is an independent predictor of adverse outcomes in HCM patients. Standardized use of GLS may provide significant incremental value over traditional variables for risk stratification.

Atrial Fibrillation in Hypertrophic Cardiomyopathy: Prevalence, Clinical Correlations, and Mortality in a Large High‐Risk Population

PubMed Central

Siontis, Konstantinos C.; Geske, Jeffrey B.; Ong, Kevin; Nishimura, Rick A.; Ommen, Steve R.; Gersh, Bernard J.

2014-01-01

Background Atrial fibrillation (AF) is a common sequela of hypertrophic cardiomyopathy (HCM), but evidence on its prevalence, risk factors, and effect on mortality is sparse. We sought to evaluate the prevalence of AF, identify clinical and echocardiographic correlates, and assess its effect on mortality in a large high‐risk HCM population. Methods and Results We identified HCM patients who underwent evaluation at our institution from 1975 to 2012. AF was defined by known history (either chronic or paroxysmal), electrocardiogram, or Holter monitoring at index visit. We examined clinical and echocardiographic variables in association with AF. The effect of AF on overall and cause‐specific mortality was evaluated with multivariate Cox proportional hazards models. Of 3673 patients with HCM, 650 (18%) had AF. Patients with AF were older and more symptomatic (P<0.001). AF was less common among patients with obstructive HCM phenotype and was associated with larger left atria, higher E/e’ ratios, and worse cardiopulmonary exercise tolerance (all P values<0.001). During median (interquartile range) follow‐up of 4.1 (0.2 to 10) years, 1069 (29%) patients died. Patients with AF had worse survival compared to those without AF (P<0.001). In multivariate analysis adjusted for established risk factors of mortality in HCM, the hazard ratio (95% confidence interval) for the effect of AF on overall mortality was 1.48 (1.27 to 1.71). AF did not have an effect on sudden or nonsudden cardiac death. Conclusions In this large referral HCM population, approximately 1 in 5 patients had AF. AF was a strong predictor of mortality, even after adjustment for established risk factors. PMID:24965028

Comparison of Maximal Wall Thickness in Hypertrophic Cardiomyopathy Differs Between Magnetic Resonance Imaging and Transthoracic Echocardiography.

PubMed

Bois, John P; Geske, Jeffrey B; Foley, Thomas A; Ommen, Steve R; Pellikka, Patricia A

2017-02-15

Left ventricular (LV) wall thickness is a prognostic marker in hypertrophic cardiomyopathy (HC). LV wall thickness ≥30 mm (massive hypertrophy) is independently associated with sudden cardiac death. Presence of massive hypertrophy is used to guide decision making for cardiac defibrillator implantation. We sought to determine whether measurements of maximal LV wall thickness differ between cardiac magnetic resonance imaging (MRI) and transthoracic echocardiography (TTE). Consecutive patients were studied who had HC without previous septal ablation or myectomy and underwent both cardiac MRI and TTE at a single tertiary referral center. Reported maximal LV wall thickness was compared between the imaging techniques. Patients with ≥1 technique reporting massive hypertrophy received subset analysis. In total, 618 patients were evaluated from January 1, 2003, to December 21, 2012 (mean [SD] age, 53 [15] years; 381 men [62%]). In 75 patients (12%), reported maximal LV wall thickness was identical between MRI and TTE. Median difference in reported maximal LV wall thickness between the techniques was 3 mm (maximum difference, 17 mm). Of the 63 patients with ≥1 technique measuring maximal LV wall thickness ≥30 mm, 44 patients (70%) had discrepant classification regarding massive hypertrophy. MRI identified 52 patients (83%) with massive hypertrophy; TTE, 30 patients (48%). Although guidelines recommend MRI or TTE imaging to assess cardiac anatomy in HC, this study shows discrepancy between the techniques for maximal reported LV wall thickness assessment. In conclusion, because this measure clinically affects prognosis and therapeutic decision making, efforts to resolve these discrepancies are critical. Copyright © 2016 Elsevier Inc. All rights reserved.

Divergent effects of adrenaline in human induced pluripotent stem cell-derived cardiomyocytes obtained from hypertrophic cardiomyopathy

PubMed Central

Prajapati, Chandra

2018-01-01

ABSTRACT Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease that affects the heart muscle with diverse clinical outcomes. HCM can cause sudden cardiac death (SCD) during or immediately after mild to rigorous physical activity in young patients. However, the mechanism causing SCD as a result of exercise remains unknown, but exercise-induced ventricular arrhythmias are thought to be responsible for this fatal consequence. To understand the disease mechanism behind HCM in a better way, we generated patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from HCM patients carrying either the MYBPC3-Gln1061X or TPM1-Asp175Asn mutation. We extensively investigated the effects of low to high concentrations of adrenaline on action potential characteristics, and the occurrence of arrhythmias in the presence of various concentrations of adrenaline and in wash-out condition. We classified and quantified different types of arrhythmias observed in hiPSC-CMs, and found that the occurrence of arrhythmias was dependent on concentrations of adrenaline and positions of mutations in genes causing HCM. In addition, we observed ventricular tachycardia types of arrhythmias in hiPSC-CMs carrying the TPM1-Asp175Asn mutation. We additionally examined the antiarrhythmic potency of bisoprolol in HCM-specific hiPSC-CMs. However, bisoprolol could not reduce the occurrence of arrhythmias during administration or during the wash-out condition of adrenaline in HCM-specific hiPSC-CMs. Our study demonstrates hiPSC-CMs as a promising tool for studying HCM. The experimental design used in this study could be suitable and beneficial for studying other components and drugs related to cardiac disease in general. PMID:29361520

MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy

PubMed Central

Li, Amy; Lal, Sean; Bos, J. Martijn; Harris, Samantha P.; van der Velden, Jolanda; Ackerman, Michael J.

2017-01-01

The “super-relaxed state” (SRX) of myosin represents a ‘reserve’ of motors in the heart. Myosin heads in the SRX are bound to the thick filament and have a very low ATPase rate. Changes in the SRX are likely to modulate cardiac contractility. We previously demonstrated that the SRX is significantly reduced in mouse cardiomyocytes lacking cardiac myosin binding protein–C (cMyBP-C). Here, we report the effect of mutations in the cMyBP-C gene (MYBPC3) using samples from human patients with hypertrophic cardiomyopathy (HCM). Left ventricular (LV) samples from 11 HCM patients were obtained following myectomy surgery to relieve LV outflow tract obstruction. HCM samples were genotyped as either MYBPC3 mutation positive (MYBPC3mut) or negative (HCMsmn) and were compared to eight non-failing donor hearts. Compared to donors, only MYBPC3mut samples display a significantly diminished SRX, characterised by a decrease in both the number of myosin heads in the SRX and the lifetime of ATP turnover. These changes were not observed in HCMsmn samples. There was a positive correlation (p < 0.01) between the expression of cMyBP-C and the proportion of myosin heads in the SRX state, suggesting cMyBP-C modulates and maintains the SRX. Phosphorylation of the myosin regulatory light chain in MYBPC3mut samples was significantly decreased compared to the other groups, suggesting a potential mechanism to compensate for the diminished SRX. We conclude that by altering both contractility and sarcomeric energy requirements, a reduced SRX may be an important disease mechanism in patients with MYBPC3 mutations. PMID:28658286

A new common mutation in the cardiac beta-myosin heavy chain gene in Finnish patients with hypertrophic cardiomyopathy.

PubMed

Jääskeläinen, Pertti; Heliö, Tiina; Aalto-Setälä, Katriina; Kaartinen, Maija; Ilveskoski, Erkki; Hämäläinen, Liisa; Melin, John; Kärkkäinen, Satu; Peuhkurinen, Keijo; Nieminen, Markku S; Laakso, Markku; Kuusisto, Johanna

2014-09-01

In the nationwide FinHCM Study including 306 Finnish patients with hypertrophic cardiomyopathy (HCM), we have previously identified two founder mutations in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes, accounting for 18% of all cases. Objective. To screen additional mutations, previously identified in eastern Finnish cohorts with HCM, in the FinHCM Study population. Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened. MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient. MYBPC3 mutations were found in 14 patients: IVS5-2A-C in two, IVS14-13G-A in two, K811del in six, and A851insT in four patients. Altogether, a HCM-causing mutation was identified in 32 patients, accounting for 10.5% of all cases. In addition, two MYBPC3 variants R326Q and V896M with uncertain pathogenicity were found in eight and in 10 patients, respectively. Combining the present findings with our previous results, a causative mutation was identified in 28% of the FinHCM cohort. MYH7-R1053Q was the third most common mutation, and should be screened in all new cases of HCM in Finland.

A case report of apical aneurysms and myocardial perfusion deficit with myocardial necrosis due to hypertrophic cardiomyopathy.

PubMed

Gao, Xiangyu; Yang, Jigang; Zhang, Xiaojie; Wang, Ping; Li, Hongwei

2018-05-01

Hypertrophic cardiomyopathy (HCM) is a disease that is characterized by inappropriate left ventricular and/or right ventricular hypertrophy and hypercontractility that is often asymmetrical and associated with microscopic evidence of myocardial fiber disarray. The aim of this study was to present a previously under-recognized subset of HCM patients with left ventricular (LV) apical aneurysms. A 33-year-old man who presented with chest discomfort for 10 days. He had an emerging apical aneurysm in the LV without midventricular obstruction. He had been diagnosed with apical HCM via abnormal electrocardiograms (ECG) and single-photon emission computed tomography (SPECT) for 10 years. This time, a new significant change in ECG and SPECT was identified. Late gadolinium enhancement (LGE) was observed by cardiac magnetic resonance imaging (MRI), and SPECT showed myocardial fibrosis or necrosis involving the apical aneurysm and proximal portion of the heart, which was confirmed by left ventriculography. We present a relatively rare case of HCM patients with apical aneurysms, accompaning by myocardial necrosis markers increased due to ventricular muscle stress increases, rather than obstructive coronary artery disease. The patient was prescribed aspirin, metoprolol tartrate, perindopril, and atorvastatin and was strongly advised to quit cigarettes and reduce weight. Follow-up at half a year turned out well. LGE with a notable progression by ECG and SPECT along with an increase in myocardial necrosis markers in HCM patients with apical aneurysms, as was noted in the present case, is a relatively rare occurrence. Our present case may provide unique insights into the adverse remodelling process and the formation of apical aneurysms in HCM patients.

Systemic inflammation is associated with myocardial fibrosis, diastolic dysfunction, and cardiac hypertrophy in patients with hypertrophic cardiomyopathy

PubMed Central

Fang, Lu; Ellims, Andris H; Beale, Anna L; Taylor, Andrew J; Murphy, Andrew; Dart, Anthony M

2017-01-01

Background: Regional or diffuse fibrosis is an early feature of hypertrophic cardiomyopathy (HCM) and is related to poor prognosis. Previous studies have documented low-grade inflammation in HCM. The aim of this study was to examine the relationships between circulating inflammatory markers and myocardial fibrosis, systolic and diastolic dysfunction, and the degree of cardiac hypertrophy in HCM patients. Methods and results: Fifty HCM patients were recruited while 20 healthy subjects served as the control group. Seventeen inflammatory cytokines/chemokines were measured in plasma. Cardiac magnetic resonance imaging and echocardiography were used to assess cardiac phenotypes. Tumour necrosis factor (TNF)-α, interleukin (IL)-6 and serum amyloid P (SAP) were significantly increased in HCM patients compared to controls. IL-6, IL-4, and monocyte chemotactic protein (MCP)-1 were correlated with regional fibrosis while stromal cell-derived factor-1 and MCP-1 were correlated with diffuse fibrosis. Fractalkine and interferon-γ were associated with left ventricular wall thickness. The above associations remained significant in a linear regression model including age, gender, body mass index and family history. TNF-α, IL-6, SAP, MCP-1 and IL-10 were associated with parameters of diastolic dysfunction. White blood cells were also increased in HCM patients and correlated with diffuse fibrosis and diastolic dysfunction. However the associations between parameters of systemic inflammation and diastolic dysfunction were weakened in the linear regression analysis. Conclusions: Systemic inflammation is associated with parameters of the disease severity of HCM patients, particularly regional and diffuse fibrosis. Modifying inflammation may reduce myocardial fibrosis in HCM patients. PMID:29218105

A novel approach to select differential pathways associated with hypertrophic cardiomyopathy based on gene co‑expression analysis.

PubMed

Chen, Xiao-Min; Feng, Ming-Jun; Shen, Cai-Jie; He, Bin; Du, Xian-Feng; Yu, Yi-Bo; Liu, Jing; Chu, Hui-Min

2017-07-01

The present study was designed to develop a novel method for identifying significant pathways associated with human hypertrophic cardiomyopathy (HCM), based on gene co‑expression analysis. The microarray dataset associated with HCM (E‑GEOD‑36961) was obtained from the European Molecular Biology Laboratory‑European Bioinformatics Institute database. Informative pathways were selected based on the Reactome pathway database and screening treatments. An empirical Bayes method was utilized to construct co‑expression networks for informative pathways, and a weight value was assigned to each pathway. Differential pathways were extracted based on weight threshold, which was calculated using a random model. In order to assess whether the co‑expression method was feasible, it was compared with traditional pathway enrichment analysis of differentially expressed genes, which were identified using the significance analysis of microarrays package. A total of 1,074 informative pathways were screened out for subsequent investigations and their weight values were also obtained. According to the threshold of weight value of 0.01057, 447 differential pathways, including folding of actin by chaperonin containing T‑complex protein 1 (CCT)/T‑complex protein 1 ring complex (TRiC), purine ribonucleoside monophosphate biosynthesis and ubiquinol biosynthesis, were obtained. Compared with traditional pathway enrichment analysis, the number of pathways obtained from the co‑expression approach was increased. The results of the present study demonstrated that this method may be useful to predict marker pathways for HCM. The pathways of folding of actin by CCT/TRiC and purine ribonucleoside monophosphate biosynthesis may provide evidence of the underlying molecular mechanisms of HCM, and offer novel therapeutic directions for HCM.

Hypertrophic Cardiomyopathy Cardiac Troponin C Mutations Differentially Affect Slow Skeletal and Cardiac Muscle Regulation

PubMed Central

Veltri, Tiago; Landim-Vieira, Maicon; Parvatiyar, Michelle S.; Gonzalez-Martinez, David; Dieseldorff Jones, Karissa M.; Michell, Clara A.; Dweck, David; Landstrom, Andrew P.; Chase, P. Bryant; Pinto, Jose R.

2017-01-01

Mutations in TNNC1—the gene encoding cardiac troponin C (cTnC)—that have been associated with hypertrophic cardiomyopathy (HCM) and cardiac dysfunction may also affect Ca2+-regulation and function of slow skeletal muscle since the same gene is expressed in both cardiac and slow skeletal muscle. Therefore, we reconstituted rabbit soleus fibers and bovine masseter myofibrils with mutant cTnCs (A8V, C84Y, E134D, and D145E) associated with HCM to investigate their effects on contractile force and ATPase rates, respectively. Previously, we showed that these HCM cTnC mutants, except for E134D, increased the Ca2+ sensitivity of force development in cardiac preparations. In the current study, an increase in Ca2+ sensitivity of isometric force was only observed for the C84Y mutant when reconstituted in soleus fibers. Incorporation of cTnC C84Y in bovine masseter myofibrils reduced the ATPase activity at saturating [Ca2+], whereas, incorporation of cTnC D145E increased the ATPase activity at inhibiting and saturating [Ca2+]. We also tested whether reconstitution of cardiac fibers with troponin complexes containing the cTnC mutants and slow skeletal troponin I (ssTnI) could emulate the slow skeletal functional phenotype. Reconstitution of cardiac fibers with troponin complexes containing ssTnI attenuated the Ca2+ sensitization of isometric force when cTnC A8V and D145E were present; however, it was enhanced for C84Y. In summary, although the A8V and D145E mutants are present in both muscle types, their functional phenotype is more prominent in cardiac muscle than in slow skeletal muscle, which has implications for the protein-protein interactions within the troponin complex. The C84Y mutant warrants further investigation since it drastically alters the properties of both muscle types and may account for the earlier clinical onset in the proband. PMID:28473771

Burkitt lymphoma beyond MYC translocation: N-MYC and DNA methyltransferases dysregulation.

PubMed

De Falco, Giulia; Ambrosio, Maria Raffaella; Fuligni, Fabio; Onnis, Anna; Bellan, Cristiana; Rocca, Bruno Jim; Navari, Mohsen; Etebari, Maryam; Mundo, Lucia; Gazaneo, Sara; Facchetti, Fabio; Pileri, Stefano A; Leoncini, Lorenzo; Piccaluga, Pier Paolo

2015-10-09

The oncogenic transcription factor MYC is pathologically activated in many human malignancies. A paradigm for MYC dysregulation is offered by Burkitt lymphoma, where chromosomal translocations leading to Immunoglobulin gene-MYC fusion are the crucial initiating oncogenic events. However, Burkitt lymphoma cases with no detectable MYC rearrangement but maintaining MYC expression have been identified and alternative mechanisms can be involved in MYC dysregulation in these cases. We studied the microRNA profile of MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases in order to uncover possible differences at the molecular level. Data was validated at the mRNA and protein level by quantitative Real-Time polymerase chain reaction and immunohistochemistry, respectively. We identified four microRNAs differentially expressed between the two groups. The impact of these microRNAs on the expression of selected genes was then investigated. Interestingly, in MYC translocation-negative cases we found over-expression of DNA-methyl transferase family members, consistent to hypo-expression of the hsa-miR-29 family. This finding suggests an alternative way for the activation of lymphomagenesis in these cases, based on global changes in methylation landscape, aberrant DNA hypermethylation, lack of epigenetic control on transcription of targeted genes, and increase of genomic instability. In addition, we observed an over-expression of another MYC family gene member, MYCN that may therefore represent a cooperating mechanism of MYC in driving the malignant transformation in those cases lacking an identifiable MYC translocation but expressing the gene at the mRNA and protein levels. Collectively, our results showed that MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases are slightly different in terms of microRNA and gene expression. MYC translocation-negative Burkitt lymphoma, similarly to other aggressive B-cell non Hodgkin

MYC Immunohistochemistry to Identify MYC-Driven B-Cell Lymphomas in Clinical Practice.

PubMed

Kluk, Michael J; Ho, Caleb; Yu, Hongbo; Chen, Benjamin J; Neuberg, Donna S; Dal Cin, Paola; Woda, Bruce A; Pinkus, Geraldine S; Rodig, Scott J

2016-02-01

Immunohistochemistry with anti-MYC antibody (MYC IHC) detects MYC protein in fixed samples of aggressive B-cell lymphomas and, according to the number of positive staining tumor nuclei, facilitates tumor subclassification, predicts underlying MYC rearrangements, and stratifies patient outcome. We aimed to determine the performance of MYC IHC in clinical practice. We reviewed MYC IHC performed on control specimens and 256 aggressive B-cell lymphomas and compared clinically reported IHC scores with experts' review. Control tissues showed less than 5% variation in daily IHC staining. Reported and expert IHC scores were well correlated (r = 0.86) with an SD of 14.2%. Reported IHC scores 30% or less and 70% or more were accurate (94.5%) compared with experts in categorizing tumors as "MYC IHC-Low" and "MYC IHC-High," respectively, but scores 40% to 60% were not (60.3%). The mean IHC score among lymphomas with MYC rearrangements was 80%, but with a large range of scores (20%-100%). There was no statistically significant association between IHC score and MYC copy number. Under optimal conditions, clinically reported MYC IHC scores are concordant with expert scores within 15%. MYC IHC does not capture all B-cell lymphomas with MYC rearrangements, however. MYC IHC and MYC fluorescence in situ hybridization are both recommended to identify MYC-driven B-cell lymphomas. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

MYC-induced cancer cell energy metabolism and therapeutic opportunities.

PubMed

Dang, Chi V; Le, Anne; Gao, Ping

2009-11-01

Although cancers have altered glucose metabolism, termed the Warburg effect, which describes the increased uptake and conversion of glucose to lactate by cancer cells under adequate oxygen tension, changes in the metabolism of glutamine and fatty acid have also been documented. The MYC oncogene, which contributes to the genesis of many human cancers, encodes a transcription factor c-Myc, which links altered cellular metabolism to tumorigenesis. c-Myc regulates genes involved in the biogenesis of ribosomes and mitochondria, and regulation of glucose and glutamine metabolism. With E2F1, c-Myc induces genes involved in nucleotide metabolism and DNA replication, and microRNAs that homeostatically attenuate E2F1 expression. With the hypoxia inducible transcription factor HIF-1, ectopic c-Myc cooperatively induces a transcriptional program for hypoxic adaptation. Myc regulates gene expression either directly, such as glycolytic genes including lactate dehydrogenase A (LDHA), or indirectly, such as repression of microRNAs miR-23a/b to increase glutaminase (GLS) protein expression and glutamine metabolism. Ectopic MYC expression in cancers, therefore, could concurrently drive aerobic glycolysis and/or oxidative phosphorylation to provide sufficient energy and anabolic substrates for cell growth and proliferation in the context of the tumor microenvironment. Collectively, these studies indicate that Myc-mediated altered cancer cell energy metabolism could be translated for the development of new anticancer therapies.

MYC2 Differentially Modulates Diverse Jasmonate-Dependent Functions in Arabidopsis[W

PubMed Central

Dombrecht, Bruno; Xue, Gang Ping; Sprague, Susan J.; Kirkegaard, John A.; Ross, John J.; Reid, James B.; Fitt, Gary P.; Sewelam, Nasser; Schenk, Peer M.; Manners, John M.; Kazan, Kemal

2007-01-01

The Arabidopsis thaliana basic helix-loop-helix Leu zipper transcription factor (TF) MYC2/JIN1 differentially regulates jasmonate (JA)-responsive pathogen defense (e.g., PDF1.2) and wound response (e.g., VSP) genes. In this study, genome-wide transcriptional profiling of wild type and mutant myc2/jin1 plants followed by functional analyses has revealed new roles for MYC2 in the modulation of diverse JA functions. We found that MYC2 negatively regulates Trp and Trp-derived secondary metabolism such as indole glucosinolate biosynthesis during JA signaling. Furthermore, MYC2 positively regulates JA-mediated resistance to insect pests, such as Helicoverpa armigera, and tolerance to oxidative stress, possibly via enhanced ascorbate redox cycling and flavonoid biosynthesis. Analyses of MYC2 cis binding elements and expression of MYC2-regulated genes in T-DNA insertion lines of a subset of MYC2–regulated TFs suggested that MYC2 might modulate JA responses via differential regulation of an intermediate spectrum of TFs with activating or repressing roles in JA signaling. MYC2 also negatively regulates its own expression, and this may be one of the mechanisms used in fine-tuning JA signaling. Overall, these results provide new insights into the function of MYC2 and the transcriptional coordination of the JA signaling pathway. PMID:17616737

Exon 2-mediated c-myc mRNA decay in vivo is independent of its translation.

PubMed Central

Pistoi, S; Roland, J; Babinet, C; Morello, D

1996-01-01

We have previously shown that the steady-state level of c-myc mRNA in vivo is primarily controlled by posttranscriptional regulatory mechanisms. To identify the sequences involved in this process, we constructed a series of H-2/myc transgenic lines in which various regions of the human c-MYC gene were placed under the control of the quasi-ubiquitous H-2K class I regulatory sequences. We demonstrated that the presence of one of the two coding exons, exon 2 or exon 3, is sufficient to confer a level of expression of transgene mRNA similar to that of endogenous c-myc in various adult tissues as well as after partial hepatectomy or after protein synthesis inhibition. We now focus on the molecular mechanisms involved in modulation of expression of mRNAs containing c-myc exon 2 sequences, with special emphasis on the coupling between translation and c-myc mRNA turnover. We have undertaken an analysis of expression, both at the mRNA level and at the protein level, of new transgenic constructs in which the translation is impaired either by disruption of the initiation codon or by addition of stop codons upstream of exon 2. Our results show that the translation of c-myc exon 2 is not required for regulated expression of the transgene in the different situations analyzed, and therefore they indicate that the mRNA destabilizing function of exon 2 is independent of translation by ribosomes. Our investigations also reveal that, in the thymus, some H-2/myc transgenes express high levels of mRNA but low levels of protein. Besides the fact that these results suggest the existence of tissue-specific mechanisms that control c-myc translatability in vivo, they also bring another indication of the uncoupling of c-myc mRNA translation and degradation. PMID:8756668

Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice.

PubMed

Jia, Yuzhi; Chang, Hsiang-Chun; Schipma, Matthew J; Liu, Jing; Shete, Varsha; Liu, Ning; Sato, Tatsuya; Thorp, Edward B; Barger, Philip M; Zhu, Yi-Jun; Viswakarma, Navin; Kanwar, Yashpal S; Ardehali, Hossein; Thimmapaya, Bayar; Reddy, Janardan K

2016-01-01

Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1-/-) during late gestational and early postnatal development by intercrossing Med1fl/fl mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure. The csMed1-/- mouse heart manifests mitochondrial damage, increased apoptosis and interstitial fibrosis. Global gene expression analysis revealed that loss of Med1 in heart down-regulates more than 200 genes including Acadm, Cacna1s, Atp2a2, Ryr2, Pde1c, Pln, PGC1α, and PGC1β that are critical for calcium signaling, cardiac muscle contraction, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and peroxisome proliferator-activated receptor regulated energy metabolism. Many genes essential for oxidative phosphorylation and proper mitochondrial function such as genes coding for the succinate dehydrogenase subunits of the mitochondrial complex II are also down-regulated in csMed1-/- heart contributing to myocardial injury. Data also showed up-regulation of about 180 genes including Tgfb2, Ace, Atf3, Ctgf, Angpt14, Col9a2, Wisp2, Nppa, Nppb, and Actn1 that are linked to cardiac muscle contraction, cardiac hypertrophy, cardiac fibrosis and myocardial injury. Furthermore, we demonstrate that cardiac specific deletion of Med1 in adult mice using tamoxifen-inducible Cre approach (TmcsMed1-/-), results in rapid development of cardiomyopathy and death within 4 weeks. We found that the key findings of the csMed1-/- studies described above are highly reproducible in TmcsMed1-/- mouse heart

Detection of a large duplication mutation in the myosin-binding protein C3 gene in a case of hypertrophic cardiomyopathy.

PubMed

Meyer, Thomas; Pankuweit, Sabine; Richter, Anette; Maisch, Bernhard; Ruppert, Volker

2013-09-15

Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with autosomal dominant inheritance caused by mutations in genes coding for sarcomeric and/or regulatory proteins expressed in cardiomyocytes. In a small cohort of HCM patients (n=8), we searched for mutations in the two most common genes responsible for HCM and found four missense mutations in the MYH7 gene encoding cardiac β-myosin heavy chain (R204H, M493V, R719W, and R870H) and three mutations in the myosin-binding protein C3 gene (MYBPC3) including one missense (A848V) and two frameshift mutations (c.3713delTG and c.702ins26bp). The c.702ins26bp insertion resulted from the duplication of a 26-bp fragment in a 54-year-old female HCM patient presenting with clinical signs of heart failure due to diastolic dysfunction. Although such large duplications (>10 bp) in the MYBPC3 gene are very rare and have been identified only in 4 families reported so far, the identical duplication mutation was found earlier in a Dutch patient, demonstrating that it may constitute a hitherto unknown founder mutation in central European populations. This observation underscores the significance of insertions into the coding sequence of the MYBPC3 gene for the development and pathogenesis of HCM. © 2013 Elsevier B.V. All rights reserved.

Current Indications for Implantable Cardioverter Defibrillators in Non-Ischemic Cardiomyopathies and Channelopathies.

PubMed

González-Torrecilla, Esteban; Arenal, Angel; Atienza, Felipe; Datino, Tomás; Bravo, Loreto; Ruiz, Pablo; Ávila, Pablo; Fernández-Avilés, Francisco

2015-01-01

Current indications for implantable cardioverter defibrillators (ICDs) in patients with channelopathies and cardiomyopathies of non-ischemic origin are mainly based on non-randomized evidence. In patients with nonischemic dilated cardiomyopathy (NIDCM), there is a tendency towards a beneficial effect on total mortality of ICD therapy in patients with significant left ventricular (LV) dysfunction. Although an important reduction in sudden cardiac death (SCD) seems to be clearly demonstrated in these patients, a net beneficial effect on total mortality is unclear mostly in cases with good functional status. Risk stratification has been changing over the last two decades in patients with hypertrophic cardiomyopathy (HCM). Its risk profile has been delineated in parallel with the beneficial effect of ICD in high risk patients. Observational results based on "appropriate" ICD interventions do support its usefulness both in primary and secondary SCD prevention in these patients. Novel risk models quantify the rate of sudden cardiac death in these patients on individual basis. Less clear risk stratification is available for cases of arrhythmogenic right ventricular cardiomyopathy (ARVC) and in other uncommon familiar cardiomyopathies. Main features of risk stratification vary among the different channelopathies (long QT syndrome -LQTS-, Brugada syndrome, etc) with great debate on the management of asymptomatic patients. For most familiar cardiomyopathies, ICD therapy is the only accepted strategy in the prevention of SCD. So far, genetic testing has a limited role in risk evaluation and management of the individual patient. This review aims to summarize these criticisms and to refine the current indications of ICD implantation in patients with cardiomyopathies and major channelopathies.

Mechanisms of pro-arrhythmic abnormalities in ventricular repolarisation and anti-arrhythmic therapies in human hypertrophic cardiomyopathy.

PubMed

Passini, Elisa; Mincholé, Ana; Coppini, Raffaele; Cerbai, Elisabetta; Rodriguez, Blanca; Severi, Stefano; Bueno-Orovio, Alfonso

2016-07-01

Hypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks. Experimental ionic current, action potential (AP) and Ca(2+)-transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n=9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block. Simulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca(2+) overload and decreased CaT amplitude, in agreement with experiments. Repolarisation abnormalities in HCM models were consistently driven by L-type Ca(2+) current (ICaL) re-activation, and ICaL block was the most effective intervention to normalise repolarisation and diastolic Ca(2+), but compromised CaT amplitude. Late Na(+) current (INaL) block partially abolished repolarisation abnormalities, with small impact on CaT. Na(+)/Ca(2+) exchanger (INCX) block effectively restored repolarisation and CaT amplitude, but increased Ca(2+) overload. Multichannel block increased efficacy in normalising repolarisation, AP biomarkers and CaT amplitude compared to selective block. Experimentally-calibrated populations of human AP models identify ICaL re-activation as the key mechanism for repolarisation abnormalities in HCM, and combined INCX, INaL and ICaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Cardiac troponin I degradation in serum of patients with hypertrophic obstructive cardiomyopathy undergoing percutaneous septal ablation.

PubMed

Madsen, Lene H; Lund, Terje; Grieg, Zanina; Nygaard, Ståle; Holmvang, Lene; Jurlander, Birgit; Grande, Peer; Christensen, Geir; Atar, Dan

2009-01-01

Troponin has become the most important marker for diagnosing acute myocardial infarction, yet knowledge is scarce regarding appearance of specific degradation fragments in the blood. We have recently described the appearance of intact cardiac troponin I (cTnI) and 7 degradation products in patients suffering from ST-elevation myocardial infarction (STEMI) using Western blot analysis. However, the time resolution in STEMI patients is hampered by the rather vague time point 'onset of pain'. We therefore sought to utilize a time-wise more reliable model of human myocardial necrosis: percutaneous transluminal septal myocardial ablation (PTSMA) of hypertrophic obstructive cardiomyopathy (HOCM). Here the iatrogenic induction of myocardial necrosis occurs in vivo, allowing us to investigate degradation of cTnI by the second. Blood samples were obtained from 8 patients with HOCM just prior to initiation of PTSMA and up to 50 h following the procedure. Western blot analysis was performed with subsequent analysis of relative intensities of the bands as compared to the degradation of cTnI in STEMI patients from the ASSENT-2 troponin substudy. We demonstrate intact cTnI and 9 degradation products [molecular weight (MW) 12.0-23.5 kDa]. The bands were comparable in MW to degradation fragments in STEMI. Their early rise in intensity, occurring within few minutes after the alcohol injection, emphasizes how susceptible troponin bands are to chemical/ischemic insults. Moreover, two additional bands were visible in the PTSMA population. This work describes the degradation products of troponin I in HOCM patients undergoing PTSMA. The detected bands appear fast and are similar to degradations following STEMI. This model contributes to our knowledge of the degradation patterns of troponin in disease states, and may thus play a role in the interpretation of elevated troponin levels. Copyright 2009 S. Karger AG, Basel.

Circulating biomarkers of hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy assessed by cardiac magnetic resonance.

PubMed

Gawor, Monika; Śpiewak, Mateusz; Kubik, Agata; Wróbel, Aleksandra; Lutyńska, Anna; Marczak, Magdalena; Grzybowski, Jacek

2018-05-23

Myocardial fibrosis in hypertrophic cardiomyopathy (HCM) is associated with worse clinical outcomes. The availability of circulating biomarkers of myocardial fibrosis and hypertrophy would be helpful in clinical practice. The aim of this study was to evaluate usefulness of various biomarkers of myocardial fibrosis and hypertrophy in HCM. Levels of biomarkers: soluble ST2 (sST2), galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), NT-proBNP and high-sensitivity cardiac troponin T (hs-cTnT) were measured in 60 patients with HCM. All patients underwent cardiac magnetic resonance imaging to calculate parameters of hypertrophy and fibrosis. We observed positive correlations among sST2 levels and left ventricular mass (LVM) (r = 0.32, p = 0.012), LV mass indexed for the body surface area (LVMI) (r = 0.27, p = 0.036) and maximal wall thickness (MWT) (r = 0.31, p = 0.015). No correlation was found between Gal-3 and GDF-15 levels and hypertrophy and fibrosis parameters. We observed positive correlations among hs-cTnT levels and LVM (r = 0.58, p < 0.0001), LVMI (r = 0.48, p = 0.0001), MWT (r = 0.31, p = 0.015) and late gadolinium enhancement (LGE) mass (r = 0.37, p = 0.003). There were positive correlations between NT-proBNP levels and LVM (r = 0.33, p = 0.01), LVMI (r = 0.41, p = 0.001), MWT (r = 0.42, p < 0.001) and LGE mass (r = 0.44, p < 0.001). Although no correlation between sST2 levels and myocardial fibrosis was found, sST2 may provide some additional information about hypertrophy extension. NT-proBNP and hs-cTnT are useful biomarkers in assessment of hypertrophy and fibrosis in HCM.

Doppler Systolic Signal Void in Hypertrophic Cardiomyopathy: Apical Aneurysm and Severe Obstruction without Elevated Intraventricular Velocities.

PubMed

Po, Jose Ricardo F; Kim, Bette; Aslam, Farhan; Arabadjian, Milla; Winson, Glenda; Cantales, Deborah; Kushner, Josef; Kornberg, Robert; Sherrid, Mark V

2015-12-01

In patients with hypertrophic cardiomyopathy (HCM), akinetic apical aneurysms are associated with ventricular tachycardia, heart failure, apical thrombus, and mortality. The cause of apical aneurysms remains unresolved, and there is controversy about prevalence and significance of mid-left ventricular (LV) obstruction, often present in these patients. The aim of this study was to test the hypothesis that low velocities in patients with aneurysms are due to near complete cessation of mid-LV flow, characteristically marked by a Doppler signal void. This was a retrospective analysis of 39 patients with HCM with segmental hypertrophy of the mid left ventricle and complete systolic emptying at the mid-LV level. The severity of dynamic obstruction was evaluated by measuring the time during which cross-sectional mid-LV cavity area was <1 cm(2). Presence or absence of an LV Doppler midsystolic signal void was determined. Akinetic apical aneurysms were present in 21 patients. The duration of two-dimensional mid-LV short-axis complete emptying was longer in patients with akinetic apical aneurysms (194 ± 45 vs 148 ± 63 msec, P = .013), nearly 50% of systole. Midsystolic signal voids were seen only in patients with akinetic apical aneurysms (P < .001), present in 86%. In patients with akinetic aneurysms, there was a strong correlation between the duration of the systolic signal void and the proportion of systole with complete emptying < 1 cm(2) (r = 0.704; P = .001). Complete emptying < 1 cm(2) for ≥ 38% of systole was associated with akinetic aneurysm (odds ratio, 9.35; P < .004). Patients with akinetic apical aneurysm HCM have near complete cessation of flow across severe dynamic mid-LV obstruction for nearly 50% of systole. This explains how the adverse effects of obstruction may occur without high velocities on echocardiography. Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

PubMed

Adalsteinsdottir, Berglind; Palsson, Runolfur; Desnick, Robert J; Gardarsdottir, Marianna; Teekakirikul, Polakit; Maron, Martin; Appelbaum, Evan; Neisius, Ulf; Maron, Barry J; Burke, Michael A; Chen, Brenden; Pagant, Silvere; Madsen, Christoffer V; Danielsen, Ragnar; Arngrimsson, Reynir; Feldt-Rasmussen, Ulla; Seidman, Jonathan G; Seidman, Christine E; Gunnarsson, Gunnar Th

2017-08-01

The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA (α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities. © 2017 American Heart Association, Inc.

DNA Methylation Mediated Downregulation of miR-449c Controls Osteosarcoma Cell Cycle Progression by Directly Targeting Oncogene c-Myc

PubMed Central

Li, Qing; Li, Hua; Zhao, Xueling; Wang, Bing; Zhang, Lin; Zhang, Caiguo; Zhang, Fan

2017-01-01

MicroRNAs (miRNAs) are critical regulators of gene expression, and they have broad roles in the pathogenesis of different diseases including cancer. Limited studies and expression profiles of miRNAs are available in human osteosarcoma cells. By applying a miRNA microarray analysis, we observed a number of miRNAs with abnormal expression in cancerous tissues from osteosarcoma patients. Of particular interest in this study was miR-449c, which was significantly downregulated in osteosarcoma cells and patients, and its expression was negatively correlated with tumor size and tumor MSTS stages. Ectopic expression of miR-449c significantly inhibited osteosarcoma cell proliferation and colony formation ability, and caused cell cycle arrest at the G1 phase. Further analysis identified that miR-449c was able to directly target the oncogene c-Myc and negatively regulated its expression. Overexpression of c-Myc partially reversed miR-449c-mimic-inhibited cell proliferation and colony formation. Moreover, DNA hypermethylation was observed in two CpG islands adjacent to the genomic locus of miR-449c in osteosarcoma cells. Conversely, treatment with the DNA methylation inhibitor AZA caused induction of miR-449c. In conclusion, our results support a model that DNA methylation mediates downregulation of miR-449c, diminishing miR-449c mediated inhibition of c-Myc and thus leading to the activation of downstream targets, eventually contributing to osteosarcoma tumorigenesis. PMID:28924385

Myc

PubMed Central

Wasylishen, Amanda R.; Penn, Linda Z.

2010-01-01

The iconic history of the Myc oncoprotein encompasses 3 decades of intense scientific discovery. There is no question that Myc has been a pioneer, advancing insight into the molecular basis of cancer as well as functioning as a critical control center for several diverse biological processes and regulatory mechanisms. This narrative chronicles the journey and milestones that have defined the understanding of Myc, and it provides an opportunity to consider future directions in this challenging yet rewarding field. PMID:21779457

Alcoholic cardiomyopathy: Pathophysiologic insights

PubMed Central

Piano, Mariann R.; Phillips, Shane A.

2014-01-01

Alcoholic cardiomyopathy is a specific heart muscle disease found in individuals with a history of long-term heavy alcohol consumption. Alcoholic cardiomyopathy is associated with a number of adverse histological, cellular, and structural changes within the myocardium. Several mechanisms are implicated in mediating the adverse effects of ethanol, including the generation of oxidative stress, apoptotic cell death, impaired mitochondrial bioenergetics/stress, derangements in fatty acid metabolism and transport, and accelerated protein catabolism. In this review, we discuss the evidence for such mechanisms and present the potential importance of drinking patterns, genetic susceptibility, nutritional factors, race, and sex. The purpose of this review is to provide a mechanistic paradigm for future research in the area of alcoholic cardiomyopathy. PMID:24671642

Rapidly Progressive Hypertrophic Cardiomyopathy in an Infant with Noonan syndrome with multiple Lentigines. Palliative Treatment with a Rapamycin Analog

PubMed Central

Hahn, Andreas; Lauriol, Jessica; Thul, Josef; Behnke-Hall, Kachina; Logeswaran, Tushiha; Schänzer, Anne; Böğürcü, Nuray; Garvalov, Boyan K.; Zenker, Martin; Gelb, Bruce D.; von Gerlach, Susanne; Kandolf, Reinhard; Kontaridis, Maria I.; Schranz, Dietmar

2015-01-01

Noonan syndrome with multiple lentigines (NSML) frequently manifests with hypertrophic cardiomyopathy (HCM). Recently, it was demonstrated that mTOR inhibition reverses HCM in NSML mice. We report for the first time on the effects of treatment with a rapamycin analog in an infant with LS and a malignant form of HCM. In the boy, progressive HCM was diagnosed during the first week of life and diagnosis of NSML was established at age 20 weeks by showing a heterozygous Q510E mutation in the PTPN11 gene. Immunoblotting with antibodies against pERK, pAkt, and pS6RP in fibroblasts demonstrated reduced RAS/MAPK and enhanced Akt/mTOR pathway activities. Because of the patient’s critical condition, everolimus therapy was started at age 24 weeks and continued until heart transplantation at age 36 weeks. Prior to surgery, heart failure improved from NYHA stage IV to II and brain natriuretic peptide values decreased from 9600 to <1000 pg/ml, but no reversal of cardiac hypertrophy was observed. Examination of the explanted heart revealed severe hypertrophy and myofiber disarray with extensive perivascular fibrosis. These findings provide evidence that Akt/mTOR activity is enhanced in NSML with HCM and suggest that rapamycin treatment could be principally feasible for infantile NSML. But the preliminary experiences made in this single patient indicate that therapy should start early to prevent irreversible cardiac remodelling. PMID:25708222

Functional, morphological and electrocardiographical abnormalities in patients with apical hypertrophic cardiomyopathy and apical aneurysm: correlation with cardiac MR

PubMed Central

Suwa, Kenichiro; Satoh, Hiroshi; Sano, Makoto; Nobuhara, Mamoru; Saitoh, Takeji; Saotome, Masao; Urushida, Tsuyoshi; Katoh, Hideki; Tawarahara, Kei; Ohtani, Hayato; Wakabayashi, Yasushi; Takase, Hiroyuki; Terada, Hajime; Takehara, Yasuo; Sakahara, Harumi; Hayashi, Hideharu

2014-01-01

Objective The prognosis of apical hypertrophic cardiomyopathy (APH) has been benign, but apical myocardial injury has prognostic importance. We studied functional, morphological and electrocardiographical abnormalities in patients with APH and with apical aneurysm and sought to find parameters that relate to apical myocardial injury. Methods Study design: a multicentre trans-sectional study. Patients: 45 patients with APH and 5 with apical aneurysm diagnosed with transthoracic echocardiography (TTE) in the database of Hamamatsu Circulation Forum. Measure: the apical contraction with cine-cardiac MR (CMR), the myocardial fibrotic scar with late gadolinium enhancement (LGE)-CMR, and QRS fragmentation (fQRS) defined when two ECG-leads exhibited RSR’s patterns. Results Cine-CMR revealed 27 patients with normal, 12 with hypokinetic and 11 with dyskinetic apical contraction. TTE misdiagnosed 11 (48%) patients with hypokinetic and dyskinetic contraction as those with normal contraction. Apical LGE was apparent in 10 (83%) and 11 (100%) patients with hypokinetic and dyskinetic contraction, whereas only in 11 patients (41%) with normal contraction (p<0.01). Patients with dyskinetic apical contraction had the lowest left ventricular ejection fraction, the highest prevalence of ventricular tachycardia, and the smallest ST depression and depth of negative T waves. The presence of fQRS was associated with impaired apical contraction and apical LGE (OR=8.32 and 8.61, p<0.05). Conclusions CMR is superior to TTE for analysing abnormalities of the apex in patients with APH and with apical aneurysm. The presence of fQRS can be a promising parameter for the early detection of apical myocardial injury. PMID:25332823

OsMYC2 mediates numerous defence-related transcriptional changes via jasmonic acid signalling in rice.

PubMed

Ogawa, Satoshi; Kawahara-Miki, Ryouka; Miyamoto, Koji; Yamane, Hisakazu; Nojiri, Hideaki; Tsujii, Yoshimasa; Okada, Kazunori

2017-05-06

Jasmonic acid (JA) plays central roles in various events in plants, especially defence against pathogens and insects. The basic helix-loop-helix (bHLH) transcription factor MYC2 has attracted attention as a master regulator of JA signalling in dicotyledonous plants. However, how MYC2 functions in monocotyledonous plants, including agriculturally important crops such as cultivated rice, has been poorly understood. To elucidate the comprehensive effects of rice MYC2 (OsMYC2) on the JA-inducible transcriptional modifications, we performed RNA-sequencing by using OsMYC2-knockdown plants (osmyc2RNAi). In osmyc2RNAi, JA-inducible expression of many defence-related genes, for example chitinases and proteinase inhibitors, was compromised. Decrease in JA-dependent activation of the biosynthetic pathways of specialised metabolites, especially defence compounds, was also evident in the osmyc2RNAi line. Furthermore, a substantial change was noted in the expression of distinct types of transcription factors, such as MYB-type factors, likely depicting the importance of OsMYC2 in not only defence responses but also other morphogenetic events. Our findings provide fundamental information to understand the overall functions of MYC2 in JA signalling in monocotyledonous plants, which might yield agricultural benefits. Copyright © 2017 Elsevier Inc. All rights reserved.

Myocardial Fibrosis in Hypertrophic Cardiomyopathy: Volumetric Assessment of Late Enhancement Provided by Cardiac Computed Tomography.

PubMed

Langer, Christoph; Schaefer, Philipp; Lutz, Matthias; Eden, Matthias; Hohnhorst, Mirko; Harders, Hauke; Faber, Lothar; Jansen, Olav; Both, Marcus; Frey, Norbert

2015-01-01

With subgroups of patients with hypertrophic cardiomyopathy (HCM) confers a 4% to 5% risk for adverse prognosis. Besides left-ventricular muscle mass (LV-MM) myocardial fibrosis (MF) assessable by late gadolinium enhancement in cardiovascular magnetic resonance (LGE-CMR) has been related to that. Myocardial fibrosis can also be demonstrated by late enhancement (LE) in late-enhanced multislice computed tomography (leMDCT). This analysis investigates leMDCT whether to enable quantification of LE load in terms of LE mass by percent LV-MM in HCM. In a prospective validation study, we included 30 consecutive patients with HCM who underwent leMDCT (64 slice) and LGE-CMR (1.5 T). The leMDCT scan was performed 7 minutes after injection of iodine contrast (Iopromid). Endocardial and epicardial planimetry served for the assessment of LV-MM. Visually detectable LE was quantified using the manual quantification method resulting in LE by percent LV-MM (%LE). The LGE-CMR data served for validation. Mean (SD) age was 64.1 (13.9) years. Myocardial fibrosis prevalence was 63.3% (19/30 patients indentified by both leMDCT and LGE-CMR). In leMDCT, tissue density in LE areas compared with normal myocardium was higher (138.2 [23.9] HU vs 98.4 [16.5] HU, P < 0.001) but lower than in the LV cavity (138.2 [23.9] HU vs 169.2 [35.9] HU, P < 0.001). Late enhancement mass in leMDCT seemed to be 7.9 (8.5) g LE versus 8.6 [11] g LGE in CMR (P = 0.497, r = 0.95) resulting in a leMDCT/LGE-CMR relation of 1.2. Referring LE mass to LV-MM gave an LE proportion measured by leMDCT of 4 (3.9) %LE versus 3.9 (4.1) %LGE in LGE-CMR (r = 0.88, P = 0.75). Intraobserver/interobserver reliability of LE mass assessment showed an intraclass correlation coefficient of 0.99 and 0.97. In patients with HCM, leMDCT provides volumetric assessment of LE mass-absolutely and by percent LV-MM.

Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy

PubMed Central

Cecconi, Massimiliano; Parodi, Maria I.; Formisano, Francesco; Spirito, Paolo; Autore, Camillo; Musumeci, Maria B.; Favale, Stefano; Forleo, Cinzia; Rapezzi, Claudio; Biagini, Elena; Davì, Sabrina; Canepa, Elisabetta; Pennese, Loredana; Castagnetta, Mauro; Degiorgio, Dario; Coviello, Domenico A.

2016-01-01

Hypertrophic cardiomyopathy (HCM) is mainly associated with myosin, heavy chain 7 (MYH7) and myosin binding protein C, cardiac (MYBPC3) mutations. In order to better explain the clinical and genetic heterogeneity in HCM patients, in this study, we implemented a target-next generation sequencing (NGS) assay. An Ion AmpliSeq™ Custom Panel for the enrichment of 19 genes, of which 9 of these did not encode thick/intermediate and thin myofilament (TTm) proteins and, among them, 3 responsible of HCM phenocopy, was created. Ninety-two DNA samples were analyzed by the Ion Personal Genome Machine: 73 DNA samples (training set), previously genotyped in some of the genes by Sanger sequencing, were used to optimize the NGS strategy, whereas 19 DNA samples (discovery set) allowed the evaluation of NGS performance. In the training set, we identified 72 out of 73 expected mutations and 15 additional mutations: the molecular diagnosis was achieved in one patient with a previously wild-type status and the pre-excitation syndrome was explained in another. In the discovery set, we identified 20 mutations, 5 of which were in genes encoding non-TTm proteins, increasing the diagnostic yield by approximately 20%: a single mutation in genes encoding non-TTm proteins was identified in 2 out of 3 borderline HCM patients, whereas co-occuring mutations in genes encoding TTm and galactosidase alpha (GLA) altered proteins were characterized in a male with HCM and multiorgan dysfunction. Our combined targeted NGS-Sanger sequencing-based strategy allowed the molecular diagnosis of HCM with greater efficiency than using the conventional (Sanger) sequencing alone. Mutant alleles encoding non-TTm proteins may aid in the complete understanding of the genetic and phenotypic heterogeneity of HCM: co-occuring mutations of genes encoding TTm and non-TTm proteins could explain the wide variability of the HCM phenotype, whereas mutations in genes encoding only the non-TTm proteins are identifiable in

Prognostic impact of MYC protein expression in central nervous system diffuse large B-cell lymphoma: comparison with MYC rearrangement and MYC mRNA expression.

PubMed

Son, Seung-Myoung; Ha, Sang-Yun; Yoo, Hae-Yong; Oh, Dongryul; Kim, Seok-Jin; Kim, Won-Seog; Ko, Young-Hyeh

2017-01-01

The prognostic role of MYC has been well documented in non-central nervous system diffuse large B-cell lymphoma; however, it remains controversial in central nervous system diffuse large B-cell lymphoma. To investigate the prognostic value of MYC, we analyzed the MYC protein expression by immunohistochemistry, mRNA expression by RNA in situ hybridization, and gene status by fluorescence in situ hybridization in 74 cases of central nervous system diffuse large B-cell lymphoma. Moreover, we examined the correlation between MYC translocation, mRNA expression, and protein expression. The mean percentage of MYC immunopositive cells was 49%. Using a 44% cutoff value, 49 (66%) cases showed MYC protein overexpression. The result of mRNA in situ hybridization using the RNA scope technology was obtained using the H-scoring system; the median value was 34.2. Using the cutoff value of 63.5, 16 (22%) cases showed MYC mRNA overexpression. MYC gene rearrangement was detected in five out of 68 (7%) cases. MYC translocation showed no statistically significant correlation with mRNA expression; however, all MYC translocation-positive cases showed MYC protein overexpression, with a higher mean percentage of MYC protein expression than that of translocation-negative cases (78 vs 48%, P=0.001). The level of MYC mRNA expression was moderately correlated with the level of MYC protein expression (P<0.001). The mean percentage of MYC protein expression in the high MYC mRNA group was higher than that in the low MYC mRNA group (70 vs 47%, P<0.001). A univariate analysis showed that age over 60 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and MYC protein overexpression were significantly associated with an increased risk of death. MYC translocation and MYC mRNA expression had no prognostic significance. On multivariate analysis, MYC protein overexpression and ECOG score retained prognostic significance.

Comparison of left ventricular diastolic function in obstructive hypertrophic cardiomyopathy in patients undergoing percutaneous septal alcohol ablation versus surgical myotomy/myectomy

NASA Technical Reports Server (NTRS)

Sitges, Marta; Shiota, Takahiro; Lever, Harry M.; Qin, Jian Xin; Bauer, Fabrice; Drinko, Jeannie K.; Agler, Deborah A.; Martin, Maureen G.; Greenberg, Neil L.; Smedira, Nicholas G.;

Hemodynamic changes in systolic and diastolic function during isoproterenol challenge predicts symptomatic response to myectomy in hypertrophic cardiomyopathy with labile obstruction.

PubMed

Prasad, Megha; Geske, Jeffrey B; Sorajja, Paul; Ommen, Steve R; Schaff, Hartzell V; Gersh, Bernard J; Nishimura, Rick A

2016-11-15

We aimed to assess the utility of changes in systolic and diastolic function by isoproterenol challenge in predicting symptom resolution post-myectomy in selected patients with hypertrophic cardiomyopathy (HCM) and labile obstruction. In a subset of symptomatic HCM patients without resting/provocable obstruction on noninvasive assessment, isoproterenol challenge during hemodynamic catheterization may elicit labile left ventricular outflow tract (LVOT) obstruction, and demonstrate the effect of obstruction on diastolic function. These changes may determine whether patients achieve complete symptom resolution post-myectomy. Between February 2003 and April 2009, 18 symptomatic HCM patients without LVOT obstruction on noninvasive testing underwent isoproterenol provocation and septal myectomy due to presence of provocable gradient and were followed for 4 (IQR 3-7) years. Thirteen (72.2%) had complete symptom resolution, while 5 (27.8%) had improved, but persistent symptoms. Those with provoked gradient >100 mm Hg or increase in left atrial pressure (LAP) with isoproterenol had symptom resolution. Symptomatic HCM patients without LVOT gradient on noninvasive testing may demonstrate labile obstruction with isoproterenol. With isoproterenol, patients with high LVOT gradient or increase in LAP concomitant with an increase in gradient achieved complete symptom resolution post-myectomy. Thus, improved diastolic filling as well as outflow gradient production in patients with HCM may predict symptom response to myectomy. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy.

PubMed

Roncarati, Roberta; Latronico, Michael V G; Musumeci, Beatrice; Aurino, Stefania; Torella, Annalaura; Bang, Marie-Louise; Jotti, Gloria Saccani; Puca, Annibale A; Volpe, Massimo; Nigro, Vincenzo; Autore, Camillo; Condorelli, Gianluigi

2011-11-01

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. Copyright © 2011 Wiley-Liss, Inc.

The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc

PubMed Central

Sun, Xiao-Xin; He, Xia; Yin, Li; Komada, Masayuki; Sears, Rosalie C.; Dai, Mu-Shui

2015-01-01

c-Myc protein stability and activity are tightly regulated by the ubiquitin-proteasome system. Aberrant stabilization of c-Myc contributes to many human cancers. c-Myc is ubiquitinated by SCFFbw7 (a SKP1-cullin-1-F-box complex that contains the F-box and WD repeat domain-containing 7, Fbw7, as the F-box protein) and several other ubiquitin ligases, whereas it is deubiquitinated and stabilized by ubiquitin-specific protease (USP) 28. The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc. This USP36 regulation of c-Myc occurs in the nucleolus. Interestingly, USP36 interacts with the nucleolar Fbw7γ but not the nucleoplasmic Fbw7α. However, it abolished c-Myc degradation mediated both by Fbw7γ and by Fbw7α. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. We further show that USP36 itself is a c-Myc target gene, suggesting that USP36 and c-Myc form a positive feedback regulatory loop. High expression levels of USP36 are found in a subset of human breast and lung cancers. Altogether, these results identified USP36 as a crucial and bono fide deubiquitinating enzyme controlling c-Myc’s nucleolar degradation pathway. PMID:25775507

Recommendations for participation in competitive sport and leisure-time physical activity in individuals with cardiomyopathies, myocarditis and pericarditis.

PubMed

Pelliccia, Antonio; Corrado, Domenico; Bjørnstad, Hans Halvor; Panhuyzen-Goedkoop, Nicole; Urhausen, Axel; Carre, Francois; Anastasakis, Aris; Vanhees, Luc; Arbustini, Eloisa; Priori, Silvia

2006-12-01

Several relatively uncommon, but important cardiovascular diseases are associated with increased risk for acute cardiac events during exercise (including sudden death), such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and myo-pericarditis. Practising cardiologists are frequently asked to advise on exercise programmes and sport participation in young individuals with these cardiovascular diseases. Indeed, many asymptomatic (or mildly symptomatic) patients with cardiomyopathies aspire to a physically active lifestyle to take advantage of the many documented benefits of exercise. While recommendations dictating the participation in competitive sport for athletes with cardiomyopathies and myo-pericarditis have recently been published as a consensus document of the European Society of Cardiology, no European guidelines have addressed the possible participation of patients with cardiomyopathies in recreational and amateur sport activities. The present document is intended to offer a comprehensive overview to practising cardiologists and sport physicians of the recommendations governing safe participation in different types of competitive sport, as well as the participation in a variety of recreational physical activities and amateur sports in individuals with cardiomyopathies and myo-pericarditis. These recommendations, based largely on the experience and insights of the expert panel appointed by the European Society of Cardiology, include the most up-to-date information concerning regular exercise and sports activity in patients with cardiomyopathies and myo-pericarditis.

Role of Doppler Diastolic Parameters in Differentiating Physiological Left Ventricular Hypertrophy from Hypertrophic Cardiomyopathy.

PubMed

Finocchiaro, Gherardo; Dhutia, Harshil; D'Silva, Andrew; Malhotra, Aneil; Sheikh, Nabeel; Narain, Rajay; Ensam, Bode; Papatheodorou, Stathis; Tome, Maite; Sharma, Rajan; Papadakis, Michael; Sharma, Sanjay

2018-05-01

The association between athletic participation and alteration in diastolic function is not well established. The aims of this study were to determine the spectrum of Doppler parameters of left ventricular (LV) diastolic function in a large cohort of healthy athletes and to quantify the overlap between physiologic LV hypertrophy and hypertrophic cardiomyopathy (HCM). A retrospective analysis of indices of LV diastolic function was performed in 1,510 healthy athletes (mean age, 22 ± 5 years; range, 13-33 years; 72% men). The results were compared with those from 58 young patients with HCM. Septal E' < 7 cm/sec and lateral E' < 10 cm/sec were found in five (0.3%) and eight (0.5%) athletes, respectively. Septal E' was >14.6 cm/sec in 170 (11%) and lateral E' was >19.9 cm/sec in 430 (28%) athletes. Athletes aged >25 years showed lower E' velocities compared with younger athletes (mean septal E', 11.8 ± 6.1 vs 12.9 ± 5.9 cm/sec [P < .001]; mean lateral E', 17.1 ± 3.6 vs 19.3 ± 4.1 cm/sec [P < .001]). Athletes with high indexed LV end-diastolic diameters (>32 mm/m 2 ) exhibited lower septal E' compared with athletes with normal indexed LV end-diastolic diameters (mean septal E', 11.9 ± 6 vs 12.7 ± 6 cm/sec; P = .002). Septal E' < 10 cm/sec and lateral E' < 12 cm/sec showed the best accuracy in differentiating between HCM and athlete's heart. Reduced septal and lateral E' are rarely observed in young elite athletes. Tissue Doppler velocities tend to decrease with increasing age and LV size, and values representative of supernormal diastolic function are found in less than one-third of young athletes. Cutoff thresholds for Doppler parameters of diastolic function should be corrected for multiple demographic and clinical variables to differentiate cardiac adaptation to exercise from HCM in young individuals. Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

Structural basis of JAZ repression of MYC transcription factors in jasmonate signalling

DOE PAGES

Zhang, Feng; Yao, Jian; Ke, Jiyuan; ...

2015-08-10

The plant hormone jasmonate plays crucial roles in regulating plant responses to herbivorous insects and microbial pathogens and is an important regulator of plant growth and development. Key mediators of jasmonate signalling include MYC transcription factors, which are repressed by jasmonate ZIM-domain (JAZ) transcriptional repressors in the resting state. In the presence of active jasmonate, JAZ proteins function as jasmonate co-receptors by forming a hormone-dependent complex with COI1, the F-box subunit of an SCF-type ubiquitin E3 ligase. The hormone-dependent formation of the COI1–JAZ co-receptor complex leads to ubiquitination and proteasome-dependent degradation of JAZ repressors and release of MYC proteins frommore » transcriptional repression. The mechanism by which JAZ proteins repress MYC transcription factors and how JAZ proteins switch between the repressor function in the absence of hormone and the co-receptor function in the presence of hormone remain enigmatic. In this paper, we show that Arabidopsis MYC3 undergoes pronounced conformational changes when bound to the conserved Jas motif of the JAZ9 repressor. The Jas motif, previously shown to bind to hormone as a partly unwound helix, forms a complete α-helix that displaces the amino (N)-terminal helix of MYC3 and becomes an integral part of the MYC N-terminal fold. In this position, the Jas helix competitively inhibits MYC3 interaction with the MED25 subunit of the transcriptional Mediator complex. Finally, our structural and functional studies elucidate a dynamic molecular switch mechanism that governs the repression and activation of a major plant hormone pathway.« less

p62/SQSTM1 enhances breast cancer stem-like properties by stabilizing MYC mRNA

PubMed Central

Xu, L-Z; Li, S-S; Zhou, W; Kang, Z-J; Zhang, Q-X; Kamran, M; Xu, J; Liang, D-P; Wang, C-L; Hou, Z-J; Wan, X-B; Wang, H-J; Lam, E W-F; Zhao, Z-W; Liu, Q

2017-01-01

Aberrant p62 overexpression has been implicated in breast cancer development. Here, we found that p62 expression was elevated in breast cancer stem cells (BCSCs), including CD44+CD24− fractions, mammospheres, ALDH1+ populations and side population cells. Indeed, short-hairpin RNA (shRNA)-mediated knockdown of p62 impaired breast cancer cells from self-renewing under anchorage-independent conditions, whereas ectopic overexpression of p62 enhanced the self-renewal ability of breast cancer cells in vitro. Genetic depletion of p62 robustly inhibited tumor-initiating frequencies, as well as growth rates of BCSC-derived tumor xenografts in immunodeficient mice. Consistently, immunohistochemical analysis of clinical breast tumor tissues showed that high p62 expression levels were linked to poorer clinical outcome. Further gene expression profiling analysis revealed that p62 was positively correlated with MYC expression level, which mediated the function of p62 in promoting breast cancer stem-like properties. MYC mRNA level was reduced upon p62 deletion by siRNA and increased with p62 overexpression in breast cancer cells, suggesting that p62 positively regulated MYC mRNA. Interestingly, p62 did not transactivate MYC promoter. Instead, p62 delayed the degradation of MYC mRNA by repressing the expression of let-7a and let-7b, thus promoting MYC mRNA stabilization at the post-transcriptional level. Consistently, let-7a and let-7b mimics attenuated p62-mediated MYC mRNA stabilization. Together, these findings unveiled a previously unappreciated role of p62 in the regulation of BCSCs, assigning p62 as a promising therapeutic target for breast cancer treatments. PMID:27345399

Provocation of left ventricular outflow tract obstruction using nitrate inhalation in hypertrophic cardiomyopathy: Relation to electromechanical delay.

PubMed

Badran, Hala Mahfouz; Ibrahim, Waleed Abdou; Faheem, Naglaa; Yassin, Rehab; Alashkar, Tamer; Yacoub, Magdi

2015-01-01

Left ventricular outflow tract obstruction (LVOT) is an independent predictor of adverse outcome in hypertrophic cardiomyopathy (HCM). It is of major importance that the provocation modalities used are validated against each other. To define the magnitude of LVOT gradients provocation during both isosorbide dinitrate (ISDN) inhalation and treadmill exercise in non-obstructive HCM and analyze the correlation to the electromechanical delay using speckle tracking. We studied 39 HCM pts (64% males, mean age 38 ± 13 years) regional LV longitudinal strain and electromechanical delay (TTP) was analyzed at rest using speckle tracking. LVOT gradient was measured at rest and after ISDN then patients underwent a treadmill exercise echocardiography (EE) and LVOT gradient was measured at peak exercise. The maximum effect of ISDN on LVOT gradient was obtained at 5 minutes, it increased to a significant level in 12 (31%) patients, and in 14 (36%) patients using EE, with 85.6% sensitivity & 100% specificity. Patients with latent obstruction had larger left atrial volume and lower E/A ratio compared to the non-obstructive group (p < 0.01). LVOTG using ISDN was significantly correlated with that using EE (p < 0.0001), resting LVOTG (p < 0.0001), SAM (p < 0.0001), EF% (p < 0.02) and regional electromechanical delay but not related to global LV longitudinal strain. Using multivariate regression, resting LVOTG (p = 0.006) & TTP mid septum (p = 0.01) were found to be independent predictors of latent LVOT obstruction using ISDN. There is a comparable diagnostic value of nitrate inhalation to exercise testing in provocation of LVOT obstruction in HCM. Latent obstruction is predominantly dependent on regional electromechanical delay.

Provocation of left ventricular outflow tract obstruction using nitrate inhalation in hypertrophic cardiomyopathy: Relation to electromechanical delay

PubMed Central

Badran, Hala Mahfouz; Ibrahim, Waleed Abdou; Faheem, Naglaa; Yassin, Rehab; Alashkar, Tamer; Yacoub, Magdi

2015-01-01

Background: Left ventricular outflow tract obstruction (LVOT) is an independent predictor of adverse outcome in hypertrophic cardiomyopathy (HCM). It is of major importance that the provocation modalities used are validated against each other. Aim: To define the magnitude of LVOT gradients provocation during both isosorbide dinitrate (ISDN) inhalation and treadmill exercise in non-obstructive HCM and analyze the correlation to the electromechanical delay using speckle tracking. Methods: We studied 39 HCM pts (64% males, mean age 38 ± 13 years) regional LV longitudinal strain and electromechanical delay (TTP) was analyzed at rest using speckle tracking. LVOT gradient was measured at rest and after ISDN then patients underwent a treadmill exercise echocardiography (EE) and LVOT gradient was measured at peak exercise. Results: The maximum effect of ISDN on LVOT gradient was obtained at 5 minutes, it increased to a significant level in 12 (31%) patients, and in 14 (36%) patients using EE, with 85.6% sensitivity & 100% specificity. Patients with latent obstruction had larger left atrial volume and lower E/A ratio compared to the non-obstructive group (p < 0.01). LVOTG using ISDN was significantly correlated with that using EE (p < 0.0001), resting LVOTG (p < 0.0001), SAM (p < 0.0001), EF% (p < 0.02) and regional electromechanical delay but not related to global LV longitudinal strain. Using multivariate regression, resting LVOTG (p = 0.006) & TTP mid septum (p = 0.01) were found to be independent predictors of latent LVOT obstruction using ISDN. Conclusion: There is a comparable diagnostic value of nitrate inhalation to exercise testing in provocation of LVOT obstruction in HCM. Latent obstruction is predominantly dependent on regional electromechanical delay. PMID:26779503

Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery

NASA Technical Reports Server (NTRS)

Qin, J. X.; Shiota, T.; Lever, H. M.; Kapadia, S. R.; Sitges, M.; Rubin, D. N.; Bauer, F.; Greenberg, N. L.; Agler, D. A.; Drinko, J. K.;

Hypertrophic Cardiomyopathy in Children, Adolescents, and Young Adults Associated With Low Cardiovascular Mortality With Contemporary Management Strategies.

PubMed

Maron, Barry J; Rowin, Ethan J; Casey, Susan A; Lesser, John R; Garberich, Ross F; McGriff, Deepa M; Maron, Martin S

2016-01-05

Youthful age has been considered the time of greatest risk for patients with hypertrophic cardiomyopathy (HCM), largely because of the possibility of sudden death. The last 2 decades have witnessed more reliable identification of at-risk patients and utilization of implantable cardioverter-defibrillators for prevention of sudden death, and other contemporary treatment options. Whether such management advances have significantly altered the considerable mortality rate for young HCM patients remains unresolved. We studied long-term outcome in 474 consecutive HCM patients between 7 and 29 years of age presenting at 2 referral institutions. Over 7.1±5.1 years of follow-up (6.0 [3.0, 10.0]), 452 patients (95%) survived, with 95% experiencing no or mild symptoms. HCM-related death occurred in 18 patients (3%; 0.54%/y): arrhythmic sudden death (n=12), progressive heart failure and heart transplant complications (n=5), or postoperatively (n=1). In contrast, aborted life-threatening events occurred in 63 other high-risk patients (13%) with implantable cardioverter-defibrillator interventions for ventricular tachyarrhythmias (n=31), resuscitated out-of-hospital cardiac arrest (n=20), or heart transplant for advanced heart failure (n=12), 1.8%/y, 3-fold higher than HCM mortality. Five- and 10-year survival (considering only HCM deaths) was high (97% and 94%, respectively), virtually identical to that reported in middle-aged adult HCM patients (98% and 94%, P=0.23). In a large hospital-based cohort of young HCM patients, representing an age group considered at greatest risk, low mortality rates can be achieved with the application of contemporary cardiovascular treatment strategies, largely because of reliable identification of high-risk patients who benefited from implantable cardioverter-defibrillators for sudden death prevention, thereby creating the opportunity for extended longevity and good quality of life. © 2015 American Heart Association, Inc.

Functional characterization of TRAP1-like protein involved in modulating fibrotic processes mediated by TGF-β/Smad signaling in hypertrophic scar fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, X.; Department of Pediatric Surgery, Shanghai Children’s Medical Center, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127; Chu, J.

2015-03-15

The transforming growth factor-β1 (TGF-β)-mediated signaling pathway is believed to be closely associated with wound healing and scar formation, in which TRAP1-like protein (TLP) plays a role in regulating the balance of Smad2 vs. Smad3 signaling. Our previous study revealed the relation between TLP and collagen synthesis in normal human skin fibroblasts. Here, we present a detailed analysis of the effects of TLP on the process of hypertrophic scar formation and contraction. To explore and verify a contribution of TLP to the pathological mechanism of hypertrophic scar fibroblasts (HSFb), we constructed lentiviral vectors that either overexpressed TLP or encoded smallmore » hairpin RNAs (shRNAs) targeting TLP, then we transfected them into HSFb. TLP knockdown in HSFb resulted in reduced levels of cell contraction, type I and type III collagen mRNA transcripts and protein expression, and higher levels of fibronectin (FN) compared to control groups. In addition, knockdown of TLP promoted the phosphorylation of Smad3 but repressed Smad2 and Erk-1/2 phosphorylation in human hypertrophic scar fibroblasts compared to control groups. The reduction of TLP did not interfere with HSF proliferative ability, but exogenous TLP cooperated with TGF-β1 to increase cell viability. Together, our findings demonstrate evidence for a contribution of TLP expression in hypertrophic scar formation and contraction. - Highlights: • TLP acted different roles in the activating of Smad2- and Smad3-dependent signaling. • TLP may induce TGF-β1-mediated collagens expression through Smad signalings and MAPK signaling. • TLP may enhance HSFb contraction by increasing the expression of α-SMA. • Exogenous TLP can cooperate with TGF-β1 to increase cell viability.« less

Cellular MYCro economics: Balancing MYC function with MYC expression.

PubMed

Levens, David

2013-11-01

The expression levels of the MYC oncoprotein have long been recognized to be associated with the outputs of major cellular processes including proliferation, cell growth, apoptosis, differentiation, and metabolism. Therefore, to understand how MYC operates, it is important to define quantitatively the relationship between MYC input and expression output for its targets as well as the higher-order relationships between the expression levels of subnetwork components and the flow of information and materials through those networks. Two different views of MYC are considered, first as a molecular microeconomic manager orchestrating specific positive and negative responses at individual promoters in collaboration with other transcription and chromatin components, and second, as a macroeconomic czar imposing an overarching rule onto all active genes. In either case, c-myc promoter output requires multiple inputs and exploits diverse mechanisms to tune expression to the appropriate levels relative to the thresholds of expression that separate health and disease.

Psoriasis and dilated cardiomyopathy: coincidence or associated diseases?

PubMed

Eliakim-Raz, Noa; Shuvy, Mony; Lotan, Chaim; Planer, David

2008-01-01

Psoriasis is a common immune-mediated disease which affects 1-3% of the population. The etiology of psoriasis is unknown. Idiopathic dilated cardiomyopathy is probably the end result of a variety of toxic, metabolic or infectious agents. During a computerized search for cardiomyopathy among all patients hospitalized with psoriasis in the Hadassah University Hospital since 1980 we found an increased prevalence of cardiomyopathy, and specifically dilated cardiomyopathy. We present 4 patients who suffer from both conditions. In accordance with previous data, an association between preexisting psoriasis and dilated cardiomyopathy is suggested. We suggest that the genetic risk factors of dilated cardiomyopathy are shared by psoriasis, and more specifically psoriatic arthritis. Alternatively, the immune reaction that is triggered in dilated cardiomyopathy leading to the progression of the disease might be enhanced in patients with psoriasis or psoriatic arthritis. Chronic inflammation and persistent secretion of proinflammatory cytokines may be considered a potential pathway, triggering the initiation and progression of dilated cardiomyopathy in psoriatic patients. Further investigation of the genetic and immune risk factors involved in dilated cardiomyopathy and in psoriasis may lead to a better understanding of the pathogenesis and treatment of dilated cardiomyopathy. Copyright 2008 S. Karger AG, Basel.

Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I

PubMed Central

Frantz, Stefan; Klaiber, Michael; Baba, Hideo A.; Oberwinkler, Heike; Völker, Katharina; Gaβner, Birgit; Bayer, Barbara; Abeβer, Marco; Schuh, Kai; Feil, Robert; Hofmann, Franz; Kuhn, Michaela

2013-01-01

Aims Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism. Methods and results To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the [Ca2+]i-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte Ca2+i homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, Ca2+i-handling, and contractility via cGKI. Conclusion These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte Ca2+i handling and contractility. PMID:22199120

European Cardiomyopathy Pilot Registry: EURObservational Research Programme of the European Society of Cardiology.

PubMed

Elliott, Perry; Charron, Philippe; Blanes, Juan Ramon Gimeno; Tavazzi, Luigi; Tendera, Michal; Konté, Marème; Laroche, Cécile; Maggioni, Aldo P

2016-01-07

Cardiomyopathies are a heterogeneous group of disorders associated with premature death due to ventricular arrhythmia or heart failure. The purpose of this study was to examine the characteristics of patients enrolled in the pilot phase of the EURObservational Research Programme (EORP) cardiomyopathy registry. Between 1 December 2012 and 30 November 2013, four cardiomyopathy phenotypes were studied: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). Twenty-seven centres in 12 countries participated; 1115 patients were enrolled. The commonest cardiomyopathy was HCM (n = 681), followed by DCM (n = 346), ARVC (n = 59), and RCM (n = 29); 423 patients (46.4% of those reported) had familial disease; and 56 (5.0%) had rare disease phenocopies. Median age at enrolment and diagnosis was 54 [interquartile range (IQR), 42-64] and 46 years (IQR, 32-58), respectively; fewer patients with ARVC and more with RCM were diagnosed in the upper age quartile (P < 0.0001). There was a male predominance for all cardiomyopathies except RCM (P = 0.0023). Most patients were in New York Heart Association functional class I (n = 813) at enrolment; 139 (12.5%) reported syncope, most frequently in ARVC (P = 0.0009). Five hundred and seven (45.5%) patients underwent cardiac magnetic resonance imaging, 117 (10.6%) endomyocardial biopsy, and 462 (41.4%) genetic testing with a causative mutation reported in 236 individuals (51.1%). 1026 patients (92.0%) were receiving drug therapy; 316 (28.3%) had received an implantable cardioverter defibrillator (highest proportion in ARVC, P < 0.0001). This pilot study shows that services for patients with cardiomyopathy are complex, requiring access to a large range of invasive and non-invasive investigations and involvement of multidisciplinary teams. Treatment regimens are equally multifaceted and show that patients are likely to need long-term follow

Distribution of late gadolinium enhancement in various types of cardiomyopathies: Significance in differential diagnosis, clinical features and prognosis

PubMed Central

Satoh, Hiroshi; Sano, Makoto; Suwa, Kenichiro; Saitoh, Takeji; Nobuhara, Mamoru; Saotome, Masao; Urushida, Tsuyoshi; Katoh, Hideki; Hayashi, Hideharu

2014-01-01

The recent development of cardiac magnetic resonance (CMR) techniques has allowed detailed analyses of cardiac function and tissue characterization with high spatial resolution. We review characteristic CMR features in ischemic and non-ischemic cardiomyopathies (ICM and NICM), especially in terms of the location and distribution of late gadolinium enhancement (LGE). CMR in ICM shows segmental wall motion abnormalities or wall thinning in a particular coronary arterial territory, and the subendocardial or transmural LGE. LGE in NICM generally does not correspond to any particular coronary artery distribution and is located mostly in the mid-wall to subepicardial layer. The analysis of LGE distribution is valuable to differentiate NICM with diffusely impaired systolic function, including dilated cardiomyopathy, end-stage hypertrophic cardiomyopathy (HCM), cardiac sarcoidosis, and myocarditis, and those with diffuse left ventricular (LV) hypertrophy including HCM, cardiac amyloidosis and Anderson-Fabry disease. A transient low signal intensity LGE in regions of severe LV dysfunction is a particular feature of stress cardiomyopathy. In arrhythmogenic right ventricular cardiomyopathy/dysplasia, an enhancement of right ventricular (RV) wall with functional and morphological changes of RV becomes apparent. Finally, the analyses of LGE distribution have potentials to predict cardiac outcomes and response to treatments. PMID:25068019

Distribution of late gadolinium enhancement in various types of cardiomyopathies: Significance in differential diagnosis, clinical features and prognosis.

PubMed

Satoh, Hiroshi; Sano, Makoto; Suwa, Kenichiro; Saitoh, Takeji; Nobuhara, Mamoru; Saotome, Masao; Urushida, Tsuyoshi; Katoh, Hideki; Hayashi, Hideharu

2014-07-26

The recent development of cardiac magnetic resonance (CMR) techniques has allowed detailed analyses of cardiac function and tissue characterization with high spatial resolution. We review characteristic CMR features in ischemic and non-ischemic cardiomyopathies (ICM and NICM), especially in terms of the location and distribution of late gadolinium enhancement (LGE). CMR in ICM shows segmental wall motion abnormalities or wall thinning in a particular coronary arterial territory, and the subendocardial or transmural LGE. LGE in NICM generally does not correspond to any particular coronary artery distribution and is located mostly in the mid-wall to subepicardial layer. The analysis of LGE distribution is valuable to differentiate NICM with diffusely impaired systolic function, including dilated cardiomyopathy, end-stage hypertrophic cardiomyopathy (HCM), cardiac sarcoidosis, and myocarditis, and those with diffuse left ventricular (LV) hypertrophy including HCM, cardiac amyloidosis and Anderson-Fabry disease. A transient low signal intensity LGE in regions of severe LV dysfunction is a particular feature of stress cardiomyopathy. In arrhythmogenic right ventricular cardiomyopathy/dysplasia, an enhancement of right ventricular (RV) wall with functional and morphological changes of RV becomes apparent. Finally, the analyses of LGE distribution have potentials to predict cardiac outcomes and response to treatments.

[Analysis of genotype and phenotype correlation of MYH7-V878A mutation among ethnic Han Chinese pedigrees affected with hypertrophic cardiomyopathy].

PubMed

Wang, Bo; Guo, Ruiqi; Zuo, Lei; Shao, Hong; Liu, Ying; Wang, Yu; Ju, Yan; Sun, Chao; Wang, Lifeng; Zhang, Yanmin; Liu, Liwen

2017-08-10

To analyze the phenotype-genotype correlation of MYH7-V878A mutation. Exonic amplification and high-throughput sequencing of 96-cardiovascular disease-related genes were carried out on probands from 210 pedigrees affected with hypertrophic cardiomyopathy (HCM). For the probands, their family members, and 300 healthy volunteers, the identified MYH7-V878A mutation was verified by Sanger sequencing. Information of the HCM patients and their family members, including clinical data, physical examination, echocardiography (UCG), electrocardiography (ECG), and conserved sequence of the mutation among various species were analyzed. A MYH7-V878A mutation was detected in five HCM pedigrees containing 31 family members. Fourteen members have carried the mutation, among whom 11 were diagnosed with HCM, while 3 did not meet the diagnostic criteria. Some of the fourteen members also carried other mutations. Family members not carrying the mutation had normal UCG and ECG. No MYH7-V878A mutation was found among the 300 healthy volunteers. Analysis of sequence conservation showed that the amino acid is located in highly conserved regions among various species. MYH7-V878A is a hot spot among ethnic Han Chinese with a high penetrance. Functional analysis of the conserved sequences suggested that the mutation may cause significant alteration of the function. MYH7-V878A has a significant value for the early diagnosis of HCM.

Myosin-driven rescue of contractile reserve and energetics in mouse hearts bearing familial hypertrophic cardiomyopathy-associated mutant troponin T is mutation-specific

PubMed Central

He, Huamei; Hoyer, Kirsten; Tao, Hai; Rice, Ronald; Jimenez, Jesus; Tardiff, Jil C; Ingwall, Joanne S

2012-01-01

The thin filament protein troponin T (TnT) is a regulator of sarcomere function. Whole heart energetics and contractile reserve are compromised in transgenic mice bearing missense mutations at R92 within the tropomyosin-binding domain of cTnT, despite being distal to the ATP hydrolysis domain of myosin. These mutations are associated with familial hypertrophic cardiomyopathy (FHC). Here we test the hypothesis that genetically replacing murine αα-MyHC with murine ββ-MyHC in hearts bearing the R92Q cTnT mutation, a particularly lethal FHC-associated mutation, leads to sufficiently large perturbations in sarcomere function to rescue whole heart energetics and decrease the cost of contraction. By comparing R92Q cTnT and R92L cTnT mutant hearts, we also test whether any rescue is mutation-specific. We defined the energetic state of the isolated perfused heart using 31P-NMR spectroscopy while simultaneously measuring contractile performance at four work states. We found that the cost of increasing contraction in intact mouse hearts with R92Q cTnT depends on the type of myosin present in the thick filament. We also found that the salutary effect of this manoeuvre is mutation-specific, demonstrating the major regulatory role of cTnT on sarcomere function at the whole heart level. PMID:22907055

Myosin-driven rescue of contractile reserve and energetics in mouse hearts bearing familial hypertrophic cardiomyopathy-associated mutant troponin T is mutation-specific.

PubMed

He, Huamei; Hoyer, Kirsten; Tao, Hai; Rice, Ronald; Jimenez, Jesus; Tardiff, Jil C; Ingwall, Joanne S

2012-11-01

The thin filament protein troponin T (TnT) is a regulator of sarcomere function. Whole heart energetics and contractile reserve are compromised in transgenic mice bearing missense mutations at R92 within the tropomyosin-binding domain of cTnT, despite being distal to the ATP hydrolysis domain of myosin. These mutations are associated with familial hypertrophic cardiomyopathy (FHC). Here we test the hypothesis that genetically replacing murine αα-MyHC with murine ββ-MyHC in hearts bearing the R92Q cTnT mutation, a particularly lethal FHC-associated mutation, leads to sufficiently large perturbations in sarcomere function to rescue whole heart energetics and decrease the cost of contraction. By comparing R92Q cTnT and R92L cTnT mutant hearts, we also test whether any rescue is mutation-specific. We defined the energetic state of the isolated perfused heart using (31)P-NMR spectroscopy while simultaneously measuring contractile performance at four work states. We found that the cost of increasing contraction in intact mouse hearts with R92Q cTnT depends on the type of myosin present in the thick filament. We also found that the salutary effect of this manoeuvre is mutation-specific, demonstrating the major regulatory role of cTnT on sarcomere function at the whole heart level.

Myc-nick: a cytoplasmic cleavage product of Myc that promotes alpha-tubulin acetylation and cell differentiation.

PubMed

Conacci-Sorrell, Maralice; Ngouenet, Celine; Eisenman, Robert N

2010-08-06

The Myc oncoprotein family comprises transcription factors that control multiple cellular functions and are widely involved in oncogenesis. Here we report the identification of Myc-nick, a cytoplasmic form of Myc generated by calpain-dependent proteolysis at lysine 298 of full-length Myc. Myc-nick retains conserved Myc box regions but lacks nuclear localization signals and the bHLHZ domain essential for heterodimerization with Max and DNA binding. Myc-nick induces alpha-tubulin acetylation and altered cell morphology by recruiting histone acetyltransferase GCN5 to microtubules. During muscle differentiation, while the levels of full-length Myc diminish, Myc-nick and acetylated alpha-tubulin levels are increased. Ectopic expression of Myc-nick accelerates myoblast fusion, triggers the expression of myogenic markers, and permits Myc-deficient fibroblasts to transdifferentiate in response to MyoD. We propose that the cleavage of Myc by calpain abrogates the transcriptional inhibition of differentiation by full-length Myc and generates Myc-nick, a driver of cytoplasmic reorganization and differentiation. Copyright 2010 Elsevier Inc. All rights reserved.

Midregional pro-atrial natriuretic peptide: a novel marker of myocardial fibrosis in patients with hypertrophic cardiomyopathy.

PubMed

Elmas, Elif; Doesch, Christina; Fluechter, Stephan; Freundt, Miriam; Weiss, Christel; Lang, Siegfried; Kälsch, Thorsten; Haghi, Dariush; Papassotiriou, Jana; Kunde, Jan; Schoenberg, Stefan O; Borggrefe, Martin; Papavassiliu, Theano

2011-04-01

We aimed to determine the diagnostic performance of biomarkers in predicting myocardial fibrosis assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR) in patients with hypertrophic cardiomyopathy (HCM). LGE CMR was performed in 40 consecutive patients with HCM. Left and right ventricular parameters, as well as the extent of LGE were determined and correlated to the plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), carboxy-terminal pro-endothelin-1 (CT-proET-1), carboxy-terminal pro-vasopressin (CT-proAVP), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8). Myocardial fibrosis was assumed positive, if CMR indicated LGE. LGE was present in 26 of 40 patients with HCM (65%) with variable extent (mean: 14%, range: 1.3-42%). The extent of LGE was positively associated with MR-proANP (r = 0.4; P = 0.01). No correlations were found between LGE and MR-proADM (r = 0.1; P = 0.5), CT-proET-1 (r = 0.07; P = 0.66), CT-proAVP (r = 0.16; P = 0.3), MMP-9 (r = 0.01; P = 0.9), TIMP-1 (r = 0.02; P = 0.85), and IL-8 (r = 0.02; P = 0.89). After adjustment for confounding factors, MR-proANP was the only independent predictor associated with the presence of LGE (P = 0.007) in multivariate analysis. The area under the ROC curve (AUC) indicated good predictive performance (AUC = 0.882) of MR-proANP with respect to LGE. The odds ratio was 1.268 (95% confidence interval 1.066-1.508). The sensitivity of MR-proANP at a cut-off value of 207 pmol/L was 69%, the specificity 94%, the positive predictive value 90% and the negative predictive value 80%. The results imply that MR-proANP serves as a novel marker of myocardial fibrosis assessed by LGE CMR in patients with HCM.

Making sense of hypertrophic scar: a role for nerves.

PubMed

Scott, Jeffrey R; Muangman, Pornprom; Gibran, Nicole S

2007-01-01

Healed partial thickness wounds including burns and donor sites cause hypertrophic scar formation and patient discomfort. For many patients with hypertrophic scars, pruritus is the most distressing symptom, which leads to wound excoriation and chronic wound formation. In spite of the clinical significance of abnormal innervation in scars, the nervous system has been largely ignored in the pathophysiology of hypertrophic scars. Evidence that neuropeptides contribute to inflammatory responses to injury include inflammatory cell chemotaxis, cytokine and growth factor production. The neuropeptide substance P, which is released from nerve endings after injury, induces inflammation and mediates angiogenesis, keratinocyte proliferation, and fibrogenesis. Substance P activity is tightly regulated by neutral endopeptidase (NEP), a membrane bound metallopeptidase that degrades substance P at the cell membrane. Altered substance P levels may contribute to impaired cutaneous healing responses associated with diabetes mellitus or hypertrophic scar formation. Topical application of exogenous substance P or an NEP inhibitor enhances wound closure kinetics in diabetic murine wounds suggesting that diabetic wounds have insufficient substance P levels to promote a neuroinflammatory response necessary for normal wound repair. Conversely, increased nerve numbers and neuropeptide levels with reduced NEP levels in human and porcine hypertrophic scar samples suggest that excessive neuropeptide activity induces exuberant inflammation in hypertrophic scars. Given these observations about the role of neuropeptides in cutaneous repair, neuronal modulation of repair processes at two extremes of abnormal wound healing, chronic non-healing ulcers in type II diabetes mellitus and hypertrophic scars in deep partial thickness wounds, may provide therapeutic targets.

Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or α-Tropomyosin Mutation for Hypertrophic Cardiomyopathy

PubMed Central

Prajapati, Chandra; Pölönen, Risto-Pekka; Rajala, Kristiina; Pekkanen-Mattila, Mari; Rasku, Jyrki; Larsson, Kim; Aalto-Setälä, Katriina

2016-01-01

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease, which affects the structure of heart muscle tissue. The clinical symptoms include arrhythmias, progressive heart failure, and even sudden cardiac death but the mutation carrier can also be totally asymptomatic. To date, over 1400 mutations have been linked to HCM, mostly in genes encoding for sarcomeric proteins. However, the pathophysiological mechanisms of the disease are still largely unknown. Two founder mutations for HCM in Finland are located in myosin-binding protein C (MYBPC3-Gln1061X) and α-tropomyosin (TPM1-Asp175Asn) genes. We studied the properties of HCM cardiomyocytes (CMs) derived from patient-specific human induced pluripotent stem cells (hiPSCs) carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn mutation. Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size, Ca2+ handling, and electrophysiological properties, as well as their gene expression profiles. These findings suggest that even though the clinical phenotypes of the patients carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation are similar, the genetic background as well as the functional properties on the cellular level might be different, indicating that the pathophysiological mechanisms behind the two mutations would be divergent as well. PMID:27057166

Urinary N-terminal fragment of titin is a marker to diagnose muscular dystrophy in patients with cardiomyopathy.

PubMed

Yoshihisa, Akiomi; Kiko, Takatoyo; Sato, Takamasa; Oikawa, Masayoshi; Kobayashi, Atsushi; Takeishi, Yasuchika

2018-06-02

The differential diagnosis of cardiomyopathy is important. It has been recently reported that urinary titin N (U-TN) is increased in patients with muscular dystrophy (MD), and is associated with muscular damage. We aimed to clarify whether U-TN is useful as a diagnostic tool for distinguishing MD from various cardiomyopathies [e.g. dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM)]. We measured and compared the U-TN/creatinine ratio (U-TN/Cr; pmol/mg/dl) in 278 control subjects and 331 patients with various cardiomyopathies (DCM, n = 199; sarcoidosis, n = 18; HCM, n = 86; amyloidosis, n = 15; Fabry disease, n = 6; MD, n = 7). The U-TN/Cr was significantly higher in MD patients than in patients with various cardiomyopathies and the control subjects (P < 0.001). From the ROC analysis, the U-TN/Cr (with a cut-off value of 8.7) identified MD with 100% sensitivity, 82% specificity, and an area under the curve (AUC) of 0.92 (95% CI 0.87-0.98, P < 0.001). The AUC of the U-TN/Cr that was able to predict MD was superior to those of U-TN, creatinine kinase, B-type natriuretic peptide, and troponin I. Urinary Titin-N is a novel marker to diagnose MD. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

PubMed Central

Lee, Y Y; Moujalled, D; Doerflinger, M; Gangoda, L; Weston, R; Rahimi, A; de Alboran, I; Herold, M; Bouillet, P; Xu, Q; Gao, X; Du, X-J; Puthalakath, H

2013-01-01

Catecholamines regulate the β-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the β-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases. PMID:23579242

Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30II accessory protein and the induction of oncogenic cellular transformation by p30II/c-MYC

PubMed Central

Romeo, Megan M.; Ko, Bookyung; Kim, Janice; Brady, Rebecca; Heatley, Hayley C.; He, Jeffrey; Harrod, Carolyn K.; Barnett, Braden; Ratner, Lee; Lairmore, Michael D.; Martinez, Ernest; Lüscher, Bernhard; Robson, Craig N.; Henriksson, Marie; Harrod, Robert

2014-01-01

The human T-cell leukemia retrovirus type-1 (HTLV-1) p30II protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30II interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30II and c-MYC remain to be completely understood. Herein we demonstrate that p30II induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30II in c-myc−/− HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30II is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30II inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30II/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis. PMID:25569455

Mechanical dispersion and global longitudinal strain by speckle tracking echocardiography: Predictors of appropriate implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy.

PubMed

Candan, Ozkan; Gecmen, Cetin; Bayam, Emrah; Guner, Ahmet; Celik, Mehmet; Doğan, Cem

2017-06-01

In this study, we investigated whether mechanical dispersion which reflects electrical abnormality and other echocardiographic and clinic parameters predict appropriate ICD shock in patients undergone ICD implantation for hypertrophic cardiomyopathy. Sixty-three patients who received ICD implantation for primary or secondary prevention were included in the study. Patients' clinical, electrocardiographic, 2D classic, and speckle tracking echocardiographic data were collected. Mechanical dispersion was defined as the standard deviation of time to peak negative strain in 18 left ventricular segments. Appropriate ICD therapy was defined as cardioversion or defibrillation due to ventricular tachycardia or fibrillation. Patients were divided into two groups as occurrence or the absence of appropriate ICD therapy. A total of 17 (26.9%) patients were observed to have an appropriate ICD therapy during follow-up periods. In patients who performed appropriate ICD therapy, a larger left atrial volume index, higher sudden cardiac death (SCD)-Risk Score, longer mechanical dispersion, and decreased global longitudinal peak strain (GLPS) were observed. In multivariate logistic regression analysis, including (GLPS, mechanical dispersion, LAVi, and SCD-Risk Score) was used to determine independent predictors of occurrence of appropriate ICD therapy during the follow-up. Mechanical dispersion, GLPS, and SCD-Risk Score were found to be independent predictors of occurrence of appropriate ICD therapy. Mechanical dispersion, GLPS, and SCD-Risk Score were found to be predictive for appropriate ICD therapy in patients receiving ICD implantation. Readily measurable mechanical dispersion and GLPS could be helpful to distinguish patients at high risk who could optimally benefit from ICD therapy. © 2017, Wiley Periodicals, Inc.

Heart rate variability analysis based on time-frequency representation and entropies in hypertrophic cardiomyopathy patients.

PubMed

Clariá, F; Vallverdú, M; Baranowski, R; Chojnowska, L; Caminal, P

2008-03-01

In hypertrophic cardiomyopathy (HCM) patients there is an increased risk of premature death, which can occur with little or no warning. Furthermore, classification for sudden cardiac death on patients with HCM is very difficult. The aim of our study was to improve the prognostic value of heart rate variability (HRV) in HCM patients, giving insight into changes of the autonomic nervous system. In this way, the suitability of linear and nonlinear measures was studied to assess the HRV. These measures were based on time-frequency representation (TFR) and on Shannon and Rényi entropies, and compared with traditional HRV measures. Holter recordings of 64 patients with HCM and 55 healthy subjects were analyzed. The HCM patients consisted of two groups: 13 high risk patients, after aborted sudden cardiac death (SCD); 51 low risk patients, without SCD. Five-hour RR signals, corresponding to the sleep period of the subjects, were considered for the analysis as a comparable standard situation. These RR signals were filtered in the three frequency bands: very low frequency band (VLF, 0-0.04 Hz), low frequency band (LF, 0.04-0.15 Hz) and high frequency band (HF, 0.15-0.45 Hz). TFR variables based on instantaneous frequency and energy functions were able to classify HCM patients and healthy subjects (control group). Results revealed that measures obtained from TFR analysis of the HRV better classified the groups of subjects than traditional HRV parameters. However, results showed that nonlinear measures improved group classification. It was observed that entropies calculated in the HF band showed the highest statistically significant levels comparing the HCM group and the control group, p-value < 0.0005. The values of entropy measures calculated in the HCM group presented lower values, indicating a decreasing of complexity, than those calculated from the control group. Moreover, similar behavior was observed comparing high and low risk of premature death, the values of the

Mechanical and energetic properties of papillary muscle from ACTC E99K transgenic mouse models of hypertrophic cardiomyopathy

PubMed Central

Song, Weihua; Vikhorev, Petr G.; Kashyap, Mavin N.; Rowlands, Christina; Ferenczi, Michael A.; Woledge, Roger C.; MacLeod, Kenneth; Curtin, Nancy A.

2013-01-01

We compared the contractile performance of papillary muscle from a mouse model of hypertrophic cardiomyopathy [α-cardiac actin (ACTC) E99K mutation] with nontransgenic (non-TG) littermates. In isometric twitches, ACTC E99K papillary muscle produced three to four times greater force than non-TG muscle under the same conditions independent of stimulation frequency and temperature, whereas maximum isometric force in myofibrils from these muscles was not significantly different. ACTC E99K muscle relaxed slower than non-TG muscle in both papillary muscle (1.4×) and myofibrils (1.7×), whereas the rate of force development after stimulation was the same as non-TG muscle for both electrical stimulation in intact muscle and after a Ca2+ jump in myofibrils. The EC50 for Ca2+ activation of force in myofibrils was 0.39 ± 0.33 μmol/l in ACTC E99K myofibrils and 0.80 ± 0.11 μmol/l in non-TG myofibrils. There were no significant differences in the amplitude and time course of the Ca2+ transient in myocytes from ACTC E99K and non-TG mice. We conclude that hypercontractility is caused by higher myofibrillar Ca2+ sensitivity in ACTC E99K muscles. Measurement of the energy (work + heat) released in actively cycling heart muscle showed that for both genotypes, the amount of energy turnover increased with work done but with decreasing efficiency as energy turnover increased. Thus, ACTC E99K mouse heart muscle produced on average 3.3-fold more work than non-TG muscle, and the cost in terms of energy turnover was disproportionately higher than in non-TG muscles. Efficiency for ACTC E99K muscle was in the range of 11–16% and for non-TG muscle was 15–18%. PMID:23604709

Erythrocyte creatine as a marker of intravascular hemolysis due to left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

PubMed

Kubo, Toru; Okumiya, Toshika; Baba, Yuichi; Hirota, Takayoshi; Tanioka, Katsutoshi; Yamasaki, Naohito; Sugiura, Tetsuro; Doi, Yoshinori L; Kitaoka, Hiroaki

2016-03-01

Erythrocyte creatine, a marker of erythrocyte age that increases with shortening of erythrocyte survival, has been reported to be a quantitative and reliable marker for intravascular hemolysis. We hypothesized that hemolysis could also occur due to intraventricular obstruction in patients with hypertrophic cardiomyopathy (HCM). The purpose of this study was to examine the presence of subclinical hemolysis and the relation between intravascular hemolysis and intraventricular pressure gradient (IVPG). We measured erythrocyte creatine in 92 HCM patients. Twelve patients had left ventricular outflow tract obstruction (LVOTO), 4 had midventricular obstruction (MVO), and the remaining 76 were non-obstructive. Erythrocyte creatine levels ranged from 0.92 to 4.36μmol/g hemoglobin. Higher levels of erythrocyte creatine were associated with higher IVPG (r=0.437, p<0.001). If erythrocyte creatine levels are high (≥1.8μmol/g hemoglobin), subclinical hemolysis is considered to be present. Half of LVOTO patients and no MVO patients showed high erythrocyte creatine levels. Although non-obstructive patients did not show significant intraventricular obstruction at rest, some showed high erythrocyte creatine levels. When LVOT-PG was measured during the strain phase of the Valsalva maneuver in 20 non-obstructive patients, 7 of those 20 patients showed LVOTO. In the 20 patients, there was no relation between erythrocyte creatine levels and LVOT-PG before the Valsalva maneuver (r=0.125, p=0.600), whereas there was a significant correlation between erythrocyte creatine and LVOT-PG provoked by the Valsalva maneuver (r=0.695, p=0.001). There is biochemical evidence of subclinical hemolysis in patients with HCM, and this hemolysis seems to be associated with LVOTO provoked by daily physical activities. Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

CCN2 plays a key role in extracellular matrix gene expression in severe hypertrophic cardiomyopathy and heart failure.

PubMed

Tsoutsman, Tatiana; Wang, Xiaoyu; Garchow, Kendra; Riser, Bruce; Twigg, Stephen; Semsarian, Christopher

2013-09-01

Hypertrophic cardiomyopathy (HCM) is the most common inherited primary myocardial disorder. HCM is characterized by interstitial fibrosis and excessive accumulation of extracellular matrix (ECM) proteins. Fibrosis in HCM has been associated with impaired cardiac function and heart failure, and has been considered a key substrate for ventricular arrhythmias and sudden death. The molecular triggers underpinning ECM production are not well established. We have previously developed a double-mutant mouse model of HCM that recapitulates the phenotype seen in humans with multiple mutations, including earlier onset of the disease, progression to a dilated phenotype, severe heart failure and premature mortality. The present study investigated the expression of ECM-encoding genes in severe HCM and heart failure. Significant upregulation of structural Fn1, regulatory Mmp14, Timp1, Serpin3A, SerpinE1, SerpineE2, Tgfβ1, and Tgfβ2; and matricellular Ccn2, Postn, Spp1, Thbs1, Thbs4, and Tnc was evident from the early, pre-phenotype stage. Non-myocytes expressed ECM genes at higher levels than cardiomyocytes in normal and diseased hearts. Synchronous increase of secreted CCN2 and TIMP1 plasma levels and decrease of MMP3 levels were observed in end-stage disease. CCN2 protein expression was increased from early disease in double-mutant hearts and played an important role in ECM responses. It was a powerful modulator of ECM regulatory (Timp1 and SerpinE1) and matricellular protein-encoding (Spp1, Thbs1, Thbs4 and Tnc) gene expression in cardiomyocytes when added exogenously in vitro. Modulation of CCN2 (CTGF, connective tissue growth factor) and associated early ECM changes may represent a new therapeutic target in the treatment and prevention of heart failure in HCM. Copyright © 2013 Elsevier Ltd. All rights reserved.

A prospective follow-up of alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy--the Baylor experience (1996-2002).

PubMed

Fernandes, Valerian L; Nagueh, Sherif F; Wang, Wei; Roberts, Robert; Spencer, William H

2005-03-01

There is a paucity of data on the long-term outcome of alcohol septal ablation (ASA) for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). The study was undertaken to evaluate the longer-term outcome of ASA therapy for symptomatic HOCM. In all, 137 patients were enrolled consecutively (1996-1999) and 130 (95%) (74 men, 56 women, aged 51 +/- 17 years) underwent ASA and had serial prospective follow-up for up to 5 years (mean follow-up 3.6 +/- 1.4 years). Evaluation included angina (Canadian Cardiovascular Society [CCS] score), dyspnea (New York Heart Association [NYHA] class), duration of exercise on treadmill, and echocardiographic indices. Ethanol (3.5 +/- 1.5 cc), injected into 1.5 +/- 0.6 arteries, induced a mean peak plasma creatine kinase (CK) of 1676 +/- 944 units. Complications of procedures included death 1.5% (2/130), heart block requiring permanent pacemaker 13% (17/130), and coronary dissection 4.4% (6/130). Baseline versus last follow-up visit: NYHA class decreased from 3.0 +/- 0.4 to 1.2 +/- 0.6 (p < 0.01); CCS angina score from 2.0 +/- 0.8 to 0.08 +/- 0.4 (p < 0.01); and duration of exercise increased from 322 +/- 207 to 443 +/- 200 s (p < 0.01). Resting left ventricular outflow tract gradient at baseline versus last follow-up visit showed a decrease from 74 +/- 30 to 4 +/- 13 (p < 0.01), and the dobutamine-provoked gradient of 88 +/- 29 decreased to 21 +/- 21 (p < 0.01) mmHg. All-cause mortality over the duration of follow-up was 7.7% (10) giving an annual rate of 2.1%, and cardiac mortality was 2.3% (3) reflecting an annual rate of 0.6%. Alcohol septal ablation decreased symptoms and improved exercise performance, indicating that it is an effective procedure for symptomatic HOCM.

Spectrum and clinical significance of systolic function and myocardial fibrosis assessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

PubMed

Olivotto, Iacopo; Maron, Barry J; Appelbaum, Evan; Harrigan, Caitlin J; Salton, Carol; Gibson, C Michael; Udelson, James E; O'Donnell, Christopher; Lesser, John R; Manning, Warren J; Maron, Martin S

2010-07-15

In hypertrophic cardiomyopathy (HCM), the clinical significance attributable to the broad range of left ventricular (LV) systolic function, assessed as the ejection fraction (EF), is incompletely resolved. We evaluated the EF using cardiovascular magnetic resonance (CMR) imaging in a large cohort of patients with HCM with respect to the clinical status and evidence of left ventricular remodeling with late gadolinium enhancement (LGE). CMR imaging was performed in 310 consecutive patients, aged 42 +/- 17 years. The EF in patients with HCM was 71 +/- 10% (range 28% to 89%), exceeding that of 606 healthy controls without cardiovascular disease (66 +/- 5%, p <0.001). LGE reflecting LV remodeling showed an independent, inverse relation to the EF (B-0.69, 95% confidence interval -0.86 to -0.52; p <0.001) and was greatest in patients with an EF <50%, in whom it constituted a median value of 29% of the LV volume (interquartile range 16% to 40%). However, the substantial subgroup with low-normal EF values of 50% to 65% (n = 45; 15% of the whole cohort), who were mostly asymptomatic or mildly symptomatic (37 or 82% with New York Heart Association functional class I to II), showed substantial LGE (median 5% of LV volume, interquartile range 2% to 10%). This overlapped with the subgroup with systolic dysfunction and significantly exceeded that of patients with an EF of 66% to 75% and >75% (median 2% of the LV volume, interquartile range 1.5% to 4%; p <0.01). In conclusion, in a large cohort of patients with HCM, a subset of patients with low-normal EF values (50% to 65%) was identified by contrast-enhanced CMR imaging as having substantial degrees of LGE, suggesting a transition phase, potentially heralding advanced LV remodeling and systolic dysfunction, with implications for clinical surveillance and management. Copyright (c) 2010. Published by Elsevier Inc.

Utility of T-wave amplitude as a non-invasive risk marker of sudden cardiac death in hypertrophic cardiomyopathy.

PubMed

Sugrue, Alan; Killu, Ammar M; DeSimone, Christopher V; Chahal, Anwar A; Vogt, Josh C; Kremen, Vaclav; Hai, JoJo; Hodge, David O; Acker, Nancy G; Geske, Jeffrey B; Ackerman, Michael J; Ommen, Steve R; Lin, Grace; Noseworthy, Peter A; Brady, Peter A

2017-01-01

Sudden cardiac arrest (SCA) is the most devastating outcome in hypertrophic cardiomyopathy (HCM). We evaluated repolarisation features on the surface electrocardiogram (ECG) to identify the potential risk factors for SCA. Data was collected from 52 patients with HCM who underwent implantable cardioverter defibrillator (ICD) implantation. Leads V2 and V5 from the ECG closest to the time of ICD implant were utilised for measuring the Tpeak-Tend interval (Tpe), QTc, Tpe/QTc, T-wave duration and T-wave amplitude. The presence of the five traditional SCA-associated risk factors was assessed, as well as the HCM risk-SCD score. 16 (30%) patients experienced aborted cardiac arrest over 8.5±4.1 years, with 9 receiving an ICD shock and 7 receiving ATP. On univariate analysis, T-wave amplitude was associated with appropriate ICD therapy (HR per 0.1 mV 0.79, 95% CI 0.56 to 0.96, p=0.02). Aborted SCA was not associated with a greater mean QTc duration, Tpeak-Tend interval, T-wave duration, or Tpe/QT ratio. Multivariate analysis (adjusting for cardinal HCM SCA-risk factors) showed T-wave amplitude in Lead V2 was an independent predictor of risk (adjusted HR per 0.1 mV 0.74, 95% CI 0.57 to 0.97, p=0.03). Addition of T-wave amplitude in Lead V2 to the traditional risk factors resulted in significant improvement in risk stratification (C-statistic from 0.65 to 0.75) but did not improve the performance of the HCM SCD-risk score. T-wave amplitude is a novel marker of SCA in this high risk HCM population and may provide incremental predictive value to established risk factors. Further work is needed to define the role of repolarisation abnormalities in predicting SCA in HCM.

Mechanical and energetic properties of papillary muscle from ACTC E99K transgenic mouse models of hypertrophic cardiomyopathy.

PubMed

Song, Weihua; Vikhorev, Petr G; Kashyap, Mavin N; Rowlands, Christina; Ferenczi, Michael A; Woledge, Roger C; MacLeod, Kenneth; Marston, Steven; Curtin, Nancy A

2013-06-01

We compared the contractile performance of papillary muscle from a mouse model of hypertrophic cardiomyopathy [α-cardiac actin (ACTC) E99K mutation] with nontransgenic (non-TG) littermates. In isometric twitches, ACTC E99K papillary muscle produced three to four times greater force than non-TG muscle under the same conditions independent of stimulation frequency and temperature, whereas maximum isometric force in myofibrils from these muscles was not significantly different. ACTC E99K muscle relaxed slower than non-TG muscle in both papillary muscle (1.4×) and myofibrils (1.7×), whereas the rate of force development after stimulation was the same as non-TG muscle for both electrical stimulation in intact muscle and after a Ca²⁺ jump in myofibrils. The EC₅₀ for Ca²⁺ activation of force in myofibrils was 0.39 ± 0.33 μmol/l in ACTC E99K myofibrils and 0.80 ± 0.11 μmol/l in non-TG myofibrils. There were no significant differences in the amplitude and time course of the Ca²⁺ transient in myocytes from ACTC E99K and non-TG mice. We conclude that hypercontractility is caused by higher myofibrillar Ca²⁺ sensitivity in ACTC E99K muscles. Measurement of the energy (work + heat) released in actively cycling heart muscle showed that for both genotypes, the amount of energy turnover increased with work done but with decreasing efficiency as energy turnover increased. Thus, ACTC E99K mouse heart muscle produced on average 3.3-fold more work than non-TG muscle, and the cost in terms of energy turnover was disproportionately higher than in non-TG muscles. Efficiency for ACTC E99K muscle was in the range of 11-16% and for non-TG muscle was 15-18%.

Contribution of mitral valve leaflet length and septal wall thickness to outflow tract obstruction in patients with hypertrophic cardiomyopathy.

PubMed

Morant, Kareem; Mikami, Yoko; Nevis, Immaculate; McCarty, David; Stirrat, John; Scholl, David; Rajchl, Martin; Giannoccaro, Peter; Kolman, Louis; Heydari, Bobby; Lydell, Carmen; Howarth, Andrew; Grant, Andrew; White, James A

2017-08-01

We sought to examine whether elongation of the mitral valve leaflets in patients with hypertrophic cardiomyopathy (HCM) is synergistic to septal wall thickness (SWT) in the development of left ventricular outflow tract obstruction (LVOTO). HCM is a common genetic cardiac disease characterized by asymmetric septal hypertrophy and predisposition towards LVOTO. It has been reported that elongation of the mitral valve leaflets may be a primary phenotypic feature and contribute to LVOTO. However, the relative contribution of this finding versus SWT has not been studied. 152 patients (76 with HCM and 76 non-diseased age, race and BSA-matched controls) and 18 young, healthy volunteers were studied. SWT and the anterior mitral valve leaflet length (AMVLL) were measured using cine MRI. The combined contribution of these variables (SWT × AMVLL) was described as the Septal Anterior Leaflet Product (SALP). Peak LVOT pressure gradient was determined by Doppler interrogation and defined as "obstructive" if ≥ 30 mmHg. Patients with HCM were confirmed to have increased AMVLL compared with controls and volunteers (p < 0.01). Among HCM patients, both SWT and SALP were significantly higher in patients with LVOTO (N = 17) versus without. SALP showed modest improvement in predictive accuracy for LVOTO (AUC = 0.81) among the HCM population versus SWT alone (AUC = 0.77). However, in isolated patients this variable identified patients with LVOTO despite modest SWT. Elongation of the AMVLL is a primary phenotypic feature of HCM. While incremental contributions to LVOTO appear modest at a population level, specific patients may have dominant contribution to LVOTO. The combined marker of SALP allows for maintained identification of such patients despite modest increases in SWT.

Quantification and significance of diffuse myocardial fibrosis and diastolic dysfunction in childhood hypertrophic cardiomyopathy.

PubMed

Hussain, Tarique; Dragulescu, Andreea; Benson, Lee; Yoo, Shi-Joon; Meng, Howard; Windram, Jonathan; Wong, Derek; Greiser, Andreas; Friedberg, Mark; Mertens, Luc; Seed, Michael; Redington, Andrew; Grosse-Wortmann, Lars

2015-06-01

The purpose of this study was to evaluate the presence of diffuse myocardial fibrosis in children and adolescents with hypertrophic cardiomyopathy (HCM) and to assess associations with echocardiographic and clinical parameters of disease. While a common end point in adults with HCM, it is unclear whether diffuse myocardial fibrosis occurs early in the disease. Cardiac magnetic resonance (CMR) estimation of myocardial post-contrast longitudinal relaxation time (T1) is an increasingly used method to estimate diffuse fibrosis. T1 measurements were taken using standard multi-breath-hold spoiled gradient echo phase-sensitive inversion-recovery CMR before and 15 min after the injection of gadolinium. The tissue-blood partition coefficient was calculated as a function of the ratio of T1 change of myocardium compared with blood. An echocardiogram and blood brain natriuretic peptide (BNP) levels were obtained on the day of the CMR. Twelve controls (mean age 12.8 years; 7 male) and 28 patients with HCM (mean age 12.8 years; 21 male) participated. The partition coefficient for both septal (0.27 ± 0.17 vs. 0.13 ± 0.09; p = 0.03) and lateral walls (0.22 ± 0.09 vs. 0.07 ± 0.10; p < 0.001) was increased in patients compared with controls. Eight patients had overt areas of late gadolinium enhancement (LGE). These patients did not show increased partition coefficient compared with those without LGE (0.27 ± 0.15 vs. 0.27 ± 0.19 and 0.22 ± 0.09 vs. 0.22 ± 0.09; p = 0.95 and 0.98, respectively). However, patients who were symptomatic (dyspnea, arrhythmia and/or chest pain) had higher lateral wall partition coefficient than asymptomatic HCM patients (0.27 ± 0.08 vs. 0.17 ± 0.08; p = 0.006). Similarly, patients with raised BNP (>100 pg/ml) had raised lateral wall coefficients (0.27 ± 0.07 vs. 0.20 ± 0.07; p = 0.03), as did those with traditional risk factors for sudden death (0.27 ± 0.06 vs. 0.18 ± 0.08; p = 0.007). Diffuse fibrosis, measured by the partition coefficient

Recent advances in the epidemiology, pathogenesis and prognosis of acute heart failure and cardiomyopathy in Africa.

PubMed

Sliwa, Karen; Mayosi, Bongani M

2013-09-01

This review addresses recent advances in the epidemiology, pathogenesis and prognosis of acute heart failure and cardiomyopathy based on research conducted in Africa. We searched Medline/PubMed for publications on acute decompensated heart failure and cardiomyopathy in Africa for the past 5 years (ie, 1 January 2008 to 31 December 2012). This was supplemented with personal communications with colleagues from Africa working in the field. A large prospective registry has shown that acute decompensated heart failure is caused by hypertension, cardiomyopathy and rheumatic heart disease in 90% of cases, a pattern that is in contrast with the dominance of coronary artery disease in North America and Europe. Furthermore, acute heart failure is a disease of the young with a mean age of 52 years, occurs equally in men and women, and is associated with high mortality at 6 months (∼18%), which is, however, similar to that observed in non-African heart failure registries, suggesting that heart failure has a dire prognosis globally, regardless of aetiology. The molecular genetics of dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy in Africans is consistent with observations elsewhere in the world; the unique founder effects in the Afrikaner provide an opportunity for the study of genotype-phenotype correlations in large numbers of individuals with cardiomyopathy due to the same mutation. Advances in the understanding of the molecular mechanisms of peripartum cardiomyopathy have led to promising clinical trials of bromocriptine in the treatment of peripartum heart failure. The key challenges of management of heart failure are the urgent need to increase the use of proven treatments by physicians, and the control of hypertension in primary care and at the population level.

c-Myc-Induced Survivin Is Essential for Promoting the Notch-Dependent T Cell Differentiation from Hematopoietic Stem Cells

PubMed Central

Haque, Rizwanul; Song, Jianyong; Haque, Mohammad; Lei, Fengyang; Sandhu, Praneet; Ni, Bing; Zheng, Songguo; Fang, Deyu; Yang, Jin-Ming; Song, Jianxun

2017-01-01

Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the precise intracellular signaling pathways by which Notch promotes T cell differentiation remain unclear. Here we report that the transcription factor c-Myc is a key mediator of the Notch signaling–regulated T cell differentiation. In a well-established in vitro differentiation model of T lymphocytes from hematopoietic stem cells, we showed that Notch1 and 4 directly promoted c-Myc expression; dominant-negative (DN) c-Myc inhibited early T cell differentiation. Moreover, the c-Myc expression activated by Notch signaling increased the expression of survivin, an inhibitor of apoptosis (IAP) protein. We further demonstrated that over-expression of c-Myc increased the abundance of survivin and the T cell differentiation thereof, whereas dn c-Myc reduced survivin levels and concomitantly retarded the differentiation. The c-Myc–dependent survivin induction is functionally germane, because Notch-dependent T cell differentiation was canceled by the depletion of survivin. These results identify both c-Myc and survivin as important mediators of the Notch signaling–regulated differentiation of T lymphocytes from hematopoietic stem cells. PMID:28272325

T1 mapping using saturation recovery single-shot acquisition at 3-tesla magnetic resonance imaging in hypertrophic cardiomyopathy: comparison to late gadolinium enhancement.

PubMed

Ogawa, Ryo; Kido, Tomoyuki; Nakamura, Masashi; Kido, Teruhito; Kurata, Akira; Uetani, Teruyoshi; Ogimoto, Akiyoshi; Miyagawa, Masao; Mochizuki, Teruhito

2017-03-01

We evaluated the T1 values of segments and slices and the reproducibility in healthy controls, using saturation recovery single-shot acquisition (SASHA) at 3T magnetic resonance imaging. Moreover, we examined the difference in T1 values between hypertrophic cardiomyopathy (HCM) and healthy controls, and compared those with late gadolinium enhancement (LGE). Twenty-one HCM patients and 10 healthy controls underwent T1 mapping before and after contrast administration. T1 values were measured in 12 segments. Native T1 values were significantly longer in HCM than in healthy controls [1373 ms (1312-1452 ms) vs. 1279 ms (1229-1326 ms); p < 0.0001]. Even in HCM segments without LGE, native T1 values were significantly longer than in healthy control segments [1366 ms (1300-1439 ms) vs. 1279 ms (1229-1326 ms); p < 0.0001]. Using a cutoff value of 1327 ms for septal native T1 values, we differentiated between HCM and healthy controls with 95% sensitivity, 90% specificity, 94% accuracy, and an area under the curve of 0.95. Native T1 values using a SASHA at 3T could differentiate HCM from healthy controls. Moreover, native T1 values have the potential to detect abnormal myocardium that cannot be identified adequately by LGE in HCM.

Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30{sup II} accessory protein and the induction of oncogenic cellular transformation by p30{sup II}/c-MYC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Romeo, Megan M.; Ko, Bookyung; Kim, Janice

2015-02-15

The human T-cell leukemia retrovirus type-1 (HTLV-1) p30{sup II} protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30{sup II} interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30{sup II} and c-MYC remain to be completely understood. Herein we demonstrate that p30{sup II} induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30{sup II} in c-myc{sup −/−}more » HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30{sup II} is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30{sup II} inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30{sup II}/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis. - Highlights: • Acetylation of c-MYC is required for oncogenic transformation by HTLV-1 p30{sup II}/c-MYC. • Acetylation-defective c-MYC mutants are impaired for foci-formation by p30{sup II}/c-MYC. • The HTLV-1 p30{sup II} protein induces lysine-acetylation of c-MYC. • p30{sup II} is present in c-MYC nucleoprotein complexes in HTLV-1-transformed T-cells. • HTLV-1 p30{sup II} inhibits apoptosis in c-MYC-expressing proliferating cells.« less

Genetic engineering and therapy for inherited and acquired cardiomyopathies.

PubMed

Day, Sharlene; Davis, Jennifer; Westfall, Margaret; Metzger, Joseph

2006-10-01

The cardiac myofilaments consist of a highly ordered assembly of proteins that collectively generate force in a calcium-dependent manner. Defects in myofilament function and its regulation have been implicated in various forms of acquired and inherited human heart disease. For example, during cardiac ischemia, cardiac myocyte contractile performance is dramatically downregulated due in part to a reduced sensitivity of the myofilaments to calcium under acidic pH conditions. Over the last several years, the thin filament regulatory protein, troponin I, has been identified as an important mediator of this response. Mutations in troponin I and other sarcomere genes are also linked to several distinct inherited cardiomyopathic phenotypes, including hypertrophic, dilated, and restrictive cardiomyopathies. With the cardiac sarcomere emerging as a central player for such a diverse array of human heart diseases, genetic-based strategies that target the myofilament will likely have broad therapeutic potential. The development of safe vector systems for efficient gene delivery will be a critical hurdle to overcome before these types of therapies can be successfully applied. Nonetheless, studies focusing on the principles of acute genetic engineering of the sarcomere hold value as they lay the essential foundation on which to build potential gene-based therapies for heart disease.

Analysis of SCN5A Gene Variants in East Slovak Patients with Cardiomyopathy.

PubMed

Priganc, Mariana; Zigová, Michaela; Boroňová, Iveta; Bernasovská, Jarmila; Dojčáková, Dana; Szabadosová, Viktória; Mydlárová Blaščáková, Marta; Tóthová, Iveta; Kmec, Ján; Bernasovský, Ivan

2017-03-01

Mutations in ion channels genes are potential cause of cardiomyopathy. The SCN5A gene (sodium channel, voltage gated, type V alpha subunit gene; 3p21) belongs to the family of cardiac sodium channel genes. Mutations in SCN5A gene lead to decreased Na+ current and ion unbalance. The SCN5A gene mutations are found in approximately 2% of patients with dilated cardiomyopathy (DCM), and they may be potential phenotype modifiers in hypertrophic cardiomyopathy (HCM). The role of SCN5A gene mutations in cardiomyopathy is not fully elucidated. Three selected exons (12, 20, and 21) of the SCN5A gene in the cohort of 58 East Slovak patients with dilated and HCM were analyzed by the Sanger sequencing method in order to detect etiopathogenic mutations associated with dilated and HCM. The mutation screening of three selected exons of SCN5A gene in the cohort of 27 DCM, 12 HCM patients, and 16 controls identified 10 missense genetic variants. Three of them (T1247I, A1260D, and G1262S), all in exon 21 of the SCN5A gene, were potentially damaging and disease-causing variants. Data from this study demonstrate that SCN5A gene variants have important role in the etiopathogenesis of dilated and HCM. © 2016 Wiley Periodicals, Inc.

Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15.

PubMed

Inoue, Satoshi; Hao, Zhenyue; Elia, Andrew J; Cescon, David; Zhou, Lily; Silvester, Jennifer; Snow, Bryan; Harris, Isaac S; Sasaki, Masato; Li, Wanda Y; Itsumi, Momoe; Yamamoto, Kazuo; Ueda, Takeshi; Dominguez-Brauer, Carmen; Gorrini, Chiara; Chio, Iok In Christine; Haight, Jillian; You-Ten, Annick; McCracken, Susan; Wakeham, Andrew; Ghazarian, Danny; Penn, Linda J Z; Melino, Gerry; Mak, Tak W

2013-05-15

Tumorigenesis results from dysregulation of oncogenes and tumor suppressors that influence cellular proliferation, differentiation, apoptosis, and/or senescence. Many gene products involved in these processes are substrates of the E3 ubiquitin ligase Mule/Huwe1/Arf-BP1 (Mule), but whether Mule acts as an oncogene or tumor suppressor in vivo remains controversial. We generated K14Cre;Mule(flox/flox(y)) (Mule kKO) mice and subjected them to DMBA/PMA-induced skin carcinogenesis, which depends on oncogenic Ras signaling. Mule deficiency resulted in increased penetrance, number, and severity of skin tumors, which could be reversed by concomitant genetic knockout of c-Myc but not by knockout of p53 or p19Arf. Notably, in the absence of Mule, c-Myc/Miz1 transcriptional complexes accumulated, and levels of p21CDKN1A (p21) and p15INK4B (p15) were down-regulated. In vitro, Mule-deficient primary keratinocytes exhibited increased proliferation that could be reversed by Miz1 knockdown. Transfer of Mule-deficient transformed cells to nude mice resulted in enhanced tumor growth that again could be abrogated by Miz1 knockdown. Our data demonstrate in vivo that Mule suppresses Ras-mediated tumorigenesis by preventing an accumulation of c-Myc/Miz1 complexes that mediates p21 and p15 down-regulation.

MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels.

PubMed

Lu, Yunqi; Hu, Zhongyi; Mangala, Lingegowda S; Stine, Zachary E; Hu, Xiaowen; Jiang, Dahai; Xiang, Yan; Zhang, Youyou; Pradeep, Sunila; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; DeMarzo, Angelo M; Sood, Anil K; Zhang, Lin; Dang, Chi V

2018-01-01

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here, we report that MYC stimulates the transcription of DANCR, a long noncoding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell-cycle inhibitor p21 (CDKN1A) and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers. Significance: These findings expand knowledge of how MYC drives cancer cell proliferation by identifying an oncogenic long noncoding RNA that is widely overexpressed in human cancers. Cancer Res; 78(1); 64-74. ©2017 AACR . ©2017 American Association for Cancer Research.

A Hypertrophic Cardiomyopathy-associated MYBPC3 Mutation Common in Populations of South Asian Descent Causes Contractile Dysfunction*

PubMed Central

Kuster, Diederik W. D.; Govindan, Suresh; Springer, Tzvia I.; Martin, Jody L.; Finley, Natosha L.; Sadayappan, Sakthivel

2015-01-01

Hypertrophic cardiomyopathy (HCM) results from mutations in genes encoding sarcomeric proteins, most often MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). A recently discovered HCM-associated 25-base pair deletion in MYBPC3 is inherited in millions worldwide. Although this mutation causes changes in the C10 domain of cMyBP-C (cMyBP-CC10mut), which binds to the light meromyosin (LMM) region of the myosin heavy chain, the underlying molecular mechanism causing HCM is unknown. In this study, adenoviral expression of cMyBP-CC10mut in cultured adult rat cardiomyocytes was used to investigate protein localization and evaluate contractile function and Ca2+ transients, compared with wild-type cMyBP-C expression (cMyBP-CWT) and controls. Forty-eight hours after infection, 44% of cMyBP-CWT and 36% of cMyBP-CC10mut protein levels were determined in total lysates, confirming equal expression. Immunofluorescence experiments showed little or no localization of cMyBP-CC10mut to the C-zone, whereas cMyBP-CWT mostly showed C-zone staining, suggesting that cMyBP-CC10mut could not properly integrate in the C-zone of the sarcomere. Subcellular fractionation confirmed that most cMyBP-CC10mut resided in the soluble fraction, with reduced presence in the myofilament fraction. Also, cMyBP-CC10mut displayed significantly reduced fractional shortening, sarcomere shortening, and relaxation velocities, apparently caused by defects in sarcomere function, because Ca2+ transients were unaffected. Co-sedimentation and protein cross-linking assays confirmed that C10mut causes the loss of C10 domain interaction with myosin LMM. Protein homology modeling studies showed significant structural perturbation in cMyBP-CC10mut, providing a potential structural basis for the alteration in its mode of interaction with myosin LMM. Therefore, expression of cMyBP-CC10mut protein is sufficient to cause contractile dysfunction in vitro. PMID:25583989

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

PubMed Central

Burke, Michael A.; Chang, Stephen; Wakimoto, Hiroko; Gorham, Joshua M.; Conner, David A.; Christodoulou, Danos C.; Parfenov, Michael G.; DePalma, Steve R.; Eminaga, Seda; Konno, Tetsuo; Seidman, Jonathan G.; Seidman, Christine E.

2016-01-01

Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10–4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10–33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM. PMID:27239561

Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice.

PubMed

Grieb, Brian C; Boyd, Kelli; Mitra, Ramkrishna; Eischen, Christine M

2016-10-30

Alterations of specific genes can modulate aging. Myc, a transcription factor that regulates the expression of many genes involved in critical cellular functions was shown to have a role in controlling longevity. Decreased expression of Myc inhibited many of the deleterious effects of aging and increased lifespan in mice. Without altering Myc expression, reduced levels of Mtbp, a recently identified regulator of Myc, limit Myc transcriptional activity and proliferation, while increased levels promote Myc-mediated effects. To determine the contribution of Mtbp to the effects of Myc on aging, we studied a large cohort of Mtbp heterozygous mice and littermate matched wild-type controls. Mtbp haploinsufficiency significantly increased longevity and maximal survival in mice. Reduced levels of Mtbp did not alter locomotor activity, litter size, or body size, but Mtbp heterozygous mice did exhibit elevated markers of metabolism, particularly in the liver. Mtbp +/- mice also had a significant delay in spontaneous cancer development, which was most prominent in the hematopoietic system, and an altered tumor spectrum compared to Mtbp +/+ mice. Therefore, the data suggest Mtbp is a regulator of longevity in mice that mimics some, but not all, of the properties of Myc in aging.

Genetic Variation in Cardiomyopathy and Cardiovascular Disorders.

PubMed

McNally, Elizabeth M; Puckelwartz, Megan J

2015-01-01

With the wider deployment of massively-parallel, next-generation sequencing, it is now possible to survey human genome data for research and clinical purposes. The reduced cost of producing short-read sequencing has now shifted the burden to data analysis. Analysis of genome sequencing remains challenged by the complexity of the human genome, including redundancy and the repetitive nature of genome elements and the large amount of variation in individual genomes. Public databases of human genome sequences greatly facilitate interpretation of common and rare genetic variation, although linking database sequence information to detailed clinical information is limited by privacy and practical issues. Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders are highly heritable. The role of rare genetic variation in predicting risk and complications of cardiovascular diseases has been well established for hypertrophic and dilated cardiomyopathy, where the number of genes that are linked to these disorders is growing. Bolstered by family data, where genetic variants segregate with disease, rare variation can be linked to specific genetic variation that offers profound diagnostic information. Understanding genetic variation in cardiomyopathy is likely to help stratify forms of heart failure and guide therapy. Ultimately, genetic variation may be amenable to gene correction and gene editing strategies.

The Basic Helix-Loop-Helix Transcription Factor MYC2 Directly Represses PLETHORA Expression during Jasmonate-Mediated Modulation of the Root Stem Cell Niche in Arabidopsis[W][OA

PubMed Central

Chen, Qian; Sun, Jiaqiang; Zhai, Qingzhe; Zhou, Wenkun; Qi, Linlin; Xu, Li; Wang, Bao; Chen, Rong; Jiang, Hongling; Qi, Jing; Li, Xugang; Palme, Klaus; Li, Chuanyou

2011-01-01

The root stem cell niche, which in the Arabidopsis thaliana root meristem is an area of four mitotically inactive quiescent cells (QCs) and the surrounding mitotically active stem cells, is critical for root development and growth. We report here that during jasmonate-induced inhibition of primary root growth, jasmonate reduces root meristem activity and leads to irregular QC division and columella stem cell differentiation. Consistently, jasmonate reduces the expression levels of the AP2-domain transcription factors PLETHORA1 (PLT1) and PLT2, which form a developmentally instructive protein gradient and mediate auxin-induced regulation of stem cell niche maintenance. Not surprisingly, the effects of jasmonate on root stem cell niche maintenance and PLT expression require the functioning of MYC2/JASMONATE INSENSITIVE1, a basic helix-loop-helix transcription factor that involves versatile aspects of jasmonate-regulated gene expression. Gel shift and chromatin immunoprecipitation experiments reveal that MYC2 directly binds the promoters of PLT1 and PLT2 and represses their expression. We propose that MYC2-mediated repression of PLT expression integrates jasmonate action into the auxin pathway in regulating root meristem activity and stem cell niche maintenance. This study illustrates a molecular framework for jasmonate-induced inhibition of root growth through interaction with the growth regulator auxin. PMID:21954460

Molecular screening by polymerase chain reaction detects panleukopenia virus DNA in formalin-fixed hearts from cats with idiopathic cardiomyopathy and myocarditis.

PubMed

Meurs, K M; Fox, P R; Magnon, A L; Liu, S; Towbin, J A

2000-01-01

Viral myocarditis has been suggested as an etiology for cardiomyopathy in several mammalian species. Myocarditis and idiopathic cardiomyopathy have been reported in the domestic cat, although a viral etiology has not been demonstrated. Because of the continuing interest in the potential relationship between viral myocarditis and cardiomyopathy, we evaluated hearts from cats with spontaneous, idiopathic cardiomyopathy for viral genomic material within myocytes by polymerase chain reaction, and for the presence of myocarditis by light microscopy. Thirty-one (31) formalin-fixed hearts from domestic cats who died of idiopathic cardiomyopathy were randomly selected from pathology archives. Seventeen (17) formalin-fixed hearts from healthy cats were similarly selected as normal controls. The polymerase chain reaction (PCR) was used to evaluate myocardial tissue for the presence of viral genome from feline panleukopenia virus, herpes virus, calici virus, and corona virus. Hearts were examined using light microscopy for histologic evidence of myocarditis according to the Dallas criteria. Panleukopenia virus was identified by PCR in 10 of 31 cats with cardiomyopathy but in none of the controls. Neither cardiomyopathic or control cats tested positive by PCR for herpes virus, calici virus, and corona virus. Myocarditis was detected by histologic examination in 18 of 31 cardiomyopathic cats and in none of 17 control cats. Myocarditis and or feline panleukopenia virus genome was detected in felines with idiopathic hypertrophic, dilated, and restrictive cardiomyopathy, suggesting a possible role of viral infection and inflammation in the pathogenesis of cardiomyopathy in this species.

Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.

PubMed

Koch, Heike B; Zhang, Ru; Verdoodt, Berlinda; Bailey, Aaron; Zhang, Chang-Dong; Yates, John R; Menssen, Antje; Hermeking, Heiko

2007-01-15

The c-MYC oncogene encodes a transcription factor, which is sufficient and necessary for the induction of cellular proliferation. However, the c-MYC protein is a relatively weak transactivator suggesting that it may have other functions. To identify protein interactors which may reveal new functions or represent regulators of c-MYC we systematically identified proteins associated with c-MYC in vivo using a proteomic approach. We combined tandem affinity purification (TAP) with the mass spectral multidimensional protein identification technology (MudPIT). Thereby, 221 c-MYC-associated proteins were identified. Among them were 17 previously known c-MYC-interactors. Selected new c-MYC-associated proteins (DBC-1, FBX29, KU70, MCM7, Mi2-beta/CHD4, RNA Pol II, RFC2, RFC3, SV40 Large T Antigen, TCP1alpha, U5-116kD, ZNF281) were confirmed independently. For association with MCM7, SV40 Large T Antigen and DBC-1 the functionally important MYC-box II region was required, whereas FBX29 and Mi2-beta interacted via MYC-box II and the BR-HLH-LZ motif. In addition, regulators of c-MYC activity were identified: ectopic expression of FBX29, an E3 ubiquitin ligase, decreased c-MYC protein levels and inhibited c-MYC transactivation, whereas knock-down of FBX29 elevated the concentration of c-MYC. Furthermore, sucrose gradient analysis demonstrated that c-MYC is present in numerous complexes with varying size and composition, which may accommodate the large number of new c-MYC-associated proteins identified here and mediate the diverse functions of c-MYC. Our results suggest that c-MYC, besides acting as a mitogenic transcription factor, regulates cellular proliferation by direct association with protein complexes involved in multiple synthetic processes required for cell division, as for example DNA-replication/repair and RNA-processing. Furthermore, this first comprehensive description of the c-MYC-associated sub-proteome will facilitate further studies aimed to elucidate the biology

Application of 3D printing in the surgical planning of hypertrophic obstructive cardiomyopathy and physician-patient communication: a preliminary study.

PubMed

Guo, Hong-Chang; Wang, Yang; Dai, Jiang; Ren, Chang-Wei; Li, Jin-Hua; Lai, Yong-Qiang

2018-02-01

The aim of this study was to evaluate the effect of 3-dimensional (3D) printing in treatment of hypertrophic obstructive cardiomyopathy (HOCM) and its roles in doctor-patient communication. 3D-printed models were constructed preoperatively and postoperatively in seven HOCM patients received surgical treatment. Based on multi-slice computed tomography (CT) images, regions of disorder were segmented using the Mimics 19.0 software (Materialise, Leuven, Belgium). After generating an STL-file (StereoLithography file) with patients' data, the 3D printer (Objet350 Connex3, Stratasys Ltd., USA) created a 3D model. The pre- and post-operative 3D-printed models were used to make the surgical plan preoperatively and evaluate the outcome postoperatively. Meanwhile, a questionnaire was designed for patients and their relatives to learn the effectiveness of the 3D-printed prototypes in the preoperative conversations. The heart anatomies were accurately printed with 3D technology. The 3D-printed prototypes were useful for preoperative evaluation, surgical planning, and practice. Preoperative and postoperative echocardiographic evaluation showed left ventricular outflow tract (LVOT) obstruction was adequately relieved (82.71±31.63 to 14.91±6.89 mmHg, P<0.001), the septal thickness was reduced from 21.57±4.65 to 17.42±5.88 mm (P<0.001), and the SAM disappeared completely after the operation. Patients highly appreciated the role of 3D model in preoperative conversations and the communication score was 9.11±0.38 points. A 3D-printed model is a useful tool in individualized planning for myectomies and represent a useful tool for physician-patient communication.

Use of a highly-sensitive cardiac troponin I assay in a screening population for hypertrophic cardiomyopathy: a case-referent study.

PubMed

McGorrian, Catherine M; Lyster, Sarah; Roy, Andrew; Tarrant, Heloise; Codd, Mary; Doran, Peter; Fitzgibbon, Maria; Galvin, Joseph; Mahon, Niall G

2013-09-11

Hypertrophic cardiomyopathy (HCM) is a genetic condition, and relatives of affected persons may be at risk. Cardiac troponin biomarkers have previously been shown to be elevated in HCM. This study examines the new highly-sensitive cardiac troponin I (hsTnI) assay in a HCM screening population. Nested case-control study of consecutive HCM sufferers and their relatives recruited from May 2010 to September 2011. After informed consent, participants provided venous blood samples and clinical and echocardiographic features were recorded. Associations between the natural log (ln) of the contemporary troponin I (cTnI) and hsTnI assays and markers of cardiac hypertrophy were examined. Multiple regression models were fitted to examine the predictive ability of hsTnI for borderline or definite HCM. Of 107 patients, 24 had borderline and 19 had definite changes of HCM. Both TnI assays showed significant, positive correlations with measures of cardiac muscle mass. After age and sex adjustment, the area under the receiver operator characteristic (AUROC) curve for the outcome of HCM was 0.78, 95% CI [0.65, 0.90], for ln(hsTnI), and 0.66, 95% CI [0.51, 0.82], for ln(cTnI) (p=0.11). Including the hsTnI assay in a multiple-adjusted "screening" model for HCM resulted in a non-significant improvement in both the AUROC and integrated discrimination index. Both cTnI and hsTnI show a graded, positive association with measures of cardiac muscle mass in persons at risk of HCM. Further studies will be required to evaluate the utility of these assays in ECG- and symptom-based identification of HCM in at-risk families.

The Incremental Value of Magnetic Resonance Imaging for Identification of Apical Pouch in Patients with Apical Variant of Hypertrophic Cardiomyopathy.

PubMed

Vucicevic, Darko; Lester, Steven J; Appleton, Christopher P; Panse, Prasad M; Schleifer, John William; Wilansky, Susan

2016-04-01

The development of a left ventricular (LV) apical pouch in patients with apical hypertrophic cardiomyopathy (aHCM) has been thought to be the transition point that can become an apical aneurysm, which is linked to higher risk of adverse events. In our study, we sought to compare the ability of transthoracic echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) to accurately identify the presence of an apical pouch or aneurysm in patients with aHCM. We retrospectively reviewed the charts of all consecutive patients that had features of aHCM on imaging. Data from cMRI and echo examinations were abstracted, and the ability of these diagnostic modalities to identify the presence of a LV apical pouch and aneurysm was analyzed. Of 31 patients with aHCM, 17 (54.8%) had an apical pouch and 2 were found to have apical aneurysm (6.5%) on cMRI. Echo with and without perflutren contrast was able to accurately identify both aneurysms, but only 47.1% (8/17) of apical pouches seen by cMRI. Two patients had apical thrombus that was identified by cMRI, but not by echo. Our findings indicate that cMRI is superior to echo in identifying apical pouches in patients with aHCM. Our results also suggest that in patients undergoing echo, the use of perflutren contrast for LV opacification increases the diagnostic yield. Further study is necessary to delineate whether earlier identification of an apical pouch will be of clinical benefit for patients with aHCM by altering clinical management and avoiding adverse cardiovascular events. © 2015, Wiley Periodicals, Inc.

Effects of benazepril in the treatment of feline hypertrophic cardiomyopathy Results of a prospective, open-label, multicenter clinical trial.

PubMed

Amberger, C N; Glardon, O; Glaus, T; Hörauf, A; King, J N; Schmidli, H; Schröter, L; Lombard, C W

1999-05-01

To evaluate the efficacy of benazepril on clinical signs and echocardiographic parameters in cats with primary hypertrophic cardiomyopathy (HCM). ACE-inhibitors have positive effects in man with HCM, and contribute to a reduction of myocardial hypertrophy. Addition of an ACE-inhibitor to the standard treatment of HCM in cats may have beneficial effects. A total of 32 cats which were either asymptomatic or in stabilised congestive heart failure (ISACHC* class Ib, II or IIIa) were included in a one-year, prospective, open-label, clinical trial in 5 centres in Switzerland. 28 of these cats were allocated to one of two treatment groups: 1) standard therapy (ST) alone (n=9), consisting of a long-acting formulation of diltiazem (6-9 mg/kg sid) and optional acetylsalicylic acid (50 mg twice weekly, or 2) the same ST plus benazepril (0.33 - 0.75 mg/kg sid, n=19). Cats treated with benazepril showed a statistically significant decrease (mean +/- SEM, 0.11 +/- 0.03 mm/month, p = 0.002) in the left ventricular wall thickness (LVWD) from baseline, while no change (increase of 0.02 +/- 0.04 mm/month, p=0.66) was observed in cats on ST alone. Differences in LVWD between the two groups reached statistical significance (p=0.02). Benazepril treated cats showed more improvement in clinical signs (20-53%) than cats receiving ST alone (0-20%) but differences between the groups were not statistically significant (p>0.1). No change in septal thickness (IVSD) or left atrial to aortic root ratio (LA/Ao) was observed in either group. Benazepril had some beneficial effects on clinical signs and cardiac remodelling in cats with HCM and was well tolerated. These results, however, need to be confirmed in additional controlled studies. * ISACHC classification is described in the previous paper (Bench-study).

Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy.

PubMed

Crocini, C; Ferrantini, C; Scardigli, M; Coppini, R; Mazzoni, L; Lazzeri, E; Pioner, J M; Scellini, B; Guo, A; Song, L S; Yan, P; Loew, L M; Tardiff, J; Tesi, C; Vanzi, F; Cerbai, E; Pavone, F S; Sacconi, L; Poggesi, C

2016-02-01

Abnormalities of cardiomyocyte Ca(2+) homeostasis and excitation-contraction (E-C) coupling are early events in the pathogenesis of hypertrophic cardiomyopathy (HCM) and concomitant determinants of the diastolic dysfunction and arrhythmias typical of the disease. T-tubule remodelling has been reported to occur in HCM but little is known about its role in the E-C coupling alterations of HCM. Here, the role of T-tubule remodelling in the electro-mechanical dysfunction associated to HCM is investigated in the Δ160E cTnT mouse model that expresses a clinically-relevant HCM mutation. Contractile function of intact ventricular trabeculae is assessed in Δ160E mice and wild-type siblings. As compared with wild-type, Δ160E trabeculae show prolonged kinetics of force development and relaxation, blunted force-frequency response with reduced active tension at high stimulation frequency, and increased occurrence of spontaneous contractions. Consistently, prolonged Ca(2+) transient in terms of rise and duration are also observed in Δ160E trabeculae and isolated cardiomyocytes. Confocal imaging in cells isolated from Δ160E mice reveals significant, though modest, remodelling of T-tubular architecture. A two-photon random access microscope is employed to dissect the spatio-temporal relationship between T-tubular electrical activity and local Ca(2+) release in isolated cardiomyocytes. In Δ160E cardiomyocytes, a significant number of T-tubules (>20%) fails to propagate action potentials, with consequent delay of local Ca(2+) release. At variance with wild-type, we also observe significantly increased variability of local Ca(2+) transient rise as well as higher Ca(2+)-spark frequency. Although T-tubule structural remodelling in Δ160E myocytes is modest, T-tubule functional defects determine non-homogeneous Ca(2+) release and delayed myofilament activation that significantly contribute to mechanical dysfunction. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All

T1 Measurements Identify Extracellular Volume Expansion in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With and Without Left Ventricular Hypertrophy

PubMed Central

Ho, Carolyn Y.; Abbasi, Siddique A.; Neilan, Tomas G.; Shah, Ravi V.; Chen, Yucheng; Heydari, Bobak; Cirino, Allison L.; Lakdawala, Neal K.; Orav, E. John; González, Arantxa; López, Begoña; Díez, Javier; Jerosch-Herold, Michael; Kwong, Raymond Y.

2013-01-01

Background Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations appear to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance (CMR) with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV). Methods and Results Sarcomere mutation carriers with LVH (G+/LVH+, n = 37) and without LVH (G+/LVH−, n = 29); HCM patients without mutations (sarcomere-negative HCM, n = 11); and healthy controls (n = 11) underwent contrast CMR, measuring T1 times pre- and post-gadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared to controls, ECV was increased in patients with overt HCM, as well as G+/LVH− mutation carriers (ECV= 0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH−, controls, respectively, P≤0.001 for all comparisons). ECV correlated with NT-proBNP levels (r = 0.58, P<0.001) and global E’ velocity (r = −0.48, P<0.001). Late gadolinium enhancement (LGE) was present in >60% of overt HCM patients but absent from G+/LVH− subjects. Both ECV and LGE were more extensive in sarcomeric HCM than sarcomere-negative HCM. Conclusions Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis. PMID:23549607

Comparison of Valsalva Maneuver, Amyl Nitrite, and Exercise Echocardiography to Demonstrate Latent Left Ventricular Outflow Obstruction in Hypertrophic Cardiomyopathy.

PubMed

Ayoub, Chadi; Geske, Jeffrey B; Larsen, Carolyn M; Scott, Christopher G; Klarich, Kyle W; Pellikka, Patricia A

2017-12-15

Guidelines recommend exercise stress echocardiogram (ESE) for patients with hypertrophic cardiomyopathy (HC) if a 50 mm Hg gradient is not present at rest or provoked with Valsalva or amyl nitrite, to direct medical and surgical management. However, no study has directly compared all 3 methods. We sought to evaluate efficacy and degree of provocation of left ventricular outflow gradients by ESE, and compare with Valsalva and amyl nitrite. In patients with HC between 2002 and 2015, resting echocardiograms and ESEs within 1 year were retrospectively reviewed. Gradients elicited by each provocation method were compared. Rest and ESE were available in 97 patients (mean age 54 ± 18 years, 57% male); 78 underwent Valsalva maneuver and 41 amyl nitrite provocation. Median gradients (interquartile range) were 10 mm Hg (7,19) at rest, 16 mm Hg (9,34) with Valsalva, 23 mm Hg (13,49) with amyl nitrite, and 26 mm Hg (13,58) with ESE. ESE and amyl nitrite were able to provoke obstruction (≥30 mm Hg) and severe obstruction (≥50 mm Hg) more frequently than Valsalva. In patients with resting gradient <30 mm Hg (n = 83), provocation maneuvers demonstrated dynamic obstruction in 51%; in those with Valsalva gradient <30 mm Hg (n = 57), ESE or amyl nitrite provoked a gradient in 44%; and in those with amyl nitrite gradient <30 mm Hg (n = 20), ESE provoked a gradient in 29%. No demographic or baseline echocardiographic parameter predicted provocable obstruction. In conclusion, ESE is clinically useful; however, different provocation maneuvers may be effective in different patients with HC, and all maneuvers may be required to provoke dynamic obstruction in symptomatic patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Electrocardiography based prediction of hypertrophy pattern and fibrosis amount in hypertrophic cardiomyopathy: comparative study with cardiac magnetic resonance imaging.

PubMed

Park, Chul Hwan; Chung, Hyemoon; Kim, Yoonjung; Kim, Jong-Youn; Min, Pil-Ki; Lee, Kyung-A; Yoon, Young Won; Kim, Tae Hoon; Lee, Byoung Kwon; Hong, Bum-Kee; Rim, Se-Joong; Kwon, Hyuck Moon; Choi, Eui-Young

2018-05-04

Although, cardiac magnetic resonance imaging (CMR) is a gold standard for risk stratification of hypertrophic cardiomyopathy (HCM), is limited in some situations. We sought to evaluate the predictive power of quantitative electrocardiography in assessing hypertrophy pattern and fibrosis in HCM. Eighty-eight patients with HCM were studied. Voltage of R-S-T waves, number of fragmented QRS (fQRS) complexes, and T wave morphology were measured by 12-lead electrocardiography. Sixteen segmental thickness, late gadolinium enhancement (LGE), native T1, extracellular volume fraction (ECV), and T2, left ventricular (LV) mass and %LGE were measured by CMR. Patterns of LV hypertrophy were classified as pure apical, mixed, or asymmetrical septal hypertrophy. Positive and negative predictive values of biphasic T wave for pure apical type were 70.4 and 63.9%, and the predictive values of precordial negative T wave sums [Formula: see text] 12.5 mm were 69.2 and 79.6%. Precordial S waves, especially Cornell voltage index, were significantly correlated to LV mass index and maximal thickness (p [Formula: see text]0.001). The number of fQRS leads was significantly correlated to %LGE, average ECV, and T2 (all p [Formula: see text]0.001). More than one lead with fQRS could predict [Formula: see text]5% of LGE mass with 58% sensitivity and 63% specificity (p = 0.049, area under the curve = 0.627). However, degree of correlation between maximal thickness and precordial S was poor in cases with fQRS more two leads. T wave morphology and precordial S helps discriminate hypertrophy pattern and maximal hypertrophy, however, in cases with more than two leads of concomitant fQRS, CMR defines fibrosis amount and hypertrophy more accurately.

Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis.

PubMed

Annibali, Daniela; Whitfield, Jonathan R; Favuzzi, Emilia; Jauset, Toni; Serrano, Erika; Cuartas, Isabel; Redondo-Campos, Sara; Folch, Gerard; Gonzàlez-Juncà, Alba; Sodir, Nicole M; Massó-Vallés, Daniel; Beaulieu, Marie-Eve; Swigart, Lamorna B; Mc Gee, Margaret M; Somma, Maria Patrizia; Nasi, Sergio; Seoane, Joan; Evan, Gerard I; Soucek, Laura

2014-08-18

Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells.

Hydra myc2, a unique pre-bilaterian member of the myc gene family, is activated in cell proliferation and gametogenesis

PubMed Central

Hartl, Markus; Glasauer, Stella; Valovka, Taras; Breuker, Kathrin; Hobmayer, Bert; Bister, Klaus

2014-01-01

ABSTRACT The myc protooncogene encodes the Myc transcription factor which is the essential part of the Myc–Max network controlling fundamental cellular processes. Deregulation of myc leads to tumorigenesis and is a hallmark of many human cancers. We have recently identified homologs of myc (myc1, myc2) and max in the early diploblastic cnidarian Hydra and have characterized myc1 in detail. Here we show that myc2 is transcriptionally activated in the interstitial stem cell system. Furthermore, in contrast to myc1, myc2 expression is also detectable in proliferating epithelial stem cells throughout the gastric region. myc2 but not myc1 is activated in cycling precursor cells during early oogenesis and spermatogenesis, suggesting that the Hydra Myc2 protein has a possible non-redundant function in cell cycle progression. The Myc2 protein displays the principal design and properties of vertebrate Myc proteins. In complex with Max, Myc2 binds to DNA with similar affinity as Myc1–Max heterodimers. Immunoprecipitation of Hydra chromatin revealed that both Myc1 and Myc2 bind to the enhancer region of CAD, a classical Myc target gene in mammals. Luciferase reporter gene assays showed that Myc1 but not Myc2 transcriptionally activates the CAD promoter. Myc2 has oncogenic potential when tested in primary avian fibroblasts but to a lower degree as compared to Myc1. The identification of an additional myc gene in Cnidaria, a phylum that diverged prior to bilaterians, with characteristic expression patterns in tissue homeostasis and developmental processes suggests that principle functions of myc genes have arisen very early in metazoan evolution. PMID:24771621

Infection by Toxoplasma gondii Specifically Induces Host c-Myc and the Genes This Pivotal Transcription Factor Regulates

PubMed Central

Franco, Magdalena; Shastri, Anjali J.

2014-01-01

Toxoplasma gondii infection has previously been described to cause dramatic changes in the host transcriptome by manipulating key regulators, including STATs, NF-κB, and microRNAs. Here, we report that Toxoplasma tachyzoites also mediate rapid and sustained induction of another pivotal regulator of host cell transcription, c-Myc. This induction is seen in cells infected with all three canonical types of Toxoplasma but not the closely related apicomplexan parasite Neospora caninum. Coinfection of cells with both Toxoplasma and Neospora still results in an increase in the level of host c-Myc, showing that c-Myc is actively upregulated by Toxoplasma infection (rather than repressed by Neospora). We further demonstrate that this upregulation may be mediated through c-Jun N-terminal protein kinase (JNK) and is unlikely to be a nonspecific host response, as heat-killed Toxoplasma parasites do not induce this increase and neither do nonviable parasites inside the host cell. Finally, we show that the induced c-Myc is active and that transcripts dependent on its function are upregulated, as predicted. Hence, c-Myc represents an additional way in which Toxoplasma tachyzoites have evolved to specifically alter host cell functions during intracellular growth. PMID:24532536

MYBPC3 hypertrophic cardiomyopathy can be detected by using advanced ECG in children and young adults.

PubMed

Fernlund, E; Liuba, P; Carlson, J; Platonov, P G; Schlegel, T T

2016-01-01

The conventional ECG is commonly used to screen for hypertrophic cardiomyopathy (HCM), but up to 25% of adults and possibly larger percentages of children with HCM have no distinctive abnormalities on the conventional ECG, whereas 5 to 15% of healthy young athletes do. Recently, a 5-min resting advanced 12-lead ECG test ("A-ECG score") showed superiority to pooled criteria from the strictly conventional ECG in correctly identifying adult HCM. The purpose of this study was to evaluate whether in children and young adults, A-ECG scoring could detect echocardiographic HCM associated with the MYBPC3 genetic mutation with greater sensitivity than conventional ECG criteria and distinguish healthy young controls and athletes from persons with MYBPC3 HCM with greater specificity. Five-minute 12-lead ECGs were obtained from 15 young patients (mean age 13.2years, range 0-30years) with MYBPC3 mutation and phenotypic HCM. The conventional and A-ECG results of these patients were compared to those of 198 healthy children and young adults (mean age 13.2, range 1month-30years) with unremarkable echocardiograms, and to those of 36 young endurance-trained athletes, 20 of whom had athletic (physiologic) left ventricular hypertrophy. Compared with commonly used, age-specific pooled criteria from the conventional ECG, a retrospectively generated A-ECG score incorporating results from just 2 derived vectorcardiographic parameters (spatial QRS-T angle and the change in the vectorcardiographic QRS azimuth angle from the second to the third eighth of the QRS interval) increased the sensitivity of ECG for identifying MYBPC3 HCM from 46% to 87% (p<0.05). Use of the same score also demonstrated superior specificity in a set of 198 healthy controls (94% vs. 87% for conventional ECG criteria; p<0.01) including in a subset of 36 healthy, young endurance-trained athletes (100% vs. 69% for conventional ECG criteria, p<0.001). In children and young adults, a 2-parameter 12-lead A-ECG score is

De novo unbalanced translocation resulting in monosomy for proximal 14q and distal 4p in a fetus with intrauterine growth retardation, Wolf-Hirschhorn syndrome, hypertrophic cardiomyopathy, and partial hemihypoplasia.

PubMed

Chen, C P; Chern, S R; Lee, C C; Chen, W L; Chen, M H; Chang, K M

1998-12-01

We present the perinatal findings of a fetus with a de novo unbalanced chromosome translocation that resulted in monosomy for proximal 14q and monosomy for distal 4p. Prenatal sonographic examination at 27 weeks of gestation showed intrauterine growth retardation, microcephaly, cardiomegaly with arrhythmia, and asymmetry of the upper limbs. Genetic amniocentesis showed an abnormal karyotype of 45,XX,der(4)t(4;14)(p16.3;q12),-14. Linkage analysis of the family confirmed the maternal origin of the deletions. Molecular refinement of the deletion breakpoints indicated that the breakpoints at 4p16.3 and 14q12 were located between loci D4S403 (present) and D4S394 (absent), and between loci D14S252 (present) and D14S64 (absent), respectively. Necropsy showed dysmorphic features compatible with Wolf-Hirschhorn syndrome, hypertrophic cardiomyopathy, partial hemihypoplasia, and a normal brain without evidence of holoprosencephaly. Our case adds to the list of clinical phenotypes associated with the proximal regions of 14q.

Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer.

PubMed

Zhao, Na; Cao, Jin; Xu, Longyong; Tang, Qianzi; Dobrolecki, Lacey E; Lv, Xiangdong; Talukdar, Manisha; Lu, Yang; Wang, Xiaoran; Hu, Dorothy Z; Shi, Qing; Xiang, Yu; Wang, Yunfei; Liu, Xia; Bu, Wen; Jiang, Yi; Li, Mingzhou; Gong, Yingyun; Sun, Zheng; Ying, Haoqiang; Yuan, Bo; Lin, Xia; Feng, Xin-Hua; Hartig, Sean M; Li, Feng; Shen, Haifa; Chen, Yiwen; Han, Leng; Zeng, Qingping; Patterson, John B; Kaipparettu, Benny Abraham; Putluri, Nagireddy; Sicheri, Frank; Rosen, Jeffrey M; Lewis, Michael T; Chen, Xi

2018-04-02

The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

Survival in cats with primary and secondary cardiomyopathies.

PubMed

Spalla, Ilaria; Locatelli, Chiara; Riscazzi, Giulia; Santagostino, Sara; Cremaschi, Elena; Brambilla, Paola

2016-06-01

Feline cardiomyopathies (CMs) represent a heterogeneous group of myocardial diseases. The most common CM is hypertrophic cardiomyopathy (HCM), followed by restrictive cardiomyopathy (RCM). Studies comparing survival and outcome for different types of CM are scant. Furthermore, little is known about the cardiovascular consequences of systemic diseases on survival. The aim of this retrospective study was to compare survival and prognostic factors in cats affected by HCM, RCM or secondary CM referred to our institution over a 10 year period. The study included 94 cats with complete case records and echocardiographic examination. Fifty cats presented HCM, 14 RCM and 30 secondary CM. A statistically significant difference in survival time was identified for cats with HCM (median survival time of 865 days), RCM (273 days) and secondary CM (<50% cardiac death rate). In the overall population and in the primary CM group (HCM + RCM), risk factors in the multivariate analysis, regardless of the CM considered, were the presence of clinical signs, an increased left atrial to aortic root (LA/Ao) ratio and a hypercoagulable state. Primary CMs in cats share some common features (ie, LA dimension and hypercoagulable state) linked to feline cardiovascular physiology, which influence survival greatly in end-stage CM. The presence of clinical signs has to be regarded as a marker of disease severity, regardless of the underlying CM. Secondary CMs are more benign conditions, but if the primary disease is not properly managed, the prognosis might also be poor in this group of patients. © ISFM and AAFP 2015.

Tissue Doppler imaging for detection of radial and longitudinal myocardial dysfunction in a family of cats affected by dystrophin-deficient hypertrophic muscular dystrophy.

PubMed

Chetboul, Valérie; Blot, Stephane; Sampedrano, Carolina Carlos; Thibaud, Jean-Laurent; Granger, Nicolas; Tissier, Renaud; Bruneval, Patrick; Gaschen, Frederic; Gouni, Vassiliki; Nicolle, Audrey P; Pouchelon, Jean-Louis

2006-01-01

Diagnosis of feline hypertrophic cardiomyopathy currently is based on the presence of myocardial hypertrophy detected using conventional echocardiography. The accuracy of tissue Doppler imaging (TDI) for earlier detection of the disease has never been described. The objective of this sudy was to quantify left ventricular free wall (LVFW) velocities in cats with hypertrophic muscular dystrophy (HFMD) during preclinical cardiomyopathy using TDI. The study animals included 22 healthy controls and 7 cats belonging to a family of cats with HFMD (2 affected adult males, 2 heterozygous adult females, one 2.5-month-old affected male kitten, and 2 phenotypically normal female kittens from the same litter). All cats were examined via conventional echocardiography and 2-dimensional color TDI. No LVFW hypertrophy was detected in the 2 carriers or in the affected kitten when using conventional echocardiography and histologic examination, respectively. The LVFW also was normal for 1 affected male and at the upper limit of normal for the 2nd male. Conversely, LVFW dysfunction was detected in all affected and carrier cats with HFMD when using TDI. TDI consistently detects LVFW dysfunction in cats with HFMD despite the absence of myocardial hypertrophy. Therefore, TDI appears more sensitive than conventional echocardiography in detecting regional myocardial abnormalities.

c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines.

PubMed Central

Harrington, E A; Bennett, M R; Fanidi, A; Evan, G I

1994-01-01

We have investigated the mechanism by which deregulated expression of c-Myc induces death by apoptosis in serum-deprived fibroblasts. We demonstrate that Myc-induced apoptosis in low serum is inhibited by a restricted group of cytokines, principally the insulin-like growth factors and PDGF. Cytokine-mediated protection from apoptosis is not linked to the cytokines' abilities to promote growth. Protection from apoptosis is evident in the post-commitment (mitogen-independent) S/G2/M phases of the cell cycle and also in cells that are profoundly blocked in cell cycle progression by drugs. Moreover, IGF-I inhibition of apoptosis occurs in the absence of protein synthesis, and so does not require immediate early gene expression. We conclude that c-Myc-induced apoptosis does not result from a conflict of growth signals but appears to be a normal physiological aspect of c-Myc function whose execution is regulated by the availability of survival factors. We discuss the possible implications of these findings for models of mammalian cell growth in vivo. Images PMID:8045259

N-Myc knockdown and apigenin treatment controlled growth of malignant neuroblastoma cells having N-Myc amplification

PubMed Central

Hossain, Md. Motarab; Banik, Naren L.; Ray, Swapan K.

2013-01-01

Malignant neuroblastomas mostly occur in children and are frequently associated with N-Myc amplification. Oncogene amplification, which is selective increase in copy number of the oncogene, provides survival advantages in solid tumors including malignant neuroblastoma. We have decreased expression of N-Myc oncogene using short hairpin RNA (shRNA) plasmid to increase anti-tumor efficacy of the isoflavonoid apigenin (APG) in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cell lines that harbor N-Myc amplification. N-Myc knockdown induced morphological and biochemical features of neuronal differentiation. Combination of N-Myc knockdown and APG most effectively induced morphological and biochemical features of apoptotic death. This combination therapy also prevented cell migration and decreased N-Myc driven survival, angiogenic, and invasive factors. Collectively, N-Myc knockdown and APG treatment is a promising strategy for controlling the growth of human malignant neuroblastoma cell lines that harbor N-Myc amplification. PMID:23941992

N-Myc knockdown and apigenin treatment controlled growth of malignant neuroblastoma cells having N-Myc amplification.

PubMed

Hossain, Md Motarab; Banik, Naren L; Ray, Swapan K

2013-10-15

Malignant neuroblastomas mostly occur in children and are frequently associated with N-Myc amplification. Oncogene amplification, which is selective increase in copy number of the oncogene, provides survival advantages in solid tumors including malignant neuroblastoma. We have decreased expression of N-Myc oncogene using short hairpin RNA (shRNA) plasmid to increase anti-tumor efficacy of the isoflavonoid apigenin (APG) in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cell lines that harbor N-Myc amplification. N-Myc knockdown induced morphological and biochemical features of neuronal differentiation. Combination of N-Myc knockdown and APG most effectively induced morphological and biochemical features of apoptotic death. This combination therapy also prevented cell migration and decreased N-Myc driven survival, angiogenic, and invasive factors. Collectively, N-Myc knockdown and APG treatment is a promising strategy for controlling the growth of human malignant neuroblastoma cell lines that harbor N-Myc amplification. © 2013 Elsevier B.V. All rights reserved.

Cardiac magnetic field map topology quantified by Kullback-Leibler entropy identifies patients with hypertrophic cardiomyopathy

NASA Astrophysics Data System (ADS)

Schirdewan, A.; Gapelyuk, A.; Fischer, R.; Koch, L.; Schütt, H.; Zacharzowsky, U.; Dietz, R.; Thierfelder, L.; Wessel, N.

2007-03-01

Hypertrophic cardiomyopathy (HCM) is a common primary inherited cardiac muscle disorder, defined clinically by the presence of unexplained left ventricular hypertrophy. The detection of affected patients remains challenging. Genetic testing is limited because only in 50%-60% of all HCM diagnoses an underlying mutation can be found. Furthermore, the disease has a varied clinical course and outcome, with many patients having little or no discernible cardiovascular symptoms, whereas others develop profound exercise limitation and recurrent arrhythmias or sudden cardiac death. Therefore prospective screening of HCM family members is strongly recommended. According to the current guidelines this includes serial echocardiographic and electrocardiographic examinations. In this study we investigated the capability of cardiac magnetic field mapping (CMFM) to detect patients suffering from HCM. We introduce for the first time a combined diagnostic approach based on map topology quantification using Kullback-Leibler (KL) entropy and regional magnetic field strength parameters. The cardiac magnetic field was recorded over the anterior chest wall using a multichannel-LT-SQUID system. CMFM was calculated based on a regular 36 point grid. We analyzed CMFM in patients with confirmed diagnosis of HCM (HCM, n =33, 43.8±13 years, 13 women, 20 men), a control group of healthy subjects (NORMAL, n =57, 39.6±8.9 years; 22 women and 35 men), and patients with confirmed cardiac hypertrophy due to arterial hypertension (HYP, n =42, 49.7±7.9 years, 15 women and 27 men). A subgroup analysis was performed between HCM patients suffering from the obstructive (HOCM, n =19) and nonobstructive (HNCM, n =14) form of the disease. KL entropy based map topology quantification alone identified HCM patients with a sensitivity of 78.8% and specificity of 86.9% (overall classification rate 84.8%). The combination of the KL parameters with a regional field strength parameter improved the overall

Glutathione Depletion Induced by c-Myc Downregulation Triggers Apoptosis on Treatment with Alkylating Agents1

PubMed Central

Biroccio, Annamaria; Benassi, Barbara; Fiorentino, Francesco; Zupi, Gabriella

2004-01-01

Abstract Here we investigate the mechanism(s) involved in the c-Myc-dependent drug response of melanoma cells. By using three M14-derived c-Myc low-expressing clones, we demonstrate that alkylating agents, cisplatin and melphalan, trigger apoptosis in the c-Myc antisense transfectants, but not in the parental line. On the contrary, topoisomerase inhibitors, adriamycin and camptothecin, induce apoptosis to the same extent regardless of c-Myc expression. Because we previously demonstrated that c-Myc downregulation decreases glutathione (GSH) content, we evaluated the role of GSH in the apoptosis induced by the different drugs. In control cells treated with one of the alkylating agents or the others, GSH depletion achieved by l-buthionine-sulfoximine preincubation opens the apoptotic pathway. The apoptosis proceeded through early Bax relocalization, cytochrome c release, and concomitant caspase-9 activation, whereas reactive oxygen species production and alteration of mitochondria membrane potential were late events. That GSH was determining in the c-Myc-dependent drug-induced apoptosis was demonstrated by altering the intracellular GSH content of the c-Myc low-expressing cells up to the level of controls. Indeed, GSH ethyl ester-mediated increase of GSH abrogated apoptosis induced by cisplatin and melphalan by inhibition of Bax/cytochrome c redistribution. The relationship among c-Myc, GSH content, and the response to alkylating agent has been also evaluated in the M14 Myc overexpressing clones as well as in the melanoma JR8 c-Myc antisense transfectants. All together, these results demonstrate that GSH plays a key role in governing c-Myc-dependent drug-induced apoptosis. PMID:15153331

Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC

PubMed Central

Liu, Wei; Le, Anne; Hancock, Chad; Lane, Andrew N.; Dang, Chi V.; Fan, Teresa W.-M.; Phang, James M.

2012-01-01

In addition to glycolysis, the oncogenic transcription factor c-MYC (MYC) stimulates glutamine catabolism to fuel growth and proliferation of cancer cells through up-regulating glutaminase (GLS). Glutamine is converted to glutamate by GLS, entering the tricarboxylic acid cycle as an important energy source. Less well-recognized, glutamate can also be converted to proline through Δ1-pyrroline-5-carboxylate (P5C) and vice versa. This study suggests that some MYC-induced cellular effects are due to MYC regulation of proline metabolism. Proline oxidase, also known as proline dehydrogenase (POX/PRODH), the first enzyme in proline catabolism, is a mitochondrial tumor suppressor that inhibits proliferation and induces apoptosis. MiR-23b* mediates POX/PRODH down-regulation in human kidney tumors. MiR-23b* is processed from the same transcript as miR-23b; the latter inhibits the translation of GLS. Using MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells, we showed that MYC suppressed POX/PRODH expression primarily through up-regulating miR-23b*. The growth inhibition in the absence of MYC was partially reversed by POX/PRODH knockdown, indicating the importance of suppression of POX/PRODH in MYC-mediated cellular effects. Interestingly, MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. MYC-induced proline biosynthesis from glutamine was directly confirmed using 13C,15N-glutamine as a tracer. The metabolic link between glutamine and proline afforded by MYC emphasizes the complexity of tumor metabolism. Further studies of the relationship between glutamine and proline metabolism should provide a deeper understanding of tumor metabolism while enabling the development of novel therapeutic strategies. PMID:22615405

Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.

PubMed

Reynolds, C; Roderick, J E; LaBelle, J L; Bird, G; Mathieu, R; Bodaar, K; Colon, D; Pyati, U; Stevenson, K E; Qi, J; Harris, M; Silverman, L B; Sallan, S E; Bradner, J E; Neuberg, D S; Look, A T; Walensky, L D; Kelliher, M A; Gutierrez, A

2014-09-01

Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3'-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on the expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes and in 33% of bim homozygous mutants (P=0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.

MINCR is a MYC-induced lncRNA able to modulate MYC's transcriptional network in Burkitt lymphoma cells.

PubMed

Doose, Gero; Haake, Andrea; Bernhart, Stephan H; López, Cristina; Duggimpudi, Sujitha; Wojciech, Franziska; Bergmann, Anke K; Borkhardt, Arndt; Burkhardt, Birgit; Claviez, Alexander; Dimitrova, Lora; Haas, Siegfried; Hoell, Jessica I; Hummel, Michael; Karsch, Dennis; Klapper, Wolfram; Kleo, Karsten; Kretzmer, Helene; Kreuz, Markus; Küppers, Ralf; Lawerenz, Chris; Lenze, Dido; Loeffler, Markus; Mantovani-Löffler, Luisa; Möller, Peter; Ott, German; Richter, Julia; Rohde, Marius; Rosenstiel, Philip; Rosenwald, Andreas; Schilhabel, Markus; Schneider, Markus; Scholz, Ingrid; Stilgenbauer, Stephan; Stunnenberg, Hendrik G; Szczepanowski, Monika; Trümper, Lorenz; Weniger, Marc A; Hoffmann, Steve; Siebert, Reiner; Iaccarino, Ingram

2015-09-22

Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.

Myocardial impairment detected by late gadolinium enhancement in hypertrophic cardiomyopathy: comparison with 99mTc-MIBI/tetrofosmin and 123I-BMIPP SPECT.

PubMed

Hashimura, Hiromi; Kiso, Keisuke; Yamada, Naoaki; Kono, Atsushi; Morita, Yoshiaki; Fukushima, Kazuto; Higashi, Masahiro; Noguchi, Teruo; Ishibashi-Ueda, Hatsue; Naito, Hiroaki; Sugimura, Kazuro

2013-06-17

Myocardial fibrosis is considered to be an important factor in myocardial dysfunction and sudden cardiac death in hypertrophic cardiomyopathy (HCM). The purpose of this study was to compare myocardial fibrosis detected by late gadolinium enhancement (LGE) on cardiac MRI with myocardial perfusion and fatty acid metabolism assessed by single photon emission computed tomography in HCM. We retrospectively evaluated 20 consecutive HCM patients (female, 7; mean age, 53.4 years) who underwent LGE, technetium-99m methoxyisobutylisonitrile/tetrofosmin (99mTc-MIBI/tetrofosmin), and iodine-123 beta-methyl-iodophenylpentadecanoic acid (123I-BMIPP) imaging. We calculated the myocardium-to-lumen signal ratio (M/L) for LGE in 17 segments based on the American Heart Association statement. Scoring of 99mTc-MIBI/tetrofosmin (PI) and 123I-BMIPP (BM) was performed for each segment using a 5-point scale (0, normal; 4, highly decreased). Nineteen of 20 patients (95%) and 153 of 340 segments (45%) showed LGE. M/Ls were 0.42±0.16, 0.55±0.17, and 0.65±0.24 in PI0/BM0, PI0/BM1-4 and PI1-4/BM1-4, respectively. All M/Ls were significantly higher than that of a normal control (0.34±0.14) (p<0.001). Myocardial fibrosis in HCM can occur despite normal perfusion and fatty acid metabolism, and is more strongly associated with disorders of fatty acid metabolism than with perfusion abnormalities. M/L may be a useful indicator of disease severity.

1H- and 31P-myocardial magnetic resonance spectroscopy in non-obstructive hypertrophic cardiomyopathy patients and competitive athletes.

PubMed

Secchi, Francesco; Di Leo, Giovanni; Petrini, Marcello; Spairani, Riccardo; Alì, Marco; Guazzi, Marco; Sardanelli, Francesco

2017-04-01

The clinical differentiation between athlete's heart and mild forms of non-obstructive hypertrophic cardiomyopathy (HCM) is crucial. We hypothesized that differences do exist between the myocardial metabolism of patients with non-obstructive HCM and competitive athletes (CAs). Our aim was to evaluate myocardial metabolism with 31 P-MRS and 1 H-MRS in HCM patients and CAs. After Ethics Committee approval, 15 CAs and 7 HCM patients were prospectively enrolled. They underwent a 1.5-T cardiac MR including electrocardiographically triggered cine images, single-voxel 1 H-MRS and multivoxel 31 P-MRS. 1 H-MRS was performed after imaging using standard coil with the patient in the supine position; thereafter, 31 P-MRS was performed using a dedicated coil, in the prone position. Data were reported as median and interquartile range. Mann-Whitney U test was used. In CAs, left ventricular mass index was 72 (66-83) g/m 2 , septal thickness 10 (10-11) mm, end diastolic volume index 95 (85-102) ml/m 2 , end systolic volume index 30 (28-32) ml/m 2 and ejection fraction 68% (65-69%); in HCM patients, 81 (76-111) g/m 2 (P = 0.052), 18 (15-21) mm (P = 0.003), 73 (58-76) ml/m 2 (P = 0.029), 20 (16-34) ml/m 2 (P = 0.274) and 68% (55-73%) (P = 1.000), respectively. At 1 H-MRS, total lipids were 35 (0-183) arbitrary units (au) for CA and 763 (155-1994) au for HCM patients (P = 0.046). At 31 P-MRS, PCr/γATP was 5 (4-6) au for CA and 4 (2-5) au for HCM patients (P = 0.230). Examination time was 20 min for imaging only, 5 min for 1 H-MRS and 15 min for 31 P-MRS. We observed a significant increase of myocardial lipids, but a preserved PCr/γATP ratio in the metabolism of HCM patients compared with competitive CAs.

Disease Severity and Exercise Testing Reduce Subcutaneous Implantable Cardioverter-Defibrillator Left Sternal ECG Screening Success in Hypertrophic Cardiomyopathy.

PubMed

Srinivasan, Neil T; Patel, Kiran H; Qamar, Kashif; Taylor, Amy; Bacà, Marco; Providência, Rui; Tome-Esteban, Maria; Elliott, Perry M; Lambiase, Pier D

2017-04-01

The features of the hypertrophic cardiomyopathy (HCM) ECG make it a challenge for subcutaneous implantable cardioverter-defibrillator (S-ICD) screening. We aimed to investigate the causes of screening failure at rest and on exercise to inform optimal S-ICD ECG vector development. One hundred and thirty-one HCM patients (age, 50±16 years; 92 males and 39 females) with ≥1 HCM risk factor for sudden death underwent S-ICD ECG screening at rest and on exercise. Fifty patients (38%) were ineligible for S-ICD because of screening failure in every lead vector: 33 (66%) failed in the supine position, 12 (24%) failed in the standing position, and 5 (10%) failed on exercise. In patients who could exercise and passed screening at rest, 31 (44%) had 1 vector safety, 16 (23%) had 2 vector safety, and 24 (33%) had 3 vector safety. Increased R:T wave ratio in the S-ICD screening ECG (odds ratio, 4.0; confidence interval, 3.0-5.3; P <0.001) was associated with screening failure, while R/T ratio <3 in aVF (odds ratio, 0.3; confidence interval, 0.12-0.69; P =0.006) and increasing age (odds ratio, 0.97; confidence interval, 0.95-0.99; P =0.03) was associated with reduced screening failure. European Society of Cardiology risk score was higher in those failing screening (risk score 5.5% [interquartile range, 3.2-8.7] in failed versus 4.5% [interquartile range, 2.9-7.4] in passed; P =0.04). HCM patients have a significant incidence of screening failure, which is determined primarily by the increased R:T ratio on the screening ECG and lead aVF. High-risk patients have an increased screening failure rate. Optimization of sensing algorithms is required to ensure that the highest risk HCM patients can benefit from S-ICD implantation. © 2017 American Heart Association, Inc.

MYC Deregulation in Primary Human Cancers

PubMed Central

Kalkat, Manpreet; De Melo, Jason; Hickman, Katherine Ashley; Lourenco, Corey; Redel, Cornelia; Resetca, Diana; Tamachi, Aaliya; Tu, William B.; Penn, Linda Z.

2017-01-01

MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, MYC is a master regulator of many processes, including cell cycle entry, ribosome biogenesis, and metabolism. In cancer, the activity of the MYC transcriptional network is frequently deregulated, contributing to the initiation and maintenance of disease. Deregulation often leads to constitutive overexpression of MYC, which can be achieved through gross genetic abnormalities, including copy number alterations, chromosomal translocations, increased enhancer activity, or through aberrant signal transduction leading to increased MYC transcription or increased MYC mRNA and protein stability. Herein, we summarize the frequency and modes of MYC deregulation and describe both well-established and more recent findings in a variety of cancer types. Notably, these studies have highlighted that with an increased appreciation for the basic mechanisms deregulating MYC in cancer, new therapeutic vulnerabilities can be discovered and potentially exploited for the inhibition of this potent oncogene in cancer. PMID:28587062

An explicitly solvated full atomistic model of the cardiac thin filament and application on the calcium binding affinity effects from familial hypertrophic cardiomyopathy linked mutations

NASA Astrophysics Data System (ADS)

Williams, Michael; Schwartz, Steven

2015-03-01

The previous version of our cardiac thin filament (CTF) model consisted of the troponin complex (cTn), two coiled-coil dimers of tropomyosin (Tm), and 29 actin units. We now present the newest revision of the model to include explicit solvation. The model was developed to continue our study of genetic mutations in the CTF proteins which are linked to familial hypertrophic cardiomyopathies. Binding of calcium to the cTnC subunit causes subtle conformational changes to propagate through the cTnC to the cTnI subunit which then detaches from actin. Conformational changes propagate through to the cTnT subunit, which allows Tm to move into the open position along actin, leading to muscle contraction. Calcium disassociation allows for the reverse to occur, which results in muscle relaxation. The inclusion of explicit TIP3 water solvation allows for the model to get better individual local solvent to protein interactions; which are important when observing the N-lobe calcium binding pocket of the cTnC. We are able to compare in silica and in vitro experimental results to better understand the physiological effects from mutants, such as the R92L/W and F110V/I of the cTnT, on the calcium binding affinity compared to the wild type.

New MYC IHC Classifier Integrating Quantitative Architecture Parameters to Predict MYC Gene Translocation in Diffuse Large B-Cell Lymphoma

PubMed Central

Dong, Wei-Feng; Canil, Sarah; Lai, Raymond; Morel, Didier; Swanson, Paul E.; Izevbaye, Iyare

2018-01-01

A new automated MYC IHC classifier based on bivariate logistic regression is presented. The predictor relies on image analysis developed with the open-source ImageJ platform. From a histologic section immunostained for MYC protein, 2 dimensionless quantitative variables are extracted: (a) relative distance between nuclei positive for MYC IHC based on euclidean minimum spanning tree graph and (b) coefficient of variation of the MYC IHC stain intensity among MYC IHC-positive nuclei. Distance between positive nuclei is suggested to inversely correlate MYC gene rearrangement status, whereas coefficient of variation is suggested to inversely correlate physiological regulation of MYC protein expression. The bivariate classifier was compared with 2 other MYC IHC classifiers (based on percentage of MYC IHC positive nuclei), all tested on 113 lymphomas including mostly diffuse large B-cell lymphomas with known MYC fluorescent in situ hybridization (FISH) status. The bivariate classifier strongly outperformed the “percentage of MYC IHC-positive nuclei” methods to predict MYC+ FISH status with 100% sensitivity (95% confidence interval, 94-100) associated with 80% specificity. The test is rapidly performed and might at a minimum provide primary IHC screening for MYC gene rearrangement status in diffuse large B-cell lymphomas. Furthermore, as this bivariate classifier actually predicts “permanent overexpressed MYC protein status,” it might identify nontranslocation-related chromosomal anomalies missed by FISH. PMID:27093450

Three-dimensional speckle tracking echocardiography allows detailed evaluation of left atrial function in hypertrophic cardiomyopathy--insights from the MAGYAR-Path Study.

PubMed

Domsik, Péter; Kalapos, Anita; Chadaide, Számi; Sepp, Róbert; Hausinger, Péter; Forster, Tamás; Nemes, Attila

2014-11-01

Hypertrophic cardiomyopathy (HCM) represents a generalized myopathic process affecting both ventricular and atrial myocardium. Reduced left atrial (LA) function was demonstrated in HCM by different methods. Three-dimensional (3D) speckle tracking echocardiography (STE) has just been introduced for the evaluation of LA. This study was designed to compare 3DSTE-derived LA volumetric and strain parameters in HCM with healthy controls. The study comprised 23 consecutive HCM patients (mean age: 48.5 ± 15.1 years, 14 men). Their results were compared to 23 age- and gender-matched healthy controls. Complete two-dimensional Doppler echocardiography and 3DSTE have been performed in all cases. Calculated LA maximum (66.4 ± 20.4 mL vs. 36.0 ± 6.1 mL, P < 0.0001) and minimum (39.2 ± 19.1 vs. 16.0 ± 4.6 mL, P < 0.0001) volumes and LA volume before atrial contraction (53.6 ± 19.9 vs. 24.0 ± 6.2 mL, P < 0.0001) were significantly increased in HCM patients. Atrial stroke volumes respecting cardiac cycles proved to be increased, while emptying fractions were decreased in subjects with HCM. Mean global radial (-12.2 ± 6.7% vs. -19.6 ± 11.7, P < 0.05), longitudinal (26.5 ± 16.5% vs. 29.8 ± 12.1%, P < 0.05) and 3D strain (-6.1 ± 4.4% vs. -12.5 ± 10.2%, P < 0.05) proved to be significantly reduced in HCM patients as compared with matched controls. Three-dimensional speckle tracking echocardiography allows detailed evaluation of LA (dys) function in HCM by volumetric and strain measurements. © 2014, Wiley Periodicals, Inc.

Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action potential changes in human iPSC cardiomyocytes.

PubMed

Wang, Lili; Kim, Kyungsoo; Parikh, Shan; Cadar, Adrian Gabriel; Bersell, Kevin R; He, Huan; Pinto, Jose R; Kryshtal, Dmytro O; Knollmann, Bjorn C

2018-01-01

Mutations in cardiac troponin T (TnT) are linked to increased risk of ventricular arrhythmia and sudden death despite causing little to no cardiac hypertrophy. Studies in mice suggest that the hypertrophic cardiomyopathy (HCM)-associated TnT-I79N mutation increases myofilament Ca sensitivity and is arrhythmogenic, but whether findings from mice translate to human cardiomyocyte electrophysiology is not known. To study the effects of the TnT-I79N mutation in human cardiomyocytes. Using CRISPR/Cas9, the TnT-I79N mutation was introduced into human induced pluripotent stem cells (hiPSCs). We then used the matrigel mattress method to generate single rod-shaped cardiomyocytes (CMs) and studied contractility, Ca handling and electrophysiology. Compared to isogenic control hiPSC-CMs, TnT-I79N hiPSC-CMs exhibited sarcomere disorganization, increased systolic function and impaired relaxation. The Ca-dependence of contractility was leftward shifted in mutation containing cardiomyocytes, demonstrating increased myofilament Ca sensitivity. In voltage-clamped hiPSC-CMs, TnT-I79N reduced intracellular Ca transients by enhancing cytosolic Ca buffering. These changes in Ca handling resulted in beat-to-beat instability and triangulation of the cardiac action potential, which are predictors of arrhythmia risk. The myofilament Ca sensitizer EMD57033 produced similar action potential triangulation in control hiPSC-CMs. The TnT-I79N hiPSC-CM model not only reproduces key cellular features of TnT-linked HCM such as myofilament disarray, hypercontractility and diastolic dysfunction, but also suggests that this TnT mutation causes pro-arrhythmic changes of the human ventricular action potential. Copyright © 2017 Elsevier Ltd. All rights reserved.

MYC and gastric adenocarcinoma carcinogenesis

PubMed Central

Calcagno, Danielle Queiroz; Leal, Mariana Ferreira; Assumpção, Paulo Pimentel; Smith, Marília de Arruda Cardoso; Burbano, Rommel Rodríguez

2008-01-01

MYC is an oncogene involved in cell cycle regulation, cell growth arrest, cell adhesion, metabolism, ribosome biogenesis, protein synthesis, and mitochondrial function. It has been described as a key element of several carcinogenesis processes in humans. Many studies have shown an association between MYC deregulation and gastric cancer. MYC deregulation is also seen in gastric preneoplastic lesions and thus it may have a role in early gastric carcinogenesis. Several studies have suggested that amplification is the main mechanism of MYC deregulation in gastric cancer. In the present review, we focus on the deregulation of the MYC oncogene in gastric adenocarcinoma carcinogenesis, including its association with Helicobacter pylori (H pylori) and clinical applications. PMID:18932273

Long Term Ablation of Protein Kinase A (PKA)-mediated Cardiac Troponin I Phosphorylation Leads to Excitation-Contraction Uncoupling and Diastolic Dysfunction in a Knock-in Mouse Model of Hypertrophic Cardiomyopathy*

PubMed Central

Dweck, David; Sanchez-Gonzalez, Marcos A.; Chang, Audrey N.; Dulce, Raul A.; Badger, Crystal-Dawn; Koutnik, Andrew P.; Ruiz, Edda L.; Griffin, Brittany; Liang, Jingsheng; Kabbaj, Mohamed; Fincham, Frank D.; Hare, Joshua M.; Overton, J. Michael; Pinto, Jose R.

2014-01-01

The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart rates and reduced cardiovagal tone. Cardiac myocytes isolated from older R21C mice demonstrate that in the presence of isoproterenol, significant delays in Ca2+ decay and sarcomere relaxation occur that are not present at 6 months of age. Although isoproterenol and stepwise increases in stimulation frequency accelerate Ca2+-transient and sarcomere shortening kinetics in R21C myocytes from older mice, they are unable to attain the corresponding WT values. When R21C myocytes from older mice are treated with isoproterenol, evidence of excitation-contraction uncoupling is indicated by an elevation in diastolic calcium that is frequency-dissociated and not coupled to shorter diastolic sarcomere lengths. Myocytes from older mice have smaller Ca2+ transient amplitudes (2.3-fold) that are associated with reductions (2.9-fold) in sarcoplasmic reticulum Ca2+ content. This abnormal Ca2+ handling within the cell may be attributed to a reduction (2.4-fold) in calsequestrin expression in conjunction with an up-regulation (1.5-fold) of Na+-Ca2+ exchanger. Incubation of permeabilized cardiac fibers from R21C mice with PKA confirmed that the mutation prevents facilitation of mechanical relaxation. Altogether, these results indicate that the inability to enhance myofilament relaxation through cTnI phosphorylation predisposes the heart to abnormal diastolic function, reduced accessibility of cardiac reserves, dysautonomia, and hypertrophy. PMID:24973218

Hypertrophic cardiomyopathy mutation R58Q in the myosin regulatory light chain perturbs thick filament-based regulation in cardiac muscle.

PubMed

Kampourakis, Thomas; Ponnam, Saraswathi; Irving, Malcolm

2018-04-01

Hypertrophic cardiomyopathy (HCM) is frequently linked to mutations in the protein components of the myosin-containing thick filaments leading to contractile dysfunction and ultimately heart failure. However, the molecular structure-function relationships that underlie these pathological effects remain largely obscure. Here we chose an example mutation (R58Q) in the myosin regulatory light chain (RLC) that is associated with a severe HCM phenotype and combined the results from a wide range of in vitro and in situ structural and functional studies on isolated protein components, myofibrils and ventricular trabeculae to create an extensive map of structure-function relationships. The results can be understood in terms of a unifying hypothesis that illuminates both the effects of the mutation and physiological signaling pathways. R58Q promotes an OFF state of the thick filaments that reduces the number of myosin head domains that are available for actin interaction and ATP utilization. Moreover this mutation uncouples two aspects of length-dependent activation (LDA), the cellular basis of the Frank-Starling relation that couples cardiac output to venous return; R58Q reduces maximum calcium-activated force with no significant effect on myofilament calcium sensitivity. Finally, phosphorylation of R58Q-RLC to levels that may be relevant both physiologically and pathologically restores the regulatory state of the thick filament and the effect of sarcomere length on maximum calcium-activated force and thick filament structure, as well as increasing calcium sensitivity. We conclude that perturbation of thick filament-based regulation may be a common mechanism in the etiology of missense mutation-associated HCM, and that this signaling pathway offers a promising target for the development of novel therapeutics. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation.

PubMed

Witjas-Paalberends, E Rosalie; Ferrara, Claudia; Scellini, Beatrice; Piroddi, Nicoletta; Montag, Judith; Tesi, Chiara; Stienen, Ger J M; Michels, Michelle; Ho, Carolyn Y; Kraft, Theresia; Poggesi, Corrado; van der Velden, Jolanda

2014-08-01

The first mutation associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β-myosin heavy chain (β-MyHC). R403Q locates in the globular head of myosin (S1), responsible for interaction with actin, and thus motor function of myosin. Increased cross-bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of tension generation; however, direct evidence is absent. Here we studied to what extent cross-bridge kinetics and energetics are related in single cardiac myofibrils and multicellular cardiac muscle strips of three HCM patients with the R403Q mutation and nine sarcomere mutation-negative HCM patients (HCMsmn). Expression of R403Q was on average 41 ± 4% of total MYH7 mRNA. Cross-bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher (P < 0.0001) than in HCMsmn myofibrils (0.47 ± 0.02 and 0.30 ± 0.02 s(-1), respectively). Moreover, compared to HCMsmn, tension cost was significantly higher in the muscle strips of the three R403Q patients (2.93 ± 0.25 and 1.78 ± 0.10 μmol l(-1) s(-1) kN(-1) m(-2), respectively) which showed a positive linear correlation with relaxation kinetics in the corresponding myofibril preparations. This correlation suggests that faster cross-bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCMsmn. Therefore, increased tension cost might contribute to HCM disease in patients carrying the R403Q mutation. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia.

PubMed

Eberhart, Charles G; Kratz, John; Wang, Yunyue; Summers, Krista; Stearns, Duncan; Cohen, Kenneth; Dang, Chi V; Burger, Peter C

2004-05-01

Several molecular and histopathological prognostic markers have been proposed for the therapeutic stratification of medulloblastoma patients. Amplification of the c-myc oncogene, elevated levels of c-myc mRNA, or tumor anaplasia have been associated with worse clinical outcomes. In contrast, high TrkC mRNA expression generally presages longer survival. The goal of this study was to evaluate the prognostic value of c-myc, N-myc and TrkC expression in medulloblastomas and compare them to histopathological classification. We used in situ hybridization to measure expression of these molecular markers. c-myc mRNA was detected in 18 of 59 (31%) cases, and was significantly associated with shorter patient survival times on both univariate and multivariate analyses (p = 0.04). The presence of c-myc mRNA was also significantly associated with tumor anaplasia. While survival rates were higher for patients with low N-myc or high TrkC expression, these differences were not statistically significant. The group of patients with either moderate or severely anaplastic tumors showed only a trend towards shorter survival (p = 0.11). However, severe anaplasia alone was significantly prognostic (p = 0.002). Given the prognostic import of c-myc, we investigated 2 potential mechanisms by which its expression might be regulated: Wnt signaling and Mxi-1 mutation. Nuclear translocation of beta-catenin, a marker of Wnt pathway activation, was more common in medulloblastomas with high c-myc than in tumors overall, but the difference was not statistically significant. No Mxi-1 mutations were detected in the 22 cases examined. The association we describe between c-myc expression, tumor anaplasia, and worse clinical outcomes provides further evidence for the importance of this oncogene in medulloblastoma pathobiology.

An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma.

PubMed

Lollies, A; Hartmann, S; Schneider, M; Bracht, T; Weiß, A L; Arnolds, J; Klein-Hitpass, L; Sitek, B; Hansmann, M-L; Küppers, R; Weniger, M A

2018-01-01

Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30 + lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30 + diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas.

Subendocardial motion in hypertrophic cardiomyopathy: assessment from long- and short-axis views by pulsed tissue Doppler imaging

NASA Technical Reports Server (NTRS)

Tabata, T.; Oki, T.; Yamada, H.; Abe, M.; Onose, Y.; Thomas, J. D.

2000-01-01

BACKGROUND: Tissue Doppler imaging (TDI) is a recently developed technique that allows the instantaneous measurement of intrinsic regional myocardial motion velocity. Pulsed TDI is capable of separately assessing left ventricular (LV) regional motion velocity caused by circumferential and longitudinal fiber contraction. This particular feature of function is still controversial in patients with hypertrophic cardiomyopathy (HC). METHODS: To better characterize intrinsic circumferential and longitudinal LV systolic myocardial function in HC, we used pulsed TDI to measure short- and long-axis LV motion velocities, respectively. The subendocardial motion velocity patterns at the middle of the LV posterior wall (PW) and ventricular septum (IVS) in LV parasternal and apical long-axis views were recorded by pulsed TDI in 19 patients with nonobstructive HC and in 21 normal controls (NC). RESULTS: Peak short- and long-axis systolic subendocardial velocities in both the LV PW and IVS were significantly smaller in the HC group than in the NC group, and the time to peak velocity was significantly delayed. Furthermore, peak PW systolic velocity was significantly greater along the long axis than along the short axis in the NC group (8.8 +/- 1.5 cm/s vs 8.2 +/- 1.4 cm/s, P <.05), whereas the opposite was observed in the HC group (6.1 +/- 1.2 cm/s vs 7.5 +/- 1.0 cm/s, P <.0001). No significant differences were found in either group between the long- and short-axis IVS velocities (HC: 5.9 +/- 1.4 cm/s vs 5.5 +/- 1.3 cm/s; NC: 7.8 +/- 1.3 cm/s vs 7.9 +/- 1.6 cm/s). CONCLUSIONS: By using the capability of pulsed TDI for the evaluation of intrinsic myocardial velocity instantaneously in a specific region and direction, we found impairment of LV myocardial systolic function in patients with HC not only in the hypertrophied IVS but also in the nonhypertrophied LV PW. We also found a greater decrease in LV PW velocities along the long axis than the short axis, suggesting greater

Enhanced washout of 99mTc-tetrofosmin in hypertrophic cardiomyopathy: quantitative comparisons with regional 123I-BMIPP uptake and wall thickness determined by MRI.

PubMed

Thet-Thet-Lwin; Takeda, Tohoru; Wu, Jin; Fumikura, Yuko; Iida, Keiji; Kawano, Satoru; Yamaguchi, Iwao; Itai, Yuji

2003-07-01

The diagnostic value of technetium-99m tetrofosmin (TF) washout in hypertrophic cardiomyopathy (HCM) was examined by investigating its relation to the metabolic abnormality depicted by iodine-123 beta-methyl- p-iodophenylpentadecanoic acid (BMIPP) uptake and the left ventricular (LV) myocardial wall thickness as measured by magnetic resonance imaging (MRI). TF washout was evaluated in 31 patients with HCM and 23 normal control subjects using 30-min (early) and 3-h (delayed) TF single-photon emission tomography images. The LV myocardial wall was divided into 19 segments and the percentage TF washout, regional BMIPP uptake and LV wall thickness were measured in each segment. Mean TF washout in the patients with HCM was significantly faster than that in normal control subjects (23.7+/-5.7 vs 13.4+/-4.1, P<0.0001). In the patients with HCM, TF washout showed an excellent correlation with MRI wall thickness ( r=0.82, P<0.0001) and a good inverse correlation with regional BMIPP uptake ( r=-0.72, P<0.0001). In addition, a good linear correlation was observed between TF uptake and MRI wall thickness in the 19 regional segments. In conclusion, the degree of TF washout corresponds well with the severity of myocardial wall thickness and the degree of metabolic abnormality in patients with HCM. These results suggest that enhanced TF washout might provide additional clinical information regarding metabolic alterations in HCM.

MYC interaction with the tumor suppressive SWI/SNF complex member INI1 regulates transcription and cellular transformation

PubMed Central

Stojanova, Angelina; Tu, William B.; Ponzielli, Romina; Kotlyar, Max; Chan, Pak-Kei; Boutros, Paul C.; Khosravi, Fereshteh; Jurisica, Igor; Raught, Brian; Penn, Linda Z.

2016-01-01

ABSTRACT MYC is a key driver of cellular transformation and is deregulated in most human cancers. Studies of MYC and its interactors have provided mechanistic insight into its role as a regulator of gene transcription. MYC has been previously linked to chromatin regulation through its interaction with INI1 (SMARCB1/hSNF5/BAF47), a core member of the SWI/SNF chromatin remodeling complex. INI1 is a potent tumor suppressor that is inactivated in several types of cancers, most prominently as the hallmark alteration in pediatric malignant rhabdoid tumors. However, the molecular and functional interaction of MYC and INI1 remains unclear. Here, we characterize the MYC-INI1 interaction in mammalian cells, mapping their minimal binding domains to functionally significant regions of MYC (leucine zipper) and INI1 (repeat motifs), and demonstrating that the interaction does not interfere with MYC-MAX interaction. Protein-protein interaction network analysis expands the MYC-INI1 interaction to the SWI/SNF complex and a larger network of chromatin regulatory complexes. Genome-wide analysis reveals that the DNA-binding regions and target genes of INI1 significantly overlap with those of MYC. In an INI1-deficient rhabdoid tumor system, we observe that with re-expression of INI1, MYC and INI1 bind to common target genes and have opposing effects on gene expression. Functionally, INI1 re-expression suppresses cell proliferation and MYC-potentiated transformation. Our findings thus establish the antagonistic roles of the INI1 and MYC transcriptional regulators in mediating cellular and oncogenic functions. PMID:27267444

Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0.

PubMed

Kollberg, Gittan; Tulinius, Már; Gilljam, Thomas; Ostman-Smith, Ingegerd; Forsander, Gun; Jotorp, Peter; Oldfors, Anders; Holme, Elisabeth

2007-10-11

Storage of glycogen is essential for glucose homeostasis and for energy supply during bursts of activity and sustained muscle work. We describe three siblings with profound muscle and heart glycogen deficiency caused by a homozygous stop mutation (R462-->ter) in the muscle glycogen synthase gene. The oldest brother died from sudden cardiac arrest at the age of 10.5 years. Two years later, an 11-year-old brother showed muscle fatigability, hypertrophic cardiomyopathy, and an abnormal heart rate and blood pressure while exercising; a 2-year-old sister had no symptoms. In muscle-biopsy specimens obtained from the two younger siblings, there was lack of glycogen, predominance of oxidative fibers, and mitochondrial proliferation. Glucose tolerance was normal. Copyright 2007 Massachusetts Medical Society.

Erythropoietin activates two distinct signaling pathways required for the initiation and the elongation of c-myc

NASA Technical Reports Server (NTRS)

Chen, C.; Sytkowski, A. J.

2001-01-01

Erythropoietin (Epo) stimulation of erythroid cells results in the activation of several kinases and a rapid induction of c-myc expression. Protein kinase C is necessary for Epo up-regulation of c-myc by promoting elongation at the 3'-end of exon 1. PKCepsilon mediates this signal. We now show that Epo triggers two signaling pathways to c-myc. Epo rapidly up-regulated Myc protein in BaF3-EpoR cells. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 blocked Myc up-regulation in a concentration-dependent manner but had no effect on the Epo-induced phosphorylation of ERK1 and ERK2. LY294002 also had no effect on Epo up-regulation of c-fos. MEK1 inhibitor PD98059 blocked both the c-myc and the c-fos responses to Epo. PD98059 and the PKC inhibitor H7 also blocked the phosphorylation of ERK1 and ERK2. PD98059 but not LY294002 inhibited Epo induction of ERK1 and ERK2 phosphorylation in normal erythroid cells. LY294002 blocked transcription of c-myc at exon 1. PD98059 had no effect on transcription from exon 1 but, rather, blocked Epo-induced c-myc elongation at the 3'-end of exon 1. These results identify two Epo signaling pathways to c-myc, one of which is PI3K-dependent operating on transcriptional initiation, whereas the other is mitogen-activated protein kinase-dependent operating on elongation.

Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype

PubMed Central

Schreiber-Agus, Nicole; Stein, David; Chen, Ken; Goltz, Jason S.; Stevens, Leslie; DePinho, Ronald A.

1997-01-01

Biochemical and biological activities of Myc oncoproteins are highly dependent upon their association with another basic region helix–loop–helix/leucine zipper (bHLH/LZ) protein, Max. Our previous observation that the DNA-binding/dimerization region of Max is absolutely conserved throughout vertebrate evolution provided the basis for a yeast two-hybrid interaction screen that led to the isolation of the Drosophila Myc (dMyc1) protein. Structural conservation in regions of known functional significance is consistent with the ability of dMyc1 to interact with vertebrate Max, to transactivate gene expression in yeast cells, and to cooperate with activated H-RAS to effect the malignant transformation of primary mammalian cells. The ability of P-element-mediated ectopic expression of dmyc1 to reverse a subset of the phenotypic alterations associated with the diminutive mutation suggests that diminutive may correspond to dmyc1. This finding, along with the localization of dmyc1 expression to zones of high proliferative activity in the embryo, implicates dMyc1 as an integral regulator of Drosophila growth and development. PMID:9037036

c-myc overexpression causes anaplasia in medulloblastoma.

PubMed

Stearns, Duncan; Chaudhry, Aneeka; Abel, Ty W; Burger, Peter C; Dang, Chi V; Eberhart, Charles G

2006-01-15

Both anaplasia and increased c-myc gene expression have been shown to be negative prognostic indicators for survival in medulloblastoma patients. myc gene amplification has been identified in many large cell/anaplastic medulloblastoma, but no causative link between c-myc and anaplastic changes has been established. To address this, we stably overexpressed c-myc in two medulloblastoma cell lines, DAOY and UW228, and examined the changes in growth characteristics. When analyzed in vitro, cell lines with increased levels of c-myc had higher rates of growth and apoptosis as well as significantly improved ability to form colonies in soft agar compared with control. When injected s.c. into nu/nu mice, flank xenograft tumors with high levels of c-myc in DAOY cell line background were 75% larger than those derived from control. Overexpression of c-myc was required for tumor formation by UW228 cells. Most remarkably, the histopathology of the Myc tumors was severely anaplastic, with large areas of necrosis/apoptosis, increased nuclear size, and macronucleoli. Indices of proliferation and apoptosis were also significantly higher in Myc xenografts. Thus, c-myc seems to play a causal role in inducing anaplasia in medulloblastoma. Because anaplastic changes are often observed in recurrent medulloblastoma, we propose that c-myc dysregulation is involved in the progression of these malignant embryonal neoplasms.

Structure and expression of canary myc family genes.

PubMed Central

Collum, R G; Clayton, D F; Alt, F W

1991-01-01

We found that the canary N-myc gene is highly related to mammalian N-myc genes in both the protein-coding region and the long 3' untranslated region. Examined coding regions of the canary c-myc gene were also highly related to their mammalian counterparts, but in contrast to N-myc, the canary and mammalian c-myc genes were quite divergent in their 3' untranslated regions. We readily detected N-myc and c-myc expression in the adult canary brain and found N-myc expression both at sites of proliferating neuronal precursors and in mature neurons. Images PMID:1996121

Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy.

PubMed

Bahrudin, Udin; Morisaki, Hiroko; Morisaki, Takayuki; Ninomiya, Haruaki; Higaki, Katsumi; Nanba, Eiji; Igawa, Osamu; Takashima, Seiji; Mizuta, Einosuke; Miake, Junichiro; Yamamoto, Yasutaka; Shirayoshi, Yasuaki; Kitakaze, Masafumi; Carrier, Lucie; Hisatome, Ichiro

2008-12-26

The ubiquitin-proteasome system is responsible for the disappearance of truncated cardiac myosin-binding protein C, and the suppression of its activity contributes to cardiac dysfunction. This study investigated whether missense cardiac myosin-binding protein C gene (MYBPC3) mutation in hypertrophic cardiomyopathy (HCM) leads to destabilization of its protein, causes UPS impairment, and is associated with cardiac dysfunction. Mutations were identified in Japanese HCM patients using denaturing HPLC and sequencing. Heterologous expression was investigated in COS-7 cells as well as neonatal rat cardiac myocytes to examine protein stability and proteasome activity. The cardiac function was measured using echocardiography. Five novel MYBPC3 mutations -- E344K, DeltaK814, Delta2864-2865GC, Q998E, and T1046M -- were identified in this study. Compared with the wild type and other mutations, the E334K protein level was significantly lower, it was degraded faster, it had a higher level of polyubiquination, and increased in cells pretreated with the proteasome inhibitor MG132 (50 microM, 6 h). The electrical charge of its amino acid at position 334 influenced its stability, but E334K did not affect its phosphorylation. The E334K protein reduced cellular 20 S proteasome activity, increased the proapoptotic/antiapoptotic protein ratio, and enhanced apoptosis in transfected Cos-7 cells and neonatal rat cardiac myocytes. Patients carrying the E334K mutation presented significant left ventricular dysfunction and dilation. The conclusion is the missense MYBPC3 mutation E334K destabilizes its protein through UPS and may contribute to cardiac dysfunction in HCM through impairment of the ubiquitin-proteasome system.

Cancer-associated fibroblasts promote endometrial cancer growth via activation of interleukin-6/STAT-3/c-Myc pathway.

PubMed

Subramaniam, Kavita S; Omar, Intan Sofia; Kwong, Soke Chee; Mohamed, Zahurin; Woo, Yin Ling; Mat Adenan, Noor Azmi; Chung, Ivy

2016-01-01

Cancer-associated fibroblasts (CAFs) secrete various pro-tumorigenic cytokines, yet the role of these cytokines in the progression of endometrial cancer remains unclear. We found that CAFs isolated from human endometrial cancer (EC) tissues secreted high levels of interleukin-6 (IL-6), which promotes EC cell proliferation in vitro. Neutralizing IL-6 in CAF-conditioned media reduced (47% inhibition) while IL-6 recombinant protein increased cell proliferation (~2.4 fold) of both EC cell lines and primary cultures. IL-6 receptors (IL-6R and gp130) were expressed only in EC epithelial cells but not in CAF, indicating a one-way paracrine signaling. In the presence of CAF-conditioned media, Janus kinase/signal transducers and activators of transcription (JAK/STAT3) pathway was activated in EC cells. Treatment with JAK and STAT3 specific inhibitors, AD412 and STATTIC, respectively, significantly abrogated CAF-mediated cell proliferation, indicating the role of IL-6 activation in EC cell proliferation. We further showed that one of STAT-3 target genes, c-Myc, was highly induced in EC cells after exposure to CAF-conditioned medium at both mRNA (>105-fold vs. control) and protein level (>2-fold vs. control). EC cell proliferation was dependent on c-Myc expression, as RNAi-mediated c-Myc down-regulation led to a significant 46% reduction in cell viability when compared with scrambled control. Interestingly, CAF-conditioned media failed to promote proliferation in EC cells with reduced c-Myc expression, suggesting that CAF-mediated cell proliferation was also dependent on c-Myc expression. Subcutaneous tumor xenograft model showed that EC cells grew at least 1.4 times larger when co-injected with CAF, when compared to those injected with EC cells alone. Mice injected with EC cells with down-regulated c-Myc expression, however, showed at least 2.5 times smaller tumor compared to those in control group. Notably, there was no increase of tumor size when co-injected with CAFs

The MYC Road to Hearing Restoration

PubMed Central

Kopecky, Benjamin; Fritzsch, Bernd

2012-01-01

Current treatments for hearing loss, the most common neurosensory disorder, do not restore perfect hearing. Regeneration of lost organ of Corti hair cells through forced cell cycle re-entry of supporting cells or through manipulation of stem cells, both avenues towards a permanent cure, require a more complete understanding of normal inner ear development, specifically the balance of proliferation and differentiation required to form and to maintain hair cells. Direct successful alterations to the cell cycle result in cell death whereas regulation of upstream genes is insufficient to permanently alter cell cycle dynamics. The Myc gene family is uniquely situated to synergize upstream pathways into downstream cell cycle control. There are three Mycs that are embedded within the Myc/Max/Mad network to regulate proliferation. The function of the two ear expressed Mycs, N-Myc and L-Myc were unknown less than two years ago and their therapeutic potentials remain speculative. In this review, we discuss the roles the Mycs play in the body and what led us to choose them to be our candidate gene for inner ear therapies. We will summarize the recently published work describing the early and late effects of N-Myc and L-Myc on hair cell formation and maintenance. Lastly, we detail the translational significance of our findings and what future work must be performed to make the ultimate hearing aid: the regeneration of the organ of Corti. PMID:24710525

Pregnancy in women with hypertrophic cardiomyopathy: data from the European Society of Cardiology initiated Registry of Pregnancy and Cardiac disease (ROPAC).

PubMed

Goland, S; van Hagen, I M; Elbaz-Greener, G; Elkayam, U; Shotan, A; Merz, W M; Enar, S C; Gaisin, I R; Pieper, P G; Johnson, M R; Hall, R; Blatt, A; Roos-Hesselink, J W

2017-09-14

We report the maternal and foetal outcomes at birth and after 6 months in a cohort of pregnant women with hypertrophic cardiomyopathy (HCM). Although most women with HCM tolerate pregnancy well, there is an increased risk of obstetric and cardiovascular complications. All pregnant women with HCM entered into the prospective worldwide Registry of Pregnancy and Cardiac disease (ROPAC) were included in this analysis. The primary endpoint was a major adverse cardiovascular event (MACE), which included death, heart failure (HF), thrombo-embolic event, and arrhythmia. Baseline and outcome data were analysed and compared for patients with MACE vs. without MACE and for patients with obstructive HCM vs. non-obstructive HCM. Sixty pregnant women (mean age 30.4 ± 6.0 years) with HCM (41.7% obstructive) were included. No maternal mortality occurred in this cohort. In 14 (23%) patients at least one MACE occurred: 9 (15.0%) HF and 7 (12%) an arrhythmia (6 ventricular and 1 atrial fibrillation). MACE occurred most commonly during the 3rd trimester and postpartum period. In total, 3 (5.0%) women experienced foetal loss. Women with MACE had a higher rate of emergency Caesarean delivery for cardiac reasons (21.4% vs. 0%, P = 0.01). No significant differences in pregnancy outcome were found between women with obstructive and non-obstructive HCM. NYHA functional class of ≥II and signs of HF before pregnancy, were associated with MACE. Although most women with HCM tolerated pregnancy well, cardiovascular complications were not uncommon and predicted by pre-pregnancy status facilitating pre-pregnancy counselling and targeted antenatal care. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Vector flow mapping in obstructive hypertrophic cardiomyopathy to assess the relationship of early systolic left ventricular flow and the mitral valve.

PubMed

Ro, Richard; Halpern, Dan; Sahn, David J; Homel, Peter; Arabadjian, Milla; Lopresto, Charles; Sherrid, Mark V

2014-11-11

The hydrodynamic cause of systolic anterior motion of the mitral valve (SAM) is unresolved. This study hypothesized that echocardiographic vector flow mapping, a new echocardiographic technique, would provide insights into the cause of early SAM in obstructive hypertrophic cardiomyopathy (HCM). We analyzed the spatial relationship of left ventricular (LV) flow and the mitral valve leaflets (MVL) on 3-chamber vector flow mapping frames, and performed mitral valve measurements on 2-dimensional frames in patients with obstructive and nonobstructive HCM and in normal patients. We compared 82 patients (22 obstructive HCM, 23 nonobstructive HCM, and 37 normal) by measuring 164 LV pre- and post-SAM velocity vector flow maps, 82 maximum isovolumic vortices, and 328 2-dimensional frames. We observed color flow and velocity vector flow posterior to the MVL impacting them in the early systolic frames of 95% of obstructive HCM, 22% of nonobstructive HCM, and 11% of normal patients (p < 0.001). In both pre- and post-SAM frames, we measured a high angle of attack >60° of local vector flow onto the posterior surface of the leaflets whether the flow was ejection (59%) or the early systolic isovolumic vortex (41%). Ricochet of vector flow, rebounding off the leaflet into the cul-de-sac, was noted in 82% of the obstructed HCM, 9% of nonobstructive HCM, and none (0%) of the control patients (p < 0.001). Flow velocities in the LV outflow tract on the pre-SAM frame 1 and 2 mm from the tip of the anterior leaflet were low: 39 and 43 cm/s, respectively. Early systolic flow impacts the posterior surfaces of protruding MVL initiating SAM in obstructive HCM. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Detecting and Targeting Oncogenic Myc in Breast Cancer

DTIC Science & Technology

2007-06-01

through an MBII- dependent interaction with TRRAP [40,41]. Inhibition of TRRAP synthesis or function blocks Myc-mediated oncogenesis, establishing an...transcribed by RNAP I and III. In fact, the various components of the ribosomal machinery are synthesised by all three RNA polymerases, RNAP I, II and III... synthesis . Remarkably, the nucleoli are en- larged in cancer cells and several ribosomal proteins are overexpressed in tumours, suggesting a

cMYC Expression in Infiltrating Gliomas: Associations with IDH1 Mutations, Clinicopathologic Features and Outcome

PubMed Central

Odia, Yazmin; Orr, Brent A.; Bell, W. Robert; Eberhart, Charles G.; Rodriguez, Fausto J.

2013-01-01

Gliomas are among the most frequent adult primary brain tumors. Mutations in IDH1, a metabolic enzyme, strongly correlate with secondary glioblastomas and increased survival. cMYC is an oncogene also implicated in aberrant metabolism, but its prognostic impact remains unclear. Recent genotyping studies also showed SNP variants near the cMYC gene locus, associate with an increased risk for development of IDH1/2 mutant gliomas suggesting a possible interaction between cMYC and IDH1. We evaluated nuclear cMYC protein levels and IDH1 (R132H) by immunohistochemistry in patients with oligodendroglioma/oligoastrocytomas (n=20), astrocytomas (grade II) (n=19), anaplastic astrocytomas (n=21) or glioblastomas (n=111). Of 158 tumors with sufficient tissue, 110 (70%) showed nuclear cMYC immunopositivity – most frequent (95%, χ2 p=0.0248) and intense (mean 1.33, ANOVA p=0.0179) in anaplastic astrocytomas versus glioblastomas (63%) or low grade gliomas (74%). cMYC expression associated with younger age as well as p53 immunopositivity (OR=3.6, p=0.0332) and mutant IDH1 (R132H) (OR=7.4, p=0.06) among malignant gliomas in our cohort. Independent analysis of the publically available TCGA glioblastoma dataset confirmed our strong association between cMYC and mutant IDH1 expression. Both IDH1 (R132H) and cMYC protein expression were associated with improved overall survival by univariate analysis. However, cMYC co-expression associated with shortened time to malignant transformation and overall survival among IDH1 (R132H) mutants in both univariate and multivariate analyses. In summary, our findings suggest that cMYC may be associated with a unique clinicopathologic and biologic group of infiltrating gliomas and help mediate the malignant transformation of IDH1 mutant gliomas. PMID:23934175

Effects of clopidogrel therapy on whole blood platelet aggregation, the Plateletworks® assay and coagulation parameters in cats with asymptomatic hypertrophic cardiomyopathy: a pilot study.

PubMed

den Toom, M L; van Leeuwen, M W; Szatmári, V; Teske, E

2017-12-01

Although scientific evidence is limited, clopidogrel is frequently used as prophylaxis for arterial thromboembolism in cats with hypertrophic cardiomyopathy (HCM). Evaluating effects of clopidogrel therapy in asymptomatic cats with HCM on (1) conventional whole blood aggregation (WBA), (2) alternative platelet aggregation assessed with tubes of the Plateletworks® assay and (3) standard coagulation parameters. Prospective, randomized, double-blind, placebo-controlled pilot study. Fourteen asymptomatic HCM cats were randomly allocated to receive placebo (n = 5) or clopidogrel (18.75 mg/cat q24h, n = 9) as part of a larger study. Aggregation responses (to 20 µM adenosine diphosphate (ADP) and 10 µg/ml collagen) in WBA and the Plateletworks® assay and standard coagulation parameters were evaluated at baseline and after seven days of therapy. Clopidogrel therapy significantly reduced aggregation responses to ADP and collagen in the Plateletworks® agonists tubes (ADP and collagen: P < 0.001), but did not significantly reduce aggregation responses to ADP and collagen in the WBA technique (ADP: P = 0.07, collagen: P = 0.30). Clopidogrel therapy did not show a significant effect on prothrombin time, activated partial thromboplastin time, antithrombin, D-dimers and fibrinogen concentrations. Clopidogrel therapy at a dose of 18.75 mg/cat q24h for seven days causes a significant decrease in in vitro platelet aggregation evaluated with the Plateletworks® assay, without affecting standard coagulation parameters in cats with asymptomatic HCM.

Hypertrophic cardiomyopathy

MedlinePlus

... heart, forcing the heart to work harder to pump blood. It also can make it harder for the heart to relax ... from defects in the genes that control heart muscle growth. Younger people are likely to ...

Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy.

PubMed

Rodriguez, Gabriela; Ueyama, Tomomi; Ogata, Takehiro; Czernuszewicz, Grazyna; Tan, Yanli; Dorn, Gerald W; Bogaev, Roberta; Amano, Katsuya; Oh, Hidemasa; Matsubara, Hiroaki; Willerson, James T; Marian, Ali J

2011-08-01

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z-line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies. We sequenced MURC in 1199 individuals, including 383 probands with DCM, 307 with HCM, and 509 healthy control subjects. We found 6 heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L, and p.S364L) in 8 unrelated probands. Variants p.N128K and p.S307T segregated with inheritance of DCM in small families (χ(2)=8.5, P=0.003). Variants p.N128K, p.R140W, p.L153P, and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in 3 independent probands, including 1 proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in 3 unrelated HCM probands, but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L907V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in 4 patients, conduction defects, and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared with wild-type MURC. MURC mutations impart loss-of-function effects on MURC functions and probably are causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain.

Use of Myocardial T1 Mapping at 3.0 T to Differentiate Anderson-Fabry Disease from Hypertrophic Cardiomyopathy.

PubMed

Karur, Gauri R; Robison, Sean; Iwanochko, Robert M; Morel, Chantal F; Crean, Andrew M; Thavendiranathan, Paaladinesh; Nguyen, Elsie T; Mathur, Shobhit; Wasim, Syed; Hanneman, Kate

2018-04-24

Purpose To compare left ventricular (LV) and right ventricular (RV) 3.0-T cardiac magnetic resonance (MR) imaging T1 values in Anderson-Fabry disease (AFD) and hypertrophic cardiomyopathy (HCM) and evaluate the diagnostic value of native T1 values beyond age, sex, and conventional imaging features. Materials and Methods For this prospective study, 30 patients with gene-positive AFD (37% male; mean age ± standard deviation, 45.0 years ± 14.1) and 30 patients with HCM (57% male; mean age, 49.3 years ± 13.5) were prospectively recruited between June 2016 and September 2017 to undergo cardiac MR imaging T1 mapping with a modified Look-Locker inversion recovery (MOLLI) acquisition scheme at 3.0 T (repetition time msec/echo time msec, 280/1.12; section thickness, 8 mm). LV and RV T1 values were evaluated. Statistical analysis included independent samples t test, receiver operating characteristic curve analysis, multivariable logistic regression, and likelihood ratio test. Results Septal LV, global LV, and RV native T1 values were significantly lower in AFD compared with those in HCM (1161 msec ± 47 vs 1296 msec ± 55, respectively [P < .001]; 1192 msec ± 52 vs 1268 msec ± 55 [P < .001]; and 1221 msec ± 54 vs 1271 msec ± 37 [P = .001], respectively). A septal LV native T1 cutoff point of 1220 msec or lower distinguished AFD from HCM with sensitivity of 97%, specificity of 93%, and accuracy of 95%. Septal LV native T1 values differentiated AFD from HCM after adjustment for age, sex, and conventional imaging features (odds ratio, 0.94; 95% confidence interval: 0.91, 0.98; P = < .001). In a nested logistic regression model with age, sex, and conventional imaging features, model fit was significantly improved by the addition of septal LV native T1 values (χ 2 [df = 1] = 33.4; P < .001). Conclusion Cardiac MR imaging native T1 values at 3.0 T are significantly lower in patients with AFD compared with those with HCM and provide independent and incremental diagnostic

Surgical septal myectomy or alcohol septal ablation: which approach offers better outcomes for patients with hypertrophic obstructive cardiomyopathy?

PubMed

Poon, Shi Sum; Field, Mark; Gupta, Dhiraj; Cameron, Duke

2017-06-01

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether surgical septal myectomy (SM) is more beneficial than alcohol septal ablation (ASA) in patients with hypertrophic obstructive cardiomyopathy. Altogether 218 articles were found using the reported search, of which 15 studies represented the best evidence to answer the clinical question. There were 14 observational studies and 1 meta-analysis study. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these articles are tabulated. Surgical SM was generally performed in younger patients whereas percutaneous ASA was favoured in patients with advanced age and significant co-morbidities. In a large study comprising 716 patients, the reduction of median residual left ventricular outflow tract (LVOT) gradient at 3 months was comparable after ASA (102 ± 52-10 mmHg) and SM (92 ± 39-9 mmHg). The New York Heart Association (NYHA) functional class and symptomatic improvement for either approach was comparable. Findings from the meta-analysis study showed that patients who underwent ASA had a higher incidence of post-procedure device implantation (odds ratio 3.09; P < 0.00001), as reported in 6 other studies. The risk of permanent pacemaker insertion during follow-up (FU) varied between 2.4-12.5% in SM and 1.7-22.0% in ASA. Isolated surgical myectomy and ASA are safe and effective in abolishing outflow obstruction, although the resolution of LVOT pressure gradient is more complete with surgery. The post-procedural and late mortality rates between the 2 groups are consistently low and comparable in carefully selected patients. Nonetheless, ASA is associated with the increased likelihood of complications such as permanent pacemaker implantation, early sustained-VT and VF, and re-intervention. Overall, when performed by experienced cardiologists and surgeons, both

Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: results from the Euro-ASA registry.

PubMed

Veselka, Josef; Jensen, Morten Kvistholm; Liebregts, Max; Januska, Jaroslav; Krejci, Jan; Bartel, Thomas; Dabrowski, Maciej; Hansen, Peter Riis; Almaas, Vibeke Marie; Seggewiss, Hubert; Horstkotte, Dieter; Tomasov, Pavol; Adlova, Radka; Bundgaard, Henning; Steggerda, Robbert; Ten Berg, Jurriën; Faber, Lothar

2016-05-14

The first cases of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) were published two decades ago. Although the outcomes of single-centre and national ASA registries have been published, the long-term survival and clinical outcome of the procedure are still debated. We report long-term outcomes from the as yet largest multinational ASA registry (the Euro-ASA registry). A total of 1275 (58 ± 14 years, median follow-up 5.7 years) highly symptomatic patients treated with ASA were included. The 30-day post-ASA mortality was 1%. Overall, 171 (13%) patients died during follow-up, corresponding to a post-ASA all-cause mortality rate of 2.42 deaths per 100 patient-years. Survival rates at 1, 5, and 10 years after ASA were 98% (95% CI 96-98%), 89% (95% CI 87-91%), and 77% (95% CI 73-80%), respectively. In multivariable analysis, independent predictors of all-cause mortality were age at ASA (P < 0.01), septum thickness before ASA (P < 0.01), NYHA class before ASA (P = 0.047), and the left ventricular (LV) outflow tract gradient at the last clinical check-up (P = 0.048). Alcohol septal ablation reduced the LV outflow tract gradient from 67 ± 36 to 16 ± 21 mmHg (P < 0.01) and NYHA class from 2.9 ± 0.5 to 1.6 ± 0.7 (P < 0.01). At the last check-up, 89% of patients reported dyspnoea of NYHA class ≤2, which was independently associated with LV outflow tract gradient (P < 0.01). The Euro-ASA registry demonstrated low peri-procedural and long-term mortality after ASA. This intervention provided durable relief of symptoms and a reduction of LV outflow tract obstruction in selected and highly symptomatic patients with obstructive HCM. As the post-procedural obstruction seems to be associated with both worse functional status and prognosis, optimal therapy should be focused on the elimination of LV outflow tract gradient. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please

Cardiopathogenic mediators generated by GATA4 signaling upon co-activation with endothelin-1 and Trypanosoma cruzi infection.

PubMed

Rigazio, Cristina S; Hernández, Matías; Corral, Ricardo S

2014-08-01

Trypanosoma cruzi (Tc), the etiological agent of Chagas disease, triggers multiple responses in the myocardium, a central organ of infection and pathology in the host. Parasite-driven induction of diverse regulators of cardiovascular function, including the vasoconstrictor endothelin-1 (ET-1), the inducible form of nitric oxide synthase (iNOS) and the B-type natriuretic peptide (BNP), has been linked to the development of severe chagasic cardiomyopathy. Our current goal was to analyze the participation of the zinc finger transcription factor GATA4, critically implicated in pathological cardiac hypertrophic response, in the generation of key mediators involved in the pathogenesis of Tc-elicited heart dysfunction. In this study, we found that the combined effects of Tc and ET-1 on atrial myocytes promoted the protein expression, phosphorylation and DNA-binding activity of GATA4, leading to augmented protein levels of iNOS and increased nitric oxide release. Moreover, Tc- and ET-1-co-activation of cardiomyocytes resulted in enhanced GATA4-dependent secretion of BNP. Accordingly, mice with chronic chagasic cardiomyopathy showed increased expression of GATA4, iNOS and BNP at inflammatory lesions in cardiac muscle. Our findings support a role for the GATA4 signaling pathway in the myocardial production of pathogenic mediators associated with Chagas heart disease, and may help define novel therapeutic targets. Copyright © 2014 Elsevier Ltd. All rights reserved.

Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations

PubMed Central

Mogensen, Jens; Kubo, Toru; Duque, Mauricio; Uribe, William; Shaw, Anthony; Murphy, Ross; Gimeno, Juan R.; Elliott, Perry; McKenna, William J.

2003-01-01

Restrictive cardiomyopathy (RCM) is an uncommon heart muscle disorder characterized by impaired filling of the ventricles with reduced volume in the presence of normal or near normal wall thickness and systolic function. The disease may be associated with systemic disease but is most often idiopathic. We recognized a large family in which individuals were affected by either idiopathic RCM or hypertrophic cardiomyopathy (HCM). Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I (TNNI3) as the likely disease gene. Subsequent mutation analysis revealed a novel missense mutation, which cosegregated with the disease in the family (lod score: 4.8). To determine if idiopathic RCM is part of the clinical expression of TNNI3 mutations, genetic investigations of the gene were performed in an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in six of these nine RCM patients. Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene. PMID:12531876

Therapeutic Approaches Targeting MYC-Driven Prostate Cancer

PubMed Central

Rebello, Richard J.; Pearson, Richard B.; Hannan, Ross D.; Furic, Luc

2017-01-01

The transcript encoding the proto-oncogene MYC is commonly overexpressed in prostate cancer (PC). MYC protein abundance is also increased in the majority of cases of advanced and metastatic castrate-resistant PC (mCRPC). Accordingly, the MYC-directed transcriptional program directly contributes to PC by upregulating the expression of a number of pro-tumorigenic factors involved in cell growth and proliferation. A key cellular process downstream of MYC activity is the regulation of ribosome biogenesis which sustains tumor growth. MYC activity also cooperates with the dysregulation of the phosphoinositol-3-kinase (PI3K)/AKT/mTOR pathway to promote PC cell survival. Recent advances in the understanding of these interactions through the use of animal models have provided significant insight into the therapeutic efficacy of targeting MYC activity by interfering with its transcriptional program, and indirectly by targeting downstream cellular events linked to MYC transformation potential. PMID:28212321

Targeting oncogenic Myc as a strategy for cancer treatment.

PubMed

Chen, Hui; Liu, Hudan; Qing, Guoliang

2018-01-01

The MYC family oncogene is deregulated in >50% of human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. Although Myc inhibition would be a powerful approach for the treatment of many types of cancers, direct targeting of Myc has been a challenge for decades owing to its "undruggable" protein structure. Hence, alternatives to Myc blockade have been widely explored to achieve desirable anti-tumor effects, including Myc/Max complex disruption, MYC transcription and/or translation inhibition, and Myc destabilization as well as the synthetic lethality associated with Myc overexpression. In this review, we summarize the latest advances in targeting oncogenic Myc, particularly for cancer therapeutic purposes.

Novel Phenotype-Genotype Correlations of Restrictive Cardiomyopathy With Myosin-Binding Protein C (MYBPC3) Gene Mutations Tested by Next-Generation Sequencing.

PubMed

Wu, Wei; Lu, Chao-Xia; Wang, Yi-Ning; Liu, Fang; Chen, Wei; Liu, Yong-Tai; Han, Ye-Chen; Cao, Jian; Zhang, Shu-Yang; Zhang, Xue

2015-07-10

MYBPC3 dysfunctions have been proven to induce dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or left ventricular noncompaction; however, the genotype-phenotype correlation between MYBPC3 and restrictive cardiomyopathy (RCM) has not been established. The newly developed next-generation sequencing method is capable of broad genomic DNA sequencing with high throughput and can help explore novel correlations between genetic variants and cardiomyopathies. A proband from a multigenerational family with 3 live patients and 1 unrelated patient with clinical diagnoses of RCM underwent a next-generation sequencing workflow based on a custom AmpliSeq panel, including 64 candidate pathogenic genes for cardiomyopathies, on the Ion Personal Genome Machine high-throughput sequencing benchtop instrument. The selected panel contained a total of 64 genes that were reportedly associated with inherited cardiomyopathies. All patients fulfilled strict criteria for RCM with clinical characteristics, echocardiography, and/or cardiac magnetic resonance findings. The multigenerational family with 3 adult RCM patients carried an identical nonsense MYBPC3 mutation, and the unrelated patient carried a missense mutation in the MYBPC3 gene. All of these results were confirmed by the Sanger sequencing method. This study demonstrated that MYBPC3 gene mutations, revealed by next-generation sequencing, were associated with familial and sporadic RCM patients. It is suggested that the next-generation sequencing platform with a selected panel provides a highly efficient approach for molecular diagnosis of hereditary and idiopathic RCM and helps build new genotype-phenotype correlations. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

dMyc is required in retinal progenitors to prevent JNK-mediated retinal glial activation

PubMed Central

Correia, Andreia; Santos, Marília A.; Relvas, João B.; Pereira, Paulo S.

2017-01-01

In the nervous system, glial cells provide crucial insulation and trophic support to neurons and are important for neuronal survival. In reaction to a wide variety of insults, glial cells respond with changes in cell morphology and metabolism to allow repair. Additionally, these cells can acquire migratory and proliferative potential. In particular, after axonal damage or pruning the clearance of axonal debris by glial cells is key for a healthy nervous system. Thus, bidirectional neuron-glial interactions are crucial in development, but little is known about the cellular sensors and signalling pathways involved. In here, we show that decreased cellular fitness in retinal progenitors caused by reduced Drosophila Myc expression triggers non cell-autonomous activation of retinal glia proliferation and overmigration. Glia migration occurs beyond its normal limit near the boundary between differentiated photoreceptors and precursor cells, extending into the progenitor domain. This overmigration is stimulated by JNK activation (and the function of its target Mmp1), while proliferative responses are mediated by Dpp/TGF-β signalling activation. PMID:28267791

The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy

PubMed Central

Savino, Mauro; Annibali, Daniela; Carucci, Nicoletta; Favuzzi, Emilia; Cole, Michael D.; Evan, Gerard I.; Soucek, Laura; Nasi, Sergio

2011-01-01

Recent evidence points to Myc – a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers – as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule – instead – appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc. PMID:21811581

Targeting c-Myc: JQ1 as a promising option for c-Myc-amplified esophageal squamous cell carcinoma.

PubMed

Wang, Jingyuan; Liu, Zhentao; Wang, Ziqi; Wang, Shubin; Chen, Zuhua; Li, Zhongwu; Zhang, Mengqi; Zou, Jianling; Dong, Bin; Gao, Jing; Shen, Lin

2018-04-10

c-Myc amplification-induced cell cycle dysregulation is a common cause for esophageal squamous cell carcinoma (ESCC), but no approved targeted drug is available so far. The bromodomain inhibitor JQ1, which targets c-Myc, exerts anti-tumor activity in multiple cancers. However, the role of JQ1 in ESCC remains unknown. In this study, we reported that JQ1 had potent anti-proliferative effects on ESCC cells in both time- and dose-dependent manners by inducing cell cycle arrest at G1 phase, cell apoptosis, and the mesenchymal-epithelial transition. Follow-up studies revealed that both c-Myc/cyclin/Rb and PI3K/AKT signaling pathways were inactivated by JQ1, as indicated by the downregulation of c-Myc, cyclin A/E, and phosphorylated Rb, AKT and S6. Tumor suppression induced by JQ1 in c-Myc amplified or highly expressed xenografts was higher than that in xenografts with low expression, suggesting its potential role in prediction. In conclusion, targeting c-Myc by JQ1 could cause significant tumor suppression in ESCC both in vitro and in vivo. Also, c-Myc amplification or high expression might serve as a potential biomarker and provide a promising therapeutic option for ESCC. Copyright © 2018 Elsevier B.V. All rights reserved.

The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling.

PubMed

Schramm, Christine; Fine, Deborah M; Edwards, Michelle A; Reeb, Ashley N; Krenz, Maike

2012-01-01

The identification of mutations in PTPN11 (encoding the protein tyrosine phosphatase Shp2) in families with congenital heart disease has facilitated mechanistic studies of various cardiovascular defects. However, the roles of normal and mutant Shp2 in the developing heart are still poorly understood. Furthermore, it remains unclear how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome (also termed Noonan Syndrome with multiple lentigines), which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). In normal hearts, Shp2 controls cardiomyocyte size by regulating signaling through protein kinase B (Akt) and mammalian target of rapamycin (mTOR). We hypothesized that Shp2 LOF mutations dysregulate this pathway, resulting in HCM. For our studies, we chose the Shp2 mutation Q510E, a dominant-negative LOF mutation associated with severe early onset HCM. Newborn mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth displayed increased cardiomyocyte sizes, heart-to-body weight ratios, interventricular septum thickness, and cardiomyocyte disarray. In 3-mo-old hearts, interstitial fibrosis was detected. Echocardiographically, ventricular walls were thickened and contractile function was depressed. In ventricular tissue samples, signaling through Akt/mTOR was hyperactivated, indicating that the presence of Q510E-Shp2 led to upregulation of this pathway. Importantly, rapamycin treatment started shortly after birth rescued the Q510E-Shp2-induced phenotype in vivo. If rapamycin was started at 6 wk of age, HCM was also ameliorated. We also generated a second mouse model in which cardiomyocyte-specific Q510E-Shp2 overexpression started after birth. In contrast to the first model, these mice did not develop HCM. In summary, our studies establish a role for mTOR signaling in HCM caused by Q510E-Shp2. Q510E-Shp2 overexpression in the cardiomyocyte population alone was sufficient to

International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (EVIDENCE-HCM).

PubMed

O'Mahony, Constantinos; Jichi, Fatima; Ommen, Steve R; Christiaans, Imke; Arbustini, Eloisa; Garcia-Pavia, Pablo; Cecchi, Franco; Olivotto, Iacopo; Kitaoka, Hiroaki; Gotsman, Israel; Carr-White, Gerald; Mogensen, Jens; Antoniades, Loizos; Mohiddin, Saidi A; Maurer, Mathew S; Tang, Hak Chiaw; Geske, Jeffrey B; Siontis, Konstantinos C; Mahmoud, Karim D; Vermeer, Alexa; Wilde, Arthur; Favalli, Valentina; Guttmann, Oliver P; Gallego-Delgado, Maria; Dominguez, Fernando; Tanini, Ilaria; Kubo, Toru; Keren, Andre; Bueser, Teofila; Waters, Sarah; Issa, Issa F; Malcolmson, James; Burns, Tom; Sekhri, Neha; Hoeger, Christopher W; Omar, Rumana Z; Elliott, Perry M

2018-03-06

Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. This was an observational, retrospective, longitudinal cohort study. The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9-3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93-1.12), C-index of 0.70 (95% CI, 0.68-0.72), and D-statistic of 1.17 (95% CI, 1.05-1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8-2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96-13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD. © 2017 American Heart Association, Inc.

N-terminal pro-brain natriuretic peptide is related with coronary flow velocity reserve and diastolic dysfunction in patients with asymmetric hypertrophic cardiomyopathy.

PubMed

Tesic, Milorad; Seferovic, Jelena; Trifunovic, Danijela; Djordjevic-Dikic, Ana; Giga, Vojislav; Jovanovic, Ivana; Petrovic, Olga; Marinkovic, Jelena; Stankovic, Sanja; Stepanovic, Jelena; Ristic, Arsen; Petrovic, Milan; Mujovic, Nebojsa; Vujisic-Tesic, Bosiljka; Beleslin, Branko; Vukcevic, Vladan; Stankovic, Goran; Seferovic, Petar

2017-10-01

The relations of elevated N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and cardiac ischemia in hypertrophic cardiomyopathy (HCM) patients is uncertain. Therefore we designed the study with the following aims: (1) to analyze plasma concentrations of NT-pro-BNP in various subsets of HCM patients; (2) to reveal the correlations of NT-pro-BNP, myocardial ischemia, and diastolic dysfunction; (3) to assess predictors of the elevated plasma levels of NT-pro-BNP. In 61 patients (mean age 48.9±16.3 years; 26 male) with asymmetric HCM plasma levels of NT-pro-BNP were obtained. Standard transthoracic examination, tissue Doppler echocardiography with measurement of transthoracic coronary flow velocity reserve (CFVR) in left anterior descending artery (LAD) was done. Mean natural logarithm value of NT-pro-BNP was 7.11±0.95pg/ml [median value 1133 (interquartile range 561-2442)pg/ml]. NT-pro-BNP was significantly higher in patients with higher NYHA class, in obstructive HCM, more severe mitral regurgitation, increased left atrial volume index (LAVI), presence of calcified mitral annulus, elevated left ventricular (LV) filling pressure and in decreased CFVR. Levels of NT-pro-BNP significantly correlated with the ratio of E/e' (r=0.534, p<0.001), LV outflow tract gradient (r=0.503, p=0.024), LAVI (r=0.443, p<0.001), while inversely correlated with CFVR LAD (r=-0.569, p<0.001). When multivariate analysis was done only CFVR LAD and E/e' emerged as independent predictors of NT-pro-BNP. Plasma levels of NT-pro-BNP were significantly higher in HCM patients with more advanced disease. Elevated NT-pro-BNP not only reflects the diastolic impairment of the LV, but it might also be the result of cardiac ischemia in patients with HCM. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma.

PubMed

Tateishi, Kensuke; Iafrate, A John; Ho, Quan; Curry, William T; Batchelor, Tracy T; Flaherty, Keith T; Onozato, Maristela L; Lelic, Nina; Sundaram, Sudhandra; Cahill, Daniel P; Chi, Andrew S; Wakimoto, Hiroaki

2016-09-01

Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma. The glycolytic dependency of Myc-driven glioblastoma was tested using (13)C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD(+) salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models. Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN-amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts. Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452-65. ©2016 AACR

Myeloma-derived macrophage inhibitory factor regulates bone marrow stromal cell-derived IL-6 via c-MYC.

PubMed

Piddock, Rachel E; Marlein, Christopher R; Abdul-Aziz, Amina; Shafat, Manar S; Auger, Martin J; Bowles, Kristian M; Rushworth, Stuart A

2018-05-16

Multiple myeloma (MM) remains an incurable malignancy despite the recent advancements in its treatment. The protective effects of the niche in which it develops has been well documented; however, little has been done to investigate the MM cell's ability to 're-program' cells within its environment to benefit disease progression. Here, we show that MM-derived macrophage migratory inhibitory factor (MIF) stimulates bone marrow stromal cells to produce the disease critical cytokines IL-6 and IL-8, prior to any cell-cell contact. Furthermore, we provide evidence that this IL-6/8 production is mediated by the transcription factor cMYC. Pharmacological inhibition of cMYC in vivo using JQ1 led to significantly decreased levels of serum IL-6-a highly positive prognostic marker in MM patients. Our presented findings show that MM-derived MIF causes BMSC secretion of IL-6 and IL-8 via BMSC cMYC. Furthermore, we show that the cMYC inhibitor JQ1 can reduce BMSC secreted IL-6 in vivo, irrespective of tumor burden. These data provide evidence for the clinical evaluation of both MIF and cMYC inhibitors in the treatment of MM.

Substance P levels and neutral endopeptidase activity in acute burn wounds and hypertrophic scar.

PubMed

Scott, Jeffrey R; Muangman, Pornprom R; Tamura, Richard N; Zhu, Kathy Q; Liang, Zhi; Anthony, Joanne; Engrav, Loren H; Gibran, Nicole S

2005-04-01

Substance P, a cutaneous neuroinflammatory mediator released from peripheral nerves, plays a role in responses to injury. Neutral endopeptidase is a cell membrane-bound metallopeptidase enzyme that regulates substance P activity. The question of substance P involvement in hypertrophic scar development has been based on observations that hypertrophic scars have increased numbers of nerves. The authors hypothesized that hypertrophic scar has greater substance P levels and decreased neutral endopeptidase activity compared with uninjured skin and acute partial-thickness burns, which may contribute to an exuberant response to injury. The authors obtained small skin samples of deep partial-thickness burns (n = 7; postburn days 7 to 78) and uninjured skin (n = 14) from patients (eight male patients and six female patients; 2 to 71 years old) undergoing burn wound excision. Hypertrophic scar samples were obtained from six patients (three male patients and three female patients; 8 to 47 years old) undergoing surgical excision 13 to 64 months after burn injury. Protein concentrations were determined using a bicinchoninic acid assay. Substance P concentration was determined by means of indirect enzyme-linked immunosorbent assay. Neutral endopeptidase activity was measured using an enzymatic assay that quantifies a fluorescent degradation product, methoxy-2-naphthylamine (MNA). Substance P and neutral endopeptidase data were standardized to sample weight. Substance P levels were greater in hypertrophic scar (3506 pg/g) compared with uninjured skin (1698 pg/g; p < 0.03) and burned skin (958 pg/g; p < 0.01). Hypertrophic scar samples had decreased neutral endopeptidase enzyme activity (8.8 pM MNA/hour/microg) compared with normal skin (16.3 pM MNA/hour/microg; p < 0.05). Acute burn wounds (27.9 pM MNA/hour/microg) demonstrated increased neutral endopeptidase enzyme activity (p < 0.05). Increased substance P concentration in hypertrophic scar correlates with histologic findings

Arginine methylation regulates c-Myc-dependent transcription by altering promoter recruitment of the acetyltransferase p300.

PubMed

Tikhanovich, Irina; Zhao, Jie; Bridges, Brian; Kumer, Sean; Roberts, Ben; Weinman, Steven A

2017-08-11

Protein arginine methyltransferase 1 (PRMT1) is an essential enzyme controlling about 85% of the total cellular arginine methylation in proteins. We have shown previously that PRMT1 is an important regulator of innate immune responses and that it is required for M2 macrophage differentiation. c-Myc is a transcription factor that is critical in regulating cell proliferation and also regulates the M2 transcriptional program in macrophages. Here, we sought to determine whether c-Myc in myeloid cells is regulated by PRMT1-dependent arginine methylation. We found that PRMT1 activity was necessary for c-Myc binding to the acetyltransferase p300. PRMT1 inhibition decreased p300 recruitment to c-Myc target promoters and increased histone deacetylase 1 (HDAC1) recruitment, thereby decreasing transcription at these sites. Moreover, PRMT1 inhibition blocked c-Myc-mediated induction of several of its target genes, including peroxisome proliferator-activated receptor γ ( PPARG ) and mannose receptor C-type 1 ( MRC1 ), suggesting that PRMT1 is necessary for c-Myc function in M2 macrophage differentiation. Of note, in primary human blood monocytes, p300-c-Myc binding was strongly correlated with PRMT1 expression, and in liver sections, PRMT1, c-Myc, and M2 macrophage levels were strongly correlated with each other. Both PRMT1 levels and M2 macrophage numbers were significantly lower in livers from individuals with a history of spontaneous bacterial peritonitis, known to have defective cellular immunity. In conclusion, our findings demonstrate that PRMT1 is an important regulator of c-Myc function in myeloid cells. PRMT1 loss in individuals with cirrhosis may contribute to their immune defects. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib

PubMed Central

Wirth, Matthias; Stojanovic, Natasa; Christian, Jan; Paul, Mariel C.; Stauber, Roland H.; Schmid, Roland M.; Häcker, Georg; Krämer, Oliver H.; Saur, Dieter; Schneider, Günter

2014-01-01

The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of MYC warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases MYC protein levels and that endogenous MYC is necessary for the induction of apoptosis. This kind of MYC-induced cell death is mediated by enhanced expression of the pro-apoptotic BCL2 family members NOXA and BIM. Quantitative promoter-scanning chromatin immunoprecipitations (qChIP) further revealed binding of MYC to the promoters of NOXA and BIM upon proteasome inhibition, correlating with increased transcription. Both promoters are further characterized by the presence of tri-methylated lysine 4 of histone H3, marking active chromatin. We provide evidence that in our apoptosis models cell death occurs independently of p53 or ARF. Furthermore, we demonstrate that recruitment of MYC to the NOXA as well as to the BIM gene promoters depends on MYC's interaction with the zinc finger transcription factor EGR1 and an EGR1-binding site in both promoters. Our study uncovers a novel molecular mechanism by showing that the functional cooperation of MYC with EGR1 is required for bortezomib-induced cell death. This observation may be important for novel therapeutic strategies engaging the inherent pro-death function of MYC. PMID:25147211

Tissue Doppler Imaging Combined with Advanced 12-Lead ECG Analysis Might Improve Early Diagnosis of Hypertrophic Cardiomyopathy in Childhood

NASA Technical Reports Server (NTRS)

Femlund, E.; Schlegel, T.; Liuba, P.

2011-01-01

Optimization of early diagnosis of childhood hypertrophic cardiomyopathy (HCM) is essential in lowering the risk of HCM complications. Standard echocardiography (ECHO) has shown to be less sensitive in this regard. In this study, we sought to assess whether spatial QRS-T angle deviation, which has shown to predict HCM in adults with high sensitivity, and myocardial Tissue Doppler Imaging (TDI) could be additional tools in early diagnosis of HCM in childhood. Methods: Children and adolescents with familial HCM (n=10, median age 16, range 5-27 years), and without obvious hypertrophy but with heredity for HCM (n=12, median age 16, range 4-25 years, HCM or sudden death with autopsy-verified HCM in greater than or equal to 1 first-degree relative, HCM-risk) were additionally investigated with TDI and advanced 12-lead ECG analysis using Cardiax(Registered trademark) (IMED Co Ltd, Budapest, Hungary and Houston). Spatial QRS-T angle (SA) was derived from Kors regression-related transformation. Healthy age-matched controls (n=21) were also studied. All participants underwent thorough clinical examination. Results: Spatial QRS-T angle (Figure/ Panel A) and septal E/Ea ratio (Figure/Panel B) were most increased in HCM group as compared to the HCM-risk and control groups (p less than 0.05). Of note, these 2 variables showed a trend toward higher levels in HCM-risk group than in control group (p=0.05 for E/Ea and 0.06 for QRS/T by ANOVA). In a logistic regression model, increased SA and septal E/Ea ratio appeared to significantly predict both the disease (Chi-square in HCM group: 9 and 5, respectively, p less than 0.05 for both) and the risk for HCM (Chi-square in HCM-risk group: 5 and 4 respectively, p less than 0.05 for both), with further increased predictability level when these 2 variables were combined (Chi-square 10 in HCM group, and 7 in HCM-risk group, p less than 0.01 for both). Conclusions: In this small material, Tissue Doppler Imaging and spatial mean QRS-T angle

Cardiac magnetic resonance in myocardial disease.

PubMed

Sechtem, U; Mahrholdt, H; Vogelsberg, H

2007-12-01

For a number of patients it is difficult to diagnose the cause of cardiac disease. In such patients cardiac magnetic resonance is useful for helping to make a differential diagnosis between ischaemic and dilated cardiomyopathy; identifying patients with myocarditis; diagnosing cardiac involvement in sarcoidosis and Chagas' disease; identifying patients with unusual forms of hypertrophic cardiomyopathy and those with continuing myocardial damage; and defining the sequelae of ablation treatment for hypertrophic obstructive cardiomyopathy.

Validation of the 2014 European Society of Cardiology Sudden Cardiac Death Risk Prediction Model in Hypertrophic Cardiomyopathy in a Reference Center in South America.

PubMed

Fernández, Adrián; Quiroga, Alejandro; Ochoa, Juan Pablo; Mysuta, Mauricio; Casabé, José Horacio; Biagetti, Marcelo; Guevara, Eduardo; Favaloro, Liliana E; Fava, Agostina M; Galizio, Néstor

2016-07-01

Sudden cardiac death (SCD) is a common cause of death in hypertrophic cardiomyopathy (HC). Our aim was to conduct an external and independent validation in South America of the 2014 European Society of Cardiology (ESC) SCD risk prediction model to identify patients requiring an implantable cardioverter defibrillator. This study included 502 consecutive patients with HC followed from March, 1993 to December, 2014. A combined end point of SCD or appropriate implantable cardioverter defibrillator therapy was assessed. For the quantitative estimation of individual 5-year SCD risk, we used the formula: 1 - 0.998(exp(Prognostic index)). Our database also included the abnormal blood pressure response to exercise as a risk marker. We analyzed the 3 categories of 5-year risk proposed by the ESC: low risk (LR) <4%; intermediate risk (IR) ≥4% to <6%, and high risk (HR) ≥6%. The LR group included 387 patients (77%); the IR group 39 (8%); and the HR group 76 (15%). Fourteen patients (3%) had SCD/appropriate implantable cardioverter defibrillator therapy (LR: 0%; IR: 2 of 39 [5%]; and HR: 12 of 76 [16%]). In a receiver-operating characteristic curve, the new model proved to be an excellent predictor because the area under the curve for the estimated risk is 0.925 (statistical C: 0.925; 95% CI 0.8884 to 0.9539, p <0.0001). In conclusion, the SCD risk prediction model in HC proposed by the 2014 ESC guidelines was validated in our population and represents an improvement compared with previous approaches. A larger multicenter, independent and external validation of the model with long-term follow-up would be advisable. Copyright © 2016 Elsevier Inc. All rights reserved.

Experimental Study of 5-fluorouracil Encapsulated Ethosomes Combined with CO2 Fractional Laser to Treat Hypertrophic Scar.

PubMed

Zhang, Zhen; Chen, Jun; Huang, Jun; Wo, Yan; Zhang, Yixin; Chen, Xiangdong

2018-01-18

This study is designed to explore permeability of ethosomes encapsulated with 5-florouracil (5-FU) mediated by CO 2 fractional laser on hypertrophic scar tissues. Moreover, therapeutic and duration effect of CO 2 fractional laser combined with 5-FU encapsulated ethosomes in rabbit ear hypertrophic scar model will be evaluated. The permeated amount of 5-FU and retention contents of 5-FU were both determined by high-performance liquid chromatography (HPLC). Fluorescence intensities of ethosomes encapsulated with 5-FU (5E) labeled with Rodanmin 6GO (Rho) were measured by confocal laser scanning microscopy (CLSM). The permeability promotion of 5E labeled with Rho in rabbit ear hypertrophic scar mediated by CO 2 fractional laser was evaluated at 0 h, 6 h, 12 h, 24 h, 3 days and 7 days after the irradiation. The opening rates of the micro-channels were calculated according to CLSM. The therapeutic effect of 5EL was evaluated on rabbit ear hypertrophic scar in vivo. Relative thickness of rabbit ear hypertrophic scar before and after the treatment was measured by caliper method. Scar elevation index (SEI) of rabbit ear hypertrophic scar was measured using H&E staining. The data showed that the penetration amount of 5EL group was higher than 5E group (4.15 ± 2.22 vs. 0.73 ± 0.33; p < 0.05) after 1-h treatment. Additionally, the penetration amount of 5EL was higher than that of the 5E group (107.61 ± 13.27 vs. 20.73 ± 3.77; p < 0.05) after 24-h treatment. The retention contents of the 5EL group also showed higher level than 5E group (24.42 ± 4.37 vs.12.25 ± 1.64; p < 0.05). The fluorescence intensity of Rho in hypertrophic scar tissues of the 5EL group was higher than that of the 5E group at different time points (1, 6, and 24 h). The opening rates of the micro-channels were decreased gradually within 24 h, and micro-channels were closed completely 3 days after the irradiation by CO 2 fractional laser. The relative thickness

Validation of the 2014 European Society of Cardiology guidelines risk prediction model for the primary prevention of sudden cardiac death in hypertrophic cardiomyopathy.

PubMed

Vriesendorp, Pieter A; Schinkel, Arend F L; Liebregts, Max; Theuns, Dominic A M J; van Cleemput, Johan; Ten Cate, Folkert J; Willems, Rik; Michels, Michelle

2015-08-01

The recently released 2014 European Society of Cardiology guidelines of hypertrophic cardiomyopathy (HCM) use a new clinical risk prediction model for sudden cardiac death (SCD), based on the HCM Risk-SCD study. Our study is the first external and independent validation of this new risk prediction model. The study population consisted of a consecutive cohort of 706 patients with HCM without prior SCD event, from 2 tertiary referral centers. The primary end point was a composite of SCD and appropriate implantable cardioverter-defibrillator therapy, identical to the HCM Risk-SCD end point. The 5-year SCD risk was calculated using the HCM Risk-SCD formula. Receiver operating characteristic curves and C-statistics were calculated for the 2014 European Society of Cardiology guidelines, and risk stratification methods of the 2003 American College of Cardiology/European Society of Cardiology guidelines and 2011 American College of Cardiology Foundation/American Heart Association guidelines. During follow-up of 7.7±5.3 years, SCD occurred in 42 (5.9%) of 706 patients (ages 49±16 years; 34% women). The C-statistic of the new model was 0.69 (95% CI, 0.57-0.82; P=0.008), which performed significantly better than the conventional risk factor models based on the 2003 guidelines (C-statistic of 0.55: 95% CI, 0.47-0.63; P=0.3), and 2011 guidelines (C-statistic of 0.60: 95% CI, 0.50-0.70; P=0.07). The HCM Risk-SCD model improves the risk stratification of patients with HCM for primary prevention of SCD, and calculating an individual risk estimate contributes to the clinical decision-making process. Improved risk stratification is important for the decision making before implantable cardioverter-defibrillator implantation for the primary prevention of SCD. © 2015 American Heart Association, Inc.

Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo.

PubMed

Parisi, Federica; Riccardo, Sara; Daniel, Margaret; Saqcena, Mahesh; Kundu, Nandini; Pession, Annalisa; Grifoni, Daniela; Stocker, Hugo; Tabak, Esteban; Bellosta, Paola

2011-09-27

Genetic studies in Drosophila melanogaster reveal an important role for Myc in controlling growth. Similar studies have also shown how components of the insulin and target of rapamycin (TOR) pathways are key regulators of growth. Despite a few suggestions that Myc transcriptional activity lies downstream of these pathways, a molecular mechanism linking these signaling pathways to Myc has not been clearly described. Using biochemical and genetic approaches we tried to identify novel mechanisms that control Myc activity upon activation of insulin and TOR signaling pathways. Our biochemical studies show that insulin induces Myc protein accumulation in Drosophila S2 cells, which correlates with a decrease in the activity of glycogen synthase kinase 3-beta (GSK3β ) a kinase that is responsible for Myc protein degradation. Induction of Myc by insulin is inhibited by the presence of the TOR inhibitor rapamycin, suggesting that insulin-induced Myc protein accumulation depends on the activation of TOR complex 1. Treatment with amino acids that directly activate the TOR pathway results in Myc protein accumulation, which also depends on the ability of S6K kinase to inhibit GSK3β activity. Myc upregulation by insulin and TOR pathways is a mechanism conserved in cells from the wing imaginal disc, where expression of Dp110 and Rheb also induces Myc protein accumulation, while inhibition of insulin and TOR pathways result in the opposite effect. Our functional analysis, aimed at quantifying the relative contribution of Myc to ommatidial growth downstream of insulin and TOR pathways, revealed that Myc activity is necessary to sustain the proliferation of cells from the ommatidia upon Dp110 expression, while its contribution downstream of TOR is significant to control the size of the ommatidia. Our study presents novel evidence that Myc activity acts downstream of insulin and TOR pathways to control growth in Drosophila. At the biochemical level we found that both these pathways

Cardiomyopathy mutations in the tail of β-cardiac myosin modify the coiled-coil structure and affect integration into thick filaments in muscle sarcomeres in adult cardiomyocytes.

PubMed

Wolny, Marcin; Colegrave, Melanie; Colman, Lucy; White, Ed; Knight, Peter J; Peckham, Michelle

2013-11-01

It is unclear why mutations in the filament-forming tail of myosin heavy chain (MHC) cause hypertrophic or dilated cardiomyopathy as these mutations should not directly affect contraction. To investigate this, we first investigated the impact of five hypertrophic cardiomyopathy-causing (N1327K, E1356K, R1382W, E1555K, and R1768K) and one dilated cardiomyopathy-causing (R1500W) tail mutations on their ability to incorporate into muscle sarcomeres in vivo. We used adenoviral delivery to express full-length wild type or mutant enhanced GFP-MHC in isolated adult cardiomyocytes. Three mutations (N1327K, E1356K, and E1555K) reduced enhanced GFP-MHC incorporation into muscle sarcomeres, whereas the remainder had no effect. No mutations significantly affected contraction. Fluorescence recovery after photobleaching showed that fluorescence recovery for the mutation that incorporated least well (N1327K) was significantly faster than that of WT with half-times of 25.1 ± 1.8 and 32.2 ± 2.5 min (mean ± S.E.), respectively. Next, we determined the effects of each mutation on the helical properties of wild type and seven mutant peptides (7, 11, or 15 heptads long) from the myosin tail by circular dichroism. R1382W and E1768K slightly increased the α-helical nature of peptides. The remaining mutations reduced α-helical content, with N1327K showing the greatest reduction. Only peptides containing residues 1301-1329 were highly α-helical suggesting that this region helps in initiation of coiled coil. These results suggest that small effects of mutations on helicity translate into a reduced ability to incorporate into sarcomeres, which may elicit compensatory hypertrophy.

Impact of left ventricular outflow tract area on systolic outflow velocity in hypertrophic cardiomyopathy: a real-time three-dimensional echocardiographic study

NASA Technical Reports Server (NTRS)

Qin, Jian Xin; Shiota, Takahiro; Lever, Harry M.; Rubin, David N.; Bauer, Fabrice; Kim, Yong Jin; Sitges, Marta; Greenberg, Neil L.; Drinko, Jeanne K.; Martin, Maureen;

Quantitative comparison of 2D and 3D late gadolinium enhancement MR imaging in patients with Fabry disease and hypertrophic cardiomyopathy.

PubMed

Morsbach, F; Gordic, S; Gruner, C; Niemann, M; Goetti, R; Gotschy, A; Kozerke, S; Alkadhi, H; Manka, R

2016-08-15

This study aims to determine whether the quantification of myocardial fibrosis in patients with Fabry disease (FD) and hypertrophic cardiomyopathy (HCM) using a late gadolinium enhancement (LGE) singlebreath-hold three-dimensional (3D) inversion recovery magnetic resonance (MR) imaging sequence is comparable with a clinically established two-dimensional (2D) multi-breath-hold sequence. In this retrospective, IRB-approved study, 40 consecutive patients (18 male; mean age 50±17years) with Fabry disease (n=18) and HCM (n=22) underwent MR imaging at 1.5T. Spatial resolution was the same for 3D and 2D images (field-of-view, 350×350mm(2); in-plane-resolution, 1.2×1.2mm(2); section-thickness, 8mm). Datasets were analyzed for subjective image quality; myocardial and fibrotic mass, and total fibrotic tissue percentage were quantified. There was no significant difference in subjective image quality between 3D and 2D acquisitions (P=0.1 and P=0.3) for either disease. In patients with Fabry disease there were no significant differences between 3D and 2D acquisitions for myocardial mass (P=0.55), fibrous tissue mass (P=0.89), and total fibrous percentage (P=0.67), with good agreement between acquisitions according to Bland-Altman analyses. In patients with HCM there were also no significant differences between acquisitions for myocardial mass (P=0.48), fibrous tissue mass (P=0.56), and total fibrous percentage (P=0.67), with good agreement according to Bland-Altman analyses. Acquisition time was significantly shorter for 3D (25±5s) as compared to the 2D sequence (349±62s, P<0.001). In patients with Fabry disease and HCM, 3D LGE imaging provides equivalent diagnostic information in regard to quantification of myocardial fibrosis as compared with a standard 2D sequence, but at superior acquisition speed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Comparison of Pulmonary Venous and Left Atrial Remodeling in Patients With Atrial Fibrillation With Hypertrophic Cardiomyopathy Versus With Hypertensive Heart Disease.

PubMed

Yoshida, Kentaro; Hasebe, Hideyuki; Tsumagari, Yasuaki; Tsuneoka, Hidekazu; Ebine, Mari; Uehara, Yoshiko; Seo, Yoshihiro; Aonuma, Kazutaka; Takeyasu, Noriyuki

2017-04-15

Left ventricular diastolic dysfunction in hypertrophic cardiomyopathy (HC) increases susceptibility to atrial fibrillation. Although phenotypical characteristics of the hypertrophied left ventricle are clear, left atrial (LA) and pulmonary venous (PV) remodeling has rarely been investigated. This study aimed to identify differences in LA and PV remodeling between HC and hypertensive heart disease (HHD) using 3-dimensional computed tomography. Included were 33 consecutive patients with HC, 25 with HHD, and 29 without any co-morbidities who were referred for catheter ablation of atrial fibrillation. Pre-ablation plasma atrial and brain natriuretic peptide levels, post-ablation troponin T level, and LA pressure were measured, and LA and PV diameters were determined 3 dimensionally. LA transverse diameter in the control group was smaller than that in the HHD or HC group (55 ± 6 vs 63 ± 9 vs 65 ± 12 mm, p = 0.0003). PV diameter in all 4 PVs was greatest in the HC group and second greatest in the HHD group (21.0 ± 3.1 vs 23.8 ± 2.8 vs 26.8 ± 4.1 mm, p <0.0001 for left superior PV). Differences in PV size between the HHD and HC groups were enhanced by indexing to the body surface area (12.4 ± 1.9 vs 13.1 ± 1.4 vs 16.1 ± 3.3 mm/m 2 , p <0.0001). The PV/LA diameter ratio was greater in the HC than in the other groups (0.38 ± 0.06 vs 0.38 ± 0.05 vs 0.42 ± 0.07, p = 0.01). Atrial natriuretic peptide, brain natriuretic peptide, troponin T levels, and LA pressure were highest in the HC group (all p <0.05). In conclusion, the stiff LA caused from atrial hypertrophy may account for higher levels of biomarkers, higher LA pressure, and PV-dominant remodeling in HC. Copyright © 2017 Elsevier Inc. All rights reserved.

The Quest for Targets Executing MYC-Dependent Cell Transformation.

PubMed

Hartl, Markus

2016-01-01

MYC represents a transcription factor with oncogenic potential converting multiple cellular signals into a broad transcriptional response, thereby controlling the expression of numerous protein-coding and non-coding RNAs important for cell proliferation, metabolism, differentiation, and apoptosis. Constitutive activation of MYC leads to neoplastic cell transformation, and deregulated MYC alleles are frequently observed in many human cancer cell types. Multiple approaches have been performed to isolate genes differentially expressed in cells containing aberrantly activated MYC proteins leading to the identification of thousands of putative targets. Functional analyses of genes differentially expressed in MYC-transformed cells had revealed that so far more than 40 upregulated or downregulated MYC targets are actively involved in cell transformation or tumorigenesis. However, further systematic and selective approaches are required for determination of the known or yet unidentified targets responsible for processing the oncogenic MYC program. The search for critical targets in MYC-dependent tumor cells is exacerbated by the fact that during tumor development, cancer cells progressively evolve in a multistep process, thereby acquiring their characteristic features in an additive manner. Functional expression cloning, combinatorial gene expression, and appropriate in vivo tests could represent adequate tools for dissecting the complex scenario of MYC-specified cell transformation. In this context, the central goal is to identify a minimal set of targets that suffices to phenocopy oncogenic MYC. Recently developed genomic editing tools could be employed to confirm the requirement of crucial transformation-associated targets. Knowledge about essential MYC-regulated genes is beneficial to expedite the development of specific inhibitors to interfere with growth and viability of human tumor cells in which MYC is aberrantly activated. Approaches based on the principle of

The Quest for Targets Executing MYC-Dependent Cell Transformation

PubMed Central

Hartl, Markus

2016-01-01

MYC represents a transcription factor with oncogenic potential converting multiple cellular signals into a broad transcriptional response, thereby controlling the expression of numerous protein-coding and non-coding RNAs important for cell proliferation, metabolism, differentiation, and apoptosis. Constitutive activation of MYC leads to neoplastic cell transformation, and deregulated MYC alleles are frequently observed in many human cancer cell types. Multiple approaches have been performed to isolate genes differentially expressed in cells containing aberrantly activated MYC proteins leading to the identification of thousands of putative targets. Functional analyses of genes differentially expressed in MYC-transformed cells had revealed that so far more than 40 upregulated or downregulated MYC targets are actively involved in cell transformation or tumorigenesis. However, further systematic and selective approaches are required for determination of the known or yet unidentified targets responsible for processing the oncogenic MYC program. The search for critical targets in MYC-dependent tumor cells is exacerbated by the fact that during tumor development, cancer cells progressively evolve in a multistep process, thereby acquiring their characteristic features in an additive manner. Functional expression cloning, combinatorial gene expression, and appropriate in vivo tests could represent adequate tools for dissecting the complex scenario of MYC-specified cell transformation. In this context, the central goal is to identify a minimal set of targets that suffices to phenocopy oncogenic MYC. Recently developed genomic editing tools could be employed to confirm the requirement of crucial transformation-associated targets. Knowledge about essential MYC-regulated genes is beneficial to expedite the development of specific inhibitors to interfere with growth and viability of human tumor cells in which MYC is aberrantly activated. Approaches based on the principle of

Myc: the beauty and the beast.

PubMed

Wasylishen, Amanda R; Penn, Linda Z

2010-06-01

The iconic history of the Myc oncoprotein encompasses 3 decades of intense scientific discovery. There is no question that Myc has been a pioneer, advancing insight into the molecular basis of cancer as well as functioning as a critical control center for several diverse biological processes and regulatory mechanisms. This narrative chronicles the journey and milestones that have defined the understanding of Myc, and it provides an opportunity to consider future directions in this challenging yet rewarding field.

MYC/BCL2/BCL6 triple hit lymphoma: a study of 40 patients with a comparison to MYC/BCL2 and MYC/BCL6 double hit lymphomas.

PubMed

Huang, Wenting; Medeiros, L Jeffrey; Lin, Pei; Wang, Wei; Tang, Guilin; Khoury, Joseph; Konoplev, Sergej; Yin, C Cameron; Xu, Jie; Oki, Yasuhiro; Li, Shaoying

2018-05-21

High-grade B-cell lymphomas with MYC, BCL2, and BCL6 rearrangements (triple hit lymphoma) are uncommon. We studied the clinicopathologic features of 40 patients with triple hit lymphoma and compared them to 157 patients with MYC/BCL2 double hit lymphoma and 13 patients with MYC/BCL6 double hit lymphoma. The triple hit lymphoma group included 25 men and 15 women with a median age of 61 years (range, 34-85). Nine patients had a history of B-cell lymphoma. Histologically, 23 (58%) cases were diffuse large B-cell lymphoma and 17 cases had features of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Most cases of triple hit lymphoma were positive for CD10 (100%), BCL2 (95%), BCL6 (82%), MYC (74%), and 71% with MYC and BCL2 coexpression. P53 was overexpressed in 29% of triple hit lymphoma cases. The clinicopathological features of triple hit lymphoma patients were similar to patients with MYC/BCL2 and MYC/BCL6 double hit lymphoma, except that triple hit lymphoma cases were more often CD10 positive compared with MYC/BCL6 double hit lymphoma (p < 0.05). Induction chemotherapy used was similar for patients with triple hit lymphoma and double hit lymphoma and overall survival in triple hit lymphoma patients was 17.6 months, similar to the overall survival of patients with double hit lymphoma (p = 0.67). Patients with triple hit lymphoma showing P53 overexpression had significantly worse overall survival compared with those without P53 overexpression (p = 0.04). On the other hand, double expressor status and prior history of B-cell lymphoma did not correlate with overall survival. In conclusion, most patients with triple hit lymphoma have an aggressive clinical course and poor prognosis and these tumors have a germinal center B-cell immunophenotype, similar to patients with double hit lymphomas. P53 expression is a poor prognostic factor in patients with triple hit lymphoma.

Nac1 promotes self-renewal of embryonic stem cells through direct transcriptional regulation of c-Myc.

PubMed

Ruan, Yan; He, Jianrong; Wu, Wei; He, Ping; Tian, Yanping; Xiao, Lan; Liu, Gaoke; Wang, Jiali; Cheng, Yuda; Zhang, Shuo; Yang, Yi; Xiong, Jiaxiang; Zhao, Ke; Wan, Ying; Huang, He; Zhang, Junlei; Jian, Rui

2017-07-18

The pluripotency transcriptional network in embryonic stem cells (ESCs) is composed of distinct functional units including the core and Myc units. It is hoped that dissection of the cellular functions and interconnections of network factors will aid our understanding of ESC and cancer biology. Proteomic and genomic approaches have identified Nac1 as a member of the core pluripotency network. However, previous studies have predominantly focused on the role of Nac1 in psychomotor stimulant response and cancer pathogenesis. In this study, we report that Nac1 is a self-renewal promoting factor, but is not required for maintaining pluripotency of ESCs. Loss of function of Nac1 in ESCs results in a reduced proliferation rate and an enhanced differentiation propensity. Nac1 overexpression promotes ESC proliferation and delays ESC differentiation in the absence of leukemia inhibitory factor (LIF). Furthermore, we demonstrated that Nac1 directly binds to the c-Myc promoter and regulates c-Myc transcription. The study also revealed that the function of Nac1 in promoting ESC self-renewal appears to be partially mediated by c-Myc. These findings establish a functional link between the core and c-Myc-centered networks and provide new insights into mechanisms of stemness regulation in ESCs and cancer.

c-MYC amplification and c-myc protein expression in pancreatic acinar cell carcinomas. New insights into the molecular signature of these rare cancers.

PubMed

La Rosa, Stefano; Bernasconi, Barbara; Vanoli, Alessandro; Sciarra, Amedeo; Notohara, Kenji; Albarello, Luca; Casnedi, Selenia; Billo, Paola; Zhang, Lizhi; Tibiletti, Maria Grazia; Sessa, Fausto

2018-05-02

The molecular alterations of pancreatic acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MANECs) are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known. We have investigated c-MYC gene amplification in a series of 35 ACCs and 4 MANECs to evaluate its frequency and a possible prognostic role. Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes. Protein expression was immunohistochemically investigated using a specific monoclonal anti-c-myc antibody. Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. All MANECs showed c-MYC amplification and/or polysomy which were observed in 54% pure ACCs. Six cases (15.3%) showed nuclear immunoreactivity for c-myc, but only 4/39 cases showed simultaneous c-MYC amplification/polysomy and nuclear protein expression. c-myc immunoreactivity as well as c-MYC amplification and/or chromosome 8 polysomy was not statistically associated with prognosis. Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy. Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs.

Comparison of two software systems for quantification of myocardial blood flow in patients with hypertrophic cardiomyopathy.

PubMed

Yalcin, Hulya; Valenta, Ines; Zhao, Min; Tahari, Abdel; Lu, Dai-Yin; Higuchi, Takahiro; Yalcin, Fatih; Kucukler, Nagehan; Soleimanifard, Yalda; Zhou, Yun; Pomper, Martin G; Abraham, Theodore P; Tsui, Ben; Lodge, Martin A; Schindler, Thomas H; Roselle Abraham, M

2018-01-22

Quantification of myocardial blood flow (MBF) by positron emission tomography (PET) is important for investigation of angina in hypertrophic cardiomyopathy (HCM). Several software programs exist for MBF quantification, but they have been mostly evaluated in patients (with normal cardiac geometry), referred for evaluation of coronary artery disease (CAD). Software performance has not been evaluated in HCM patients who frequently have hyperdynamic LV function, LV outflow tract (LVOT) obstruction, small LV cavity size, and variation in the degree/location of LV hypertrophy. We compared results of MBF obtained using PMod, which permits manual segmentation, to those obtained by FDA-approved QPET software which has an automated segmentation algorithm. 13 N-ammonia PET perfusion data were acquired in list mode at rest and during pharmacologic vasodilation, in 76 HCM patients and 10 non-HCM patients referred for evaluation of CAD (CAD group.) Data were resampled to create static, ECG-gated and 36-frame-dynamic images. Myocardial flow reserve (MFR) and MBF (in ml/min/g) were calculated using QPET and PMod softwares. All HCM patients had asymmetric septal hypertrophy, and 50% had evidence of LVOT obstruction, whereas non-HCM patients (CAD group) had normal wall thickness and ejection fraction. PMod yielded significantly higher values for global and regional stress-MBF and MFR than for QPET in HCM. Reasonably fair correlation was observed for global rest-MBF, stress-MBF, and MFR using these two softwares (rest-MBF: r = 0.78; stress-MBF: r = 0.66.; MFR: r = 0.7) in HCM patients. Agreement between global MBF and MFR values improved when HCM patients with high spillover fractions (> 0.65) were excluded from the analysis (rest-MBF: r = 0.84; stress-MBF: r = 0.72; MFR: r = 0.8.) Regionally, the highest agreement between PMod and QPET was observed in the LAD territory (rest-MBF: r = 0.82, Stress-MBF: r = 0.68) where spillover fraction was the lowest. Unlike HCM

Update on hypertrophic scar treatment

PubMed Central

Rabello, Felipe Bettini; Souza, Cleyton Dias; Júnior, Jayme Adriano Farina

2014-01-01

Scar formation is a consequence of the wound healing process that occurs when body tissues are damaged by a physical injury. Hypertrophic scars and keloids are pathological scars resulting from abnormal responses to trauma and can be itchy and painful, causing serious functional and cosmetic disability. The current review will focus on the definition of hypertrophic scars, distinguishing them from keloids and on the various methods for treating hypertrophic scarring that have been described in the literature, including treatments with clearly proven efficiency and therapies with doubtful benefits. Numerous methods have been described for the treatment of abnormal scars, but to date, the optimal treatment method has not been established. This review will explore the differences between different types of nonsurgical management of hypertrophic scars, focusing on the indications, uses, mechanisms of action, associations and efficacies of the following therapies: silicone, pressure garments, onion extract, intralesional corticoid injections and bleomycin. PMID:25141117