Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration

PubMed Central

O’Meara, Caitlin C.; Wamstad, Joseph A.; Gladstone, Rachel; Fomovsky, Gregory M.; Butty, Vincent L.; Shrikumar, Avanti; Gannon, Joseph; Boyer, Laurie A.; Lee, Richard T.

2014-01-01

Rationale Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. Objective The objectives of our study were to determine if myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. Methods and Results We derived a core transcriptional signature of injury-induced cardiac myocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiac myocyte differentiation, in vitro cardiac myocyte explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of cardiac myocyte differentiation processes including reactivation of latent developmental programs similar to those observed during de-stabilization of a mature cardiac myocyte phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13 (IL13), which induced cardiac myocyte cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of IL13 signaling in cardiac myocytes. These downstream signaling molecules are also modulated in the regenerating mouse heart. Conclusions Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration. PMID:25477501

Obesity, metabolic dysfunction and cardiac fibrosis: pathophysiologic pathways, molecular mechanisms and therapeutic opportunities

PubMed Central

Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G

2014-01-01

Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias and sudden cardiac death in obese subjects. Our review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiologic alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiologic alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the Renin-Angiotensin-Aldosterone System, induction of Transforming Growth Factor-β, oxidative stress, advanced glycation end-products (AGEs), endothelin-1, Rho-kinase signaling, leptin-mediated actions and upregulation of matricellular proteins (such as thrombospondin-1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response following cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to development of novel therapies to prevent heart failure and to attenuate post-infarction cardiac remodeling in obese patients. PMID:24880146

Development and Psychometric Validation of HIPER-Q to Assess Knowledge of Hypertensive Patients in Cardiac Rehabilitation.

PubMed

Santos, Rafaella Zulianello Dos; Bonin, Christiani Decker Batista; Martins, Eliara Ten Caten; Pereira Junior, Moacir; Ghisi, Gabriela Lima de Melo; Macedo, Kassia Rosangela Paz de; Benetti, Magnus

2018-01-01

The absence of instruments capable of measuring the level of knowledge of hypertensive patients in cardiac rehabilitation programs about their disease reflects the lack of specific recommendations for these patients. To develop and validate a questionnaire to evaluate the knowledge of hypertensive patients in cardiac rehabilitation programs about their disease. A total of 184 hypertensive patients (mean age 60.5 ± 10 years, 66.8% men) were evaluated. Reproducibility was assessed by calculation of the intraclass correlation coefficient using the test-retest method. Internal consistency was assessed by the Cronbach's alpha and the construct validity by the exploratory factorial analysis. The final version of the instrument had 17 questions organized in areas considered important for patient education. The instrument proposed showed a clarity index of 8.7 (0.25). The intraclass correlation coefficient was 0.804 and the Cronbach's correlation coefficient was 0.648. Factor analysis revealed five factors associated with knowledge areas. Regarding the criterion validity, patients with higher education level and higher family income showed greater knowledge about hypertension. The instrument has a satisfactory clarity index and adequate validity, and can be used to evaluate the knowledge of hypertensive participants in cardiac rehabilitation programs.

The Involvement of Danger-Associated Molecular Patterns in the Development of Immunoparalysis in Cardiac Arrest Patients.

PubMed

Timmermans, Kim; Kox, Matthijs; Gerretsen, Jelle; Peters, Esther; Scheffer, Gert Jan; van der Hoeven, Johannes G; Pickkers, Peter; Hoedemaekers, Cornelia W

2015-11-01

After cardiac arrest, patients are highly vulnerable toward infections, possibly due to a suppressed state of the immune system called "immunoparalysis." We investigated if immunoparalysis develops following cardiac arrest and whether the release of danger-associated molecular patterns could be involved. Observational study. ICU of a university medical center. Fourteen post-cardiac arrest patients treated with mild therapeutic hypothermia for 24 hours and 11 control subjects. Plasma cytokines showed highest levels within 24 hours after cardiac arrest and decreased during the next 2 days. By contrast, ex vivo production of cytokines interleukin-6, tumor necrosis factor-α, and interleukin-10 by lipopolysaccharide-stimulated leukocytes was severely impaired compared with control subjects, with most profound effects observed at day 0, and only partially recovering afterward. Compared with incubation at 37°C, incubation at 32°C resulted in higher interleukin-6 and lower interleukin-10 production by lipopolysaccharide-stimulated leukocytes of control subjects, but not of patients. Plasma nuclear DNA, used as a marker for general danger-associated molecular pattern release, and the specific danger-associated molecular patterns (EN-RAGE and heat shock protein 70) were substantially higher in patients at days 0 and 1 compared with control subjects. Furthermore, plasma heat shock protein 70 levels were negatively correlated with ex vivo production of inflammatory mediators interleukin-6, tumor necrosis factor-α, and interleukin-10. Extracellular newly identified receptor for advanced glycation end products-binding protein levels only showed a significant negative correlation with ex vivo production of interleukin-6 and tumor necrosis factor-α and a borderline significant inverse correlation with interleukin-10. No significant correlations were observed between plasma nuclear DNA levels and ex vivo cytokine production. None. Release of danger-associated molecular

Towards optical spectroscopic anatomical mapping (OSAM) for lesion validation in cardiac tissue (Conference Presentation)

NASA Astrophysics Data System (ADS)

Singh-Moon, Rajinder P.; Zaryab, Mohammad; Hendon, Christine P.

2017-02-01

Electroanatomical mapping (EAM) is an invaluable tool for guiding cardiac radiofrequency ablation (RFA) therapy. The principle roles of EAM is the identification of candidate ablation sites by detecting regions of abnormal electrogram activity and lesion validation subsequent to RF energy delivery. However, incomplete lesions may present interim electrical inactivity similar to effective treatment in the acute setting, despite efforts to reveal them with pacing or drugs, such as adenosine. Studies report that the misidentification and recovery of such lesions is a leading cause of arrhythmia recurrence and repeat procedures. In previous work, we demonstrated spectroscopic characterization of cardiac tissues using a fiber optic-integrated RF ablation catheter. In this work, we introduce OSAM (optical spectroscopic anatomical mapping), the application of this spectroscopic technique to obtain 2-dimensional biodistribution maps. We demonstrate its diagnostic potential as an auxiliary method for lesion validation in treated swine preparations. Endocardial lesion sets were created on fresh swine cardiac samples using a commercial RFA system. An optically-integrated catheter console fabricated in-house was used for measurement of tissue optical spectra between 600-1000nm. Three dimensional, Spatio-spectral datasets were generated by raster scanning of the optical catheter across the treated sample surface in the presence of whole blood. Tissue optical parameters were recovered at each spatial position using an inverse Monte Carlo method. OSAM biodistribution maps showed stark correspondence with gross examination of tetrazolium chloride stained tissue specimens. Specifically, we demonstrate the ability of OSAM to readily distinguish between shallow and deeper lesions, a limitation faced by current EAM techniques. These results showcase the OSAMs potential for lesion validation strategies for the treatment of cardiac arrhythmias.

IN VITRO CARDIAC CELLULAR AND MOLECULAR EFFECTS OF AIR POLLUTION PARTICLE CONSTITUENTS

EPA Science Inventory

In Vitro Cardiac Cellular and Molecular Effects of Air Pollution Particle Constituents
Travis L. Knuckles1, Richard Jaskot2, Judy Richards2, and Kevin L. Dreher2. 1North Carolina State University, College of Veterinary Medicine, Raleigh, NC 27606, 2USEPA, Research Triangle Pa...

An empirical assessment of validation practices for molecular classifiers

PubMed Central

Castaldi, Peter J.; Dahabreh, Issa J.

2011-01-01

Proposed molecular classifiers may be overfit to idiosyncrasies of noisy genomic and proteomic data. Cross-validation methods are often used to obtain estimates of classification accuracy, but both simulations and case studies suggest that, when inappropriate methods are used, bias may ensue. Bias can be bypassed and generalizability can be tested by external (independent) validation. We evaluated 35 studies that have reported on external validation of a molecular classifier. We extracted information on study design and methodological features, and compared the performance of molecular classifiers in internal cross-validation versus external validation for 28 studies where both had been performed. We demonstrate that the majority of studies pursued cross-validation practices that are likely to overestimate classifier performance. Most studies were markedly underpowered to detect a 20% decrease in sensitivity or specificity between internal cross-validation and external validation [median power was 36% (IQR, 21–61%) and 29% (IQR, 15–65%), respectively]. The median reported classification performance for sensitivity and specificity was 94% and 98%, respectively, in cross-validation and 88% and 81% for independent validation. The relative diagnostic odds ratio was 3.26 (95% CI 2.04–5.21) for cross-validation versus independent validation. Finally, we reviewed all studies (n = 758) which cited those in our study sample, and identified only one instance of additional subsequent independent validation of these classifiers. In conclusion, these results document that many cross-validation practices employed in the literature are potentially biased and genuine progress in this field will require adoption of routine external validation of molecular classifiers, preferably in much larger studies than in current practice. PMID:21300697

Validation of a Portuguese version of the Information Needs in Cardiac Rehabilitation (INCR) scale in Brazil.

PubMed

Ghisi, Gabriela Lima de Melo; Dos Santos, Rafaella Zulianello; Bonin, Christiani Batista Decker; Roussenq, Suellen; Grace, Sherry L; Oh, Paul; Benetti, Magnus

2014-01-01

To translate, culturally adapt and psychometrically validate the Information Needs in Cardiac Rehabilitation (INCR) tool to Portuguese. The identification of information needs is considered the first step to improve knowledge that ultimately could improve health outcomes. The Portuguese version generated was tested in 300 cardiac rehabilitation patients (CR) (34% women; mean age = 61.3 ± 2.1 years old). Test-retest reliability was assessed using intraclass correlation coefficient (ICC), the internal consistency using Cronbach's alpha, and the criterion validity was assessed with regard to patients' education and duration in CR. All 9 subscales were considered internally consistent (á > 0.7). Significant differences between mean total needs and educational level (p < 0.05) and duration in CR (p = 0.03) supported criterion validity. The overall mean (4.6 ± 0.4), as well as the means of the 9 subscales were high (emergency/safety was the greatest need). The Portuguese INCR was demonstrated to have sufficient reliability, consistency and validity. Copyright © 2014 Elsevier Inc. All rights reserved.

TNNI3K, a novel cardiac-specific kinase, emerging as a molecular target for the treatment of cardiac disease

PubMed Central

Lal, Hind; Ahmad, Firdos; Parikh, Shan; Force, Thomas

2014-01-01

Coronary heart disease (AHD) is the leading cause of death and disability worldwide. In patients with acute coronary syndromes (ACS), timely and effective myocardial reperfusion by percutaneous coronary intervention (PCI) is the primary treatment of choice to minimize the ischemic injury and limit MI size. However, reperfusion can itself promote cardiomyocyte death which leads to cardiac dysfunction via reperfusion injury. The molecular mechanisms of ischemia/reperfusion (I/R) injury are not completely understood and new drug targets are needed. Recently we reported that cardiac troponin I-interacting protein kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes I/R injury via profound oxidative stress, thereby promoting cardiomyocyte death. By using novel genetic animal models and newly developed small-molecule TNNI3K inhibitors, we demonstrate that TNNI3K-mediated I/R injury occurs through impaired mitochondrial function and is in part dependent on p38 MAPK. Herein we discuss the emerging role of TNNI3K as a promising new drug target to limit the I/R-induced myocardial injury. We will also examine the underlying mechanisms that drive the profoundly reduced infarct size in mice in which TNNI3K is specifically deleted in cardiomyocytes. Since TNNI3K is a cardiac-specific kinase, it could be an ideal molecular target since inhibiting it would have little or no effect on other organ systems, a serious problem associated with the use of kinase inhibitors targeting kinases that are more widely expressed. PMID:24899531

Development and validation of risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team.

PubMed

Harrison, David A; Patel, Krishna; Nixon, Edel; Soar, Jasmeet; Smith, Gary B; Gwinnutt, Carl; Nolan, Jerry P; Rowan, Kathryn M

2014-08-01

The National Cardiac Arrest Audit (NCAA) is the UK national clinical audit for in-hospital cardiac arrest. To make fair comparisons among health care providers, clinical indicators require case mix adjustment using a validated risk model. The aim of this study was to develop and validate risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team in UK hospitals. Risk models for two outcomes-return of spontaneous circulation (ROSC) for greater than 20min and survival to hospital discharge-were developed and validated using data for in-hospital cardiac arrests between April 2011 and March 2013. For each outcome, a full model was fitted and then simplified by testing for non-linearity, combining categories and stepwise reduction. Finally, interactions between predictors were considered. Models were assessed for discrimination, calibration and accuracy. 22,479 in-hospital cardiac arrests in 143 hospitals were included (14,688 development, 7791 validation). The final risk model for ROSC>20min included: age (non-linear), sex, prior length of stay in hospital, reason for attendance, location of arrest, presenting rhythm, and interactions between presenting rhythm and location of arrest. The model for hospital survival included the same predictors, excluding sex. Both models had acceptable performance across the range of measures, although discrimination for hospital mortality exceeded that for ROSC>20min (c index 0.81 versus 0.72). Validated risk models for ROSC>20min and hospital survival following in-hospital cardiac arrest have been developed. These models will strengthen comparative reporting in NCAA and support local quality improvement. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Development and validation of risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team☆

PubMed Central

Harrison, David A.; Patel, Krishna; Nixon, Edel; Soar, Jasmeet; Smith, Gary B.; Gwinnutt, Carl; Nolan, Jerry P.; Rowan, Kathryn M.

2014-01-01

Aim The National Cardiac Arrest Audit (NCAA) is the UK national clinical audit for in-hospital cardiac arrest. To make fair comparisons among health care providers, clinical indicators require case mix adjustment using a validated risk model. The aim of this study was to develop and validate risk models to predict outcomes following in-hospital cardiac arrest attended by a hospital-based resuscitation team in UK hospitals. Methods Risk models for two outcomes—return of spontaneous circulation (ROSC) for greater than 20 min and survival to hospital discharge—were developed and validated using data for in-hospital cardiac arrests between April 2011 and March 2013. For each outcome, a full model was fitted and then simplified by testing for non-linearity, combining categories and stepwise reduction. Finally, interactions between predictors were considered. Models were assessed for discrimination, calibration and accuracy. Results 22,479 in-hospital cardiac arrests in 143 hospitals were included (14,688 development, 7791 validation). The final risk model for ROSC > 20 min included: age (non-linear), sex, prior length of stay in hospital, reason for attendance, location of arrest, presenting rhythm, and interactions between presenting rhythm and location of arrest. The model for hospital survival included the same predictors, excluding sex. Both models had acceptable performance across the range of measures, although discrimination for hospital mortality exceeded that for ROSC > 20 min (c index 0.81 versus 0.72). Conclusions Validated risk models for ROSC > 20 min and hospital survival following in-hospital cardiac arrest have been developed. These models will strengthen comparative reporting in NCAA and support local quality improvement. PMID:24830872

Phenotype-driven molecular autopsy for sudden cardiac death.

PubMed

Cann, F; Corbett, M; O'Sullivan, D; Tennant, S; Hailey, H; Grieve, J H K; Broadhurst, P; Rankin, R; Dean, J C S

2017-01-01

A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Validation and Trustworthiness of Multiscale Models of Cardiac Electrophysiology

PubMed Central

Pathmanathan, Pras; Gray, Richard A.

2018-01-01

Computational models of cardiac electrophysiology have a long history in basic science applications and device design and evaluation, but have significant potential for clinical applications in all areas of cardiovascular medicine, including functional imaging and mapping, drug safety evaluation, disease diagnosis, patient selection, and therapy optimisation or personalisation. For all stakeholders to be confident in model-based clinical decisions, cardiac electrophysiological (CEP) models must be demonstrated to be trustworthy and reliable. Credibility, that is, the belief in the predictive capability, of a computational model is primarily established by performing validation, in which model predictions are compared to experimental or clinical data. However, there are numerous challenges to performing validation for highly complex multi-scale physiological models such as CEP models. As a result, credibility of CEP model predictions is usually founded upon a wide range of distinct factors, including various types of validation results, underlying theory, evidence supporting model assumptions, evidence from model calibration, all at a variety of scales from ion channel to cell to organ. Consequently, it is often unclear, or a matter for debate, the extent to which a CEP model can be trusted for a given application. The aim of this article is to clarify potential rationale for the trustworthiness of CEP models by reviewing evidence that has been (or could be) presented to support their credibility. We specifically address the complexity and multi-scale nature of CEP models which makes traditional model evaluation difficult. In addition, we make explicit some of the credibility justification that we believe is implicitly embedded in the CEP modeling literature. Overall, we provide a fresh perspective to CEP model credibility, and build a depiction and categorisation of the wide-ranging body of credibility evidence for CEP models. This paper also represents a step

Next generation sequencing for molecular confirmation of hereditary sudden cardiac death syndromes.

PubMed

Márquez, Manlio F; Cruz-Robles, David; Ines-Real, Selene; Vargas-Alarcón, Gilberto; Cárdenas, Manuel

2015-01-01

Hereditary sudden cardiac death syndromes comprise a wide range of diseases resulting from alteration in cardiac ion channels. Genes involved in these syndromes represent diverse mutations that cause the altered encoding of the diverse proteins constituting these channels, thus affecting directly the currents of the corresponding ions. In the present article we will briefly review how to arrive to a clinical diagnosis and we will present the results of molecular genetic studies made in Mexican subjects attending the SCD Syndromes Clinic of the National Institute of Cardiology of Mexico City. Copyright © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

Modulating Beta-Cardiac Myosin Function at the Molecular and Tissue Levels

PubMed Central

Tang, Wanjian; Blair, Cheavar A.; Walton, Shane D.; Málnási-Csizmadia, András; Campbell, Kenneth S.; Yengo, Christopher M.

2017-01-01

Inherited cardiomyopathies are a common form of heart disease that are caused by mutations in sarcomeric proteins with beta cardiac myosin (MYH7) being one of the most frequently affected genes. Since the discovery of the first cardiomyopathy associated mutation in beta-cardiac myosin, a major goal has been to correlate the in vitro myosin motor properties with the contractile performance of cardiac muscle. There has been substantial progress in developing assays to measure the force and velocity properties of purified cardiac muscle myosin but it is still challenging to correlate results from molecular and tissue-level experiments. Mutations that cause hypertrophic cardiomyopathy are more common than mutations that lead to dilated cardiomyopathy and are also often associated with increased isometric force and hyper-contractility. Therefore, the development of drugs designed to decrease isometric force by reducing the duty ratio (the proportion of time myosin spends bound to actin during its ATPase cycle) has been proposed for the treatment of hypertrophic cardiomyopathy. Para-Nitroblebbistatin is a small molecule drug proposed to decrease the duty ratio of class II myosins. We examined the impact of this drug on human beta cardiac myosin using purified myosin motor assays and studies of permeabilized muscle fiber mechanics. We find that with purified human beta-cardiac myosin para-Nitroblebbistatin slows actin-activated ATPase and in vitro motility without altering the ADP release rate constant. In permeabilized human myocardium, para-Nitroblebbistatin reduces isometric force, power, and calcium sensitivity while not changing shortening velocity or the rate of force development (ktr). Therefore, designing a drug that reduces the myosin duty ratio by inhibiting strong attachment to actin while not changing detachment can cause a reduction in force without changing shortening velocity or relaxation. PMID:28119616

OC19 - Measuring feasibility, reliability and validity of the Greek version of PedsQL cardiac module.

PubMed

Drakouli, Maria; Petsios, Konstantinos; Matziou, Vasiliki

2016-05-09

Theme: Cardiology Introduction: Measuring quality of life (QoL) in children and adolescents with congenital heart disease (CHD) is of great clinical importance. The aim of the study was: (a) to adapt the PedsQL Cardiac Module for children aged two to 18 years with CHD in a sample of the Greek population; (b) to determine its reliability and validity. Forward and backward translation methodology was used. Parents and children completed the instrument during: (a) hospitalization and (b) visits in the paediatric cardiology outpatient department. Cross-informant variance between children and parents was thoroughly assessed. Missing item responses did not exceed 5%. All internal consistency reliability coefficients for the inventory exceeded the minimum standards for group comparisons, over 0.75. Hypothesized correlations between cardiac module and core scales were statistically significant, (p<0.05). Agreement between children and parents was relatively high. Pilot study results will be additionally presented. The findings support the feasibility, reliability and validity of the Greek translation of the PedsQL Cardiac Module in children with congenital heart defect (CHD).

Molecular evaluation of five cardiac genes in Doberman Pinschers with dilated cardiomyopathy.

PubMed

Meurs, Kathryn M; Hendrix, Kristina P; Norgard, Michelle M

2008-08-01

To sequence the exonic and splice site regions of 5 cardiac genes associated with the human form of familial dilated cardiomyopathy (DCM) in Doberman Pinschers with DCM and to identify a causative mutation. 5 unrelated Doberman Pinschers with DCM and 2 unaffected Labrador Retrievers (control dogs). Exonic and splice site regions of the 5 genes encoding the cardiac proteins troponin C, lamin A/C, cysteine- and glycine-rich protein 3, cardiac troponin T, and the beta-myosin heavy chain were sequenced. Sequences were compared for nucleotide changes between affected dogs and the published canine sequences and 2 control dogs. Base pair changes were considered to be causative for DCM if they were present in an affected dog but not in the control dogs or published sequences and if they involved a conserved amino acid and changed that amino acid to a different polarity, acid-base status, or structure. A causative mutation for DCM in Doberman Pinschers was not identified, although single nucleotide polymorphisms were detected in some dogs in the cysteine- and glycine-rich protein 3, beta-myosin heavy chain, and troponin T genes. Mutations in 5 of the cardiac genes associated with the development of DCM in humans did not appear to be causative for DCM in Doberman Pinschers. Continued evaluation of additional candidate genes or a focused approach with an association analysis is warranted to elucidate the molecular cause of this important cardiac disease in Doberman Pinschers.

Validity of cardiac output measurement by the thermodilution method in the presence of acute tricuspid regurgitation.

PubMed

Boerboom, L E; Kinney, T E; Olinger, G N; Hoffmann, R G

1993-10-01

Evaluation of patients with acute tricuspid insufficiency may include assessment of cardiac output by the thermodilution method. The accuracy of estimates of thermodilution-derived cardiac output in the presence of tricuspid insufficiency has been questioned. This study was designed to determine the validity of the thermodilution technique in a canine model of acute reversible tricuspid insufficiency. Cardiac output as measured by thermodilution and electromagnetic flowmeter was compared at two grades of regurgitation. The relationship between these two methods (thermodilution/electromagnetic) changed significantly from a regression slope of 1.01 +/- 0.18 (mean +/- standard deviation) during control conditions to a slope of 0.86 +/- 0.23 (p < 0.02) during severe regurgitation. No significant change was observed between control and mild regurgitation or between the initial control value and a control measurement repeated after tricuspid insufficiency was reversed at the termination of the study. This study shows that in a canine model of severe acute tricuspid regurgitation the thermodilution method underestimates cardiac output by an amount that is proportional to the level of cardiac output and to the grade of regurgitation.

Raman Spectroscopy Detects Cardiac Allograft Rejection with Molecular Specificity

PubMed Central

Chung, Yoon Gi; Tu, Qiang; Cao, Dianjun; Harada, Shuko; Eisen, Howard J; Chang, Chang

2009-01-01

Abstract Spatially resolved Raman spectroscopy is shown here to be capable of molecular‐specific detection without exogenous labeling. This molecular specificity is achieved by detecting the strong and characteristic Raman spectral signature of an indole derivative, serotonin, whose selective existence in rejected heart transplants serves as the biomarker. The study also corroborates the increasingly recognized role of serotonin receptors in various immune responses, including cardiac allograft rejection. Combining both medical and physical sciences, this work demonstrates the potential use of Raman spectroscopy in replacing the invasive endomyocardial biopsy as the standard for post‐transplantation rejection surveillance and presents a new paradigm in advancing clinical care through interdisciplinary studies. PMID:20443894

Translation and validation of the Cardiac Depression Scale to Arabic.

PubMed

Papasavvas, T; Al-Amin, H; Ghabrash, H F; Micklewright, D

2016-08-01

The Cardiac Depression Scale (CDS) has been designed to measure depressive symptoms in patients with heart disease. There is no Arabic version of the CDS. We translated and validated the CDS in an Arabic sample of patients with heart disease. Forward and back translation of the CDS was followed by assessment of cultural relevance and content validity. The Arabic version of the CDS (A-CDS) and the Arabic version of the Hospital Anxiety and Depression Scale (A-HADS) were then administered to 260 Arab in-patients with heart disease from 18 Arabic countries. Construct validity was assessed using exploratory factor analysis with polychoric correlations. Internal consistency was assessed using ordinal reliability alpha and item-to-factor polychoric correlations. Concurrent validity was assessed using Pearson's correlation coefficient between the A-CDS and the depression subscale of the A-HADS (A-HADS-D). Cultural relevance and content validity of the A-CDS were satisfactory. Exploratory factor analysis revealed three robust factors, without cross-loadings, that formed a single dimension. Internal consistency was high (ordinal reliability alpha for the total scale and the three factors were .94, .91, .86, and .87, respectively; item-to-factor correlations ranged from .77 to .91). Concurrent validity was high (r=.72). The A-CDS demonstrated a closer to normal distribution of scores than the A-HADS-D. Sensitivity and specificity of the A-CDS were not objectively assessed. The A-CDS appears to be a valid and reliable instrument to measure depressive symptoms in a representative sample of Arab in-patients with heart disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Validation of cardiac output studies from the Mostcare compared to a pulmonary artery catheter in septic patients.

PubMed

Gopal, S; Do, T; Pooni, J S; Martinelli, G

2014-03-01

The Mostcare monitor is a non-invasive cardiac output monitor. It has been well validated in cardiac surgical patients but there is limited evidence on its use in patients with severe sepsis and septic shock. The study included the first 22 consecutive patients with severe sepsis and septic shock in whom the floatation of a pulmonary artery catheter was deemed necessary to guide clinical management. Cardiac output measurements including cardiac output, cardiac index and stroke volume were simultaneously calculated and recorded from a thermodilution pulmonary artery catheter and from the Mostcare monitor respectively. The two methods of measuring cardiac output were compared by Bland-Altman statistics and linear regression analysis. A percentage error of less than 30% was defined as acceptable for this study. Bland-Altman analysis for cardiac output showed a Bias of 0.31 L.min-1, precision (=SD) of 1.97 L.min-1 and a percentage error of 62.54%. For Cardiac Index the bias was 0.21 L.min-1.m-2, precision of 1.10 L.min-1.m-2 and a percentage error of 64%. For stroke volume the bias was 5 mL, precision of 24.46 mL and percentage error of 70.21%. Linear regression produced a correlation coefficient r2 for cardiac output, cardiac index, and stroke volume, of 0.403, 0.306, and 0.3 respectively. Compared to thermodilution cardiac output, cardiac output studies obtained from the Mostcare monitor have an unacceptably high error rate. The Mostcare monitor demonstrated to be an unreliable monitoring device to measure cardiac output in patients with severe sepsis and septic shock on an intensive care unit.

External validation of the Revised Cardiac Risk Index and update of its renal variable to predict 30-day risk of major cardiac complications after non-cardiac surgery: rationale and plan for analyses of the VISION study.

PubMed

Roshanov, Pavel S; Walsh, Michael; Devereaux, P J; MacNeil, S Danielle; Lam, Ngan N; Hildebrand, Ainslie M; Acedillo, Rey R; Mrkobrada, Marko; Chow, Clara K; Lee, Vincent W; Thabane, Lehana; Garg, Amit X

2017-01-09

The Revised Cardiac Risk Index (RCRI) is a popular classification system to estimate patients' risk of postoperative cardiac complications based on preoperative risk factors. Renal impairment, defined as serum creatinine >2.0 mg/dL (177 µmol/L), is a component of the RCRI. The estimated glomerular filtration rate has become accepted as a more accurate indicator of renal function. We will externally validate the RCRI in a modern cohort of patients undergoing non-cardiac surgery and update its renal component. The Vascular Events in Non-cardiac Surgery Patients Cohort Evaluation (VISION) study is an international prospective cohort study. In this prespecified secondary analysis of VISION, we will test the risk estimation performance of the RCRI in ∼34 000 participants who underwent elective non-cardiac surgery between 2007 and 2013 from 29 hospitals in 15 countries. Using data from the first 20 000 eligible participants (the derivation set), we will derive an optimal threshold for dichotomising preoperative renal function quantified using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) glomerular filtration rate estimating equation in a manner that preserves the original structure of the RCRI. We will also develop a continuous risk estimating equation integrating age and CKD-Epi with existing RCRI risk factors. In the remaining (approximately) 14 000 participants, we will compare the risk estimation for cardiac complications of the original RCRI to this modified version. Cardiac complications will include 30-day non-fatal myocardial infarction, non-fatal cardiac arrest and death due to cardiac causes. We have examined an early sample to estimate the number of events and the distribution of predictors and missing data, but have not seen the validation data at the time of writing. The research ethics board at each site approved the VISION protocol prior to recruitment. We will publish our results and make our models available online at http

Cardiac registers: the adult cardiac surgery register.

PubMed

Bridgewater, Ben

2010-09-01

AIMS OF THE SCTS ADULT CARDIAC SURGERY DATABASE: To measure the quality of care of adult cardiac surgery in GB and Ireland and provide information for quality improvement and research. Feedback of structured data to hospitals, publication of named hospital and surgeon mortality data, publication of benchmarked activity and risk adjusted clinical outcomes through intermittent comprehensive database reports, annual screening of all hospital and individual surgeon risk adjusted mortality rates by the professional society. All NHS hospitals in England, Scotland and Wales with input from some private providers and hospitals in Ireland. 1994-ongoing. Consecutive patients, unconsented. Current number of records: 400000. Adult cardiac surgery operations excluding cardiac transplantation and ventricular assist devices. 129 fields covering demographic factors, pre-operative risk factors, operative details and post-operative in-hospital outcomes. Entry onto local software systems by direct key board entry or subsequent transcription from paper records, with subsequent electronic upload to the central cardiac audit database. Non-financial incentives at hospital level. Local validation processes exist in the hospitals. There is currently no external data validation process. All cause mortality is obtained through linkage with Office for National Statistics. No other linkages exist at present. Available for research and audit by application to the SCTS database committee at http://www.scts.org.

Analytical validation and establishment of reference intervals for a 'high-sensitivity' cardiac troponin-T assay in horses.

PubMed

Shields, E; Seiden-Long, I; Massie, S; Passante, S; Leguillette, R

2016-06-13

Cardiac troponin-I assays have been validated in horses.'High-sensitivity' cardiac troponin assays are now the standard in human cardiology. Appropriately validate the'high-sensitivity' cardiac Troponin-T (hscTnT) assay for clinical use in horses, establish reference intervals, determine the biological variation, and demonstrate assay utility in selected clinical cases. Analytical validation of the Roche hscTnT assay included within- and between-run precision, linear dose response, limit of quantitation (LoQ), stability, and comparison with cTn-I (iSTAT). Reference intervals and biological variation were determined using adult, healthy, Non-Competition Horses (N = 125) and Racing-Thoroughbreds (N = 178). HscTnT levels were measured in two horses with cardiac pathology. The hscTnT demonstrates acceptable within-run (L1 = 6.5 ng/L, CV 14.9 %, L2 = 10.1 ng/L, CV 8.7 %, L3 = 15.3 ng/L, CV 5.4 %) and between-run precision (L1 = 12.2 ng/L, CV 8.4 %, L2 = 57.0 ng/L, CV 8.4 %, L3 = 256.0 ng/L, CV 9.0 %). The assay was linear from 3 to 391 ng/L. The LoQ was validated at 3 ng/L. Samples demonstrated insignificant decay over freeze-thaw cycle. Comparison with cTnI assay showed excellent correlation (range: 8.0-3535.0 ng/L, R(2) = 0.9996). Reference intervals: The upper 95(th) and 99(th) percentile of the hscTnT population distribution were 6.8 and 16.2 ng/L in Non-Competition Horses, and 14.0 and 23.2 ng/L in Racing-Thoroughbreds. Between-breed, diurnal effect, and between-day variation was below LoQ. Two clinical cases with presumed cardiac pathology had hscTnT levels of 220.9 ng/L and 5723.0 ng/L. This benchmark study is the first to comply with CLSI guidelines, thus further establishing the performance characteristics of the hscTnT assay, and reference intervals in healthy horses. Two clinical cases demonstrated further the clinical utility of the assay.

Design and characterization of the first peptidomimetic molecule that prevents acidification-induced closure of cardiac gap junctions

PubMed Central

Verma, Vandana; Larsen, Bjarne Due; Coombs, Wanda; Lin, Xianming; Sarrou, Eliana; Taffet, Steven M.; Delmar, Mario

2010-01-01

Background Gap junctions are potential targets for pharmacological intervention. We have previously developed a series of peptide sequences that prevent closure of Cx43 channels, bind to cardiac Cx43 and prevent acidification-induced uncoupling of cardiac gap junctions. Objective We aimed to identify and validate the minimum core active structure in peptides containing an RR-N/Q-Y motif. Based on that information, we sought to generate a peptidomimetic molecule that acts on the chemical regulation of Cx43 channels. Methods Experiments were based on a combination of biochemical, spectroscopic and electrophysiological techniques, as well as molecular modeling of active pharmacophores with Cx43 activity. Results Molecular modeling analysis indicated that the functional elements of the side chains in the motif RRXY form a triangular structure. Experimental data revealed that compounds containing such a structure bind to Cx43 and prevent Cx43 chemical gating. These results provided us with the first platform for drug design targeted to the carboxyl terminal of Cx43. Using that platform, we designed and validated a peptidomimetic compound (ZP2519; molecular weight 619 Da) that prevented octanol-induced uncoupling of Cx43 channels, and pH gating of cardiac gap junctions. Conclusion Structure-based drug design can be applied to the development of pharmacophores that act directly on Cx43. Small molecules containing these pharmacophores can serve as tools to determine the role of gap junction regulation in the control of cardiac rhythm. Future studies will determine whether these compounds can function as pharmacological agents for the treatment of a selected subset of cardiac arrhythmias. PMID:20601149

Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo

PubMed Central

White, JD; Thesier, DM; Swain, JBD; Katz, MG; Tomasulo, C; Henderson, A; Wang, L; Yarnall, C; Fargnoli, A; Sumaroka, M; Isidro, A; Petrov, M; Holt, D; Nolen-Walston, R; Koch, WJ; Stedman, HH; Rabinowitz, J; Bridges, CR

2013-01-01

We use a novel technique that allows for closed recirculation of vector genomes in the cardiac circulation using cardiopulmonary bypass, referred to here as molecular cardiac surgery with recirculating delivery (MCARD). We demonstrate that this platform technology is highly efficient in isolating the heart from the systemic circulation in vivo. Using MCARD, we compare the relative efficacy of single-stranded (ss) adeno-associated virus (AAV)6, ssAAV9 and self-complimentary (sc)AAV6-encoding enhanced green fluorescent protein, driven by the constitutive cytomegalovirus promoter to transduce the ovine myocardium in situ. MCARD allows for the unprecedented delivery of up to 48 green fluorescent protein genome copies per cell globally in the sheep left ventricular (LV) myocardium. We demonstrate that scAAV6-mediated MCARD delivery results in global, cardiac-specific LV gene expression in the ovine heart and provides for considerably more robust and cardiac-specific gene delivery than other available delivery techniques such as intramuscular injection or intracoronary injection; thus, representing a potential, clinically translatable platform for heart failure gene therapy. PMID:21228882

Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: Role of TNF and TGF-β.

PubMed

Cruz, Jader Santos; Machado, Fabiana Simão; Ropert, Catherine; Roman-Campos, Danilo

2017-02-01

Chagas disease is caused by the trypanosomatid Trypanosoma cruzi, which chronically causes heart problems in up to 30% of infected patients. Chagas disease was initially restricted to Latin America. However, due to migratory events, this disease may become a serious worldwide health problem. During Chagas disease, many patients die of cardiac arrhythmia despite the apparent benefits of anti-arrhythmic therapy (e.g., amiodarone). Here, we assimilate the cardiac form of Chagas disease to an inflammatory cardiac disease. Evidence from the literature, mostly provided using experimental models, supports this view and argues in favor of new strategies for treating cardiac arrhythmias in Chagas disease by modulating cytokine production and/or action. But the complex nature of myocardial inflammation underlies the need to better understand the molecular mechanisms of the inflammatory response during Chagas disease. Here, particular attention has been paid to tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGF-β) although other cytokines may be involved in the chagasic cardiomyopathy. Copyright © 2016 Elsevier Inc. All rights reserved.

Low molecular weight fucan prevents transplant coronaropathy in rat cardiac allograft model.

PubMed

Alkhatib, Bassam; Freguin-Bouilland, Caroline; Lallemand, Françoise; Henry, Jean Paul; Litzler, Pierre-Yves; Marie, Jean Paul; Richard, Vincent; Thuillez, Christian; Plissonnier, Didier

2006-06-01

Transplant arteriosclerosis is the main cause of long-term failure after cardiac transplantation. Vascular rejection is thought to be due to intimal proliferation occurring in response to arterial wall immune-mediated injury. A low molecular weight fucan (LMWF) compound, a sulfated polysaccharide, has been demonstrated to increase plasma levels of stromal cell-derived factor 1 (SDF-1) and consequently to mobilize bone marrow-derived vascular progenitor cells (BMVPC). The aim of this study was to evaluate the capacity of LMWF to prevent coronary intimal proliferation in a rat cardiac allograft model. Heterotopic abdominal cardiac graftings were performed in Brown Norway (BN) and Lewis (LEW) rats. Animals were divided into 4 groups of 10 rats. Two groups were treated intramuscularly with LMWF (5 mg/kg/day) (one BN to BN isograft group, and one BN to LEW allograft group); and two control groups were LMWF-untreated (one BN to BN isograft group and one BN to LEW allograft group). All animals were treated by cyclosporin (15 mg/kg/day) sub-cutaneously and sacrificed at day 30. The cardiac grafts were assessed by morphometry of structural parameters and by histological and immunohistochemical analyses. All cardiac isografts were devoid of any coronary and parenchymal lesions. In contrast, the majority of untreated allografts developed coronary intimal proliferation in close association with intimal and adventitial inflammatory CD68(+) cell infiltration. Further, the parenchyma exhibited large areas of actin(+) cells (myofibroblasts) of recipient origin colocalized with the CD68(+) infiltrating cells. Interestingly, all LMWF-treated allografts were well protected against coronary and parenchymal lesions and the coronary arteries exhibited an intimal monolayer of flat cells, which however were CD34 negative. treatment with LMWF appeared very effective in this rat cardiac allograft model to prevent arterial and parenchymal lesions occurring in response to alloimmune injury

Validation of cardiac output using real-time measurement of oxygen consumption during cardiac catheterization in children under 3 years of age.

PubMed

Seckeler, Michael D; Hirsch, Russel; Beekman, Robert H; Goldstein, Bryan H

2014-01-01

To validate a method for determination of cardiac index (CI) using real-time measurement of oxygen consumption (VO2 ) in young children undergoing cardiac catheterization. Retrospective review comparing thermodilution cardiac index (TDCI) to CI calculated by the Fick equation using real-time measured VO2 (RT-VO2 ) and VO2 derived from 2 published predictive equations. Paired t-test and Bland-Altman analysis were used to compare TDCI to Fick CI. A survey to ascertain pediatric cardiac catheterization practices regarding VO2 determination was also conducted. Quaternary care children's hospital cardiac catheterization laboratory. Children <3 years old with structurally normal hearts undergoing cardiac catheterization under general anesthesia with at least one set of contemporaneous TDCI and RT-VO2 measurements. Thirty-six paired measurements of TDCI and RT-VO2 were made in 27 patients over a 2-year period. Indications for catheterization included congenital diaphragmatic hernia postrepair (n = 13), heart disease post-orthotopic heart transplant (n = 13), and suspected cardiomyopathy (n = 1). Mean age was 21.5 ± 8 months; median weight was 9.9 kg (IQR 8.57, 12.2). RT-VO2 was higher than VO2 predicted by the LaFarge equation (190 ± 31 vs. 173.8 ± 12.8 mL/min/m(2), P < .001), but there was no difference between TDCI and Fick CI calculated using VO2 from any method. Bland-Altman analysis showed excellent agreement between TDCI and Fick CI using RT-VO2 and VO2 predicted by the Lundell equation; Fick CI using VO2 predicted by the LaFarge equation showed fair agreement with TDCI. In children <3 years with a structurally normal heart, RT-VO2 generates highly accurate determinations of Fick CI as compared with TDCI. Additionally, in this population, VO2 derived from the LaFarge and Lundell equations generates accurate Fick CI compared with TDCI. Future studies are needed to identify factors associated with inaccurate VO2 generated from these predictive equations. © 2013

CARFMAP: A Curated Pathway Map of Cardiac Fibroblasts.

PubMed

Nim, Hieu T; Furtado, Milena B; Costa, Mauro W; Kitano, Hiroaki; Rosenthal, Nadia A; Boyd, Sarah E

2015-01-01

The adult mammalian heart contains multiple cell types that work in unison under tightly regulated conditions to maintain homeostasis. Cardiac fibroblasts are a significant and unique population of non-muscle cells in the heart that have recently gained substantial interest in the cardiac biology community. To better understand this renaissance cell, it is essential to systematically survey what has been known in the literature about the cellular and molecular processes involved. We have built CARFMAP (http://visionet.erc.monash.edu.au/CARFMAP), an interactive cardiac fibroblast pathway map derived from the biomedical literature using a software-assisted manual data collection approach. CARFMAP is an information-rich interactive tool that enables cardiac biologists to explore the large body of literature in various creative ways. There is surprisingly little overlap between the cardiac fibroblast pathway map, a foreskin fibroblast pathway map, and a whole mouse organism signalling pathway map from the REACTOME database. Among the use cases of CARFMAP is a common task in our cardiac biology laboratory of identifying new genes that are (1) relevant to cardiac literature, and (2) differentially regulated in high-throughput assays. From the expression profiles of mouse cardiac and tail fibroblasts, we employed CARFMAP to characterise cardiac fibroblast pathways. Using CARFMAP in conjunction with transcriptomic data, we generated a stringent list of six genes that would not have been singled out using bioinformatics analyses alone. Experimental validation showed that five genes (Mmp3, Il6, Edn1, Pdgfc and Fgf10) are differentially regulated in the cardiac fibroblast. CARFMAP is a powerful tool for systems analyses of cardiac fibroblasts, facilitating systems-level cardiovascular research.

Recent Advances in Cardiac Computed Tomography: Dual Energy, Spectral and Molecular CT Imaging

PubMed Central

Danad, Ibrahim; Fayad, Zahi A.; Willemink, Martin J.; Min, James K.

2015-01-01

Computed tomography (CT) evolved into a powerful diagnostic tool and it is impossible to imagine current clinical practice without CT imaging. Due to its widespread availability, ease of clinical application, superb sensitivity for detection of CAD, and non-invasive nature, CT has become a valuable tool within the armamentarium of the cardiologist. In the last few years, numerous technological advances in CT have occurred—including dual energy CT (DECT), spectral CT and CT-based molecular imaging. By harnessing the advances in technology, cardiac CT has advanced beyond the mere evaluation of coronary stenosis to an imaging modality tool that permits accurate plaque characterization, assessment of myocardial perfusion and even probing of molecular processes that are involved in coronary atherosclerosis. Novel innovations in CT contrast agents and pre-clinical spectral CT devices have paved the way for CT-based molecular imaging. PMID:26068288

Translation, Cross-cultural Adaptation and Psychometric Validation of the Korean-Language Cardiac Rehabilitation Barriers Scale (CRBS-K).

PubMed

Baek, Sora; Park, Hee-Won; Lee, Yookyung; Grace, Sherry L; Kim, Won-Seok

2017-10-01

To perform a translation and cross-cultural adaptation of the Cardiac Rehabilitation Barriers Scale (CRBS) for use in Korea, followed by psychometric validation. The CRBS was developed to assess patients' perception of the degree to which patient, provider and health system-level barriers affect their cardiac rehabilitation (CR) participation. The CRBS consists of 21 items (barriers to adherence) rated on a 5-point Likert scale. The first phase was to translate and cross-culturally adapt the CRBS to the Korean language. After back-translation, both versions were reviewed by a committee. The face validity was assessed in a sample of Korean patients (n=53) with history of acute myocardial infarction that did not participate in CR through semi-structured interviews. The second phase was to assess the construct and criterion validity of the Korean translation as well as internal reliability, through administration of the translated version in 104 patients, principle component analysis with varimax rotation and cross-referencing against CR use, respectively. The length, readability, and clarity of the questionnaire were rated well, demonstrating face validity. Analysis revealed a six-factor solution, demonstrating construct validity. Cronbach's alpha was greater than 0.65. Barriers rated highest included not knowing about CR and not being contacted by a program. The mean CRBS score was significantly higher among non-attendees (2.71±0.26) than CR attendees (2.51±0.18) (p<0.01). The Korean version of CRBS has demonstrated face, content and criterion validity, suggesting it may be useful for assessing barriers to CR utilization in Korea.

Molecular Cardiac Surgery with Recirculating Delivery (MCARD): Procedure and Vector Transfer.

PubMed

Katz, Michael G; Fargnoli, Anthony S; Kendle, Andrew P; Bridges, Charles R

2017-01-01

Despite progress in clinical treatment, cardiovascular diseases are still the leading cause of morbidity and mortality worldwide. Therefore, novel therapeutic approaches are needed, targeting the underlying molecular mechanisms of disease with improved outcomes for patients. Gene therapy is one of the most promising fields for the development of new treatments for the advanced stages of cardiovascular diseases. The establishment of clinically relevant methods of gene transfer remains one of the principal limitations on the effectiveness of gene therapy. Recently, there have been significant advances in direct and transvascular gene delivery methods. The ideal gene transfer method should be explored in clinically relevant large animal models of heart disease to evaluate the roles of specific molecular pathways in disease pathogenesis. Characteristics of the optimal technique for gene delivery include low morbidity, an increased myocardial transcapillary gradient, esxtended vector residence time in the myocytes, and the exclusion of residual vector from the systemic circulation after delivery to minimize collateral expression and immune response. Here we describe myocardial gene transfer techniques with molecular cardiac surgery with recirculating delivery in a large animal model of post ischemic heart failure.

External Validation of the Universal Termination of Resuscitation Rule for Out-of-Hospital Cardiac Arrest in British Columbia.

PubMed

Grunau, Brian; Taylor, John; Scheuermeyer, Frank X; Stenstrom, Robert; Dick, William; Kawano, Takahisa; Barbic, David; Drennan, Ian; Christenson, Jim

2017-09-01

The Universal Termination of Resuscitation Rule (TOR Rule) was developed to identify out-of-hospital cardiac arrests eligible for field termination of resuscitation, avoiding futile transportation to the hospital. The validity of the rule in emergency medical services (EMS) systems that do not routinely transport out-of-hospital cardiac arrest patients to the hospital is unknown. We seek to validate the TOR Rule in British Columbia. This study included consecutive, nontraumatic, adult, out-of-hospital cardiac arrests treated by EMS in British Columbia from April 2011 to September 2015. We excluded patients with active do-not-resuscitate orders and those with missing data. Following consensus guidelines, we examined the validity of the TOR Rule after 6 minutes of resuscitation (to approximate three 2-minute cycles of resuscitation). To ascertain rule performance at the different time junctures, we recalculated TOR Rule classification accuracy at subsequent 1-minute resuscitation increments. Of 6,994 consecutive, adult, EMS-treated, out-of-hospital cardiac arrests, overall survival was 15%. At 6 minutes of resuscitation, rule performance was sensitivity 0.72, specificity 0.91, positive predictive value 0.98, and negative predictive value 0.36. The TOR Rule recommended care termination for 4,367 patients (62%); of these, 92 survived to hospital discharge (false-positive rate 2.1%; 95% confidence interval 1.7% to 2.5%); however, this proportion steadily decreased with later application. The TOR Rule recommended continuation of resuscitation in 2,627 patients (38%); of these, 1,674 died (false-negative rate 64%; 95% confidence interval 62% to 66%). Compared with 6-minute application, test characteristics at 30 minutes demonstrated nearly perfect positive predictive value (1.0) and specificity (1.0) but a lower sensitivity (0.46) and negative predictive value (0.25). In this cohort of adult out-of-hospital cardiac arrest patients, the TOR Rule applied at 6 minutes

Translation and Validation of the Thai Version of a Modified Brief Pain Inventory: A Concise Instrument for Pain Assessment in Postoperative Cardiac Surgery.

PubMed

Keawnantawat, Pakamas; Thanasilp, Sureeporn; Preechawong, Sunida

2017-07-01

Acute pain after cardiac surgery can be assessed using validated instruments such as the modified interference subscale of the Brief Pain Inventory (mod-BPI). Despite the available knowledge, the Thai version of a mod-BPI has not yet been presented. To translate a mod-BPI into the Thai language (BPI-T) and to validate it in acute pain after cardiac surgery. This multisetting, cross-sectional study was done from 4 cardiac centers. With a convenience sampling technique, 132 cardiac surgery patients were enrolled during the first 72 postoperative hours. A BPI-T composed of 4 items on the intensity subscale and 6 items on the interference subscale was translated following Brislin's model. Convergent validity against the numeric rating scale (NRS), confirmatory factor analysis (CFA), and internal consistency reliability were examined. Of the total sample, 70% experienced moderate to severe pain (cutoff points of worst pain ≥ 4/10), and 65% had moderate to severe interference with deep breathing and coughing, 53% with general activity, and 49% with walking. The CFA confirmed the 2-factor structure of intensity and interference subscales consistent with the original version (root-mean-square error of approximation = 0.08, comparative fit index = 0.95, χ 2 = 39.00, df = 27, χ 2 /df = 1.44, P = 0.06). The physical and mental subdimensions under the interference subscale were determined (standardized factor loading = 0.70 and 0.42, respectively). The BPI-T also has good internal consistency (Cronbach's alpha coefficients 0.76 and 0.85). Pearson's correlation coefficients at 0.35 to 0.70 supported the convergent validity to the NRS. The BPI-T is a concise instrument for pain assessment in postoperative cardiac surgery. © 2016 World Institute of Pain.

Translation, Cross-cultural Adaptation and Psychometric Validation of the Korean-Language Cardiac Rehabilitation Barriers Scale (CRBS-K)

PubMed Central

2017-01-01

Objective To perform a translation and cross-cultural adaptation of the Cardiac Rehabilitation Barriers Scale (CRBS) for use in Korea, followed by psychometric validation. The CRBS was developed to assess patients' perception of the degree to which patient, provider and health system-level barriers affect their cardiac rehabilitation (CR) participation. Methods The CRBS consists of 21 items (barriers to adherence) rated on a 5-point Likert scale. The first phase was to translate and cross-culturally adapt the CRBS to the Korean language. After back-translation, both versions were reviewed by a committee. The face validity was assessed in a sample of Korean patients (n=53) with history of acute myocardial infarction that did not participate in CR through semi-structured interviews. The second phase was to assess the construct and criterion validity of the Korean translation as well as internal reliability, through administration of the translated version in 104 patients, principle component analysis with varimax rotation and cross-referencing against CR use, respectively. Results The length, readability, and clarity of the questionnaire were rated well, demonstrating face validity. Analysis revealed a six-factor solution, demonstrating construct validity. Cronbach's alpha was greater than 0.65. Barriers rated highest included not knowing about CR and not being contacted by a program. The mean CRBS score was significantly higher among non-attendees (2.71±0.26) than CR attendees (2.51±0.18) (p<0.01). Conclusion The Korean version of CRBS has demonstrated face, content and criterion validity, suggesting it may be useful for assessing barriers to CR utilization in Korea. PMID:29201826

Development and Validation of a Heart Atlas to Study Cardiac Exposure to Radiation Following Treatment for Breast Cancer

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

Feng, Mary, E-mail: maryfeng@umich.ed; Moran, Jean M.; Koelling, Todd

2011-01-01

Purpose: Cardiac toxicity is an important sequela of breast radiotherapy. However, the relationship between dose to cardiac structures and subsequent toxicity has not been well defined, partially due to variations in substructure delineation, which can lead to inconsistent dose reporting and the failure to detect potential correlations. Here we have developed a heart atlas and evaluated its effect on contour accuracy and concordance. Methods and Materials: A detailed cardiac computed tomography scan atlas was developed jointly by cardiology, cardiac radiology, and radiation oncology. Seven radiation oncologists were recruited to delineate the whole heart, left main and left anterior descending interventricularmore » branches, and right coronary arteries on four cases before and after studying the atlas. Contour accuracy was assessed by percent overlap with gold standard atlas volumes. The concordance index was also calculated. Standard radiation fields were applied. Doses to observer-contoured cardiac structures were calculated and compared with gold standard contour doses. Pre- and post-atlas values were analyzed using a paired t test. Results: The cardiac atlas significantly improved contour accuracy and concordance. Percent overlap and concordance index of observer-contoured cardiac and gold standard volumes were 2.3-fold improved for all structures (p < 0.002). After application of the atlas, reported mean doses to the whole heart, left main artery, left anterior descending interventricular branch, and right coronary artery were within 0.1, 0.9, 2.6, and 0.6 Gy, respectively, of gold standard doses. Conclusions: This validated University of Michigan cardiac atlas may serve as a useful tool in future studies assessing cardiac toxicity and in clinical trials which include dose volume constraints to the heart.« less

The molecular autopsy: an indispensable step following sudden cardiac death in the young?

PubMed Central

Boczek, Nicole J.; Tester, David J.; Ackerman, Michael J.

2013-01-01

Annually thousands of sudden deaths involving young individuals (< 35 years of age) remain unexplained following a complete medicolegal investigation that includes an autopsy. In fact, epidemiological studies have estimated that over half of sudden deaths involving previously healthy young individuals have no morphological abnormalities identifiable at autopsy. Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS), leave no evidence to be found at autopsy, leaving investigators to only speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD). In cases of autopsy-negative SUD, continued investigation, through the use of a cardiological and genetic evaluation of first- or second-degree relatives and/or a molecular autopsy, may pinpoint the underlying mechanism attributing to the sudden death and allow for the identification of living family members with the pathogenic substrate that renders them vulnerable to an increased risk for cardiac events, including sudden death. PMID:22993115

Assessing Cardiac Metabolism

PubMed Central

Taegtmeyer, Heinrich; Young, Martin E.; Lopaschuk, Gary D.; Abel, E. Dale; Brunengraber, Henri; Darley-Usmar, Victor; Des Rosiers, Christine; Gerszten, Robert; Glatz, Jan F.; Griffin, Julian L.; Gropler, Robert J.; Holzhuetter, Hermann-Georg; Kizer, Jorge R.; Lewandowski, E. Douglas; Malloy, Craig R.; Neubauer, Stefan; Peterson, Linda R.; Portman, Michael A.; Recchia, Fabio A.; Van Eyk, Jennifer E.; Wang, Thomas J.

2016-01-01

In a complex system of interrelated reactions, the heart converts chemical energy to mechanical energy. Energy transfer is achieved through coordinated activation of enzymes, ion channels, and contractile elements, as well as structural and membrane proteins. The heart’s needs for energy are difficult to overestimate. At a time when the cardiovascular research community is discovering a plethora of new molecular methods to assess cardiac metabolism, the methods remain scattered in the literature. The present statement on “Assessing Cardiac Metabolism” seeks to provide a collective and curated resource on methods and models used to investigate established and emerging aspects of cardiac metabolism. Some of those methods are refinements of classic biochemical tools, whereas most others are recent additions from the powerful tools of molecular biology. The aim of this statement is to be useful to many and to do justice to a dynamic field of great complexity. PMID:27012580

Cardiac transcriptome profiling of diabetic Akita mice using microarray and next generation sequencing

PubMed Central

Kesherwani, Varun; Shahshahan, Hamid R.

2017-01-01

Although diabetes mellitus (DM) causes cardiomyopathy and exacerbates heart failure, the underlying molecular mechanisms for diabetic cardiomyopathy/heart failure are poorly understood. Insulin2 mutant (Ins2+/-) Akita is a mouse model of T1DM, which manifests cardiac dysfunction. However, molecular changes at cardiac transcriptome level that lead to cardiomyopathy remain unclear. To understand the molecular changes in the heart of diabetic Akita mice, we profiled cardiac transcriptome of Ins2+/- Akita and Ins2+/+ control mice using next generation sequencing (NGS) and microarray, and determined the implications of differentially expressed genes on various heart failure signaling pathways using Ingenuity pathway (IPA) analysis. First, we validated hyperglycemia, increased cardiac fibrosis, and cardiac dysfunction in twelve-week male diabetic Akita. Then, we analyzed the transcriptome levels in the heart. NGS analyses on Akita heart revealed 137 differentially expressed transcripts, where Bone Morphogenic Protein-10 (BMP10) was the most upregulated and hairy and enhancer of split-related (HELT) was the most downregulated gene. Moreover, twelve long non-coding RNAs (lncRNAs) were upregulated. The microarray analyses on Akita heart showed 351 differentially expressed transcripts, where vomeronasal-1 receptor-180 (Vmn1r180) was the most upregulated and WD Repeat Domain 83 Opposite Strand (WDR83OS) was the most downregulated gene. Further, miR-101c and H19 lncRNA were upregulated but Neat1 lncRNA was downregulated in Akita heart. Eleven common genes were upregulated in Akita heart in both NGS and microarray analyses. IPA analyses revealed the role of these differentially expressed genes in key signaling pathways involved in diabetic cardiomyopathy. Our results provide a platform to initiate focused future studies by targeting these genes and/or non-coding RNAs, which are differentially expressed in Akita hearts and are involved in diabetic cardiomyopathy. PMID:28837672

Quantification of mitral regurgitation by automated cardiac output measurement: experimental and clinical validation

NASA Technical Reports Server (NTRS)

Sun, J. P.; Yang, X. S.; Qin, J. X.; Greenberg, N. L.; Zhou, J.; Vazquez, C. J.; Griffin, B. P.; Stewart, W. J.; Thomas, J. D.

1998-01-01

OBJECTIVES: To develop and validate an automated noninvasive method to quantify mitral regurgitation. BACKGROUND: Automated cardiac output measurement (ACM), which integrates digital color Doppler velocities in space and in time, has been validated for the left ventricular (LV) outflow tract but has not been tested for the LV inflow tract or to assess mitral regurgitation (MR). METHODS: First, to validate ACM against a gold standard (ultrasonic flow meter), 8 dogs were studied at 40 different stages of cardiac output (CO). Second, to compare ACM to the LV outflow (ACMa) and inflow (ACMm) tracts, 50 normal volunteers without MR or aortic regurgitation (44+/-5 years, 31 male) were studied. Third, to compare ACM with the standard pulsed Doppler-two-dimensional echocardiographic (PD-2D) method for quantification of MR, 51 patients (61+/-14 years, 30 male) with MR were studied. RESULTS: In the canine studies, CO by ACM (1.32+/-0.3 liter/min, y) and flow meter (1.35+/-0.3 liter/min, x) showed good correlation (r=0.95, y=0.89x+0.11) and agreement (deltaCO(y-x)=0.03+/-0.08 [mean+/-SD] liter/min). In the normal subjects, CO measured by ACMm agreed with CO by ACMa (r=0.90, p < 0.0001, deltaCO=-0.09+/-0.42 liter/min), PD (r=0.87, p < 0.0001, deltaCO=0.12+/-0.49 liter/min) and 2D (r=0.84, p < 0.0001, deltaCO=-0.16+/-0.48 liter/min). In the patients, mitral regurgitant volume (MRV) by ACMm-ACMa agreed with PD-2D (r= 0.88, y=0.88x+6.6, p < 0.0001, deltaMRV=2.68+/-9.7 ml). CONCLUSIONS: We determined that ACM is a feasible new method for quantifying LV outflow and inflow volume to measure MRV and that ACM automatically performs calculations that are equivalent to more time-consuming Doppler and 2D measurements. Additionally, ACM should improve MR quantification in routine clinical practice.

Are classic predictors of voltage valid in cardiac amyloidosis? A contemporary analysis of electrocardiographic findings.

PubMed

Sperry, Brett W; Vranian, Michael N; Hachamovitch, Rory; Joshi, Hariom; McCarthy, Meghann; Ikram, Asad; Hanna, Mazen

2016-07-01

Low voltage electrocardiography (ECG) coupled with increased ventricular wall thickness is the hallmark of cardiac amyloidosis. However, patient characteristics influencing voltage in the general population, including bundle branch block, have not been evaluated in amyloid heart disease. A retrospective analysis was performed of patients with newly diagnosed cardiac amyloidosis from 2002 to 2014. ECG voltage was calculated using limb (sum of QRS complex in leads I, II and III) and precordial (Sokolow: S in V1 plus R in V5-V6) criteria. The associations between voltage and clinical variables were tested using multivariable linear regression. A Cox model assessed the association of voltage with mortality. In 389 subjects (transthyretin ATTR 186, light chain AL 203), 30% had conduction delay (QRS >120ms). In those with narrow QRS, 68% met low limb, 72% low Sokolow and 57% both criteria, with lower voltages found in AL vs ATTR. LV mass index as well as other typical factors that impact voltage (age, sex, race, hypertension, BSA, and smoking) in the general population were not associated with voltage in this cardiac amyloidosis cohort. Patients with LBBB and IVCD had similar voltages when compared to those with narrow QRS. Voltage was significantly associated with mortality (p<0.001 for both criteria) after multivariable adjustment. Classic predictors of ECG voltage in the general population are not valid in cardiac amyloidosis. In this cohort, the prevalence estimates of ventricular conduction delay and low voltage are higher than previously reported. Voltage predicts mortality after multivariable adjustment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

An integrative view of cisplatin-induced renal and cardiac toxicities: molecular mechanisms, current treatment challenges and potential protective measures

PubMed Central

Dugbartey, George J.; Peppone, Luke J.; de Graaf, Inge A.M.

2017-01-01

Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell’s antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide. PMID:27717837

Measuring cardiac waste: the premier cardiac waste measures.

PubMed

Lowe, Timothy J; Partovian, Chohreh; Kroch, Eugene; Martin, John; Bankowitz, Richard

2014-01-01

The authors developed 8 measures of waste associated with cardiac procedures to assist hospitals in comparing their performance with peer facilities. Measure selection was based on review of the research literature, clinical guidelines, and consultation with key stakeholders. Development and validation used the data from 261 hospitals in a split-sample design. Measures were risk adjusted using Premier's CareScience methodologies or mean peer value based on Medicare Severity Diagnosis-Related Group assignment. High variability was found in resource utilization across facilities. Validation of the measures using item-to-total correlations (range = 0.27-0.78), Cronbach α (.88), and Spearman rank correlation (0.92) showed high reliability and discriminatory power. Because of the level of variability observed among hospitals, this study suggests that there is opportunity for facilities to design successful waste reduction programs targeting cardiac-device procedures.

Validation of Pre-operative Patient Self-Assessment of Cardiac Risk for Non-Cardiac Surgery: Foundations for Decision Support

PubMed Central

Manaktala, Sharad; Rockwood, Todd; Adam, Terrence J.

2013-01-01

Objectives: To better characterize patient understanding of their risk of cardiac complications from non-cardiac surgery and to develop a patient driven clinical decision support system for preoperative patient risk management. Methods: A patient-driven preoperative self-assessment decision support tool for perioperative assessment was created. Patient’ self-perception of cardiac risk and self-report data for risk factors were compared with gold standard preoperative physician assessment to evaluate agreement. Results: The patient generated cardiac risk profile was used for risk score generation and had excellent agreement with the expert physician assessment. However, patient subjective self-perception risk of cardiovascular complications had poor agreement with expert assessment. Conclusion: A patient driven cardiac risk assessment tool provides a high degree of agreement with expert provider assessment demonstrating clinical feasibility. The limited agreement between provider risk assessment and patient self-perception underscores a need for further work including focused preoperative patient education on cardiac risk. PMID:24551384

Applying the termination of resuscitation rules to out-of-hospital cardiac arrests of both cardiac and non-cardiac etiologies: a prospective cohort study.

PubMed

Kashiura, Masahiro; Hamabe, Yuichi; Akashi, Akiko; Sakurai, Atsushi; Tahara, Yoshio; Yonemoto, Naohiro; Nagao, Ken; Yaguchi, Arino; Morimura, Naoto

2016-03-01

The 2015 American Heart Association Guidelines for Cardiopulmonary Resuscitation recommend Basic Life Support (BLS) and Advanced Life Support (ALS) rules for termination of resuscitation (TOR). However, it is unclear whether the TOR rules are valid for out-of-hospital cardiac arrests (OHCAs) of both cardiac and non-cardiac etiologies. In this study, we validated the TOR rules for OHCA resulting from both etiologies. This was a prospective multicenter observational study of OHCA patients transported to 67 emergency hospitals between January 2012 and March 2013 in the Kanto region of Japan. We calculated the specificity and positive predictive value (PPV) for neurologically unfavorable outcomes at one month in patients with OHCA of cardiac and non-cardiac etiologies. Of 11,505 eligible cases, 6,138 and 5,367 cases were of cardiac and non-cardiac etiology, respectively. BLS was performed on 2,818 and 2,606 patients with OHCA of cardiac and non-cardiac etiology, respectively. ALS was performed on 3,320 and 2,761 patients with OHCA of cardiac and non-cardiac etiology, respectively. The diagnostic accuracy of the TOR rules for predicting unfavorable outcomes in patients with OHCA of cardiac etiology who received BLS included a specificity of 0.985 (95% confidence interval [CI]: 0.956-0.997) and a PPV of 0.999 (95% CI: 0.996-1.000). In patients with OHCA from cardiac etiologies who received ALS, the TOR rules had a specificity of 0.963 (95% CI: 0.896-0.992) and a PPV of 0.997 (95% CI: 0.991-0.999). In patients with OHCA from non-cardiac etiologies who received BLS, the specificity was 0.915 (95% CI: 0.796-0.976) and PPV was 0.998 (95% CI: 0.995-0.999). For patients with OHCA from non-cardiac etiologies who received ALS, the specificity was 0.833 (95% CI: 0.586-0.964) and PPV was 0.996 (95% CI: 0.988-0.999). Both TOR rules have high specificity and PPV in patients with OHCA from cardiac etiologies. For patients with OHCA from non-cardiac etiologies, the rules had a high

Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac HspB2 Interactome.

PubMed

Grose, Julianne H; Langston, Kelsey; Wang, Xiaohui; Squires, Shayne; Mustafi, Soumyajit Banerjee; Hayes, Whitney; Neubert, Jonathan; Fischer, Susan K; Fasano, Matthew; Saunders, Gina Moore; Dai, Qiang; Christians, Elisabeth; Lewandowski, E Douglas; Ping, Peipei; Benjamin, Ivor J

2015-01-01

Small Heat Shock Proteins (sHSPs) are molecular chaperones that transiently interact with other proteins, thereby assisting with quality control of proper protein folding and/or degradation. They are also recruited to protect cells from a variety of stresses in response to extreme heat, heavy metals, and oxidative-reductive stress. Although ten human sHSPs have been identified, their likely diverse biological functions remain an enigma in health and disease, and much less is known about non-redundant roles in selective cells and tissues. Herein, we set out to comprehensively characterize the cardiac-restricted Heat Shock Protein B-2 (HspB2), which exhibited ischemic cardioprotection in transgenic overexpressing mice including reduced infarct size and maintenance of ATP levels. Global yeast two-hybrid analysis using HspB2 (bait) and a human cardiac library (prey) coupled with co-immunoprecipitation studies for mitochondrial target validation revealed the first HspB2 "cardiac interactome" to contain many myofibril and mitochondrial-binding partners consistent with the overexpression phenotype. This interactome has been submitted to the Biological General Repository for Interaction Datasets (BioGRID). A related sHSP chaperone HspB5 had only partially overlapping binding partners, supporting specificity of the interactome as well as non-redundant roles reported for these sHSPs. Evidence that the cardiac yeast two-hybrid HspB2 interactome targets resident mitochondrial client proteins is consistent with the role of HspB2 in maintaining ATP levels and suggests new chaperone-dependent functions for metabolic homeostasis. One of the HspB2 targets, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), has reported roles in HspB2 associated phenotypes including cardiac ATP production, mitochondrial function, and apoptosis, and was validated as a potential client protein of HspB2 through chaperone assays. From the clientele and phenotypes identified herein, it is tempting to

Mechanical regulation of cardiac development

PubMed Central

Lindsey, Stephanie E.; Butcher, Jonathan T.; Yalcin, Huseyin C.

2014-01-01

Mechanical forces are essential contributors to and unavoidable components of cardiac formation, both inducing and orchestrating local and global molecular and cellular changes. Experimental animal studies have contributed substantially to understanding the mechanobiology of heart development. More recent integration of high-resolution imaging modalities with computational modeling has greatly improved our quantitative understanding of hemodynamic flow in heart development. Merging these latest experimental technologies with molecular and genetic signaling analysis will accelerate our understanding of the relationships integrating mechanical and biological signaling for proper cardiac formation. These advances will likely be essential for clinically translatable guidance for targeted interventions to rescue malforming hearts and/or reconfigure malformed circulations for optimal performance. This review summarizes our current understanding on the levels of mechanical signaling in the heart and their roles in orchestrating cardiac development. PMID:25191277

Molecular motions that shape the cardiac action potential: Insights from voltage clamp fluorometry.

PubMed

Zhu, Wandi; Varga, Zoltan; Silva, Jonathan R

2016-01-01

Very recently, voltage-clamp fluorometry (VCF) protocols have been developed to observe the membrane proteins responsible for carrying the ventricular ionic currents that form the action potential (AP), including those carried by the cardiac Na(+) channel, NaV1.5, the L-type Ca(2+) channel, CaV1.2, the Na(+)/K(+) ATPase, and the rapid and slow components of the delayed rectifier, KV11.1 and KV7.1. This development is significant, because VCF enables simultaneous observation of ionic current kinetics with conformational changes occurring within specific channel domains. The ability gained from VCF, to connect nanoscale molecular movement to ion channel function has revealed how the voltage-sensing domains (VSDs) control ion flux through channel pores, mechanisms of post-translational regulation and the molecular pathology of inherited mutations. In the future, we expect that this data will be of great use for the creation of multi-scale computational AP models that explicitly represent ion channel conformations, connecting molecular, cell and tissue electrophysiology. Here, we review the VCF protocol, recent results, and discuss potential future developments, including potential use of these experimental findings to create novel computational models. Copyright © 2015 Elsevier Ltd. All rights reserved.

Boosters and barriers for direct cardiac reprogramming.

PubMed

Talkhabi, Mahmood; Zonooz, Elmira Rezaei; Baharvand, Hossein

2017-06-01

Heart disease is currently the most significant cause of morbidity and mortality worldwide, which accounts for approximately 33% of all deaths. Recently, a promising and alchemy-like strategy has been developed called direct cardiac reprogramming, which directly converts somatic cells such as fibroblasts to cardiac lineage cells such as cardiomyocytes (CMs), termed induced CMs or iCMs. The first in vitro cardiac reprogramming study, mediated by cardiac transcription factors (TFs)-Gata4, Tbx5 and Mef2C-, was not enough efficient to produce an adequate number of fully reprogrammed, functional iCMs. As a result, numerous combinations of cardiac TFs exist for direct cardiac reprogramming of mouse and human fibroblasts. However, the efficiency of direct cardiac reprogramming remains low. Recently, a number of cellular and molecular mechanisms have been identified to increase the efficiency of direct cardiac reprogramming and the quality of iCMs. For example, microgrooved substrate, cardiogenic growth factors [VEGF, FGF, BMP4 and Activin A], and an appropriate stoichiometry of TFs boost the direct cardiac reprogramming. On the other hand, serum, TGFβ signaling, activators of epithelial to mesenchymal transition, and some epigenetic factors (Bmi1 and Ezh2) are barriers for direct cardiac reprogramming. Manipulating these mechanisms by the application of boosters and removing barriers can increase the efficiency of direct cardiac reprogramming and possibly make iCMs reliable for cell-based therapy or other potential applications. In this review, we summarize the latest trends in cardiac TF- or miRNA-based direct cardiac reprogramming and comprehensively discuses all molecular and cellular boosters and barriers affecting direct cardiac reprogramming. Copyright © 2017 Elsevier Inc. All rights reserved.

In vivo validation of cardiac output assessment in non-standard 3D echocardiographic images

NASA Astrophysics Data System (ADS)

Nillesen, M. M.; Lopata, R. G. P.; de Boode, W. P.; Gerrits, I. H.; Huisman, H. J.; Thijssen, J. M.; Kapusta, L.; de Korte, C. L.

2009-04-01

Automatic segmentation of the endocardial surface in three-dimensional (3D) echocardiographic images is an important tool to assess left ventricular (LV) geometry and cardiac output (CO). The presence of speckle noise as well as the nonisotropic characteristics of the myocardium impose strong demands on the segmentation algorithm. In the analysis of normal heart geometries of standardized (apical) views, it is advantageous to incorporate a priori knowledge about the shape and appearance of the heart. In contrast, when analyzing abnormal heart geometries, for example in children with congenital malformations, this a priori knowledge about the shape and anatomy of the LV might induce erroneous segmentation results. This study describes a fully automated segmentation method for the analysis of non-standard echocardiographic images, without making strong assumptions on the shape and appearance of the heart. The method was validated in vivo in a piglet model. Real-time 3D echocardiographic image sequences of five piglets were acquired in radiofrequency (rf) format. These ECG-gated full volume images were acquired intra-operatively in a non-standard view. Cardiac blood flow was measured simultaneously by an ultrasound transit time flow probe positioned around the common pulmonary artery. Three-dimensional adaptive filtering using the characteristics of speckle was performed on the demodulated rf data to reduce the influence of speckle noise and to optimize the distinction between blood and myocardium. A gradient-based 3D deformable simplex mesh was then used to segment the endocardial surface. A gradient and a speed force were included as external forces of the model. To balance data fitting and mesh regularity, one fixed set of weighting parameters of internal, gradient and speed forces was used for all data sets. End-diastolic and end-systolic volumes were computed from the segmented endocardial surface. The cardiac output derived from this automatic segmentation was

External validity of the pediatric cardiac quality of life inventory

PubMed Central

Marino, Bradley S.; Drotar, Dennis; Cassedy, Amy; Davis, Richard; Tomlinson, Ryan S.; Mellion, Katelyn; Mussatto, Kathleen; Mahony, Lynn; Newburger, Jane W.; Tong, Elizabeth; Cohen, Mitchell I.; Helfaer, Mark A.; Kazak, Anne E.; Wray, Jo; Wernovsky, Gil; Shea, Judy A.; Ittenbach, Richard

2012-01-01

Purpose The Pediatric Cardiac Quality of Life Inventory (PCQLI) is a disease-specific, health-related quality of life (HRQOL) measure for pediatric heart disease (HD). The purpose of this study was to demonstrate the external validity of PCQLI scores. Methods The PCQLI development site (Development sample) and six geographically diverse centers in the United States (Composite sample) recruited pediatric patients with acquired or congenital HD. Item response option variability, scores [Total (TS); Disease Impact (DI) and Psychosocial Impact (PI) subscales], patterns of correlation, and internal consistency were compared between samples. Results A total of 3,128 patients and parent participants (1,113 Development; 2,015 Composite) were analyzed. Response option variability patterns of all items in both samples were acceptable. Inter-sample score comparisons revealed no differences. Median item–total (Development, 0.57; Composite, 0.59) and item–subscale (Development, DI 0.58, PI 0.59; Composite, DI 0.58, PI 0.56) correlations were moderate. Subscale–subscale (0.79 for both samples) and subscale–total (Development, DI 0.95, PI 0.95; Composite, DI 0.95, PI 0.94) correlations and internal consistency (Development, TS 0.93, DI 0.90, PI 0.84; Composite, TS 0.93, DI 0.89, PI 0.85) were high in both samples. Conclusion PCQLI scores are externally valid across the US pediatric HD population and may be used for multi-center HRQOL studies. PMID:21188538

Global outbreak of severe Mycobacterium chimaera disease after cardiac surgery: a molecular epidemiological study.

PubMed

van Ingen, Jakko; Kohl, Thomas A; Kranzer, Katharina; Hasse, Barbara; Keller, Peter M; Katarzyna Szafrańska, Anna; Hillemann, Doris; Chand, Meera; Schreiber, Peter Werner; Sommerstein, Rami; Berger, Christoph; Genoni, Michele; Rüegg, Christian; Troillet, Nicolas; Widmer, Andreas F; Becker, Sören L; Herrmann, Mathias; Eckmanns, Tim; Haller, Sebastian; Höller, Christiane; Debast, Sylvia B; Wolfhagen, Maurice J; Hopman, Joost; Kluytmans, Jan; Langelaar, Merel; Notermans, Daan W; Ten Oever, Jaap; van den Barselaar, Peter; Vonk, Alexander B A; Vos, Margreet C; Ahmed, Nada; Brown, Timothy; Crook, Derrick; Lamagni, Theresa; Phin, Nick; Smith, E Grace; Zambon, Maria; Serr, Annerose; Götting, Tim; Ebner, Winfried; Thürmer, Alexander; Utpatel, Christian; Spröer, Cathrin; Bunk, Boyke; Nübel, Ulrich; Bloemberg, Guido V; Böttger, Erik C; Niemann, Stefan; Wagner, Dirk; Sax, Hugo

2017-10-01

Since 2013, over 100 cases of Mycobacterium chimaera prosthetic valve endocarditis and disseminated disease were notified in Europe and the USA, linked to contaminated heater-cooler units (HCUs) used during cardiac surgery. We did a molecular epidemiological investigation to establish the source of these patients' disease. We included 24 M chimaera isolates from 21 cardiac surgery-related patients in Switzerland, Germany, the Netherlands, and the UK, 218 M chimaera isolates from various types of HCUs in hospitals, from LivaNova (formerly Sorin; London, UK) and Maquet (Rastatt, Germany) brand HCU production sites, and unrelated environmental sources and patients, as well as eight Mycobacterium intracellulare isolates. Isolates were analysed by next-generation whole-genome sequencing using Illumina and Pacific Biosciences technologies, and compared with published M chimaera genomes. Phylogenetic analysis based on whole-genome sequencing of 250 isolates revealed two major M chimaera groups. Cardiac surgery-related patient isolates were all classified into group 1, in which all, except one, formed a distinct subgroup. This subgroup also comprised isolates from 11 cardiac surgery-related patients reported from the USA, most isolates from LivaNova HCUs, and one from their production site. Isolates from other HCUs and unrelated patients were more widely distributed in the phylogenetic tree. HCU contamination with M chimaera at the LivaNova factory seems a likely source for cardiothoracic surgery-related severe M chimaera infections diagnosed in Switzerland, Germany, the Netherlands, the UK, the USA, and Australia. Protective measures and heightened clinician awareness are essential to guarantee patient safety. Partly funded by the EU Horizon 2020 programme, its FP7 programme, the German Center for Infection Research (DZIF), the Swiss National Science Foundation, the Swiss Federal Office of Public Health, and National Institute of Health Research Oxford Health Protection

Positive predictive value of cardiac examination, procedure and surgery codes in the Danish National Patient Registry: a population-based validation study

PubMed Central

Adelborg, Kasper; Sundbøll, Jens; Munch, Troels; Frøslev, Trine; Sørensen, Henrik Toft; Bøtker, Hans Erik; Schmidt, Morten

2016-01-01

Objective Danish medical registries are widely used for cardiovascular research, but little is known about the data quality of cardiac interventions. We computed positive predictive values (PPVs) of codes for cardiac examinations, procedures and surgeries registered in the Danish National Patient Registry during 2010–2012. Design Population-based validation study. Setting We randomly sampled patients from 1 university hospital and 2 regional hospitals in the Central Denmark Region. Participants 1239 patients undergoing different cardiac interventions. Main outcome measure PPVs with medical record review as reference standard. Results A total of 1233 medical records (99% of the total sample) were available for review. PPVs ranged from 83% to 100%. For examinations, the PPV was overall 98%, reflecting PPVs of 97% for echocardiography, 97% for right heart catheterisation and 100% for coronary angiogram. For procedures, the PPV was 98% overall, with PPVs of 98% for thrombolysis, 92% for cardioversion, 100% for radiofrequency ablation, 98% for percutaneous coronary intervention, and 100% for both cardiac pacemakers and implantable cardiac defibrillators. For cardiac surgery, the overall PPVs was 99%, encompassing PPVs of 100% for mitral valve surgery, 99% for aortic valve surgery, 98% for coronary artery bypass graft surgery, and 100% for heart transplantation. The accuracy of coding was consistent within age, sex, and calendar year categories, and the agreement between independent reviewers was high (99%). Conclusions Cardiac examinations, procedures and surgeries have high PPVs in the Danish National Patient Registry. PMID:27940630

Construct, concurrent and discriminant validity of Type D personality in the general population: associations with anxiety, depression, stress and cardiac output.

PubMed

Howard, Siobhán; Hughes, Brian M

2012-01-01

The Type D personality, identified by high negative affectivity paired with high social inhibition, has been associated with a number of health-related outcomes in (mainly) cardiac populations. However, despite its prevalence in the health-related literature, how this personality construct fits within existing personality theory has not been directly tested. Using a sample of 134 healthy university students, this study examined the Type D personality in terms of two well-established personality traits; introversion and neuroticism. Construct, concurrent and discriminant validity of this personality type was established through examination of the associations between the Type D personality and psychometrically assessed anxiety, depression and stress, as well as measurement of resting cardiovascular function. Results showed that while the Type D personality was easily represented using alternative measures of both introversion and neuroticism, associations with anxiety, depression and stress were mainly accounted for by neuroticism. Conversely, however, associations with resting cardiac output were attributable to the negative affectivity-social inhibition synergy, explicit within the Type D construct. Consequently, both the construct and concurrent validity of this personality type were confirmed, with discriminant validity evident on examination of physiological indices of well-being.

Functional Tissue Engineering: A Prevascularized Cardiac Muscle Construct for Validating Human Mesenchymal Stem Cells Engraftment Potential In Vitro

PubMed Central

Fuseler, John W.; Potts, Jay D.; Davis, Jeffrey M.; Price, Robert L.

2018-01-01

The influence of somatic stem cells in the stimulation of mammalian cardiac muscle regeneration is still in its early stages, and so far, it has been difficult to determine the efficacy of the procedures that have been employed. The outstanding question remains whether stem cells derived from the bone marrow or some other location within or outside of the heart can populate a region of myocardial damage and transform into tissue-specific differentiated progenies, and also exhibit functional synchronization. Consequently, this necessitates the development of an appropriate in vitro three-dimensional (3D) model of cardiomyogenesis and prompts the development of a 3D cardiac muscle construct for tissue engineering purposes, especially using the somatic stem cell, human mesenchymal stem cells (hMSCs). To this end, we have created an in vitro 3D functional prevascularized cardiac muscle construct using embryonic cardiac myocytes (eCMs) and hMSCs. First, to generate the prevascularized scaffold, human cardiac microvascular endothelial cells (hCMVECs) and hMSCs were cocultured onto a 3D collagen cell carrier (CCC) for 7 days under vasculogenic culture conditions; hCMVECs/hMSCs underwent maturation, differentiation, and morphogenesis characteristic of microvessels, and formed dense vascular networks. Next, the eCMs and hMSCs were cocultured onto this generated prevascularized CCCs for further 7 or 14 days in myogenic culture conditions. Finally, the vascular and cardiac phenotypic inductions were characterized at the morphological, immunological, biochemical, molecular, and functional levels. Expression and functional analyses of the differentiated progenies revealed neo-cardiomyogenesis and neo-vasculogenesis. In this milieu, for instance, not only were hMSCs able to couple electromechanically with developing eCMs but were also able to contribute to the developing vasculature as mural cells, respectively. Hence, our unique 3D coculture system provides us a reproducible

Validation of cardiac accelerometer sensor measurements.

PubMed

Remme, Espen W; Hoff, Lars; Halvorsen, Per Steinar; Naerum, Edvard; Skulstad, Helge; Fleischer, Lars A; Elle, Ole Jakob; Fosse, Erik

2009-12-01

In this study we have investigated the accuracy of an accelerometer sensor designed for the measurement of cardiac motion and automatic detection of motion abnormalities caused by myocardial ischaemia. The accelerometer, attached to the left ventricular wall, changed its orientation relative to the direction of gravity during the cardiac cycle. This caused a varying gravity component in the measured acceleration signal that introduced an error in the calculation of myocardial motion. Circumferential displacement, velocity and rotation of the left ventricular apical region were calculated from the measured acceleration signal. We developed a mathematical method to separate translational and gravitational acceleration components based on a priori assumptions of myocardial motion. The accuracy of the measured motion was investigated by comparison with known motion of a robot arm programmed to move like the heart wall. The accuracy was also investigated in an animal study. The sensor measurements were compared with simultaneously recorded motion from a robot arm attached next to the sensor on the heart and with measured motion by echocardiography and a video camera. The developed compensation method for the varying gravity component improved the accuracy of the calculated velocity and displacement traces, giving very good agreement with the reference methods.

The Manchester Acute Coronary Syndromes (MACS) decision rule for suspected cardiac chest pain: derivation and external validation.

PubMed

Body, Richard; Carley, Simon; McDowell, Garry; Pemberton, Philip; Burrows, Gillian; Cook, Gary; Lewis, Philip S; Smith, Alexander; Mackway-Jones, Kevin

2014-09-15

We aimed to derive and validate a clinical decision rule (CDR) for suspected cardiac chest pain in the emergency department (ED). Incorporating information available at the time of first presentation, this CDR would effectively risk-stratify patients and immediately identify: (A) patients for whom hospitalisation may be safely avoided; and (B) high-risk patients, facilitating judicious use of resources. In two sequential prospective observational cohort studies at heterogeneous centres, we included ED patients with suspected cardiac chest pain. We recorded clinical features and drew blood on arrival. The primary outcome was major adverse cardiac events (MACE) (death, prevalent or incident acute myocardial infarction, coronary revascularisation or new coronary stenosis >50%) within 30 days. The CDR was derived by logistic regression, considering reliable (κ>0.6) univariate predictors (p<0.05) for inclusion. In the derivation study (n=698) we derived a CDR including eight variables (high sensitivity troponin T; heart-type fatty acid binding protein; ECG ischaemia; diaphoresis observed; vomiting; pain radiation to right arm/shoulder; worsening angina; hypotension), which had a C-statistic of 0.95 (95% CI 0.93 to 0.97) implying near perfect diagnostic performance. On external validation (n=463) the CDR identified 27.0% of patients as 'very low risk' and potentially suitable for discharge from the ED. 0.0% of these patients had prevalent acute myocardial infarction and 1.6% developed MACE (n=2; both coronary stenoses without revascularisation). 9.9% of patients were classified as 'high-risk', 95.7% of whom developed MACE. The Manchester Acute Coronary Syndromes (MACS) rule has the potential to safely reduce unnecessary hospital admissions and facilitate judicious use of high dependency resources. 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.

The Manchester Acute Coronary Syndromes (MACS) decision rule for suspected cardiac chest pain: derivation and external validation

PubMed Central

Body, Richard; Carley, Simon; McDowell, Garry; Pemberton, Philip; Burrows, Gillian; Cook, Gary; Lewis, Philip S; Smith, Alexander; Mackway-Jones, Kevin

2014-01-01

Objective We aimed to derive and validate a clinical decision rule (CDR) for suspected cardiac chest pain in the emergency department (ED). Incorporating information available at the time of first presentation, this CDR would effectively risk-stratify patients and immediately identify: (A) patients for whom hospitalisation may be safely avoided; and (B) high-risk patients, facilitating judicious use of resources. Methods In two sequential prospective observational cohort studies at heterogeneous centres, we included ED patients with suspected cardiac chest pain. We recorded clinical features and drew blood on arrival. The primary outcome was major adverse cardiac events (MACE) (death, prevalent or incident acute myocardial infarction, coronary revascularisation or new coronary stenosis >50%) within 30 days. The CDR was derived by logistic regression, considering reliable (κ>0.6) univariate predictors (p<0.05) for inclusion. Results In the derivation study (n=698) we derived a CDR including eight variables (high sensitivity troponin T; heart-type fatty acid binding protein; ECG ischaemia; diaphoresis observed; vomiting; pain radiation to right arm/shoulder; worsening angina; hypotension), which had a C-statistic of 0.95 (95% CI 0.93 to 0.97) implying near perfect diagnostic performance. On external validation (n=463) the CDR identified 27.0% of patients as ‘very low risk’ and potentially suitable for discharge from the ED. 0.0% of these patients had prevalent acute myocardial infarction and 1.6% developed MACE (n=2; both coronary stenoses without revascularisation). 9.9% of patients were classified as ‘high-risk’, 95.7% of whom developed MACE. Conclusions The Manchester Acute Coronary Syndromes (MACS) rule has the potential to safely reduce unnecessary hospital admissions and facilitate judicious use of high dependency resources. PMID:24780911

Pharmacological targeting of CDK9 in cardiac hypertrophy.

PubMed

Krystof, Vladimír; Chamrád, Ivo; Jorda, Radek; Kohoutek, Jirí

2010-07-01

Cardiac hypertrophy allows the heart to adapt to workload, but persistent or unphysiological stimulus can result in pump failure. Cardiac hypertrophy is characterized by an increase in the size of differentiated cardiac myocytes. At the molecular level, growth of cells is linked to intensive transcription and translation. Several cyclin-dependent kinases (CDKs) have been identified as principal regulators of transcription, and among these CDK9 is directly associated with cardiac hypertrophy. CDK9 phosphorylates the C-terminal domain of RNA polymerase II and thus stimulates the elongation phase of transcription. Chronic activation of CDK9 causes not only cardiac myocyte enlargement but also confers predisposition to heart failure. Due to the long interest of molecular oncologists and medicinal chemists in CDKs as potential targets of anticancer drugs, a portfolio of small-molecule inhibitors of CDK9 is available. Recent determination of CDK9's crystal structure now allows the development of selective inhibitors and their further optimization in terms of biochemical potency and selectivity. CDK9 may therefore constitute a novel target for drugs against cardiac hypertrophy.

Prospective validation of a clinical decision rule to identify patients presenting to the emergency department with chest pain who can safely be removed from cardiac monitoring

PubMed Central

Syed, Shahbaz; Gatien, Mathieu; Perry, Jeffrey J.; Chaudry, Hina; Kim, Soo-Min; Kwong, Kenneth; Mukarram, Muhammad; Thiruganasambandamoorthy, Venkatesh

2017-01-01

BACKGROUND: Most patients with chest pain in the emergency department are assigned to cardiac monitoring for several hours, blocking access for patients in greater need. We sought to validate a previously derived decision rule for safe removal of patients from cardiac monitoring after initial evaluation in the emergency department. METHODS: We prospectively enrolled adults (age ≥ 18 yr) who presented with chest pain and were assigned to cardiac monitoring at 2 academic emergency departments over 18 months. We collected standardized baseline characteristics, findings from clinical evaluations and predictors for the Ottawa Chest Pain Cardiac Monitoring Rule: whether the patient is currently free of chest pain, and whether the electrocardiogram is normal or shows only nonspecific changes. The outcome was an arrhythmia requiring intervention in the emergency department or within 8 hours of presentation to the emergency department. We calculated diagnostic characteristics for the clinical prediction rule. RESULTS: We included 796 patients (mean age 63.8 yr, 55.8% male, 8.9% admitted to hospital). Fifteen patients (1.9%) had an arrhythmia, and the rule performed with the following characteristics: sensitivity 100% (95% confidence interval [CI] 78.2%–100%) and specificity 36.4% (95% CI 33.0%–39.6%). Application of the Ottawa Chest Pain Cardiac Monitoring Rule would have allowed 284 out of 796 patients (35.7%) to be safely removed from cardiac monitoring. INTERPRETATION: We successfully validated the decision rule for safe removal of a large subset of patients with chest pain from cardiac monitoring after initial evaluation in the emergency department. Implementation of this simple yet highly sensitive rule will allow for improved use of health care resources. PMID:28246315

Pregnancy as a cardiac stress model

PubMed Central

Chung, Eunhee; Leinwand, Leslie A.

2014-01-01

Cardiac hypertrophy occurs during pregnancy as a consequence of both volume overload and hormonal changes. Both pregnancy- and exercise-induced cardiac hypertrophy are generally thought to be similar and physiological. Despite the fact that there are shared transcriptional responses in both forms of cardiac adaptation, pregnancy results in a distinct signature of gene expression in the heart. In some cases, however, pregnancy can induce adverse cardiac events in previously healthy women without any known cardiovascular disease. Peripartum cardiomyopathy is the leading cause of non-obstetric mortality during pregnancy. To understand how pregnancy can cause heart disease, it is first important to understand cardiac adaptation during normal pregnancy. This review provides an overview of the cardiac consequences of pregnancy, including haemodynamic, functional, structural, and morphological adaptations, as well as molecular phenotypes. In addition, this review describes the signalling pathways responsible for pregnancy-induced cardiac hypertrophy and angiogenesis. We also compare and contrast cardiac adaptation in response to disease, exercise, and pregnancy. The comparisons of these settings of cardiac hypertrophy provide insight into pregnancy-associated cardiac adaptation. PMID:24448313

Effects of Hypertension and Exercise on Cardiac Proteome Remodelling

PubMed Central

Petriz, Bernardo A.; Franco, Octavio L.

2014-01-01

Left ventricle hypertrophy is a common outcome of pressure overload stimulus closely associated with hypertension. This process is triggered by adverse molecular signalling, gene expression, and proteome alteration. Proteomic research has revealed that several molecular targets are associated with pathologic cardiac hypertrophy, including angiotensin II, endothelin-1 and isoproterenol. Several metabolic, contractile, and stress-related proteins are shown to be altered in cardiac hypertrophy derived by hypertension. On the other hand, exercise is a nonpharmacologic agent used for hypertension treatment, where cardiac hypertrophy induced by exercise training is characterized by improvement in cardiac function and resistance against ischemic insult. Despite the scarcity of proteomic research performed with exercise, healthy and pathologic heart proteomes are shown to be modulated in a completely different way. Hence, the altered proteome induced by exercise is mostly associated with cardioprotective aspects such as contractile and metabolic improvement and physiologic cardiac hypertrophy. The present review, therefore, describes relevant studies involving the molecular characteristics and alterations from hypertensive-induced and exercise-induced hypertrophy, as well as the main proteomic research performed in this field. Furthermore, proteomic research into the effect of hypertension on other target-demerged organs is examined. PMID:24877123

Genome-wide computational analysis reveals cardiomyocyte-specific transcriptional Cis-regulatory motifs that enable efficient cardiac gene therapy.

PubMed

Rincon, Melvin Y; Sarcar, Shilpita; Danso-Abeam, Dina; Keyaerts, Marleen; Matrai, Janka; Samara-Kuko, Ermira; Acosta-Sanchez, Abel; Athanasopoulos, Takis; Dickson, George; Lahoutte, Tony; De Bleser, Pieter; VandenDriessche, Thierry; Chuah, Marinee K

2015-01-01

Gene therapy is a promising emerging therapeutic modality for the treatment of cardiovascular diseases and hereditary diseases that afflict the heart. Hence, there is a need to develop robust cardiac-specific expression modules that allow for stable expression of the gene of interest in cardiomyocytes. We therefore explored a new approach based on a genome-wide bioinformatics strategy that revealed novel cardiac-specific cis-acting regulatory modules (CS-CRMs). These transcriptional modules contained evolutionary-conserved clusters of putative transcription factor binding sites that correspond to a "molecular signature" associated with robust gene expression in the heart. We then validated these CS-CRMs in vivo using an adeno-associated viral vector serotype 9 that drives a reporter gene from a quintessential cardiac-specific α-myosin heavy chain promoter. Most de novo designed CS-CRMs resulted in a >10-fold increase in cardiac gene expression. The most robust CRMs enhanced cardiac-specific transcription 70- to 100-fold. Expression was sustained and restricted to cardiomyocytes. We then combined the most potent CS-CRM4 with a synthetic heart and muscle-specific promoter (SPc5-12) and obtained a significant 20-fold increase in cardiac gene expression compared to the cytomegalovirus promoter. This study underscores the potential of rational vector design to improve the robustness of cardiac gene therapy.

Cardiac Channel Molecular Autopsy: Insights From 173 Consecutive Cases of Autopsy-Negative Sudden Unexplained Death Referred for Postmortem Genetic Testing

PubMed Central

Tester, David J.; Medeiros-Domingo, Argelia; Will, Melissa L.; Haglund, Carla M.; Ackerman, Michael J.

2012-01-01

Objective To perform long QT syndrome and catecholaminergic polymorphic ventricular tachycardia cardiac channel postmortem genetic testing (molecular autopsy) for a large cohort of cases of autopsy-negative sudden unexplained death (SUD). Methods From September 1, 1998, through October 31, 2010, 173 cases of SUD (106 males; mean ± SD age, 18.4±12.9 years; age range, 1-69 years; 89% white) were referred by medical examiners or coroners for a cardiac channel molecular autopsy. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, a comprehensive mutational analysis of the long QT syndrome susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) and a targeted analysis of the catecholaminergic polymorphic ventricular tachycardia type 1–associated gene (RYR2) were conducted. Results Overall, 45 putative pathogenic mutations absent in 400 to 700 controls were identified in 45 autopsy-negative SUD cases (26.0%). Females had a higher yield (26/67 [38.8%]) than males (19/106 [17.9%]; P<.005). Among SUD cases with exercise-induced death, the yield trended higher among the 1- to 10-year-olds (8/12 [66.7%]) compared with the 11- to 20-year-olds (4/27 [14.8%]; P=.002). In contrast, for those who died during a period of sleep, the 11- to 20-year-olds had a higher yield (9/25 [36.0%]) than the 1- to 10-year-olds (1/24 [4.2%]; P=.01). Conclusion Cardiac channel molecular autopsy should be considered in the evaluation of autopsy-negative SUD. Several interesting genotype-phenotype observations may provide insight into the expected yields of postmortem genetic testing for SUD and assist in selecting cases with the greatest potential for mutation discovery and directing genetic testing efforts. PMID:22677073

Low molecular weight fucoidan alleviates cardiac dysfunction in diabetic Goto-Kakizaki rats by reducing oxidative stress and cardiomyocyte apoptosis.

PubMed

Yu, Xinfeng; Zhang, Quanbin; Cui, Wentong; Zeng, Zheng; Yang, Wenzhe; Zhang, Chao; Zhao, Hongwei; Gao, Weidong; Wang, Xiaomin; Luo, Dali

2014-01-01

Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and cardiomyocyte apoptosis. Oxidative stress is suggested to be the major contributor to the development of DCM. This study was intended to evaluate the protective effect of low molecular weight fucoidan (LMWF) against cardiac dysfunction in diabetic rats. Type 2 diabetic goto-kakizaki rats were untreated or treated with LMWF (50 and 100 mg/kg/day) for three months. The establishment of DCM model and the effects of LMWF on cardiac function were evaluated by echocardiography and isolated heart perfusion. Ventricle staining with H-E or Sirius Red was performed to investigate the structural changes in myocardium. Functional evaluation demonstrated that LMWF has a beneficial effect on DCM by enhancing myocardial contractility and mitigating cardiac fibrosis. Additionally, LMWF exerted significant inhibitory effects on the reactive oxygen species production and myocyte apoptosis in diabetic hearts. The depressed activity of superoxide dismutase in diabetic heart was also improved by intervention with LMWF. Moreover, LMWF robustly inhibited the enhanced expression of protein kinase C β, an important contributor to oxidative stress, in diabetic heart and high glucose-treated cardiomyocytes. In conclusion, LMWF possesses a protective effect against DCM through ameliorations of PKCβ-mediated oxidative stress and subsequent cardiomyocyte apoptosis in diabetes.

Cellular and Molecular Mechanisms of High Pressure Inotropy in Cardiac Muscle

DTIC Science & Technology

1989-08-01

on reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP Membranes, Cardiac Muscle , Contraction Force, uW - Calcium, Inotropy...elevated hydrostatic pressure over the range of 2 to 150 atmospheres causes an increase in the force of cardiac muscle contraction (1). In the first year...The present findings indicate that elevated hydrostatic pressure enhances cardiac muscle contraction by somehow affecting the disposition of calcium as

Hierarchical approaches for systems modeling in cardiac development.

PubMed

Gould, Russell A; Aboulmouna, Lina M; Varner, Jeffrey D; Butcher, Jonathan T

2013-01-01

Ordered cardiac morphogenesis and function are essential for all vertebrate life. The heart begins as a simple contractile tube, but quickly grows and morphs into a multichambered pumping organ complete with valves, while maintaining regulation of blood flow and nutrient distribution. Though not identical, cardiac morphogenesis shares many molecular and morphological processes across vertebrate species. Quantitative data across multiple time and length scales have been gathered through decades of reductionist single variable analyses. These range from detailed molecular signaling pathways at the cellular levels to cardiac function at the tissue/organ levels. However, none of these components act in true isolation from others, and each, in turn, exhibits short- and long-range effects in both time and space. With the absence of a gene, entire signaling cascades and genetic profiles may be shifted, resulting in complex feedback mechanisms. Also taking into account local microenvironmental changes throughout development, it is apparent that a systems level approach is an essential resource to accelerate information generation concerning the functional relationships across multiple length scales (molecular data vs physiological function) and structural development. In this review, we discuss relevant in vivo and in vitro experimental approaches, compare different computational frameworks for systems modeling, and the latest information about systems modeling of cardiac development. Finally, we conclude with some important future directions for cardiac systems modeling. Copyright © 2013 Wiley Periodicals, Inc.

Targeted Nuclear Imaging Probes for Cardiac Amyloidosis.

PubMed

Bravo, Paco E; Dorbala, Sharmila

2017-07-01

The aim of the present manuscript is to review the latest advancements of radionuclide molecular imaging in the diagnosis and prognosis of individuals with cardiac amyloidosis. 99m Technetium labeled bone tracer scintigraphy had been known to image cardiac amyloidosis, since the 1980s; over the past decade, bone scintigraphy has been revived specifically to diagnose transthyretin cardiac amyloidosis. 18 F labeled and 11 C labeled amyloid binding radiotracers developed for imaging Alzheimer's disease, have been repurposed since 2013, to image light chain and transthyretin cardiac amyloidosis. 99m Technetium bone scintigraphy for transthyretin cardiac amyloidosis, and amyloid binding targeted PET imaging for light chain and transthyretin cardiac amyloidosis, are emerging as highly accurate methods. Targeted radionuclide imaging may soon replace endomyocardial biopsy in the evaluation of patients with suspected cardiac amyloidosis. Further research is warranted on the role of targeted imaging to quantify cardiac amyloidosis and to guide therapy.

[The analysis of the low and medium molecular weight substances for differential diagnostics of deaths from acute small-focal myocardial infarction and other forms of cardiac pathology].

PubMed

Edelev, N S; Obuhova, L M; Edelev, I S; Katirkina, A A

The objective of the present study was to analyze the possibilities for the use of the low and medium molecular weight substances for differential diagnostics of deaths from acute small-focal myocardial infarction and other forms of cardiac pathology. We determined the amount of the low and medium molecular weight substances in the urine obtained from the subjects who had died as a result of chronic coronary heart disease, acute myocardial infarction, and alcoholic cardiomyopathy. The levels of the low and medium molecular weight substances in the urine were measured by the method of N.Ya. Malakhov in the modification of T.V. Kopytova [5]. The study has demonstrated the appearance of the products of cardiomyocyte degradation (giving rise to a peak at a wavelength of 278 nm) in the fraction of the low and medium molecular weight substances of the urine from the patients suffering from acute small-focal myocardial infarction and some other forms of cardiac pathology.

Validation of a Radiosensitivity Molecular Signature in Breast Cancer

PubMed Central

Eschrich, Steven A.; Fulp, William J.; Pawitan, Yudi; Foekens, John A.; Smid, Marcel; Martens, John W. M.; Echevarria, Michelle; Kamath, Vidya; Lee, Ji-Hyun; Harris, Eleanor E.; Bergh, Jonas; Torres-Roca, Javier F.

2014-01-01

Purpose Previously, we developed a radiosensitivity molecular signature (RSI) that was clinically-validated in three independent datasets (rectal, esophageal, head and neck) in 118 patients. Here, we test RSI in radiotherapy (RT) treated breast cancer patients. Experimental Design RSI was tested in two previously published breast cancer datasets. Patients were treated at the Karolinska University Hospital (n=159) and Erasmus Medical Center (n=344). RSI was applied as previously described. Results We tested RSI in RT-treated patients (Karolinska). Patients predicted to be radiosensitive (RS) had an improved 5 yr relapse-free survival when compared with radioresistant (RR) patients (95% vs. 75%, p=0.0212) but there was no difference between RS/RR patients treated without RT (71% vs. 77%, p=0.6744), consistent with RSI being RT-specific (interaction term RSIxRT, p=0.05). Similarly, in the Erasmus dataset RT-treated RS patients had an improved 5-year distant-metastasis-free survival over RR patients (77% vs. 64%, p=0.0409) but no difference was observed in patients treated without RT (RS vs. RR, 80% vs. 81%, p=0.9425). Multivariable analysis showed RSI is the strongest variable in RT-treated patients (Karolinska, HR=5.53, p=0.0987, Erasmus, HR=1.64, p=0.0758) and in backward selection (removal alpha of 0.10) RSI was the only variable remaining in the final model. Finally, RSI is an independent predictor of outcome in RT-treated ER+ patients (Erasmus, multivariable analysis, HR=2.64, p=0.0085). Conclusions RSI is validated in two independent breast cancer datasets totaling 503 patients. Including prior data, RSI is validated in five independent cohorts (621 patients) and represents, to our knowledge, the most extensively validated molecular signature in radiation oncology. PMID:22832933

Obesity Alters Molecular and Functional Cardiac Responses to Ischemia-Reperfusion and Glucagon-Like Peptide-1 Receptor Agonism

PubMed Central

Sassoon, Daniel J; Goodwill, Adam G; Noblet, Jillian N; Conteh, Abass M; Herring, B. Paul; McClintick, Jeanette N; Tune, Johnathan D; Mather, Kieren J

2016-01-01

This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miR) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-min coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca2+ binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion. PMID:27234258

Molecular and immunohistochemical analyses of cardiac troponin T during cardiac development in the Mexican axolotl, Ambystoma mexicanum.

PubMed

Zhang, C; Pietras, K M; Sferrazza, G F; Jia, P; Athauda, G; Rueda-de-Leon, E; Rveda-de-Leon, E; Maier, J A; Dube, D K; Lemanski, S L; Lemanski, L F

2007-01-01

The Mexican axolotl, Ambystoma mexicanum, is an excellent animal model for studying heart development because it carries a naturally occurring recessive genetic mutation, designated gene c, for cardiac nonfunction. The double recessive mutants (c/c) fail to form organized myofibrils in the cardiac myoblasts resulting in hearts that fail to beat. Tropomyosin expression patterns have been studied in detail and show dramatically decreased expression in the hearts of homozygous mutant embryos. Because of the direct interaction between tropomyosin and troponin T (TnT), and the crucial functions of TnT in the regulation of striated muscle contraction, we have expanded our studies on this animal model to characterize the expression of the TnT gene in cardiac muscle throughout normal axolotl development as well as in mutant axolotls. In addition, we have succeeded in cloning the full-length cardiac troponin T (cTnT) cDNA from axolotl hearts. Confocal microscopy has shown a substantial, but reduced, expression of TnT protein in the mutant hearts when compared to normal during embryonic development. 2006 Wiley-Liss, Inc.

Discovery and progress of direct cardiac reprogramming.

PubMed

Kojima, Hidenori; Ieda, Masaki

2017-06-01

Cardiac disease remains a major cause of death worldwide. Direct cardiac reprogramming has emerged as a promising approach for cardiac regenerative therapy. After the discovery of MyoD, a master regulator for skeletal muscle, other single cardiac reprogramming factors (master regulators) have been sought. Discovery of cardiac reprogramming factors was inspired by the finding that multiple, but not single, transcription factors were needed to generate induced pluripotent stem cells (iPSCs) from fibroblasts. We first reported a combination of cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (GMT), that could convert mouse fibroblasts into cardiomyocyte-like cells, which were designated as induced cardiomyocyte-like cells (iCMs). Following our first report of cardiac reprogramming, many researchers, including ourselves, demonstrated an improvement in cardiac reprogramming efficiency, in vivo direct cardiac reprogramming for heart regeneration, and cardiac reprogramming in human cells. However, cardiac reprogramming in human cells and adult fibroblasts remains inefficient, and further efforts are needed. We believe that future research elucidating epigenetic barriers and molecular mechanisms of direct cardiac reprogramming will improve the reprogramming efficiency, and that this new technology has great potential for clinical applications.

A computer case definition for sudden cardiac death.

PubMed

Chung, Cecilia P; Murray, Katherine T; Stein, C Michael; Hall, Kathi; Ray, Wayne A

2010-06-01

To facilitate studies of medications and sudden cardiac death, we developed and validated a computer case definition for these deaths. The study of community dwelling Tennessee Medicaid enrollees 30-74 years of age utilized a linked database with Medicaid inpatient/outpatient files, state death certificate files, and a state 'all-payers' hospital discharge file. The computerized case definition was developed from a retrospective cohort study of sudden cardiac deaths occurring between 1990 and 1993. Medical records for 926 potential cases had been adjudicated for this study to determine if they met the clinical definition for sudden cardiac death occurring in the community and were likely to be due to ventricular tachyarrhythmias. The computerized case definition included deaths with (1) no evidence of a terminal hospital admission/nursing home stay in any of the data sources; (2) an underlying cause of death code consistent with sudden cardiac death; and (3) no terminal procedures inconsistent with unresuscitated cardiac arrest. This definition was validated in an independent sample of 174 adjudicated deaths occurring between 1994 and 2005. The positive predictive value of the computer case definition was 86.0% in the development sample and 86.8% in the validation sample. The positive predictive value did not vary materially for deaths coded according to the ICO-9 (1994-1998, positive predictive value = 85.1%) or ICD-10 (1999-2005, 87.4%) systems. A computerized Medicaid database, linked with death certificate files and a state hospital discharge database, can be used for a computer case definition of sudden cardiac death. Copyright (c) 2009 John Wiley & Sons, Ltd.

Validation of a next-generation sequencing assay for clinical molecular oncology.

PubMed

Cottrell, Catherine E; Al-Kateb, Hussam; Bredemeyer, Andrew J; Duncavage, Eric J; Spencer, David H; Abel, Haley J; Lockwood, Christina M; Hagemann, Ian S; O'Guin, Stephanie M; Burcea, Lauren C; Sawyer, Christopher S; Oschwald, Dayna M; Stratman, Jennifer L; Sher, Dorie A; Johnson, Mark R; Brown, Justin T; Cliften, Paul F; George, Bijoy; McIntosh, Leslie D; Shrivastava, Savita; Nguyen, Tudung T; Payton, Jacqueline E; Watson, Mark A; Crosby, Seth D; Head, Richard D; Mitra, Robi D; Nagarajan, Rakesh; Kulkarni, Shashikant; Seibert, Karen; Virgin, Herbert W; Milbrandt, Jeffrey; Pfeifer, John D

2014-01-01

Currently, oncology testing includes molecular studies and cytogenetic analysis to detect genetic aberrations of clinical significance. Next-generation sequencing (NGS) allows rapid analysis of multiple genes for clinically actionable somatic variants. The WUCaMP assay uses targeted capture for NGS analysis of 25 cancer-associated genes to detect mutations at actionable loci. We present clinical validation of the assay and a detailed framework for design and validation of similar clinical assays. Deep sequencing of 78 tumor specimens (≥ 1000× average unique coverage across the capture region) achieved high sensitivity for detecting somatic variants at low allele fraction (AF). Validation revealed sensitivities and specificities of 100% for detection of single-nucleotide variants (SNVs) within coding regions, compared with SNP array sequence data (95% CI = 83.4-100.0 for sensitivity and 94.2-100.0 for specificity) or whole-genome sequencing (95% CI = 89.1-100.0 for sensitivity and 99.9-100.0 for specificity) of HapMap samples. Sensitivity for detecting variants at an observed 10% AF was 100% (95% CI = 93.2-100.0) in HapMap mixes. Analysis of 15 masked specimens harboring clinically reported variants yielded concordant calls for 13/13 variants at AF of ≥ 15%. The WUCaMP assay is a robust and sensitive method to detect somatic variants of clinical significance in molecular oncology laboratories, with reduced time and cost of genetic analysis allowing for strategic patient management. Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Feature tracking cardiac magnetic resonance imaging: A review of a novel non-invasive cardiac imaging technique

PubMed Central

Rahman, Zia Ur; Sethi, Pooja; Murtaza, Ghulam; Virk, Hafeez Ul Hassan; Rai, Aitzaz; Mahmod, Masliza; Schoondyke, Jeffrey; Albalbissi, Kais

2017-01-01

Cardiovascular disease is a leading cause of morbidity and mortality globally. Early diagnostic markers are gaining popularity for better patient care disease outcomes. There is an increasing interest in noninvasive cardiac imaging biomarkers to diagnose subclinical cardiac disease. Feature tracking cardiac magnetic resonance imaging is a novel post-processing technique that is increasingly being employed to assess global and regional myocardial function. This technique has numerous applications in structural and functional diagnostics. It has been validated in multiple studies, although there is still a long way to go for it to become routine standard of care. PMID:28515849

Technical aspects of cardiac PET/MRI.

PubMed

Masuda, Atsuro; Nemoto, Ayaka; Takeishi, Yasuchika

2018-06-01

PET/MRI is a novel modality that enables to combine PET and MR images, and has significant potential to evaluate various cardiac diseases through the combination of PET molecular imaging and MRI functional imaging. Precise management of technical issues, however, is necessary for cardiac PET/MRI. This article describes several technical points, including patient preparation, MR attenuation correction, parallel acquisition of PET with MRI, clinical aspects, and image quality control.

Development and psychometric validation of a scale to assess information needs in cardiac rehabilitation: the INCR Tool.

PubMed

Ghisi, Gabriela Lima de Melo; Grace, Sherry L; Thomas, Scott; Evans, Michael F; Oh, Paul

2013-06-01

To develop and psychometrically validate a tool to assess information needs in cardiac rehabilitation (CR) patients. After a literature search, 60 information items divided into 11 areas of needs were identified. To establish content validity, they were reviewed by an expert panel (N=10). Refined items were pilot-tested in 34 patients on a 5-point Likert-scale from 1 "really not helpful" to 5 "very important". A final version was generated and psychometrically tested in 203 CR patients. Test-retest reliability was assessed via the intraclass correlation coefficient (ICC), the internal consistency using Cronbach's alpha, and criterion validity was assessed with regard to patient's education and duration in CR. Five items were excluded after ICC analysis as well as one area of needs. All 10 areas were considered internally consistent (Cronbach's alpha>0.7). Criterion validity was supported by significant differences in mean scores by educational level (p<0.05) and duration in CR (p<0.001). The mean total score was 4.08 ± 0.53. Patients rated safety as their greatest information need. The INCR Tool was demonstrated to have good reliability and validity. This is an appropriate tool for application in clinical and research settings, assessing patients' needs during CR and as part of education programming. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Content validation of the operational definitions of the nursing diagnoses of activity intolerance, excess fluid volume, and decreased cardiac output in patients with heart failure.

PubMed

de Souza, Vanessa; Zeitoun, Sandra Salloum; Lopes, Camila Takao; de Oliveira, Ana Paula Dias; Lopes, Juliana de Lima; de Barros, Alba Lucia Botura Leite

2014-06-01

To consensually validate the operational definitions of the nursing diagnoses activity intolerance, excessive fluid volume, and decreased cardiac output in patients with decompensated heart failure. Consensual validation was performed in two stages: analogy by similarity of defining characteristics, and development of operational definitions and validation with experts. A total of 38 defining characteristics were found. Operational definitions were developed and content-validated. One hundred percent of agreement was achieved among the seven experts after five rounds. "Ascites" was added in the nursing diagnosis excessive fluid volume. The consensual validation improves interpretation of human response, grounding the selection of nursing interventions and contributing to improved nursing outcomes. Support the assessment of patients with decompensated heart failure. © 2013 NANDA International.

Cardiac Delayed Rectifier Potassium Channels in Health and Disease.

PubMed

Chen, Lei; Sampson, Kevin J; Kass, Robert S

2016-06-01

Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this article, we will review their molecular identities and biophysical properties. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiac Delayed Rectifier Potassium Channels in Health and Disease

PubMed Central

Chen, Lei; Sampson, Kevin J.; Kass, Robert S.

2016-01-01

Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this chapter, we will review the molecular identities and biophysical properties of these channels. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the possibility and prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia. PMID:27261823

Human cardiac telocytes: 3D imaging by FIB-SEM tomography.

PubMed

Cretoiu, D; Hummel, E; Zimmermann, H; Gherghiceanu, M; Popescu, L M

2014-11-01

Telocyte (TC) is a newly identified type of cell in the cardiac interstitium (www.telocytes.com). TCs are described by classical transmission electron microscopy as cells with very thin and long telopodes (Tps; cellular prolongations) having podoms (dilations) and podomers (very thin segments). TCs' three-dimensional (3D) morphology is still unknown. Cardiac TCs seem to be particularly involved in long and short distance intercellular signalling and, therefore, their 3D architecture is important for understanding their spatial connections. Using focused ion beam scanning electron microscopy (FIB-SEM) we show, for the first time, the whole ultrastructural anatomy of cardiac TCs. 3D reconstruction of cardiac TCs by FIB-SEM tomography confirms that they have long, narrow but flattened (ribbon-like) telopodes, with humps generated by the podoms. FIB-SEM tomography also confirms the network made by TCs in the cardiac interstitium through adherens junctions. This study provides the first FIB-SEM tomography of a human cell type. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Validity of body composition assessment methods for older men with cardiac disease.

PubMed

Young, H; Porcari, J; Terry, L; Brice, G

1998-01-01

This study was designed to determine which of several body composition assessment methods was most accurate for patients with cardiac disease for the purpose of outcome measurement. Six body composition assessment methods were administered to each of 24 men with cardiac disease. Methods included circumference measurement, skinfold measurement, near-infrared interactance via the Futrex-5000, bioelectrical impedance via the BioAnalogics ElectroLipoGraph and Tanita TBF-150, and hydrostatic weighing, the criterion measure. A repeated measures analysis of variance indicated no significant (P > .05) difference between circumference and skinfold measurements compared to hydrostatic weighing. Near-infrared interactance presented the best standard error of estimates (3.5%) and the best correlation (r = .84) with hydrostatic weighing; however, the constant error was 3.76%. Bioelectrical impedance measured by the ElectroLipoGraph and TBF-150 instruments significantly underestimated percent body fat by 8.81% and 4.8%, respectively. In this study of middle-aged to older men with cardiac disease, the best method for determining body fat was circumferences. This technique was accurate, easy to administer, inexpensive, and had a lower error potential than the other techniques. Skinfold measurements were also closely related to hydrostatic weighing, but should be performed only by experienced practitioners because there is a greater potential for tester error in certain patients. In the future, near-infrared interactance measurements may be a viable technique for body composition assessment in patients with cardiac disease. However, algorithms specific to the population of patients with cardiac disease being tested must be developed before this technique can be routinely recommended for body composition assessment. Bioelectrical impedance assessment by either method is not recommended for patients with cardiac disease, as it consistently underestimated percent body fat when

Novel System for Real-Time Integration of 3-D Echocardiography and Fluoroscopy for Image-Guided Cardiac Interventions: Preclinical Validation and Clinical Feasibility Evaluation.

PubMed

Arujuna, Aruna V; Housden, R James; Ma, Yingliang; Rajani, Ronak; Gao, Gang; Nijhof, Niels; Cathier, Pascal; Bullens, Roland; Gijsbers, Geert; Parish, Victoria; Kapetanakis, Stamatis; Hancock, Jane; Rinaldi, C Aldo; Cooklin, Michael; Gill, Jaswinder; Thomas, Martyn; O'neill, Mark D; Razavi, Reza; Rhode, Kawal S

2014-01-01

Real-time imaging is required to guide minimally invasive catheter-based cardiac interventions. While transesophageal echocardiography allows for high-quality visualization of cardiac anatomy, X-ray fluoroscopy provides excellent visualization of devices. We have developed a novel image fusion system that allows real-time integration of 3-D echocardiography and the X-ray fluoroscopy. The system was validated in the following two stages: 1) preclinical to determine function and validate accuracy; and 2) in the clinical setting to assess clinical workflow feasibility and determine overall system accuracy. In the preclinical phase, the system was assessed using both phantom and porcine experimental studies. Median 2-D projection errors of 4.5 and 3.3 mm were found for the phantom and porcine studies, respectively. The clinical phase focused on extending the use of the system to interventions in patients undergoing either atrial fibrillation catheter ablation (CA) or transcatheter aortic valve implantation (TAVI). Eleven patients were studied with nine in the CA group and two in the TAVI group. Successful real-time view synchronization was achieved in all cases with a calculated median distance error of 2.2 mm in the CA group and 3.4 mm in the TAVI group. A standard clinical workflow was established using the image fusion system. These pilot data confirm the technical feasibility of accurate real-time echo-fluoroscopic image overlay in clinical practice, which may be a useful adjunct for real-time guidance during interventional cardiac procedures.

Current perspectives on cardiac amyloidosis

PubMed Central

Guan, Jian; Mishra, Shikha; Falk, Rodney H.

2012-01-01

Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed “cardiac amyloidosis” or “amyloid cardiomyopathy.” Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis. PMID:22058156

Analyzing Gene Expression Profiles with Preliminary Validations in Cardiac Hypertrophy Induced by Pressure-overload.

PubMed

Gao, Jing; Li, Yuhong; Wang, Tongmei; Shi, Zhuo; Zhang, Yiqi; Liu, Shuang; Wen, Pushuai; Ma, Chunyan

2018-03-06

The aim of this study was to identify the key genes involved in the cardiac hypertrophy (CH) induced by pressure overload. mRNA microarray dataset GSE5500 and GSE18801 were downloaded from GEO database, and differentially expressed genes (DEGs) were screened using Limma package; then, functional and pathway enrichment analysis were performed for common DEGs using DAVID database. Furthermore, the top DEGs were further validated using qPCR in the hypertrophic heart tissue induced by Isoprenaline (ISO). A total of 113 common DEGs with absolute fold change >0.5, including 60 significantly up-regulated DEGs and 53 down-regulated DEGs were obtained. GO term enrichment analysis suggested that common up-regulated DEG mainly enriched in neutrophil chemotaxis, extracellular fibril organization and cell proliferation, and the common down-regulated genes were significantly enriched in ion transport, endoplasmic reticulum and dendritic spine. KEGG pathway analysis found that the common DEGs were mainly enriched in ECM-receptor interaction, phagosome, and focal adhesion. Additionally, the expression of Mfap4, Ltbp2, Aspn, Serpina3n, and Cnksr1 were up-regulated in the model of cardiac hypertrophy, while the expression of Anp32a was down-regulated. The current study identified the key deregulated genes and pathways involved in the CH, which could shed new light to understand the mechanism of CH.

Cardiac Mechano-Gated Ion Channels and Arrhythmias

PubMed Central

Peyronnet, Remi; Nerbonne, Jeanne M.; Kohl, Peter

2015-01-01

Mechanical forces will have been omnipresent since the origin of life, and living organisms have evolved mechanisms to sense, interpret and respond to mechanical stimuli. The cardiovascular system in general, and the heart in particular, are exposed to constantly changing mechanical signals, including stretch, compression, bending, and shear. The heart adjusts its performance to the mechanical environment, modifying electrical, mechanical, metabolic, and structural properties over a range of time scales. Many of the underlying regulatory processes are encoded intra-cardially, and are thus maintained even in heart transplant recipients. Although mechano-sensitivity of heart rhythm has been described in the medical literature for over a century, its molecular mechanisms are incompletely understood. Thanks to modern biophysical and molecular technologies, the roles of mechanical forces in cardiac biology are being explored in more detail, and detailed mechanisms of mechano-transduction have started to emerge. Mechano-gated ion channels are cardiac mechano-receptors. They give rise to mechano-electric feedback, thought to contribute to normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute mechanical effects on cardiac electrophysiology, explore molecular candidates underlying observed responses, and discuss their pharmaceutical regulation. From this, we identify open research questions and highlight emerging technologies that may help in addressing them. Cardiac electrophysiology is acutely affected by the heart’s mechanical environment. Mechano-electric feedback affects excitability, conduction, and electrical load, and remains an underestimated player in arrhythmogenesis. The utility of therapeutic interventions targeting acute mechano-electrical transduction is an open field worthy of further study. PMID:26838316

Primary Cardiac Allograft Dysfunction-Validation of a Clinical Definition.

PubMed

Dronavalli, Vamsidhar B; Rogers, Chris A; Banner, Nicholas R

2015-09-01

Heart transplantation is an established treatment for advanced heart failure. Primary allograft dysfunction (PGD) is reported in up to 40% of transplants and is associated with a poor outcome. As part of Heart Evaluation and Retrieval for Transplantation study, an investigation of the assessment of donor hearts for transplantation, we proposed a clinical definition for cardiac PGD comprising severely impaired systolic function affecting one or both ventricles accompanied by hypotension, low cardiac output, and high filling pressures occurring in the first 72 hours (in the absence of hyper acute rejection and technical surgical factors, such as cardiac tamponade). Here, we examine the prospective application of this definition to 290 heart transplants. We compared the clinical outcome of PGD and non-PGD cases. Ninety-four of 290 transplants developed PGD (32.4%). Inotrope use (score) was higher in the PGD group at 24, 48, and 72 hours after transplantation (P < 0.01). In the PGD group, there was a greater requirement for, intra-aortic balloon pump (50% vs 15%, P < 0.01), mechanical support (27% vs 0%, P < 0.01), and renal replacement therapy (61% vs 26%, P < 0.01). Intensive care stay was longer for recipients with PGD (median 14 vs 5 days, P < 0.01) and early mortality was higher (37% vs 4% at 30 days, 42% vs 8% at 1 year, P < 0.01). In conclusion, our definition of PGD could be applied in a national multicenter study, and the cases it defined had more frequent complications and higher mortality.

On the Evolution of the Cardiac Pacemaker

PubMed Central

Burkhard, Silja; van Eif, Vincent; Garric, Laurence; Christoffels, Vincent M.; Bakkers, Jeroen

2017-01-01

The rhythmic contraction of the heart is initiated and controlled by an intrinsic pacemaker system. Cardiac contractions commence at very early embryonic stages and coordination remains crucial for survival. The underlying molecular mechanisms of pacemaker cell development and function are still not fully understood. Heart form and function show high evolutionary conservation. Even in simple contractile cardiac tubes in primitive invertebrates, cardiac function is controlled by intrinsic, autonomous pacemaker cells. Understanding the evolutionary origin and development of cardiac pacemaker cells will help us outline the important pathways and factors involved. Key patterning factors, such as the homeodomain transcription factors Nkx2.5 and Shox2, and the LIM-homeodomain transcription factor Islet-1, components of the T-box (Tbx), and bone morphogenic protein (Bmp) families are well conserved. Here we compare the dominant pacemaking systems in various organisms with respect to the underlying molecular regulation. Comparative analysis of the pathways involved in patterning the pacemaker domain in an evolutionary context might help us outline a common fundamental pacemaker cell gene programme. Special focus is given to pacemaker development in zebrafish, an extensively used model for vertebrate development. Finally, we conclude with a summary of highly conserved key factors in pacemaker cell development and function. PMID:29367536

Validation of an ultrasound dilution technology for cardiac output measurement and shunt detection in infants and children.

PubMed

Lindberg, Lars; Johansson, Sune; Perez-de-Sa, Valeria

2014-02-01

To validate cardiac output measurements by ultrasound dilution technology (COstatus monitor) against those obtained by a transit-time ultrasound technology with a perivascular flow probe and to investigate ultrasound dilution ability to estimate pulmonary to systemic blood flow ratio in children. Prospective observational clinical trial. Pediatric cardiac operating theater in a university hospital. In 21 children (6.1 ± 2.6 kg, mean ± SD) undergoing heart surgery, cardiac output was simultaneously recorded by ultrasound dilution (extracorporeal arteriovenous loop connected to existing arterial and central venous catheters) and a transit-time ultrasound probe applied to the ascending aorta, and when possible, the main pulmonary artery. The pulmonary to systemic blood flow ratio estimated from ultrasound dilution curve analysis was compared with that estimated from transit-time ultrasound technology. Bland-Altman analysis of the whole cohort (90 pairs, before and after surgery) showed a bias between transit-time ultrasound (1.01 ± 0.47 L/min) and ultrasound dilution technology (1.03 ± 0.51 L/min) of -0.02 L/min, limits of agreement -0.3 to 0.3 L/min, and percentage error of 31%. In children with no residual shunts, the bias was -0.04 L/min, limits of agreement -0.28 to 0.2 L/min, and percentage error 19%. The pooled co efficient of variation was for the whole cohort 3.5% (transit-time ultrasound) and 6.3% (ultrasound dilution), and in children without shunt, it was 2.9% (transit-time ultrasound) and 4% (ultrasound dilution), respectively. Ultrasound dilution identified the presence of shunts (pulmonary to systemic blood flow ≠ 1) with a sensitivity of 100% and a specificity of 92%. Mean pulmonary to systemic blood flow ratio by transit-time ultrasound was 2.6 ± 1.0 and by ultrasound dilution 2.2 ± 0.7 (not significant). The COstatus monitor is a reliable technique to measure cardiac output in children with high sensitivity and specificity for detecting the

What does it cost to prevent on-duty firefighter cardiac events? A content valid method for calculating costs.

PubMed

Patterson, P Daniel; Suyama, Joe; Reis, Steven E; Weaver, Matthew D; Hostler, David

2013-01-01

Cardiac arrest is a leading cause of mortality among firefighters. We sought to develop a valid method for determining the costs of a workplace prevention program for firefighters. In 2012, we developed a draft framework using human resource accounting and in-depth interviews with experts in the firefighting and insurance industries. The interviews produced a draft cost model with 6 components and 26 subcomponents. In 2013, we randomly sampled 100 fire chiefs out of >7,400 affiliated with the International Association of Fire Chiefs. We used the Content Validity Index (CVI) to identify the content valid components of the draft cost model. This was accomplished by having fire chiefs rate the relevancy of cost components using a 4-point Likert scale (highly relevant to not relevant). We received complete survey data from 65 fire chiefs (65% response rate). We retained 5 components and 21 subcomponents based on CVI scores ≥0.70. The five main components include, (1) investment costs, (2) orientation and training costs, (3) medical and pharmaceutical costs, (4) education and continuing education costs, and (5) maintenance costs. Data from a diverse sample of fire chiefs has produced a content valid method for calculating the cost of a prevention program among firefighters.

What Does It Cost to Prevent On-Duty Firefighter Cardiac Events? A Content Valid Method for Calculating Costs

PubMed Central

Patterson, P. Daniel; Suyama, Joe; Reis, Steven E.; Weaver, Matthew D.; Hostler, David

2013-01-01

Cardiac arrest is a leading cause of mortality among firefighters. We sought to develop a valid method for determining the costs of a workplace prevention program for firefighters. In 2012, we developed a draft framework using human resource accounting and in-depth interviews with experts in the firefighting and insurance industries. The interviews produced a draft cost model with 6 components and 26 subcomponents. In 2013, we randomly sampled 100 fire chiefs out of >7,400 affiliated with the International Association of Fire Chiefs. We used the Content Validity Index (CVI) to identify the content valid components of the draft cost model. This was accomplished by having fire chiefs rate the relevancy of cost components using a 4-point Likert scale (highly relevant to not relevant). We received complete survey data from 65 fire chiefs (65% response rate). We retained 5 components and 21 subcomponents based on CVI scores ≥0.70. The five main components include, (1) investment costs, (2) orientation and training costs, (3) medical and pharmaceutical costs, (4) education and continuing education costs, and (5) maintenance costs. Data from a diverse sample of fire chiefs has produced a content valid method for calculating the cost of a prevention program among firefighters. PMID:24455288

ADAPTIVE REAL-TIME CARDIAC MRI USING PARADISE: VALIDATION BY THE PHYSIOLOGICALLY IMPROVED NCAT PHANTOM

PubMed Central

Sharif, Behzad; Bresler, Yoram

2013-01-01

Patient-Adaptive Reconstruction and Acquisition Dynamic Imaging with Sensitivity Encoding (PARADISE) is a dynamic MR imaging scheme that optimally combines parallel imaging and model-based adaptive acquisition. In this work, we propose the application of PARADISE to real-time cardiac MRI. We introduce a physiologically improved version of a realistic four-dimensional cardiac-torso (NCAT) phantom, which incorporates natural beat-to-beat heart rate and motion variations. Cardiac cine imaging using PARADISE is simulated and its performance is analyzed by virtue of the improved phantom. Results verify the effectiveness of PARADISE for high resolution un-gated real-time cardiac MRI and its superiority over conventional acquisition methods. PMID:24398475

Diagnostic value of quantitative assessment of cardiac 18F-fluoro-2-deoxyglucose uptake in suspected cardiac sarcoidosis.

PubMed

Lebasnier, Adrien; Legallois, Damien; Bienvenu, Boris; Bergot, Emmanuel; Desmonts, Cédric; Zalcman, Gérard; Agostini, Denis; Manrique, Alain

2018-06-01

The identification of cardiac sarcoidosis is challenging as there is no gold standard consensually admitted for its diagnosis. The aim of this study was to evaluate the diagnostic value of the assessment of cardiac dynamic 18 F-fluoro-2-deoxyglucose positron emission tomography ( 18 F-FDG PET/CT) and net influx constant (Ki) in patients suspected of cardiac sarcoidosis. Data obtained from 30 biopsy-proven sarcoidosis patients suspected of cardiac sarcoidosis who underwent a 50-min list-mode cardiac dynamic 18 F-FDG PET/CT after a 24 h high-fat and low-carbohydrate diet were analyzed. A normalized coefficient of variation of quantitative glucose influx constant, calculated as the ratio: standard deviation of the segmental Ki (min -1 )/global Ki (min -1 ) was determined using a validated software (Carimas ® 2.4, Turku PET Centre). Cardiac sarcoidosis was diagnosed according to the Japanese Ministry of Health and Welfare criteria. Receiving operating curve analysis was performed to determine sensitivity and specificity of cardiac dynamic 18 F-FDG PET/CT analysis to diagnose cardiac sarcoidosis. Six out of 30 patients (20%) were diagnosed as having cardiac sarcoidosis. Myocardial glucose metabolism was significantly heterogeneous in patients with cardiac sarcoidosis who showed significantly higher normalized coefficient of variation values compared to patients without cardiac sarcoidosis (0.513 ± 0.175 vs. 0.205 ± 0.081; p = 0.0007). Using ROC curve analysis, we found a cut-off value of 0.38 for the diagnosis of cardiac sarcoidosis with a sensitivity of 100% and a specificity of 91%. Our results suggest that quantitative analysis of cardiac dynamic 18 F-FDG PET/CT could be a useful tool for the diagnosis of cardiac sarcoidosis.

Classification of cardiac rhythm using heart rate dynamical measures: validation in MIT-BIH databases.

PubMed

Carrara, Marta; Carozzi, Luca; Moss, Travis J; de Pasquale, Marco; Cerutti, Sergio; Lake, Douglas E; Moorman, J Randall; Ferrario, Manuela

2015-01-01

Identification of atrial fibrillation (AF) is a clinical imperative. Heartbeat interval time series are increasingly available from personal monitors, allowing new opportunity for AF diagnosis. Previously, we devised numerical algorithms for identification of normal sinus rhythm (NSR), AF, and SR with frequent ectopy using dynamical measures of heart rate. Here, we wished to validate them in the canonical MIT-BIH ECG databases. We tested algorithms on the NSR, AF and arrhythmia databases. When the databases were combined, the positive predictive value of the new algorithms exceeded 95% for NSR and AF, and was 40% for SR with ectopy. Further, dynamical measures did not distinguish atrial from ventricular ectopy. Inspection of individual 24hour records showed good correlation of observed and predicted rhythms. Heart rate dynamical measures are effective ingredients in numerical algorithms to classify cardiac rhythm from the heartbeat intervals time series alone. Copyright © 2015 Elsevier Inc. All rights reserved.

Validation and application of single breath cardiac output determinations in man

NASA Technical Reports Server (NTRS)

Loeppky, J. A.; Fletcher, E. R.; Myhre, L. G.; Luft, U. C.

1986-01-01

The results of a procedure for estimating cardiac output by a single-breath technique (Qsb), obtained in healthy males during supine rest and during exercise on a bicycle ergometer, were compared with the results on cardiac output obtained by the direct Fick method (QF). The single breath maneuver consisted of a slow exhalation to near residual volume following an inspiration somewhat deeper than normal. The Qsb calculations incorporated an equation of the CO2 dissociation curve and a 'moving spline' sequential curve-fitting technique to calculate the instantaneous R from points on the original expirogram. The resulting linear regression equation indicated a 24-percent underestimation of QF by the Qsb technique. After applying a correction, the Qsb-QF relationship was improved. A subsequent study during upright rest and exercise to 80 percent of VO2(max) in 6 subjects indicated a close linear relationship between Qsb and VO2 for all 95 values obtained, with slope and intercept close to those in published studies in which invasive cardiac output measurements were used.

Conceptual Foundations of Systems Biology Explaining Complex Cardiac Diseases.

PubMed

Louridas, George E; Lourida, Katerina G

2017-02-21

Systems biology is an important concept that connects molecular biology and genomics with computing science, mathematics and engineering. An endeavor is made in this paper to associate basic conceptual ideas of systems biology with clinical medicine. Complex cardiac diseases are clinical phenotypes generated by integration of genetic, molecular and environmental factors. Basic concepts of systems biology like network construction, modular thinking, biological constraints (downward biological direction) and emergence (upward biological direction) could be applied to clinical medicine. Especially, in the field of cardiology, these concepts can be used to explain complex clinical cardiac phenotypes like chronic heart failure and coronary artery disease. Cardiac diseases are biological complex entities which like other biological phenomena can be explained by a systems biology approach. The above powerful biological tools of systems biology can explain robustness growth and stability during disease process from modulation to phenotype. The purpose of the present review paper is to implement systems biology strategy and incorporate some conceptual issues raised by this approach into the clinical field of complex cardiac diseases. Cardiac disease process and progression can be addressed by the holistic realistic approach of systems biology in order to define in better terms earlier diagnosis and more effective therapy.

TRIMS: Validating T2 Molecular Effects for Neutrino Mass Experiments

NASA Astrophysics Data System (ADS)

Lin, Ying-Ting; Trims Collaboration

2017-09-01

The Tritium Recoil-Ion Mass Spectrometer (TRIMS) experiment examines the branching ratio of the molecular tritium (T2) beta decay to the bound state (3HeT+). Measuring this branching ratio helps to validate the current molecular final-state theory applied in neutrino mass experiments such as KATRIN and Project 8. TRIMS consists of a magnet-guided time-of-flight mass spectrometer with a detector located on each end. By measuring the kinetic energy and time-of-flight difference of the ions and beta particles reaching the detectors, we will be able to distinguish molecular ions from atomic ones and hence derive the ratio in question. We will give an update on the apparatus, simulation software, and analysis tools, including efforts to improve the resolution of our detectors and to characterize the stability and uniformity of our field sources. We will also share our commissioning results and prospects for physics data. The TRIMS experiment is supported by U.S. Department of Energy Office of Science, Office of Nuclear Physics, Award Number DE-FG02-97ER41020.

Development and validation of risk models and molecular diagnostics to permit personalized management of cancer.

PubMed

Pu, Xia; Ye, Yuanqing; Wu, Xifeng

2014-01-01

Despite the advances made in cancer management over the past few decades, improvements in cancer diagnosis and prognosis are still poor, highlighting the need for individualized strategies. Toward this goal, risk prediction models and molecular diagnostic tools have been developed, tailoring each step of risk assessment from diagnosis to treatment and clinical outcomes based on the individual's clinical, epidemiological, and molecular profiles. These approaches hold increasing promise for delivering a new paradigm to maximize the efficiency of cancer surveillance and efficacy of treatment. However, they require stringent study design, methodology development, comprehensive assessment of biomarkers and risk factors, and extensive validation to ensure their overall usefulness for clinical translation. In the current study, the authors conducted a systematic review using breast cancer as an example and provide general guidelines for risk prediction models and molecular diagnostic tools, including development, assessment, and validation. © 2013 American Cancer Society.

Transcriptional profile of isoproterenol-induced cardiomyopathy and comparison to exercise-induced cardiac hypertrophy and human cardiac failure

PubMed Central

2009-01-01

Background Isoproterenol-induced cardiac hypertrophy in mice has been used in a number of studies to model human cardiac disease. In this study, we compared the transcriptional response of the heart in this model to other animal models of heart failure, as well as to the transcriptional response of human hearts suffering heart failure. Results We performed microarray analyses on RNA from mice with isoproterenol-induced cardiac hypertrophy and mice with exercise-induced physiological hypertrophy and identified 865 and 2,534 genes that were significantly altered in pathological and physiological cardiac hypertrophy models, respectively. We compared our results to 18 different microarray data sets (318 individual arrays) representing various other animal models and four human cardiac diseases and identified a canonical set of 64 genes that are generally altered in failing hearts. We also produced a pairwise similarity matrix to illustrate relatedness of animal models with human heart disease and identified ischemia as the human condition that most resembles isoproterenol treatment. Conclusion The overall patterns of gene expression are consistent with observed structural and molecular differences between normal and maladaptive cardiac hypertrophy and support a role for the immune system (or immune cell infiltration) in the pathology of stress-induced hypertrophy. Cross-study comparisons such as the results presented here provide targets for further research of cardiac disease that might generally apply to maladaptive cardiac stresses and are also a means of identifying which animal models best recapitulate human disease at the transcriptional level. PMID:20003209

Force Generation via β-Cardiac Myosin, Titin, and α-Actinin Drives Cardiac Sarcomere Assembly from Cell-Matrix Adhesions.

PubMed

Chopra, Anant; Kutys, Matthew L; Zhang, Kehan; Polacheck, William J; Sheng, Calvin C; Luu, Rebeccah J; Eyckmans, Jeroen; Hinson, J Travis; Seidman, Jonathan G; Seidman, Christine E; Chen, Christopher S

2018-01-08

Truncating mutations in the sarcomere protein titin cause dilated cardiomyopathy due to sarcomere insufficiency. However, it remains mechanistically unclear how these mutations decrease sarcomere content in cardiomyocytes. Utilizing human induced pluripotent stem cell-derived cardiomyocytes, CRISPR/Cas9, and live microscopy, we characterize the fundamental mechanisms of human cardiac sarcomere formation. We observe that sarcomerogenesis initiates at protocostameres, sites of cell-extracellular matrix adhesion, where nucleation and centripetal assembly of α-actinin-2-containing fibers provide a template for the fusion of Z-disk precursors, Z bodies, and subsequent striation. We identify that β-cardiac myosin-titin-protocostamere form an essential mechanical connection that transmits forces required to direct α-actinin-2 centripetal fiber assembly and sarcomere formation. Titin propagates diastolic traction stresses from β-cardiac myosin, but not α-cardiac myosin or non-muscle myosin II, to protocostameres during sarcomerogenesis. Ablating protocostameres or decoupling titin from protocostameres abolishes sarcomere assembly. Together these results identify the mechanical and molecular components critical for human cardiac sarcomerogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Predictors of operating room extubation in adult cardiac surgery.

PubMed

Subramaniam, Kathirvel; DeAndrade, Diana S; Mandell, Daniel R; Althouse, Andrew D; Manmohan, Rajan; Esper, Stephen A; Varga, Jeffrey M; Badhwar, Vinay

2017-11-01

The primary objective of the study was to identify perioperative factors associated with successful immediate extubation in the operating room after adult cardiac surgery. The secondary objective was to derive a simplified predictive scoring system to guide clinicians in operating room extubation. All 1518 patients in this retrospective cohort study underwent standardized fast-track cardiac anesthetic protocol during adult cardiac surgery. Perioperative variables between patients who had successful extubation in the operating room versus in the intensive care unit were retrospectively analyzed using both univariate and multivariable logistic regression analyses. A predictive score of successful operating room extubation was constructed from the multivariable results of 800 patients (derivation set), and the scoring system was further tested using a validation set of 398 patients. Younger age, lower body mass index, higher preoperative serum albumin, absence of chronic lung disease and diabetes, less-invasive surgical approach, isolated coronary bypass surgery, elective surgery, and lower doses of intraoperative intravenous fentanyl were independently associated with higher probability of operating room extubation. The extubation prediction score created in a derivation set of patients performed well in the validation set. Patient scores less than 0 had a minimal probability of successful operating room extubation. Operating room extubation was highly predicted with scores of 5 or greater. Perioperative factors that are independently associated with successful operating room extubation after adult cardiac operations were identified, and an operating room extubation prediction scoring system was validated. This scoring system may be used to guide safe operating room extubation after cardiac operations. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Ultrasound molecular imaging of acute cardiac transplantation rejection using nanobubbles targeted to T lymphocytes.

PubMed

Liu, Jinfeng; Chen, Yihan; Wang, Guohua; Lv, Qing; Yang, Yali; Wang, Jing; Zhang, Pingyu; Liu, Jie; Xie, Yu; Zhang, Li; Xie, Mingxing

2018-04-01

Clinical surveillance of acute heart transplantation rejection requires repeated invasive endomyocardial biopsies and noninvasive diagnostic techniques are desperately needed. It is acknowledged that T lymphocyte infiltration is the central process of acute rejection. We hypothesized that ultrasound molecular imaging with T lymphocyte-targeted nanobubbles could be used to detect acute rejection in heart transplantation. In this study, nanobubbles bearing anti-CD3 antibody (NB CD3 ) or isotype antibody (NB con ) were prepared and characterized. There was significant adhesion of NB CD3 to T lymphocytes compared with NB con in vitro. The signal intensity of the adherent NB CD3 was significantly higher than that of the NB con in allograft rats, but not significantly different in isograft rats. Furthermore, the signal intensity of NB CD3 in allograft rats was significantly higher than that in isograft rats, indicating more T lymphocyte infiltration in allograft rats compared with isograft rats. These results were further confirmed by immunohistochemistry examination, and the signal intensity of NB CD3 was positively correlated with the number of T lymphocytes in allograft rats. In summary, ultrasound molecular imaging with T lymphocyte-targeted nanobubbles can detect T lymphocyte infiltration in acute rejection and could be used as a noninvasive method in acute rejection detection after cardiac transplantation. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Frailty and cardiac rehabilitation: A call to action from the EAPC Cardiac Rehabilitation Section.

PubMed

Vigorito, Carlo; Abreu, Ana; Ambrosetti, Marco; Belardinelli, Romualdo; Corrà, Ugo; Cupples, Margaret; Davos, Constantinos H; Hoefer, Stefan; Iliou, Marie-Christine; Schmid, Jean-Paul; Voeller, Heinz; Doherty, Patrick

2017-04-01

Frailty is a geriatric syndrome characterised by a vulnerability status associated with declining function of multiple physiological systems and loss of physiological reserves. Two main models of frailty have been advanced: the phenotypic model (primary frailty) or deficits accumulation model (secondary frailty), and different instruments have been proposed and validated to measure frailty. However measured, frailty correlates to medical outcomes in the elderly, and has been shown to have prognostic value for patients in different clinical settings, such as in patients with coronary artery disease, after cardiac surgery or transvalvular aortic valve replacement, in patients with chronic heart failure or after left ventricular assist device implantation. The prevalence, clinical and prognostic relevance of frailty in a cardiac rehabilitation setting has not yet been well characterised, despite the increasing frequency of elderly patients in cardiac rehabilitation, where frailty is likely to influence the onset, type and intensity of the exercise training programme and the design of tailored rehabilitative interventions for these patients. Therefore, we need to start looking for frailty in elderly patients entering cardiac rehabilitation programmes and become more familiar with some of the tools to recognise and evaluate the severity of this condition. Furthermore, we need to better understand whether exercise-based cardiac rehabilitation may change the course and the prognosis of frailty in cardiovascular patients.

Psychosocial Screening and Assessment Practice within Cardiac Rehabilitation: A Survey of Cardiac Rehabilitation Coordinators in Australia.

PubMed

Jackson, Alun C; Le Grande, Michael R; Higgins, Rosemary O; Rogerson, Michelle; Murphy, Barbara M

2017-01-01

Many cardiac rehabilitation (CR) guidelines and position statements recommend screening for psychosocial risk factors, although there is wide variation in the recommended factors and recommended screening tools. Little is known about screening in CR in Australia. Cardiac rehabilitation coordinators at the 314 CR programs operating across Australia, drawn from the 2014 Australian Directory of Cardiac Rehabilitation Services were invited to participate in an online survey. Of 165 complete responses, 157 (95%) CR coordinators indicated that they screened at entry with 132 (80%) screening on exit. At CR entry, programs screened for - depression (83%), anxiety (75%), stress (75%), and sleep disturbance (57%). The use of standardised instruments by those screening at entry varied from 89% for depression to only 9% for sleep disturbance. Organisational, resource and personal barriers inhibited the routine screening for many psychosocial factors. Surveys such as this are useful for monitoring the rate of adoption of guideline recommendations and identifying barriers to implementation. Findings can also inform discussions about what should be included in minimum data sets for CR programs, and the identification of brief screening tools that have been validated not just in the general population but in cardiac patients. Copyright © 2016 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.

Cardiac surgery outcomes.

PubMed

Halpin, Linda S; Barnett, Scott D; Beachy, Jim

2003-01-01

Accrediting organizations and payers are demanding valid and reliable data that demonstrate the value of services. Federal agencies, healthcare industry groups, and healthcare watchdog groups are increasing the demand for public access to outcomes data. A new and growing outcomes dynamic is the information requested by prospective patients in an increasingly consumer-oriented business. Patients demand outcomes, and resources are developing to meet these demands. Physicians are increasingly confronted with requests for information about their mortality and morbidity rates, malpractice suits, and disciplinary actions received. For example, in Virginia, prospective patients have access to data provided by the nonprofit group Virginia Health Information. After numerous resolutions by the Virginia Senate since 1999, the prospective Virginia medical consumer now has access to several annual publications: Virginia Hospitals: A Consumer's Guide, 1999 Annual Report and Strategic Plan Update, and the 1999 Industry Report: Virginia Hospitals and Nursing Facilities. Consumers have access to cardiac outcomes data stratified by hospital, gender, and cardiac service line (cardiac surgery, noninvasive cardiology, and invasive cardiology). This is particularly relevant to IHI because Virginia Health Information specifically targets cardiac care. IHI has a sizable investment in cardiovascular outcomes and has found outcomes measurement and research are key to providing quality care. IHI's goal is to move from an outcomes management model to a disease management model. The hope is to incorporate all aspects of the patient's continuum of care, from preoperative and diagnostic services through cardiac interventions to postoperative rehabilitation. Furthermore, every step along the way will be supported with functional status and quality of life assessments. Although these goals are ambitious and expensive, the return on investment is high.

FGF2 modulates cardiac remodeling in an isoform- and sex-specific manner

PubMed Central

Nusayr, Eyad; Sadideen, Doraid Tarek; Doetschman, Tom

2013-01-01

Pathological cardiac hypertrophy and cardiac fibrosis are remodeling events that result in mechanical stiffness and pathophysiological changes in the myocardium. Both humans and animal models display a sexual dimorphism where females are more protected from pathological remodeling. Fibroblast growth factor 2 (FGF2) mediates cardiac hypertrophy, cardiac fibrosis, and protection against cardiac injury, and is made in high molecular weight and low molecular weight isoforms (Hi FGF2 and Lo FGF2, respectively). Although some light has been shed on isoform-specific functions in cardiac pathophysiology, their roles in pathologic cardiac remodeling have yet to be determined. We tested the hypothesis that Lo FGF2 and Hi FGF2 modulate pathological cardiac remodeling in an isoform-specific manner. Young adult male and female mice between 8 and 12 weeks of age of mixed background that were deficient in either Hi FGF2 or Lo FGF2 (Hi KO or Lo KO, respectively) were subjected to daily injections of isoproterenol (Iso) for 4 days after which their hearts were compared to wild-type cohorts. Post-Iso treatment, female Lo KO hearts do not exhibit significant differences in their hypertrophic and fibrotic response, whereas female Hi KO hearts present with a blunted hypertrophic response. In male animals, Lo KO hearts present with an exacerbated fibrotic response and increased α-smooth muscle actin protein expression, whereas Hi KO hearts present with a blunted fibrotic response and increased atrial natriuretic factor protein expression Thus, in female hearts Hi FGF2 mediates cardiac hypertrophy, whereas in male hearts Lo FGF2 and Hi FGF2 display an antithetical role in cardiac fibrosis where Lo FGF2 is protective while Hi FGF2 is damaging. In conclusion, cardiac remodeling following catecholamine overactivation is modulated by FGF2 in isoform- and sex-specific manners. PMID:24244869

Cardiac myofilaments: mechanics and regulation

NASA Technical Reports Server (NTRS)

de Tombe, Pieter P.; Bers, D. M. (Principal Investigator)

2003-01-01

The mechanical properties of the cardiac myofilament are an important determinant of pump function of the heart. This report is focused on the regulation of myofilament function in cardiac muscle. Calcium ions form the trigger that induces activation of the thin filament which, in turn, allows for cross-bridge formation, ATP hydrolysis, and force development. The structure and protein-protein interactions of the cardiac sarcomere that are responsible for these processes will be reviewed. The molecular mechanism that underlies myofilament activation is incompletely understood. Recent experimental approaches have been employed to unravel the mechanism and regulation of myofilament mechanics and energetics by activator calcium and sarcomere length, as well as contractile protein phosphorylation mediated by protein kinase A. Central to these studies is the question whether such factors impact on muscle function simply by altering thin filament activation state, or whether modulation of cross-bridge cycling also plays a part in the responses of muscle to these stimuli.

Spatiotemporal control to eliminate cardiac alternans using isostable reduction

NASA Astrophysics Data System (ADS)

Wilson, Dan; Moehlis, Jeff

2017-03-01

Cardiac alternans, an arrhythmia characterized by a beat-to-beat alternation of cardiac action potential durations, is widely believed to facilitate the transition from normal cardiac function to ventricular fibrillation and sudden cardiac death. Alternans arises due to an instability of a healthy period-1 rhythm, and most dynamical control strategies either require extensive knowledge of the cardiac system, making experimental validation difficult, or are model independent and sacrifice important information about the specific system under study. Isostable reduction provides an alternative approach, in which the response of a system to external perturbations can be used to reduce the complexity of a cardiac system, making it easier to work with from an analytical perspective while retaining many of its important features. Here, we use isostable reduction strategies to reduce the complexity of partial differential equation models of cardiac systems in order to develop energy optimal strategies for the elimination of alternans. Resulting control strategies require significantly less energy to terminate alternans than comparable strategies and do not require continuous state feedback.

Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis.

PubMed

Park, Shuin; Ranjbarvazirj, Sara; Lay, Fides D; Zhao, Peng; Miller, Mark J; Dhaliwal, Jasmeet S; Huertas-Vazquez, Adriana; Wu, Xiuju; Qiao, Rong; Soffer, Justin M; Mikkola, Hanna K A; Lusis, Aldons J; Ardehali, Reza

2018-06-27

Background -Genetic diversity and the heterogeneous nature of cardiac fibroblasts (CFbs) have hindered characterization of the molecular mechanisms that regulate cardiac fibrosis. The Hybrid Mouse Diversity Panel (HMDP) offers a valuable tool to examine genetically diverse cardiac fibroblasts and their role in fibrosis. Methods -Three strains of mice (C57BL/6J, C3H/HeJ, and KK/HlJ) were selected from the HMDP and treated with either isoproterenol (ISO) or saline by an intraperitoneally implanted osmotic pump. After 21 days, cardiac function and levels of fibrosis were measured by echocardiography and trichrome staining, respectively. Activation and proliferation of CFbs were measured by in vitro and in vivo assays under normal and injury conditions. RNA-sequencing was done on isolated CFbs from each strain and results were analyzed by Ingenuity Pathway Analysis (IPA) and validated by reverse transcription-qPCR, immunohistochemistry, and ELISA. Results -ISO treatment in C57BL/6J, C3H/HeJ, and KK/HlJ mice resulted in minimal, moderate, and extensive levels of fibrosis, respectively (n = 7-8 hearts/condition). Isolated CFbs treated with ISO exhibited strain-specific increases in the levels of activation but showed comparable levels of proliferation. Similar results were found in vivo , with fibroblast activation, and not proliferation, correlating with the differential levels of cardiac fibrosis after ISO treatment. RNA-sequencing revealed that CFbs from each strain exhibit unique gene expression changes in response to ISO. We identified Ltbp2 as a commonly upregulated gene after ISO treatment. Expression of LTBP2 was elevated and specifically localized in the fibrotic regions of the myocardium after injury in mice and in human heart failure patients. Conclusions -This study highlights the importance of genetic variation in cardiac fibrosis by using multiple inbred mouse strains to characterize CFbs and their response to ISO treatment. Our data suggest that, while

Development and initial validation of the Cardiovascular Disease Acceptance and Action Questionnaire (CVD-AAQ) in an Italian sample of cardiac patients

PubMed Central

Spatola, Chiara A. M.; Cappella, Emanuele A. M.; Goodwin, Christina L.; Baruffi, Matteo; Malfatto, Gabriella; Facchini, Mario; Castelnuovo, Gianluca; Manzoni, Gian Mauro; Molinari, Enrico

2014-01-01

Psychological inflexibility refers to the attempt to decrease internal distress even when doing so is inconsistent with life values, and has been identified as a potential barrier to making and maintaining health behavior changes that are consistent with a heart-healthy lifestyle. Disease- and behavior-specific measures of psychological inflexibility have been developed and utilized in treatment research. However, no specific measure has been created for patients with heart disease. Thus, the CardioVascular Disease Acceptance and Action Questionnaire (CVD-AAQ) was developed. The present study is aimed to evaluate the psychometric properties of the CVD-AAQ and to explore its association with measures of psychological adjustment and cardiovascular risk factors in an Italian sample of 275 cardiac patients. Exploratory factor analysis showed a structural one-factor solution with satisfactory internal consistency and test–retest reliability. The relation with other measures was in the expected direction with stronger correlations for the theoretically consistent variables, supporting convergent and divergent validity. CVD-AAQ scores were associated with general psychological inflexibility, anxiety and depression and inversely correlated with psychological well-being. Moreover, the results showed that CVD-AAQ scores are associated with two relevant risk factors for cardiac patients, namely low adherence to medication and being overweight. In sum, results suggest that the CVD-AAQ is a reliable and valid measure of heart disease-specific psychological inflexibility with interesting clinical applications for secondary prevention care. PMID:25452737

Cardiac troponins--Translational biomarkers in cardiology: Theory and practice of cardiac troponin high-sensitivity assays.

PubMed

Adamcova, Michaela; Popelova-Lencova, Olga; Jirkovsky, Eduard; Simko, Fedor; Gersl, Vladimir; Sterba, Martin

2016-01-01

Tn is a unique translational biomarker in cardiology whose potential has not been diminished in the new era of high sensitive assays. cTns can be valuable markers in cardiac diseases as well as in infectious diseases and respiratory diseases. Furthermore, the role of cTns is growing in the routine evaluation of cardioxicity and in determining the efficacy/safety ratio of novel cardioprotective strategies in clinical settings. cTns can detect myocardial injury not only in a wide spectrum of laboratory animals in experimental studies in vivo, but also in isolated heart models or cardiomyocytes in vitro. The crucial issue regarding the cross-species usage of cardiac troponin investigation remains the choice of cardiac troponin testing. This review summarizes the recent proteomic data on aminoacid sequences of cTnT and cTnI in various species, as well as selected analytical characteristics of human cardiac troponin high-sensitivity assays. Due to the highly phylogenetically conserved structure of troponins, the same bioindicator can be investigated using the same method in both clinical and experimental cardiology, thus contributing to a better understanding of the pathogenesis of cardiac diseases as well as to increased effectiveness of troponin use in clinical practice. Measuring cardiac troponins using commercially available human high-sensitivity cardiac troponin tests with convenient antibodies selected on the basis of adequate proteomic knowledge can solve many issues which would otherwise be difficult to address in clinical settings for various ethical and practical reasons. Our survey could help elaborate the practical guidelines for optimizing the choice of cTns assay in cardiology. © 2016 International Union of Biochemistry and Molecular Biology.

Biophysics and Molecular Biology of Cardiac Ion Channels for the Safety Pharmacologist.

PubMed

Pugsley, Michael K; Curtis, Michael J; Hayes, Eric S

2015-01-01

Cardiac safety pharmacology is a continuously evolving discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment of a new chemical entity (NCE). The aim of cardiac safety pharmacology is to characterise the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects on the heart using continuously evolving methodology. Unlike Toxicology, safety pharmacology includes within its remit a regulatory requirement to predict the risk of rare cardiotoxic (potentially lethal) events such as torsades de pointes (TdP), which is statistically associated with drug-induced changes in the QT interval of the ECG due to blockade of I Kr or K v11.1 current encoded by hERG. This gives safety pharmacology its unique character. The key issues for the safety pharmacology assessment of a drug on the heart are detection of an adverse effect liability, projection of the data into safety margin calculation and clinical safety monitoring. This chapter will briefly review the current cardiac safety pharmacology paradigm outlined in the ICH S7A and ICH S7B guidance documents and the non-clinical models and methods used in the evaluation of new chemical entities in order to define the integrated risk assessment for submission to regulatory authorities. An overview of how the present cardiac paradigm was developed will be discussed, explaining how it was based upon marketing authorisation withdrawal of many non-cardiovascular compounds due to unanticipated proarrhythmic effects. The role of related biomarkers (of cardiac repolarisation, e.g. prolongation of the QT interval of the ECG) will be considered. We will also provide an overview of the 'non-hERG-centric' concepts utilised in the evolving comprehensive in vitro proarrhythmia assay (CIPA) that details conduct of the proposed ion channel battery test, use of human stem cells and application of in silico models to early cardiac safety

A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

NASA Astrophysics Data System (ADS)

Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

2016-02-01

Purpose: Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a ;priming; dose of protons on the cardiac cellular and molecular response to a ;challenge; dose of 56Fe in a mouse model. Methods: Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results: Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions: This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions.

A priming dose of protons alters the early cardiac cellular and molecular response to (56)Fe irradiation.

PubMed

Ramadan, Samy S; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R; Hauer-Jensen, Martin; Nelson, Gregory A; Boerma, Marjan

2016-02-01

Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a "priming" dose of protons on the cardiac cellular and molecular response to a "challenge" dose of (56)Fe in a mouse model. Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of (56)Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of (56)Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Exposure to (56)Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before (56)Fe prevented all of the responses to (56)Fe. This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. Copyright © 2015 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

PubMed Central

Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

2015-01-01

Purpose Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a “priming” dose of protons on the cardiac cellular and molecular response to a “challenge” dose of 56Fe in a mouse model. Methods Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. PMID:26948008

Neuropeptide tyrosine (NPY)--a major cardiac neuropeptide.

PubMed

Gu, J; Polak, J M; Adrian, T E; Allen, J M; Tatemoto, K; Bloom, S R

1983-05-07

A newly discovered bioactive peptide, neuropeptide tyrosine (NPY), has been found in the human cardiac nervous system. Dense concentrations of NPY-immunoreactive nerve fibres were found in association with nodal tissue (atrioventricular node 22.1 +/- 3.7 pmol/g). NPY nerve fibres were seen in close contact with cardiac muscle fibres and were also found around the coronary vessels (19.6 +/- 6.2 pmol/g). Analysis of the peptide by high-performance liquid chromatography demonstrated that it was present in a single molecular form, closely similar or identical to that of the isolated bioactive peptide. Cardiac function in man has long been known to be influenced by cholinergic and adrenergic nerves. There now appears to be a further component of the nervous system in the human heart, involving peptidergic nerves containing NPY.

PET imaging of cardiac hypoxia: Opportunities and challenges

PubMed Central

Handley, M.G.; Medina, R.A.; Nagel, E.; Blower, P.J.; Southworth, R.

2012-01-01

Myocardial hypoxia is a major factor in the pathology of cardiac ischemia and myocardial infarction. Hypoxia also occurs in microvascular disease and cardiac hypertrophy, and is thought to be a prime determinant of the progression to heart failure, as well as the driving force for compensatory angiogenesis. The non-invasive delineation and quantification of hypoxia in cardiac tissue therefore has the potential to be an invaluable experimental, diagnostic and prognostic biomarker for applications in cardiology. However, at this time there are no validated methodologies sufficiently sensitive or reliable for clinical use. PET imaging provides real-time spatial information on the biodistribution of injected radiolabeled tracer molecules. Its inherent high sensitivity allows quantitative imaging of these tracers, even when injected at sub-pharmacological (≥pM) concentrations, allowing the non-invasive investigation of biological systems without perturbing them. PET is therefore an attractive approach for the delineation and quantification of cardiac hypoxia and ischemia. In this review we discuss the key concepts which must be considered when imaging hypoxia in the heart. We summarize the PET tracers which are currently available, and we look forward to the next generation of hypoxia-specific PET imaging agents currently being developed. We describe their potential advantages and shortcomings compared to existing imaging approaches, and what is needed in terms of validation and characterization before these agents can be exploited clinically. PMID:21781973

Impact of gestational chronodisruption on fetal cardiac genomics.

PubMed

Galdames, Hugo A; Torres-Farfan, Claudia; Spichiger, Carlos; Mendez, Natalia; Abarzua-Catalan, Lorena; Alonso-Vazquez, Pamela; Richter, Hans G

2014-01-01

We recently reported that gestational chronodisruption induces fetal growth restriction and marked effects on fetal adrenal physiology. Here, whole-transcriptome profiling was used to test whether gestational chronodisruption modifies gene expression in the fetal heart, potentially altering cardiac development. At day 10 of gestation (E10), pregnant rats were randomized in two groups: constant light (LL) and control 12 h light/12 h dark photoperiod (LD). RNA isolated from E18 heart was subjected to microarray analysis (Affymetrix platform for 28,000 genes). Integrated transcriptional changes were assessed by gene ontology and pathway analysis. Significant differential expression was found for 383 transcripts in LL relative to LD fetal heart (280 up-regulated and 103 down-regulated); with 42 of them displaying a 1.5-fold or greater change in gene expression. Deregulated markers of cardiovascular disease accounted for alteration of diverse gene networks in LL fetal heart, including local steroidogenesis and vascular calcification, as well as cardiac hypertrophy, stenosis and necrosis/cell death. DNA integrity was also overrepresented, including a 2.1-fold increase of Hmga1 mRNA, which encodes for a profuse architectural transcription factor. microRNA analysis revealed up-regulation of miRNAs 218-1 and 501 and concurrent down-regulation of their validated target genes. In addition, persistent down-regulation of Kcnip2 mRNA and hypertrophy of the left ventricle were found in the heart from 90 days-old offspring from LL mothers. The dysregulation of a relevant fraction of the fetal cardiac transcriptome, together with the diversity and complexity of the gene networks altered by gestational chronodisruption, suggest enduring molecular changes which may shape the hypertrophy observed in the left ventricle of adult LL offspring. © 2013.

Cardiac Iron Determines Cardiac T2*, T2, and T1 in the Gerbil Model of Iron Cardiomyopathy

PubMed Central

Wood, John C.; Otto-Duessel, Maya; Aguilar, Michelle; Nick, Hanspeter; Nelson, Marvin D.; Coates, Thomas D.; Pollack, Harvey; Moats, Rex

2010-01-01

Background Transfusional therapy for thalassemia major and sickle cell disease can lead to iron deposition and damage to the heart, liver, and endocrine organs. Iron causes the MRI parameters T1, T2, and T2* to shorten in these organs, which creates a potential mechanism for iron quantification. However, because of the danger and variability of cardiac biopsy, tissue validation of cardiac iron estimates by MRI has not been performed. In this study, we demonstrate that iron produces similar T1, T2, and T2* changes in the heart and liver using a gerbil iron-overload model. Methods and Results Twelve gerbils underwent iron dextran loading (200 mg · kg−1 · wk−1) from 2 to 14 weeks; 5 age-matched controls were studied as well. Animals had in vivo assessment of cardiac T2* and hepatic T2 and T2* and postmortem assessment of cardiac and hepatic T1 and T2. Relaxation measurements were performed in a clinical 1.5-T magnet and a 60-MHz nuclear magnetic resonance relaxometer. Cardiac and liver iron concentrations rose linearly with administered dose. Cardiac 1/T2*, 1/T2, and 1/T1 rose linearly with cardiac iron concentration. Liver 1/T2*, 1/T2, and 1/T1 also rose linearly, proportional to hepatic iron concentration. Liver and heart calibrations were similar on a dry-weight basis. Conclusions MRI measurements of cardiac T2 and T2* can be used to quantify cardiac iron. The similarity of liver and cardiac iron calibration curves in the gerbil suggests that extrapolation of human liver calibration curves to heart may be a rational approximation in humans. PMID:16027257

Integrated imaging of cardiac anatomy, physiology, and viability.

PubMed

Arrighi, James A

2009-03-01

Technologic developments in imaging will have a significant impact on cardiac imaging over the next decade. These advances will permit more detailed assessment of cardiac anatomy, complex assessment of cardiac physiology, and integration of anatomic and physiologic data. The distinction between anatomic and physiologic imaging is important. For assessing patients with known or suspected coronary artery disease, physiologic and anatomic imaging data are complementary. The strength of anatomic imaging rests in its ability to detect the presence of disease, whereas physiologic imaging techniques assess the impact of disease, such as whether a coronary atherosclerotic lesion limits myocardial blood flow. Research indicates that physiologic data are more prognostically important than anatomic data, but both may be important in patient management decisions. Integrated cardiac imaging is an evolving field, with many potential indications. These include assessment of coronary stenosis, myocardial viability, anatomic and physiologic characterization of atherosclerotic plaque, and advanced molecular imaging.

Long-term administration of pyridostigmine attenuates pressure overload-induced cardiac hypertrophy by inhibiting calcineurin signalling.

PubMed

Lu, Yi; Zhao, Ming; Liu, Jin-Jun; He, Xi; Yu, Xiao-Jiang; Liu, Long-Zhu; Sun, Lei; Chen, Li-Na; Zang, Wei-Jin

2017-09-01

Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload-induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β-myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4

Cleaning and Sterilization of Used Cardiac Implantable Electronic Devices With Process Validation: The Next Hurdle in Device Recycling.

PubMed

Crawford, Thomas C; Allmendinger, Craig; Snell, Jay; Weatherwax, Kevin; Lavan, Balasundaram; Baman, Timir S; Sovitch, Pat; Alyesh, Daniel; Carrigan, Thomas; Klugman, Noah; Kune, Denis; Hughey, Andrew; Lautenbach, Daniel; Sovitch, Nathan; Tandon, Karman; Samson, George; Newman, Charles; Davis, Sheldon; Brown, Archie; Wasserman, Brad; Goldman, Ed; Arlinghaus, Sandra L; Oral, Hakan; Eagle, Kim A

2017-06-01

This study sought to develop a validated, reproducible sterilization protocol, which could be used in the reprocessing of cardiac implantable electronic devices (CIEDs). Access to cardiac CIED therapy in high-income and in low- and middle-income countries varies greatly. CIED reuse may reduce this disparity. A cleaning and sterilization protocol was developed that includes washing CIEDs in an enzymatic detergent, screw cap and set screw replacement, brushing, inspection, and sterilization in ethylene oxide. Validation testing was performed to assure compliance with accepted standards. With cleaning, the total mean bioburden for each of 3 batches of 10 randomly chosen devices was reduced from 754 to 10.1 colony-forming units. After sterilization with ethylene oxide, with 3 half-cycle and 3 full-cycle processes, none of the 90 biological indicator testers exhibited growth after 7 days. Through cleaning and sterilization, protein and hemoglobin concentrations were reduced from 99.2 to 1.42 μg/cm 2 and from 21.4 to 1.03 μg/cm 2 , respectively. Mean total organic carbon residual was 1.44 parts per million (range 0.36 to 2.9 parts per million). Endotoxin concentration was not detectable at the threshold of <0.03 endotoxin units/ml or <3.0 endotoxin units/device. Cytotoxicity and intracutaneous reactivity tests met the standards set by the Association for Advancement of Medical Instrumentation and the International Organization for Standardization. CIEDs can be cleaned and sterilized according to a standardized protocol achieving a 12-log reduction of inoculated product, resulting in sterility assurance level of 10 -6 . Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Complex versus simple models: ion-channel cardiac toxicity prediction.

PubMed

Mistry, Hitesh B

2018-01-01

There is growing interest in applying detailed mathematical models of the heart for ion-channel related cardiac toxicity prediction. However, a debate as to whether such complex models are required exists. Here an assessment in the predictive performance between two established large-scale biophysical cardiac models and a simple linear model B net was conducted. Three ion-channel data-sets were extracted from literature. Each compound was designated a cardiac risk category using two different classification schemes based on information within CredibleMeds. The predictive performance of each model within each data-set for each classification scheme was assessed via a leave-one-out cross validation. Overall the B net model performed equally as well as the leading cardiac models in two of the data-sets and outperformed both cardiac models on the latest. These results highlight the importance of benchmarking complex versus simple models but also encourage the development of simple models.

(99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses.

PubMed

Bokhari, Sabahat; Castaño, Adam; Pozniakoff, Ted; Deslisle, Susan; Latif, Farhana; Maurer, Mathew S

2013-03-01

Differentiating immunoglobulin light-chain (AL) from transthyretin-related cardiac amyloidoses (ATTR) is imperative given implications for prognosis, therapy, and genetic counseling. We validated the discriminatory ability of (99m)Tc-pyrophosphate ((99m)Tc-PYP) scintigraphy in AL versus ATTR. Forty-five subjects (12 AL, 16 ATTR wild type, and 17 ATTR mutants) underwent (99m)Tc-PYP planar and single-photon positive emission computed tomography cardiac imaging. Scans were performed by experienced nuclear cardiologists blinded to the subjects' cohort assignment. Cardiac retention was assessed with both a semiquantitative visual score (range, 0; no uptake to 3, diffuse uptake) and by quantitative analysis by drawing a region of interest over the heart corrected for contralateral counts and calculating a heart-to-contralateral ratio. Subjects with ATTR cardiac amyloid had a significantly higher semiquantitative cardiac visual score than the AL cohort (2.9±0.06 versus 0.8±0.27; P<0.0001) as well as a higher quantitative score (1.80±0.04 versus 1.21±0.04; P<0.0001). Using a heart-to-contralateral ratio >1.5 consistent with intensely diffuse myocardial tracer retention had a 97% sensitivity and 100% specificity with area under the curve 0.992, P<0.0001 for identifying ATTR cardiac amyloidosis. (99m)Tc-PYP cardiac imaging distinguishes AL from ATTR cardiac amyloidosis and may be a simple, widely available method for identifying subjects with ATTR cardiac amyloidosis, which should be studied in a larger prospective manner.

Decoding the Long Noncoding RNA During Cardiac Maturation: A Roadmap for Functional Discovery.

PubMed

Touma, Marlin; Kang, Xuedong; Zhao, Yan; Cass, Ashley A; Gao, Fuying; Biniwale, Reshma; Coppola, Giovanni; Xiao, Xinshu; Reemtsen, Brian; Wang, Yibin

2016-10-01

Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated. From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes. The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects. © 2016 American Heart Association, Inc.

Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts

PubMed Central

Zlatanova, Ivana; Pinto, Cristina; Silvestre, Jean-Sébastien

2016-01-01

The accumulation of immune cells is among the earliest responses that manifest in the cardiac tissue after injury. Both innate and adaptive immunity coordinate distinct and mutually non-exclusive events governing cardiac repair, including elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, and formation of a fibrotic scar. The present review summarizes the mounting evidence suggesting that the inflammatory response also guides the regenerative process following cardiac damage. In particular, recent literature has reinforced the central role of monocytes/macrophages in poising the refreshment of cardiomyocytes in myocardial infarction- or apical resection-induced cardiac insult. Macrophages dictate cardiac myocyte renewal through stimulation of preexisting cardiomyocyte proliferation and/or neovascularization. Nevertheless, substantial efforts are required to identify the nature of these macrophage-derived factors as well as the molecular mechanisms engendered by the distinct subsets of macrophages pertaining in the cardiac tissue. Among the growing inflammatory intermediaries that have been recognized as essential player in heart regeneration, we will focus on the role of interleukin (IL)-6 and IL-13. Finally, it is likely that within the mayhem of the injured cardiac tissue, additional types of inflammatory cells, such as neutrophils, will enter the dance to ignite and refresh the broken heart. However, the protective and detrimental inflammatory pathways have been mainly deciphered in animal models. Future research should be focused on understanding the cellular effectors and molecular signals regulating inflammation in human heart to pave the way for the development of factual therapies targeting the inflammatory compartment in cardiac diseases. PMID:27790620

Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts.

PubMed

Zlatanova, Ivana; Pinto, Cristina; Silvestre, Jean-Sébastien

2016-01-01

The accumulation of immune cells is among the earliest responses that manifest in the cardiac tissue after injury. Both innate and adaptive immunity coordinate distinct and mutually non-exclusive events governing cardiac repair, including elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, and formation of a fibrotic scar. The present review summarizes the mounting evidence suggesting that the inflammatory response also guides the regenerative process following cardiac damage. In particular, recent literature has reinforced the central role of monocytes/macrophages in poising the refreshment of cardiomyocytes in myocardial infarction- or apical resection-induced cardiac insult. Macrophages dictate cardiac myocyte renewal through stimulation of preexisting cardiomyocyte proliferation and/or neovascularization. Nevertheless, substantial efforts are required to identify the nature of these macrophage-derived factors as well as the molecular mechanisms engendered by the distinct subsets of macrophages pertaining in the cardiac tissue. Among the growing inflammatory intermediaries that have been recognized as essential player in heart regeneration, we will focus on the role of interleukin (IL)-6 and IL-13. Finally, it is likely that within the mayhem of the injured cardiac tissue, additional types of inflammatory cells, such as neutrophils, will enter the dance to ignite and refresh the broken heart. However, the protective and detrimental inflammatory pathways have been mainly deciphered in animal models. Future research should be focused on understanding the cellular effectors and molecular signals regulating inflammation in human heart to pave the way for the development of factual therapies targeting the inflammatory compartment in cardiac diseases.

Isolation of RNA From Peripheral Blood Cells: A Validation Study for Molecular Diagnostics by Microarray and Kinetic RT-PCR Assays - Application in Aerospace Medicine

DTIC Science & Technology

2004-01-01

of RNA From Peripheral Blood Cells: A Validation Study for Molecular Diagnostics by Microarray and Kinetic RT-PCR Assays  Application in...VALIDATION STUDY FOR MOLECULAR DIAGNOSTICS BY MICROARRAY AND KINETIC RT-PCR ASSAYS  APPLICATION IN AEROSPACE MEDICINE INTRODUCTION Extraction of cellular

Pay attention to cardiac remodeling in cancer cachexia.

PubMed

Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

2016-07-01

Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival.

Surface-modified polymers for cardiac tissue engineering.

PubMed

Moorthi, Ambigapathi; Tyan, Yu-Chang; Chung, Tze-Wen

2017-09-26

Cardiovascular disease (CVD), leading to myocardial infarction and heart failure, is one of the major causes of death worldwide. The physiological system cannot significantly regenerate the capabilities of a damaged heart. The current treatment involves pharmacological and surgical interventions; however, less invasive and more cost-effective approaches are sought. Such new approaches are developed to induce tissue regeneration following injury. Hence, regenerative medicine plays a key role in treating CVD. Recently, the extrinsic stimulation of cardiac regeneration has involved the use of potential polymers to stimulate stem cells toward the differentiation of cardiomyocytes as a new therapeutic intervention in cardiac tissue engineering (CTE). The therapeutic potentiality of natural or synthetic polymers and cell surface interactive factors/polymer surface modifications for cardiac repair has been demonstrated in vitro and in vivo. This review will discuss the recent advances in CTE using polymers and cell surface interactive factors that interact strongly with stem cells to trigger the molecular aspects of the differentiation or formulation of cardiomyocytes for the functional repair of heart injuries or cardiac defects.

Ultrasound molecular imaging of acute cellular cardiac allograft rejection in rat with T-cell-specific nanobubbles.

PubMed

Wu, Wei; Zhang, Zhe; Zhuo, Lisha; Zhou, Lina; Liu, Ping; He, Yun; Gao, Yunhua; Li, Rui; Chen, Qinghai; Hua, Xing

2013-09-01

Acute rejection (AR) is one of the main obstacles of cardiac transplantation; however, a noninvasive diagnostic method, which reflects its pathologic nature, has not been developed yet. In this study, we prepared a specific nanobubbles targeting to the activated T cells and applied it in the ultrasound molecular imaging of AR in heart transplantation by myocardial contrast echocardiography (MCE). Nanobubbles loading anti-CD25 antibody (NB(specific)) or isotype control antibody (NB(nonspecific)) were prepared and then applied in the ultrasound molecular imaging by MCE in a rat model. MCE was performed in 24 allografts and 18 isografts that were divided into three groups, including days 2, 4, and 6 after transplantation. Confocal laser scanning microscopy was used to evaluate the binding of nanobubbles and T cells in four allografts and four isografts. MCE with NB(specific) in allograft showed a "delayed enhancement," and the time-intensity curve presented a second peak. The intensity and time of second peak were both positively correlated with the transplant time (P<0.01) and the pathologic grade of AR (P<0.01). Confocal laser scanning microscopy demonstrated the binding of nanobubbles and lymphocytes in myocardium post-MCE with NB(specific). Ultrasound molecular imaging of AR after heart transplantation can be achieved by using MCE with the nanobubbles targeted to T cells. The appearance of delayed enhancement indicates the occurrence of AR, and the intensity and time of the second peak in time-intensity curve provide potential quantitative indications for diagnosis and severity of AR.

Assessing Cardiac Metabolism: A Scientific Statement From the American Heart Association.

PubMed

Taegtmeyer, Heinrich; Young, Martin E; Lopaschuk, Gary D; Abel, E Dale; Brunengraber, Henri; Darley-Usmar, Victor; Des Rosiers, Christine; Gerszten, Robert; Glatz, Jan F; Griffin, Julian L; Gropler, Robert J; Holzhuetter, Hermann-Georg; Kizer, Jorge R; Lewandowski, E Douglas; Malloy, Craig R; Neubauer, Stefan; Peterson, Linda R; Portman, Michael A; Recchia, Fabio A; Van Eyk, Jennifer E; Wang, Thomas J

2016-05-13

In a complex system of interrelated reactions, the heart converts chemical energy to mechanical energy. Energy transfer is achieved through coordinated activation of enzymes, ion channels, and contractile elements, as well as structural and membrane proteins. The heart's needs for energy are difficult to overestimate. At a time when the cardiovascular research community is discovering a plethora of new molecular methods to assess cardiac metabolism, the methods remain scattered in the literature. The present statement on "Assessing Cardiac Metabolism" seeks to provide a collective and curated resource on methods and models used to investigate established and emerging aspects of cardiac metabolism. Some of those methods are refinements of classic biochemical tools, whereas most others are recent additions from the powerful tools of molecular biology. The aim of this statement is to be useful to many and to do justice to a dynamic field of great complexity. © 2016 American Heart Association, Inc.

Extracellular high-mobility group box 1 mediates pressure overload-induced cardiac hypertrophy and heart failure.

PubMed

Zhang, Lei; Liu, Ming; Jiang, Hong; Yu, Ying; Yu, Peng; Tong, Rui; Wu, Jian; Zhang, Shuning; Yao, Kang; Zou, Yunzeng; Ge, Junbo

2016-03-01

Inflammation plays a key role in pressure overload-induced cardiac hypertrophy and heart failure, but the mechanisms have not been fully elucidated. High-mobility group box 1 (HMGB1), which is increased in myocardium under pressure overload, may be involved in pressure overload-induced cardiac injury. The objectives of this study are to determine the role of HMGB1 in cardiac hypertrophy and cardiac dysfunction under pressure overload. Pressure overload was imposed on the heart of male wild-type mice by transverse aortic constriction (TAC), while recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the LV wall. Moreover, cardiac myocytes were cultured and given sustained mechanical stress. Transthoracic echocardiography was performed after the operation and sections for histological analyses were generated from paraffin-embedded hearts. Relevant proteins and genes were detected. Cardiac HMGB1 expression was increased after TAC, which was accompanied by its translocation from nucleus to both cytoplasm and intercellular space. Exogenous HMGB1 aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Nevertheless, the aforementioned pathological change induced by TAC could partially be reversed by HMGB1 inhibition. Consistent with the in vivo observations, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. This study indicates that the activated and up-regulated HMGB1 in myocardium, which might partially be derived from cardiac myocytes under pressure overload, may be of crucial importance in pressure overload-induced cardiac hypertrophy and cardiac dysfunction. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Hypothyroidism and its rapid correction alter cardiac remodeling.

PubMed

Hajje, Georges; Saliba, Youakim; Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

2014-01-01

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.

Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

PubMed Central

Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

2014-01-01

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. PMID:25333636

Validation of On-Orbit Methodology for the Assessment of Cardiac Function and Changes in the Circulating Volume Using Ultrasound and Braslet-M Occlusion Cuffs

NASA Technical Reports Server (NTRS)

Hamilton, Douglas; Sargsyan, Ashot E.; Ebert, Douglas; Duncan, Michael; Bogomolov, Valery V.; Alferova, Irina V.; Matveev, Vladimir P.; Dulchavsky, Scott A.

2010-01-01

The objective of this joint U.S. - Russian project was the development and validation of an in-flight methodology to assess a number of cardiac and vascular parameters associated with circulating volume and its manipulation in long-duration space flight. Responses to modified Valsalva and Mueller maneuvers were measured by cardiac and vascular ultrasound (US) before, during, and after temporary volume reduction by means of Braslet-M thigh occlusion cuffs (Russia). Materials and Methods: The study protocol was conducted in 14 sessions on 9 ISS crewmembers, with an average exposure to microgravity of 122 days. Baseline cardiovascular measurements were taken by echocardiography in multiple modes (including tissue Doppler of both ventricles) and femoral and jugular vein imaging on the International Space Station (ISS). The Braslet devices were then applied and measurements were repeated after >10 minutes. The cuffs were then released and the hemodynamic recovery process was monitored. Modified Valsalva and Mueller maneuvers were used throughout the protocol. All US data were acquired by the HDI-5000 ultrasound system aboard the ISS (ATL/Philips, USA) during remotely guided sessions. The study protocol, including the use of Braslet-M for this purpose, was approved by the ISS Human Research Multilateral Review Board (HRMRB). Results: The effects of fluid sequestration on a number of echocardiographic and vascular parameters were readily detectable by in-flight US, as were responses to respiratory maneuvers. The overall volume status assessment methodology appears to be valid and practical, with a decrease in left heart lateral E (tissue Doppler) as one of the most reliable measures. Increase in the femoral vein cross-sectional areas was consistently observed with Braslet application. Other significant differences and trends within the extensive cardiovascular data were also observed. (Decreased - RV and LV preload indices, Cardiac Output, LV E all maneuvers, LV Stroke

Cardiac Tropism of Borrelia burgdorferi: An Autopsy Study of Sudden Cardiac Death Associated with Lyme Carditis.

PubMed

Muehlenbachs, Atis; Bollweg, Brigid C; Schulz, Thadeus J; Forrester, Joseph D; DeLeon Carnes, Marlene; Molins, Claudia; Ray, Gregory S; Cummings, Peter M; Ritter, Jana M; Blau, Dianna M; Andrew, Thomas A; Prial, Margaret; Ng, Dianna L; Prahlow, Joseph A; Sanders, Jeanine H; Shieh, Wun Ju; Paddock, Christopher D; Schriefer, Martin E; Mead, Paul; Zaki, Sherif R

2016-05-01

Fatal Lyme carditis caused by the spirochete Borrelia burgdorferi rarely is identified. Here, we describe the pathologic, immunohistochemical, and molecular findings of five case patients. These sudden cardiac deaths associated with Lyme carditis occurred from late summer to fall, ages ranged from young adult to late 40s, and four patients were men. Autopsy tissue samples were evaluated by light microscopy, Warthin-Starry stain, immunohistochemistry, and PCR for B. burgdorferi, and immunohistochemistry for complement components C4d and C9, CD3, CD79a, and decorin. Post-mortem blood was tested by serology. Interstitial lymphocytic pancarditis in a relatively characteristic road map distribution was present in all cases. Cardiomyocyte necrosis was minimal, T cells outnumbered B cells, plasma cells were prominent, and mild fibrosis was present. Spirochetes in the cardiac interstitium associated with collagen fibers and co-localized with decorin. Rare spirochetes were seen in the leptomeninges of two cases by immunohistochemistry. Spirochetes were not seen in other organs examined, and joint tissue was not available for evaluation. Although rare, sudden cardiac death caused by Lyme disease might be an under-recognized entity and is characterized by pancarditis and marked tropism of spirochetes for cardiac tissues. Published by Elsevier Inc.

Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure.

PubMed

Ishikawa, Kiyotake; Fish, Kenneth M; Tilemann, Lisa; Rapti, Kleopatra; Aguero, Jaume; Santos-Gallego, Carlos G; Lee, Ahyoung; Karakikes, Ioannis; Xie, Chaoqin; Akar, Fadi G; Shimada, Yuichi J; Gwathmey, Judith K; Asokan, Aravind; McPhee, Scott; Samulski, Jade; Samulski, Richard Jude; Sigg, Daniel C; Weber, Thomas; Kranias, Evangelia G; Hajjar, Roger J

2014-12-01

Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 × 10(13) vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 × 10(12) vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload-recruitable stroke work obtained from pressure-volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF.

Cardiac I-1c Overexpression With Reengineered AAV Improves Cardiac Function in Swine Ischemic Heart Failure

PubMed Central

Ishikawa, Kiyotake; Fish, Kenneth M; Tilemann, Lisa; Rapti, Kleopatra; Aguero, Jaume; Santos-Gallego, Carlos G; Lee, Ahyoung; Karakikes, Ioannis; Xie, Chaoqin; Akar, Fadi G; Shimada, Yuichi J; Gwathmey, Judith K; Asokan, Aravind; McPhee, Scott; Samulski, Jade; Samulski, Richard Jude; Sigg, Daniel C; Weber, Thomas; Kranias, Evangelia G; Hajjar, Roger J

2014-01-01

Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 × 1013 vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 × 1012 vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload-recruitable stroke work obtained from pressure–volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF. PMID:25023328

Animal models of cardiac cachexia.

PubMed

Molinari, Francesca; Malara, Natalia; Mollace, Vincenzo; Rosano, Giuseppe; Ferraro, Elisabetta

2016-09-15

Cachexia is the loss of body weight associated with several chronic diseases including chronic heart failure (CHF). The cachectic condition is mainly due to loss of skeletal muscle mass and adipose tissue depletion. The majority of experimental in vivo studies on cachexia rely on animal models of cancer cachexia while a reliable and appropriate model for cardiac cachexia has not yet been established. A critical issue in generating a cardiac cachexia model is that genetic modifications or pharmacological treatments impairing the heart functionality and used to obtain the heart failure model might likely impair the skeletal muscle, this also being a striated muscle and sharing with the myocardium several molecular and physiological mechanisms. On the other hand, often, the induction of heart damage in the several existing models of heart failure does not necessarily lead to skeletal muscle loss and cachexia. Here we describe the main features of cardiac cachexia and illustrate some animal models proposed for cardiac cachexia studies; they include the genetic calsequestrin and Dahl salt-sensitive models, the monocrotaline model and the surgical models obtained by left anterior descending (LAD) ligation, transverse aortic constriction (TAC) and ascending aortic banding. The availability of a specific animal model for cardiac cachexia is a crucial issue since, besides the common aspects of cachexia in the different syndromes, each disease has some peculiarities in its etiology and pathophysiology leading to cachexia. Such peculiarities need to be unraveled in order to find new targets for effective therapies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epigenomic Reprogramming of Adult Cardiomyocyte-Derived Cardiac Progenitor Cells

PubMed Central

Zhang, Yiqiang; Zhong, Jiang F; Qiu, Hongyu; Robb MacLellan, W.; Marbán, Eduardo; Wang, Charles

2015-01-01

It has been believed that mammalian adult cardiomyocytes (ACMs) are terminally-differentiated and are unable to proliferate. Recently, using a bi-transgenic ACM fate mapping mouse model and an in vitro culture system, we demonstrated that adult mouse cardiomyocytes were able to dedifferentiate into cardiac progenitor-like cells (CPCs). However, little is known about the molecular basis of their intrinsic cellular plasticity. Here we integrate single-cell transcriptome and whole-genome DNA methylation analyses to unravel the molecular mechanisms underlying the dedifferentiation and cell cycle reentry of mouse ACMs. Compared to parental cardiomyocytes, dedifferentiated mouse cardiomyocyte-derived CPCs (mCPCs) display epigenomic reprogramming with many differentially-methylated regions, both hypermethylated and hypomethylated, across the entire genome. Correlated well with the methylome, our transcriptomic data showed that the genes encoding cardiac structure and function proteins are remarkably down-regulated in mCPCs, while those for cell cycle, proliferation, and stemness are significantly up-regulated. In addition, implantation of mCPCs into infarcted mouse myocardium improves cardiac function with augmented left ventricular ejection fraction. Our study demonstrates that the cellular plasticity of mammalian cardiomyocytes is the result of a well-orchestrated epigenomic reprogramming and a subsequent global transcriptomic alteration. PMID:26657817

Constitutional H19 hypermethylation in a patient with isolated cardiac tumor.

PubMed

Descartes, Maria; Romp, Robb; Franklin, Judy; Biggio, Joseph R; Zehnbauer, Barbara

2008-08-15

Beckwith-Wiedemann syndrome (BWS) is clinically and molecularly very heterogenous. Molecular findings characteristic of BWS have been reported in individuals with no or few associated features. We report on a child with isolated cardiac tumor and a constitutional H19 hypermethylation with none of the features of BWS. Copyright 2008 Wiley-Liss, Inc.

[A basis for application of cardiac contractility variability in the Evaluation and assessment of exercise and fitness].

PubMed

Bu, Bin; Wang, Aihua; Han, Haijun; Xiao, Shouzhong

2010-06-01

Cardiac contractility variability (CCV) is a new concept which is introduced in the research field of cardiac contractility in recent years, that is to say, there are some disparities between cardiac contractilities when heart contracts. The changing signals of cardiac contractility contain a plenty of information on the cardiovascular function and disorder. In order to collect and analyze the message, we could quantitatively evaluate the tonicity and equilibrium of cardiac sympathetic nerve and parasympathetic nerve, and the effects of bio-molecular mechanism on the cardiovascular activities. By analyzing CCV, we could further understand the background of human being's heritage characteristics, nerve types, the adjusting mechanism, the molecular biology, and the adjustment of cardiac automatic nerve. With the development of the computing techniques, the digital signal processing method and its application in medical field, this analysis has been progressing greatly. By now, the assessment of CCV, just like the analysis of heart rate variability, is mainly via time domain and frequency domain analysis. CCV is one of the latest research fields in human cardiac signals being scarcely reported in the field of sports medicine; however, its research progresses are of important value for cardiac physiology and pathology in sports medicine and rehabilitation medicine.

HSP70: therapeutic potential in acute and chronic cardiac disease settings.

PubMed

Bernardo, Bianca C; Weeks, Kate L; Patterson, Natalie L; McMullen, Julie R

2016-12-01

Heat shock proteins are a family of proteins that are produced by cells in response to exposure to stressful conditions. The best studied heat shock protein is HSP70, which is known to act as a molecular chaperone to maintain cellular homeostasis and inhibit protein aggregation in response to stress. While early animal studies suggested that increasing HSP70 in the heart (using a transgenic, gene transfer or pharmacological approach) provided cardiac protection against acute cardiac stress, recent studies have found no benefit of increasing HSP70 in mouse models of chronic cardiac stress. As HSP70 has been considered a potential therapeutic target, it is important to comprehensively assess HSP70 therapies in preclinical models of acute and chronic cardiac disease.

Modeling beta-adrenergic control of cardiac myocyte contractility in silico.

PubMed

Saucerman, Jeffrey J; Brunton, Laurence L; Michailova, Anushka P; McCulloch, Andrew D

2003-11-28

The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

Modeling beta-adrenergic control of cardiac myocyte contractility in silico

NASA Technical Reports Server (NTRS)

Saucerman, Jeffrey J.; Brunton, Laurence L.; Michailova, Anushka P.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

2003-01-01

The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

A computational model-based validation of Guyton's analysis of cardiac output and venous return curves

NASA Technical Reports Server (NTRS)

Mukkamala, R.; Cohen, R. J.; Mark, R. G.

2002-01-01

Guyton developed a popular approach for understanding the factors responsible for cardiac output (CO) regulation in which 1) the heart-lung unit and systemic circulation are independently characterized via CO and venous return (VR) curves, and 2) average CO and right atrial pressure (RAP) of the intact circulation are predicted by graphically intersecting the curves. However, this approach is virtually impossible to verify experimentally. We theoretically evaluated the approach with respect to a nonlinear, computational model of the pulsatile heart and circulation. We developed two sets of open circulation models to generate CO and VR curves, differing by the manner in which average RAP was varied. One set applied constant RAPs, while the other set applied pulsatile RAPs. Accurate prediction of intact, average CO and RAP was achieved only by intersecting the CO and VR curves generated with pulsatile RAPs because of the pulsatility and nonlinearity (e.g., systemic venous collapse) of the intact model. The CO and VR curves generated with pulsatile RAPs were also practically independent. This theoretical study therefore supports the validity of Guyton's graphical analysis.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications.

PubMed

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

: Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.

Isolation, electron microscopic imaging, and 3-D visualization of native cardiac thin myofilaments.

PubMed

Spiess, M; Steinmetz, M O; Mandinova, A; Wolpensinger, B; Aebi, U; Atar, D

1999-06-15

An increasing number of cardiac diseases are currently pinpointed to reside at the level of the thin myofilaments (e.g., cardiomyopathies, reperfusion injury). Hence the aim of our study was to develop a new method for the isolation of mammalian thin myofilaments suitable for subsequent high-resolution electron microscopic imaging. Native cardiac thin myofilaments were extracted from glycerinated porcine myocardial tissue in the presence of protease inhibitors. Separation of thick and thin myofilaments was achieved by addition of ATP and several centrifugation steps. Negative staining and subsequent conventional and scanning transmission electron microscopy (STEM) of thin myofilaments permitted visualization of molecular details; unlike conventional preparations of thin myofilaments, our method reveals the F-actin moiety and allows direct recognition of thin myofilament-associated porcine cardiac troponin complexes. They appear as "bulges" at regular intervals of approximately 36 nm along the actin filaments. Protein analysis using SDS-polyacrylamide gel electrophoresis revealed that only approximately 20% troponin I was lost during the isolation procedure. In a further step, 3-D helical reconstructions were calculated using STEM dark-field images. These 3-D reconstructions will allow further characterization of molecular details, and they will be useful for directly visualizing molecular alterations related to diseased cardiac thin myofilaments (e.g., reperfusion injury, alterations of Ca2+-mediated tropomyosin switch). Copyright 1999 Academic Press.

Optogenetic Light Crafting Tools for the Control of Cardiac Arrhythmias.

PubMed

Richter, Claudia; Christoph, Jan; Lehnart, Stephan E; Luther, Stefan

2016-01-01

The control of spatiotemporal dynamics in biological systems is a fundamental problem in nonlinear sciences and has important applications in engineering and medicine. Optogenetic tools combined with advanced optical technologies provide unique opportunities to develop and validate novel approaches to control spatiotemporal complexity in neuronal and cardiac systems. Understanding of the mechanisms and instabilities underlying the onset, perpetuation, and control of cardiac arrhythmias will enable the development and translation of novel therapeutic approaches. Here we describe in detail the preparation and optical mapping of transgenic channelrhodopsin-2 (ChR2) mouse hearts, cardiac cell cultures, and the optical setup for photostimulation using digital light processing.

Cardiac catheterization

MedlinePlus

Catheterization - cardiac; Heart catheterization; Angina - cardiac catheterization; CAD - cardiac catheterization; Coronary artery disease - cardiac catheterization; Heart valve - cardiac catheterization; Heart failure - ...

Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

PubMed Central

Wang, Xinchen; Tucker, Nathan R; Rizki, Gizem; Mills, Robert; Krijger, Peter HL; de Wit, Elzo; Subramanian, Vidya; Bartell, Eric; Nguyen, Xinh-Xinh; Ye, Jiangchuan; Leyton-Mange, Jordan; Dolmatova, Elena V; van der Harst, Pim; de Laat, Wouter; Ellinor, Patrick T; Newton-Cheh, Christopher; Milan, David J; Kellis, Manolis; Boyer, Laurie A

2016-01-01

Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits. DOI: http://dx.doi.org/10.7554/eLife.10557.001 PMID:27162171

Metabonomics Indicates Inhibition of Fatty Acid Synthesis, β-Oxidation, and Tricarboxylic Acid Cycle in Triclocarban-Induced Cardiac Metabolic Alterations in Male Mice.

PubMed

Xie, Wenping; Zhang, Wenpeng; Ren, Juan; Li, Wentao; Zhou, Lili; Cui, Yuan; Chen, Huiming; Yu, Wenlian; Zhuang, Xiaomei; Zhang, Zhenqing; Shen, Guolin; Li, Haishan

2018-02-14

Triclocarban (TCC) has been identified as a new environmental pollutant that is potentially hazardous to human health; however, the effects of short-term TCC exposure on cardiac function are not known. The aim of this study was to use metabonomics and molecular biology techniques to systematically elucidate the molecular mechanisms of TCC-induced effects on cardiac function in mice. Our results show that TCC inhibited the uptake, synthesis, and oxidation of fatty acids, suppressed the tricarboxylic acid (TCA) cycle, and increased aerobic glycolysis levels in heart tissue after short-term TCC exposure. TCC also inhibited the nuclear peroxisome proliferator-activated receptor α (PPARα), confirming its inhibitory effects on fatty acid uptake and oxidation. Histopathology and other analyses further confirm that TCC altered mouse cardiac physiology and pathology, ultimately affecting normal cardiac metabolic function. We elucidate the molecular mechanisms of TCC-induced harmful effects on mouse cardiac metabolism and function from a new perspective, using metabonomics and bioinformatics analysis data.

Cardiac outflow tract anomalies

PubMed Central

Neeb, Zachary; Lajiness, Jacquelyn D.; Bolanis, Esther; Conway, Simon J

2014-01-01

The mature outflow tract (OFT) is, in basic terms, a short conduit. It is a simple, although vital, connection situated between contracting muscular heart chambers and a vast embryonic vascular network. Unfortunately, it is also a focal point underlying many multifactorial congenital heart defects (CHDs). Through the use of various animal models combined with human genetic investigations, we are beginning to comprehend the molecular and cellular framework that controls OFT morphogenesis. Clear roles of neural crest cells (NCC) and second heart field (SHF) derivatives have been established during OFT formation and remodeling. The challenge now is to determine how the SHF and cardiac NCC interact, the complex reciprocal signaling that appears to be occurring at various stages of OFT morphogenesis, and finally how endocardial progenitors and primary heart field (PHF) communicate with both these colonizing extra-cardiac lineages. Although we are beginning to understand that this dance of progenitor populations is wonderfully intricate, the underlying pathogenesis and the spatiotemporal cell lineage interactions remain to be fully elucidated. What is now clear is that OFT alignment and septation are independent processes, invested via separate SHF and cardiac neural crest (CNC) lineages. This review will focus on our current understanding of the respective contributions of the SHF and CNC lineage during OFT development and pathogenesis. PMID:24014420

MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures.

PubMed

Muraoka, Naoto; Yamakawa, Hiroyuki; Miyamoto, Kazutaka; Sadahiro, Taketaro; Umei, Tomohiko; Isomi, Mari; Nakashima, Hanae; Akiyama, Mizuha; Wada, Rie; Inagawa, Kohei; Nishiyama, Takahiko; Kaneda, Ruri; Fukuda, Toru; Takeda, Shu; Tohyama, Shugo; Hashimoto, Hisayuki; Kawamura, Yoshifumi; Goshima, Naoki; Aeba, Ryo; Yamagishi, Hiroyuki; Fukuda, Keiichi; Ieda, Masaki

2014-07-17

Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors or microRNAs. However, induction of functional cardiomyocytes is inefficient, and molecular mechanisms of direct reprogramming remain undefined. Here, we demonstrate that addition of miR-133a (miR-133) to Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and Myocd improved cardiac reprogramming from mouse or human fibroblasts by directly repressing Snai1, a master regulator of epithelial-to-mesenchymal transition. MiR-133 overexpression with GMT generated sevenfold more beating iCMs from mouse embryonic fibroblasts and shortened the duration to induce beating cells from 30 to 10 days, compared to GMT alone. Snai1 knockdown suppressed fibroblast genes, upregulated cardiac gene expression, and induced more contracting iCMs with GMT transduction, recapitulating the effects of miR-133 overexpression. In contrast, overexpression of Snai1 in GMT/miR-133-transduced cells maintained fibroblast signatures and inhibited generation of beating iCMs. MiR-133-mediated Snai1 repression was also critical for cardiac reprogramming in adult mouse and human cardiac fibroblasts. Thus, silencing fibroblast signatures, mediated by miR-133/Snai1, is a key molecular roadblock during cardiac reprogramming. © 2014 The Authors.

MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures

PubMed Central

Muraoka, Naoto; Yamakawa, Hiroyuki; Miyamoto, Kazutaka; Sadahiro, Taketaro; Umei, Tomohiko; Isomi, Mari; Nakashima, Hanae; Akiyama, Mizuha; Wada, Rie; Inagawa, Kohei; Nishiyama, Takahiko; Kaneda, Ruri; Fukuda, Toru; Takeda, Shu; Tohyama, Shugo; Hashimoto, Hisayuki; Kawamura, Yoshifumi; Goshima, Naoki; Aeba, Ryo; Yamagishi, Hiroyuki; Fukuda, Keiichi; Ieda, Masaki

2014-01-01

Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors or microRNAs. However, induction of functional cardiomyocytes is inefficient, and molecular mechanisms of direct reprogramming remain undefined. Here, we demonstrate that addition of miR-133a (miR-133) to Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and Myocd improved cardiac reprogramming from mouse or human fibroblasts by directly repressing Snai1, a master regulator of epithelial-to-mesenchymal transition. MiR-133 overexpression with GMT generated sevenfold more beating iCMs from mouse embryonic fibroblasts and shortened the duration to induce beating cells from 30 to 10 days, compared to GMT alone. Snai1 knockdown suppressed fibroblast genes, upregulated cardiac gene expression, and induced more contracting iCMs with GMT transduction, recapitulating the effects of miR-133 overexpression. In contrast, overexpression of Snai1 in GMT/miR-133-transduced cells maintained fibroblast signatures and inhibited generation of beating iCMs. MiR-133-mediated Snai1 repression was also critical for cardiac reprogramming in adult mouse and human cardiac fibroblasts. Thus, silencing fibroblast signatures, mediated by miR-133/Snai1, is a key molecular roadblock during cardiac reprogramming. PMID:24920580

Cardiac Recovery During Long-Term Left Ventricular Assist Device Support.

PubMed

Wever-Pinzon, Omar; Drakos, Stavros G; McKellar, Stephen H; Horne, Benjamin D; Caine, William T; Kfoury, Abdallah G; Li, Dean Y; Fang, James C; Stehlik, Josef; Selzman, Craig H

2016-10-04

The number of centers with left ventricular assist device (LVAD) research programs focused on cardiac recovery is very small. Therefore, this phenomenon has been reported in real-world multi-center registries as a rare event. This study evaluated the incidence of cardiac recovery with an a priori LVAD implantation strategy of bridge-to-recovery (BTR) and constructed a recovery predictive model. The study included LVAD recipients registered in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). Cardiac recovery was evaluated in BTR and non-BTR patients. A weighted score was derived and externally validated in patients of the Utah Cardiac Recovery (UCAR) program. Of 15,138 INTERMACS patients, cardiac recovery occurred in 192 (1.3%). The incidence of recovery was 11.2% (n = 14) in BTR compared with 1.2% (n = 178) in non-BTR patients (p < 0.0001). Independent predictors of recovery included: age <50 years, non-ischemic cardiomyopathy, time from cardiac diagnosis <2 years, absence of ICD, creatinine ≤1.2 mg/dl, and LVEDD <6.5 cm (c-index: 0.85; p < 0.0001). A weighted score termed I-CARS, effectively stratified patients based on their probability of recovery. I-CARS was validated in the UCAR cohort (n = 190) with good performance (AUC: 0.94; 95% CI: 0.91 to 0.98). One-year survival after LVAD explantation, available in INTERMACS for 21 (11%) patients, was 86%. The incidence of cardiac recovery is higher in patients implanted with an a priori BTR strategy. We developed a simple tool to help identify patients in whom recovery is feasible. In BTR patients with favorable characteristics, I-CARS suggests a 24% probability of successful LVAD explantation. Large-scale studies to better address post-explantation outcomes are warranted. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

G protein-coupled receptor kinase 2 promotes cardiac hypertrophy

PubMed Central

Tscheschner, Henrike; Gao, Erhe; Schumacher, Sarah M.; Yuan, Ancai; Backs, Johannes; Most, Patrick; Wieland, Thomas; Koch, Walter J.; Katus, Hugo A.; Raake, Philip W.

2017-01-01

The increase in protein activity and upregulation of G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal heart failure models. The aim of the present study was to investigate the effects of GRK2 on cardiac hypertrophy and dissect potential molecular mechanisms. In mice we observed increased GRK2 mRNA and protein levels following transverse aortic constriction (TAC). Conditional GRK2 knockout mice showed attenuated hypertrophic response with preserved ventricular geometry 6 weeks after TAC operation compared to wild-type animals. In isolated neonatal rat ventricular cardiac myocytes stimulation with angiotensin II and phenylephrine enhanced GRK2 expression leading to enhanced signaling via protein kinase B (PKB or Akt), consecutively inhibiting glycogen synthase kinase 3 beta (GSK3β), such promoting nuclear accumulation and activation of nuclear factor of activated T-cells (NFAT). Cardiac myocyte hypertrophy induced by in vitro GRK2 overexpression increased the cytosolic interaction of GRK2 and phosphoinositide 3-kinase γ (PI3Kγ). Moreover, inhibition of PI3Kγ as well as GRK2 knock down prevented Akt activation resulting in halted NFAT activity and reduced cardiac myocyte hypertrophy. Our data show that enhanced GRK2 expression triggers cardiac hypertrophy by GRK2-PI3Kγ mediated Akt phosphorylation and subsequent inactivation of GSK3β, resulting in enhanced NFAT activity. PMID:28759639

Gene Regulatory Networks in Cardiac Conduction System Development

PubMed Central

Munshi, Nikhil V.

2014-01-01

The cardiac conduction system is a specialized tract of myocardial cells responsible for maintaining normal cardiac rhythm. Given its critical role in coordinating cardiac performance, a detailed analysis of the molecular mechanisms underlying conduction system formation should inform our understanding of arrhythmia pathophysiology and affect the development of novel therapeutic strategies. Historically, the ability to distinguish cells of the conduction system from neighboring working myocytes presented a major technical challenge for performing comprehensive mechanistic studies. Early lineage tracing experiments suggested that conduction cells derive from cardiomyocyte precursors, and these claims have been substantiated by using more contemporary approaches. However, regional specialization of conduction cells adds an additional layer of complexity to this system, and it appears that different components of the conduction system utilize unique modes of developmental formation. The identification of numerous transcription factors and their downstream target genes involved in regional differentiation of the conduction system has provided insight into how lineage commitment is achieved. Furthermore, by adopting cutting-edge genetic techniques in combination with sophisticated phenotyping capabilities, investigators have made substantial progress in delineating the regulatory networks that orchestrate conduction system formation and their role in cardiac rhythm and physiology. This review describes the connectivity of these gene regulatory networks in cardiac conduction system development and discusses how they provide a foundation for understanding normal and pathological human cardiac rhythms. PMID:22628576

Murine Electrophysiological Models of Cardiac Arrhythmogenesis

PubMed Central

2016-01-01

Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca2+ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias. PMID:27974512

Comparative Analysis of Telomerase Activity in CD117⁺ CD34⁺ Cardiac Telocytes with Bone Mesenchymal Stem Cells, Cardiac Fibroblasts and Cardiomyocytes.

PubMed

Li, Yuan-Yuan; Lu, Shan-Shan; Xu, Ting; Zhang, Hong-Qi; Li, Hua

2015-07-20

This study characterized the cardiac telocyte (TC) population both in vivo and in vitro, and investigated its telomerase activity related to mitosis. Using transmission electron microscopy and a phase contrast microscope, the typical morphological features of cardiac TCs were observed; by targeting the cell surface proteins CD117 and CD34, CD117 + CD34 + cardiac TCs were sorted via flow cytometry and validated by immunofluorescence based on the primary cell culture. Then the optimized basal nutrient medium for selected population was examined with the cell counting kit 8. Under this conditioned medium, the process of cell division was captured, and the telomerase activity of CD117 + CD34 + cardiac TCs was detected in comparison with bone mesenchymal stem cells (BMSCs), cardiac fibroblasts (CFBs), cardiomyocytes (CMs). Cardiac TCs projected characteristic telopodes with thin segments (podomers) in alternation with dilation (podoms). In addition, 64% of the primary cultured cardiac TCs were composed of CD117 + CD34 + cardiac TCs; which was verified by immunofluorescence. In a live cell imaging system, CD117 + CD34 + cardiac TCs were observed to enter into cell division in a short time, followed by an significant invagination forming across the middle of the cell body. Using a real-time quantitative telomeric-repeat amplification assay, the telomerase concentration in CD117 + CD34 + cardiac TCs was obviously lower than in BMSCs and CFBs, and significantly higher than in CMs. Cardiac TCs represent a unique cell population and CD117 + CD34 + cardiac TCs have relative low telomerase activity that differs from BMSCs, CFBs and CMs and thus they might play an important role in maintaining cardiac homeostasis.

Short-term exercise worsens cardiac oxidative stress and fibrosis in 8-month-old db/db mice by depleting cardiac glutathione.

PubMed

Laher, Ismail; Beam, Julianne; Botta, Amy; Barendregt, Rebekah; Sulistyoningrum, Dian; Devlin, Angela; Rheault, Mark; Ghosh, Sanjoy

2013-01-01

Moderate exercise improves cardiac antioxidant status in young humans and animals with Type-2 diabetes (T2D). Given that both diabetes and advancing age synergistically decrease antioxidant expression in most tissues, it is unclear whether exercise can upregulate cardiac antioxidants in chronic animal models of T2D. To this end, 8-month-old T2D and normoglycemic mice were exercised for 3 weeks, and cardiac redox status was evaluated. As expected, moderate exercise increased cardiac antioxidants and attenuated oxidative damage in normoglycemic mice. In contrast, similar exercise protocol in 8-month-old db/db mice worsened cardiac oxidative damage, which was associated with a specific dysregulation of glutathione (GSH) homeostasis. Expression of enzymes for GSH biosynthesis [γ-glutamylcysteine synthase, glutathione reductase] as well as for GSH-mediated detoxification (glutathione peroxidase, glutathione-S-transferase) was lower, while toxic metabolites dependent on GSH for clearance (4-hydroxynonenal) were increased in exercised diabetic mice hearts. To validate GSH loss as an important factor for such aggravated damage, daily administration of GSH restored cardiac GSH levels in exercised diabetic mice. Such supplementation attenuated both oxidative damage and fibrotic changes in the myocardium. Expression of transforming growth factor beta (TGF-β) and its regulated genes which are responsible for such profibrotic changes were also attenuated with GSH supplementation. These novel findings in a long-term T2D animal model demonstrate that short-term exercise by itself can deplete cardiac GSH and aggravate cardiac oxidative stress. As GSH administration conferred protection in 8-month-old diabetic mice undergoing exercise, supplementation with GSH-enhancing agents may be beneficial in elderly diabetic patients undergoing exercise.

Patient-specific cardiac phantom for clinical training and preprocedure surgical planning.

PubMed

Laing, Justin; Moore, John; Vassallo, Reid; Bainbridge, Daniel; Drangova, Maria; Peters, Terry

2018-04-01

Minimally invasive mitral valve repair procedures including MitraClip ® are becoming increasingly common. For cases of complex or diseased anatomy, clinicians may benefit from using a patient-specific cardiac phantom for training, surgical planning, and the validation of devices or techniques. An imaging compatible cardiac phantom was developed to simulate a MitraClip ® procedure. The phantom contained a patient-specific cardiac model manufactured using tissue mimicking materials. To evaluate accuracy, the patient-specific model was imaged using computed tomography (CT), segmented, and the resulting point cloud dataset was compared using absolute distance to the original patient data. The result, when comparing the molded model point cloud to the original dataset, resulted in a maximum Euclidean distance error of 7.7 mm, an average error of 0.98 mm, and a standard deviation of 0.91 mm. The phantom was validated using a MitraClip ® device to ensure anatomical features and tools are identifiable under image guidance. Patient-specific cardiac phantoms may allow for surgical complications to be accounted for preoperative planning. The information gained by clinicians involved in planning and performing the procedure should lead to shorter procedural times and better outcomes for patients.

Evaluation of the Cardiac Depression Visual Analogue Scale in a medical and non-medical sample.

PubMed

Di Benedetto, Mirella; Sheehan, Matthew

2014-01-01

Comorbid depression and medical illness is associated with a number of adverse health outcomes such as lower medication adherence and higher rates of subsequent mortality. Reliable and valid psychological measures capable of detecting a range of depressive symptoms found in medical settings are needed. The Cardiac Depression Visual Analogue Scale (CDVAS) is a recently developed, brief six-item measure originally designed to assess the range and severity of depressive symptoms within a cardiac population. The current study aimed to further investigate the psychometric properties of the CDVAS in a general and medical sample. The sample consisted of 117 participants, whose mean age was 40.0 years (SD = 19.0, range 18-84). Participants completed the CDVAS, the Cardiac Depression Scale (CDS), the Depression Anxiety Stress Scales (DASS) and a demographic and health questionnaire. The CDVAS was found to have adequate internal reliability (α = .76), strong concurrent validity with the CDS (r = .89) and the depression sub-scale of the DASS (r = .70), strong discriminant validity and strong predictive validity. The principal components analysis revealed that the CDVAS measured only one component, providing further support for the construct validity of the scale. Results of the current study indicate that the CDVAS is a short, simple, valid and reliable measure of depressive symptoms suitable for use in a general and medical sample.

Concise Review: Fluorescent Reporters in Human Pluripotent Stem Cells: Contributions to Cardiac Differentiation and Their Applications in Cardiac Disease and Toxicity.

PubMed

Den Hartogh, Sabine C; Passier, Robert

2016-01-01

In the last decade, since the first report of induced pluripotent stem cells, the stem cell field has made remarkable progress in the differentiation to specialized cell-types of various tissues and organs, including the heart. Cardiac lineage- and tissue-specific human pluripotent stem cell (hPSC) reporter lines have been valuable for the identification, selection, and expansion of cardiac progenitor cells and their derivatives, and for our current understanding of the underlying molecular mechanisms. In order to further advance the use of hPSCs in the fields of regenerative medicine, disease modeling, and preclinical drug development in cardiovascular research, it is crucial to identify functionally distinct cardiac subtypes and to study their biological signaling events and functional aspects in healthy and diseased conditions. In this review, we discuss the various strategies that have been followed to generate and study fluorescent reporter lines in hPSCs and provide insights how these reporter lines contribute to a better understanding and improvement of cell-based therapies and preclinical drug and toxicity screenings in the cardiac field. © AlphaMed Press.

Extracting cardiac myofiber orientations from high frequency ultrasound images

NASA Astrophysics Data System (ADS)

Qin, Xulei; Cong, Zhibin; Jiang, Rong; Shen, Ming; Wagner, Mary B.; Kirshbom, Paul; Fei, Baowei

2013-03-01

Cardiac myofiber plays an important role in stress mechanism during heart beating periods. The orientation of myofibers decides the effects of the stress distribution and the whole heart deformation. It is important to image and quantitatively extract these orientations for understanding the cardiac physiological and pathological mechanism and for diagnosis of chronic diseases. Ultrasound has been wildly used in cardiac diagnosis because of its ability of performing dynamic and noninvasive imaging and because of its low cost. An extraction method is proposed to automatically detect the cardiac myofiber orientations from high frequency ultrasound images. First, heart walls containing myofibers are imaged by B-mode high frequency (<20 MHz) ultrasound imaging. Second, myofiber orientations are extracted from ultrasound images using the proposed method that combines a nonlinear anisotropic diffusion filter, Canny edge detector, Hough transform, and K-means clustering. This method is validated by the results of ultrasound data from phantoms and pig hearts.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications

PubMed Central

Girolami, Francesca; Frisso, Giulia; Benelli, Matteo; Crotti, Lia; Iascone, Maria; Mango, Ruggiero; Mazzaccara, Cristina; Pilichou, Kalliope; Arbustini, Eloisa; Tomberli, Benedetta; Limongelli, Giuseppe; Basso, Cristina; Olivotto, Iacopo

2018-01-01

Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype–phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, ‘real-world’ experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines. PMID:29176389

Low molecular weight fibroblast growth factor-2 signals via protein kinase C and myofibrillar proteins to protect against postischemic cardiac dysfunction.

PubMed

Manning, Janet R; Perkins, Sarah O; Sinclair, Elizabeth A; Gao, Xiaoqian; Zhang, Yu; Newman, Gilbert; Pyle, W Glen; Schultz, Jo El J

2013-05-15

Among its many biological roles, fibroblast growth factor-2 (FGF2) acutely protects the heart from dysfunction associated with ischemia/reperfusion (I/R) injury. Our laboratory has demonstrated that this is due to the activity of the low molecular weight (LMW) isoform of FGF2 and that FGF2-mediated cardioprotection relies on the activity of protein kinase C (PKC); however, which PKC isoforms are responsible for LMW FGF2-mediated cardioprotection, and their downstream targets, remain to be elucidated. To identify the PKC pathway(s) that contributes to postischemic cardiac recovery by LMW FGF2, mouse hearts expressing only LMW FGF2 (HMWKO) were bred to mouse hearts not expressing PKCα (PKCαKO) or subjected to a selective PKCε inhibitor (εV(1-2)) before and during I/R. Hearts only expressing LMW FGF2 showed significantly improved postischemic recovery of cardiac function following I/R (P < 0.05), which was significantly abrogated in the absence of PKCα (P < 0.05) or presence of PKCε inhibition (P < 0.05). Hearts only expressing LMW FGF2 demonstrated differences in actomyosin ATPase activity as well as increases in the phosphorylation of troponin I and T during I/R compared with wild-type hearts; several of these effects were dependent on PKCα activity. This evidence indicates that both PKCα and PKCε play a role in LMW FGF2-mediated protection from cardiac dysfunction and that PKCα signaling to the contractile apparatus is a key step in the mechanism of LMW FGF2-mediated protection against myocardial dysfunction.

Quantitative phosphoproteomics using acetone-based peptide labeling: Method evaluation and application to a cardiac ischemia/reperfusion model

PubMed Central

Wijeratne, Aruna B.; Manning, Janet R.; Schultz, Jo El J.; Greis, Kenneth D.

2013-01-01

Mass spectrometry (MS) techniques to globally profile protein phosphorylation in cellular systems that are relevant to physiological or pathological changes have been of significant interest in biological research. In this report, an MS-based strategy utilizing an inexpensive acetone-based peptide labeling technique known as reductive alkylation by acetone (RABA) for quantitative phosphoproteomics was explored to evaluate its capacity. Since the chemistry for RABA-labeling for phosphorylation profiling had not been previously reported, it was first validated using a standard phosphoprotein and identical phosphoproteomes from cardiac tissue extracts. A workflow was then utilized to compare cardiac tissue phosphoproteomes from mouse hearts not expressing FGF2 vs. hearts expressing low molecular weight fibroblast growth factor-2 (LMW FGF2) to relate low molecular weight fibroblast growth factor-2 (LMW FGF2) mediated cardioprotective phenomena induced by ischemia/reperfusion (I/R) injury of hearts, with downstream phosphorylation changes in LMW FGF2 signaling cascades. Statistically significant phosphorylation changes were identified at 14 different sites on 10 distinct proteins including some with mechanisms already established for LMW FGF2-mediated cardioprotective signaling (e.g. connexin-43), some with new details linking LMW FGF2 to the cardioprotective mechanisms (e.g. cardiac myosin binding protein C or cMyBPC), and also several new downstream effectors not previously recognized for cardio-protective signaling by LMW FGF2. Additionally, one of the phosphopeptides, cMyBPC/pSer-282, identified was further verified with site-specific quantification using an SRM (selected reaction monitoring)-based approach that also relies on isotope labeling of a synthetic phosphopeptide with deuterated acetone as an internal standard. Overall, this study confirms that the inexpensive acetone-based peptide labeling can be used in both exploratory and targeted quantification

Evidence of cardiac involvement in the fetal inflammatory response syndrome: disruption of gene networks programming cardiac development in nonhuman primates.

PubMed

Mitchell, Timothy; MacDonald, James W; Srinouanpranchanh, Sengkeo; Bammler, Theodor K; Merillat, Sean; Boldenow, Erica; Coleman, Michelle; Agnew, Kathy; Baldessari, Audrey; Stencel-Baerenwald, Jennifer E; Tisoncik-Go, Jennifer; Green, Richard R; Gale, Michael J; Rajagopal, Lakshmi; Adams Waldorf, Kristina M

2018-04-01

Most early preterm births are associated with intraamniotic infection and inflammation, which can lead to systemic inflammation in the fetus. The fetal inflammatory response syndrome describes elevations in the fetal interleukin-6 level, which is a marker for inflammation and fetal organ injury. An understanding of the effects of inflammation on fetal cardiac development may lead to insight into the fetal origins of adult cardiovascular disease. The purpose of this study was to determine whether the fetal inflammatory response syndrome is associated with disruptions in gene networks that program fetal cardiac development. We obtained fetal cardiac tissue after necropsy from a well-described pregnant nonhuman primate model (pigtail macaque, Macaca nemestrina) of intrauterine infection (n=5) and controls (n=5). Cases with the fetal inflammatory response syndrome (fetal plasma interleukin-6 >11 pg/mL) were induced by either choriodecidual inoculation of a hypervirulent group B streptococcus strain (n=4) or intraamniotic inoculation of Escherichia coli (n=1). RNA and protein were extracted from fetal hearts and profiled by microarray and Luminex (Millipore, Billerica, MA) for cytokine analysis, respectively. Results were validated by quantitative reverse transcriptase polymerase chain reaction. Statistical and bioinformatics analyses included single gene analysis, gene set analysis, Ingenuity Pathway Analysis (Qiagen, Valencia, CA), and Wilcoxon rank sum. Severe fetal inflammation developed in the context of intraamniotic infection and a disseminated bacterial infection in the fetus. Interleukin-6 and -8 in fetal cardiac tissues were elevated significantly in fetal inflammatory response syndrome cases vs controls (P<.05). A total of 609 probe sets were expressed differentially (>1.5-fold change, P<.05) in the fetal heart (analysis of variance). Altered expression of select genes was validated by quantitative reverse transcriptase polymerase chain reaction that included

Caffeic acid phenethyl ester attenuates pathological cardiac hypertrophy by regulation of MEK/ERK signaling pathway in vivo and vitro.

PubMed

Ren, Jie; Zhang, Nan; Liao, Haihan; Chen, Si; Xu, Ling; Li, Jing; Yang, Zheng; Deng, Wei; Tang, Qizhu

2017-07-15

To explore the effects of caffeic acid phenethyl ester (CAPE) on cardiac hypertrophy induced by pressure overload. Male wild-type C57 mice, aged 8-10weeks, were used for aortic banding (AB) to induce cardiac hypertrophy. CAPE or (resveratrol) RS was administered from the 3rd day after AB surgery for 6weeks. Echocardiography and hemodynamic analysis were performed to estimate cardiac function. Mice hearts were collected for H&E and PSR staining. Western blot analysis and quantitative PCR were performed for to investigate molecular mechanism. We further confirmed our findings in H9c2 cardiac fibroblasts treated with PE or CAPE. CAPE protected against cardiac hypertrophy induced by pressure overload, as evidenced by inhibition of cardiac hypertrophy and improvement in mouse cardiac function. The effect of CAPE on cardiac hypertrophy was mediated via inhibition of the MEK/ERK and TGFβ-Smad signaling pathways. We also demonstrated that CAPE protected H9c2 cells from PE-induced hypertrophy in vitro via a similar molecular mechanism as seen in the mouse heart. Finally, CAPE seemed to be as effective as RS for treatment of pressure overload induced mouse cardiac hypertrophy. Our results suggest that CAPE may play an important role in the regulation of cardiac hypertrophy induced by pressure overload via negative regulation of the MEK/ERK and TGFβ/Smad signaling pathways. These results indicate that CAPE could potentially be used for treatment of cardiac hypertrophy. Copyright © 2017 Elsevier Inc. All rights reserved.

External Validation of European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) for Risk Prioritization in an Iranian Population

PubMed Central

Atashi, Alireza; Amini, Shahram; Tashnizi, Mohammad Abbasi; Moeinipour, Ali Asghar; Aazami, Mathias Hossain; Tohidnezhad, Fariba; Ghasemi, Erfan; Eslami, Saeid

2018-01-01

Introduction The European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) is a prediction model which maps 18 predictors to a 30-day post-operative risk of death concentrating on accurate stratification of candidate patients for cardiac surgery. Objective The objective of this study was to determine the performance of the EuroSCORE II risk-analysis predictions among patients who underwent heart surgeries in one area of Iran. Methods A retrospective cohort study was conducted to collect the required variables for all consecutive patients who underwent heart surgeries at Emam Reza hospital, Northeast Iran between 2014 and 2015. Univariate and multivariate analysis were performed to identify covariates which significantly contribute to higher EuroSCORE II in our population. External validation was performed by comparing the real and expected mortality using area under the receiver operating characteristic curve (AUC) for discrimination assessment. Also, Brier Score and Hosmer-Lemeshow goodness-of-fit test were used to show the overall performance and calibration level, respectively. Results Two thousand five hundred eight one (59.6% males) were included. The observed mortality rate was 3.3%, but EuroSCORE II had a prediction of 4.7%. Although the overall performance was acceptable (Brier score=0.047), the model showed poor discriminatory power by AUC=0.667 (sensitivity=61.90, and specificity=66.24) and calibration (Hosmer-Lemeshow test, P<0.01). Conclusion Our study showed that the EuroSCORE II discrimination power is less than optimal for outcome prediction and less accurate for resource allocation programs. It highlights the need for recalibration of this risk stratification tool aiming to improve post cardiac surgery outcome predictions in Iran. PMID:29617500

Strategies for Analyzing Cardiac Phenotypes in the Zebrafish Embryo

PubMed Central

Houk, Andrew R.; Yelon, Deborah

2017-01-01

The molecular mechanisms underlying cardiogenesis are of critical biomedical importance due to the high prevalence of cardiac birth defects. Over the past two decades, the zebrafish has served as a powerful model organism for investigating heart development, facilitated by its powerful combination of optical access to the embryonic heart and plentiful opportunities for genetic analysis. Work in zebrafish has identified numerous factors that are required for various aspects of heart formation, including the specification and differentiation of cardiac progenitor cells, the morphogenesis of the heart tube, cardiac chambers, and atrioventricular canal, and the establishment of proper cardiac function. However, our current roster of regulators of cardiogenesis is by no means complete. It is therefore valuable for ongoing studies to continue pursuit of additional genes and pathways that control the size, shape, and function of the zebrafish heart. An extensive arsenal of techniques is available to distinguish whether particular mutations, morpholinos, or small molecules disrupt specific processes during heart development. In this chapter, we provide a guide to the experimental strategies that are especially effective for the characterization of cardiac phenotypes in the zebrafish embryo. PMID:27312497

The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.

PubMed

Calvier, Laurent; Martinez-Martinez, Ernesto; Miana, Maria; Cachofeiro, Victoria; Rousseau, Elodie; Sádaba, J Rafael; Zannad, Faiez; Rossignol, Patrick; López-Andrés, Natalia

2015-01-01

This study investigated whether galectin (Gal)-3 inhibition could block aldosterone-induced cardiac and renal fibrosis and improve cardiorenal dysfunction. Aldosterone is involved in cardiac and renal fibrosis that is associated with the development of cardiorenal injury. However, the mechanisms of these interactions remain unclear. Gal-3, a β-galactoside-binding lectin, is increased in heart failure and kidney injury. Rats were treated with aldosterone-salt combined with spironolactone (a mineralocorticoid receptor antagonist) or modified citrus pectin (a Gal-3 inhibitor), for 3 weeks. Wild-type and Gal-3 knockout mice were treated with aldosterone for 3 weeks. Hemodynamic, cardiac, and renal parameters were analyzed. Hypertensive aldosterone-salt-treated rats presented cardiac and renal hypertrophy (at morphometric, cellular, and molecular levels) and dysfunction. Cardiac and renal expressions of Gal-3 as well as levels of molecular markers attesting fibrosis were also augmented by aldosterone-salt treatment. Spironolactone or modified citrus pectin treatment reversed all of these effects. In wild-type mice, aldosterone did not alter blood pressure levels but increased cardiac and renal Gal-3 expression, fibrosis, and renal epithelial-mesenchymal transition. Gal-3 knockout mice were resistant to aldosterone effects. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction but was prevented by pharmacological inhibition (modified citrus pectin) or genetic disruption of Gal-3. These data suggest a key role for Gal-3 in cardiorenal remodeling and dysfunction induced by aldosterone. Gal-3 could be used as a new biotarget for specific pharmacological interventions. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Top-down Mass Spectrometry of Cardiac Myofilament Proteins in Health and Disease

PubMed Central

Ying, Peng; Serife, Ayaz-Guner; Deyang, Yu; Ying, Ge

2014-01-01

Myofilaments are composed of thin and thick filaments which coordinate with each other to regulate muscle contraction and relaxation. Posttranslational modifications (PTMs) together with genetic variations and alternative splicing of the myofilament proteins play essential roles in regulating cardiac contractility in health and disease. Therefore, a comprehensive characterization of the myofilament proteins in physiological and pathological conditions is essential for better understanding the molecular basis of cardiac function and dysfunction. Due to the vast complexity and dynamic nature of proteins, it is challenging to obtain a holistic view of myofilament protein modifications. In recent years, top-down mass spectrometry (MS) has emerged as a powerful approach to study isoform composition and PTMs of proteins owing to its advantage of complete sequence coverage and its ability to identify PTMs and sequence variants without a priori knowledge. In this review, we will discuss the application of top-down MS to study cardiac myofilaments and highlight the insights it provides into the understanding of molecular mechanisms in contractile dysfunction of heart failure. Particularly, recent results of cardiac troponin and tropomyosin modifications will be elaborated. The limitations and perspectives on the use of top-down MS for myofilament protein characterization will also be briefly discussed. PMID:24945106

In vivo quantification of amyloid burden in TTR-related cardiac amyloidosis

PubMed Central

Kollikowski, Alexander Marco; Kahles, Florian; Kintsler, Svetlana; Hamada, Sandra; Reith, Sebastian; Knüchel, Ruth; Röcken, Christoph; Mottaghy, Felix Manuel; Marx, Nikolaus; Burgmaier, Mathias

2017-01-01

Summary Cardiac transthyretin-related (ATTR) amyloidosis is a severe cardiomyopathy for which therapeutic approaches are currently under development. Because non-invasive imaging techniques such as cardiac magnetic resonance imaging and echocardiography are non-specific, the diagnosis of ATTR amyloidosis is still based on myocardial biopsy. Thus, diagnosis of ATTR amyloidosis is difficult in patients refusing myocardial biopsy. Furthermore, myocardial biopsy does not allow 3D-mapping and quantification of myocardial ATTR amyloid. In this report we describe a 99mTc-DPD-based molecular imaging technique for non-invasive single-step diagnosis, three-dimensional mapping and semiquantification of cardiac ATTR amyloidosis in a patient with suspected amyloid heart disease who initially rejected myocardial biopsy. This report underlines the clinical value of SPECT-based nuclear medicine imaging to enable non-invasive diagnosis of cardiac ATTR amyloidosis, particularly in patients rejecting biopsy. PMID:29259858

Characterization and validation of new tools for measuring site-specific cardiac troponin I phosphorylation.

PubMed

Thoemmes, Stephen F; Stutzke, Crystal A; Du, Yanmei; Browning, Michael D; Buttrick, Peter M; Walker, Lori A

2014-01-31

Phosphorylation of cardiac troponin I is a well established mechanism by which cardiac contractility is modulated. However, there are a number of phosphorylation sites on TnI which contribute singly or in combination to influence cardiac function. Accordingly, methods for accurately measuring site-specific TnI phosphorylation are needed. Currently, two strategies are employed: mass spectrometry, which is costly, difficult and has a low throughput; and Western blotting using phospho-specific antibodies, which is limited by the availability of reagents. In this report, we describe a cohort of new site-specific TnI phosphoantibodies, generated against physiologically relevant phosphorylation sites, that are superior to the current commercially available antibodies: to phospho-serine 22/23 which shows a >5-fold phospho-specificity for phosphorylated TnI; to phospho-serine 43, which has >3-fold phospho-specificity for phosphorylated TnI; and phospho-serine 150 which has >2-fold phospho-specificity for phosphorylated TnI. These new antibodies demonstrated greater sensitivity and specificity for the phosphorylated TnI than the most widely used commercially available reagents. For example, at a protein load of 20 μg of total cardiac extract, a commercially available antibody recognized both phosphorylated and dephosphorylated TnI to the same degree. At the same protein load our phospho-serine 22/23 antibody exhibited no cross-reactivity with dephosphorylated TnI. These new tools should allow a more accurate assessment and a better understanding of the role of TnI phosphorylation in the response of the heart to pathologic stress. Copyright © 2013 Elsevier B.V. All rights reserved.

Simultaneous electrical recording of cardiac electrophysiology and contraction on chip

DOE PAGES

Qian, Fang; Huang, Chao; Lin, Yi-Dong; ...

2017-04-18

Prevailing commercialized cardiac platforms for in vitro drug development utilize planar microelectrode arrays to map action potentials, or impedance sensing to record contraction in real time, but cannot record both functions on the same chip with high spatial resolution. We report a novel cardiac platform that can record cardiac tissue adhesion, electrophysiology, and contractility on the same chip. The platform integrates two independent yet interpenetrating sensor arrays: a microelectrode array for field potential readouts and an interdigitated electrode array for impedance readouts. Together, these arrays provide real-time, non-invasive data acquisition of both cardiac electrophysiology and contractility under physiological conditions andmore » under drug stimuli. Furthermore, we cultured human induced pluripotent stem cell-derived cardiomyocytes as a model system, and used to validate the platform with an excitation–contraction decoupling chemical. Preliminary data using the platform to investigate the effect of the drug norepinephrine are combined with computational efforts. Finally, this platform provides a quantitative and predictive assay system that can potentially be used for comprehensive assessment of cardiac toxicity earlier in the drug discovery process.« less

Simultaneous electrical recording of cardiac electrophysiology and contraction on chip

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

Qian, Fang; Huang, Chao; Lin, Yi-Dong

Prevailing commercialized cardiac platforms for in vitro drug development utilize planar microelectrode arrays to map action potentials, or impedance sensing to record contraction in real time, but cannot record both functions on the same chip with high spatial resolution. We report a novel cardiac platform that can record cardiac tissue adhesion, electrophysiology, and contractility on the same chip. The platform integrates two independent yet interpenetrating sensor arrays: a microelectrode array for field potential readouts and an interdigitated electrode array for impedance readouts. Together, these arrays provide real-time, non-invasive data acquisition of both cardiac electrophysiology and contractility under physiological conditions andmore » under drug stimuli. Furthermore, we cultured human induced pluripotent stem cell-derived cardiomyocytes as a model system, and used to validate the platform with an excitation–contraction decoupling chemical. Preliminary data using the platform to investigate the effect of the drug norepinephrine are combined with computational efforts. Finally, this platform provides a quantitative and predictive assay system that can potentially be used for comprehensive assessment of cardiac toxicity earlier in the drug discovery process.« less

The Potential Role of Aerobic Exercise to Modulate Cardiotoxicity of Molecularly Targeted Cancer Therapeutics

PubMed Central

Lakoski, Susan; Mackey, John R.; Douglas, Pamela S.; Haykowsky, Mark J.; Jones, Lee W.

2013-01-01

Molecularly targeted therapeutics (MTT) are the future of cancer systemic therapy. They have already moved from palliative therapy for advanced solid malignancies into the setting of curative-intent treatment for early-stage disease. Cardiotoxicity is a frequent and potentially serious adverse complication of some targeted therapies, leading to a broad range of potentially life-threatening complications, therapy discontinuation, and poor quality of life. Low-cost pleiotropic interventions are therefore urgently required to effectively prevent and/or treat MTT-induced cardiotoxicity. Aerobic exercise therapy has the unique capacity to modulate, without toxicity, multiple gene expression pathways in several organ systems, including a plethora of cardiac-specific molecular and cell-signaling pathways implicated in MTT-induced cardiac toxicity. In this review, we examine the molecular signaling of antiangiogenic and HER2-directed therapies that may underpin cardiac toxicity and the hypothesized molecular mechanisms underlying the cardioprotective properties of aerobic exercise. It is hoped that this knowledge can be used to maximize the benefits of small molecule inhibitors, while minimizing cardiac damage in patients with solid malignancies. PMID:23335619

Double-Edge Molecular Measurement of Lidar Wind Profiles in the VALID Campaign

NASA Technical Reports Server (NTRS)

Korb, C. Laurence; Flesia, Cristina; Lolli, Simone; Hirt, Christian

2000-01-01

We have developed a transportable container based direct detection Doppler lidar based on the double-edge molecular technique. The pulsed solid state system was built at the University of Geneva. It was used to make range resolved measurements of the atmospheric wind field as part of the VALID campaign at the Observatoire de Haute Provence in Provence, France in July 1999. Comparison of our lidar wind measurements, which were analyzed without knowledge of the results of rawinsonde measurements made under the supervision of ESA, show good agreement with these rawinsondes. These are the first Doppler lidar field measurements made with an eyesafe direct detection molecular-based system at 355 nm and serve as a demonstrator for future spaceborne direct detection wind systems such as the Atmospheric Dynamics mission. Winds are an important contributor to sea surface temperature measurements made with the Tropical Rainfall Measuring Mission (TRMM) and also affect the TRMM rainfall estimates.

CIP, a cardiac Isl1-interacting protein, represses cardiomyocyte hypertrophy

PubMed Central

Huang, Zhan-Peng; Seok, Hee Young; Zhou, Bin; Chen, Jinghai; Chen, Jian-Fu; Tao, Yazhong; Pu, William T.; Wang, Da-Zhi

2012-01-01

Rationale Mammalian heart has minimal regenerative capacity. In response to mechanical or pathological stress, the heart undergoes cardiac remodeling. Pressure and volume overload in the heart cause increased size (hypertrophic growth) of cardiomyocytes. Whereas the regulatory pathways that activate cardiac hypertrophy have been well established, the molecular events that inhibit or repress cardiac hypertrophy are less known. Objective To identify and investigate novel regulators that modulate cardiac hypertrophy. Methods and Results Here, we report the identification, characterization and functional examination of CIP, a novel cardiac Isl1-interacting protein. CIP was identified from a bioinformatic search for novel cardiac-expressed genes in mouse embryonic hearts. CIP encodes a nuclear protein without recognizable motifs. Northern blotting, in situ hybridization and reporter gene tracing demonstrated that CIP is highly expressed in cardiomyocytes of developing and adult hearts. Yeast-two-hybrid screening identified Isl1, a LIM/homeodomain transcription factor essential for the specification of cardiac progenitor cells in the second heart field, as a co-factor of CIP. CIP directly interacted with Isl1 and we mapped the domains of these two proteins which mediate their interaction. We show that CIP represses the transcriptional activity of Isl1 in the activation of the MEF2C enhancer. The expression of CIP was dramatically reduced in hypertrophic cardiomyocytes. Most importantly, overexpression of CIP repressed agonist-induced cardiomyocyte hypertrophy. Conclusions Our studies therefore identify CIP a novel regulator of cardiac hypertrophy. PMID:22343712

CIP, a cardiac Isl1-interacting protein, represses cardiomyocyte hypertrophy.

PubMed

Huang, Zhan-Peng; Young Seok, Hee; Zhou, Bin; Chen, Jinghai; Chen, Jian-Fu; Tao, Yazhong; Pu, William T; Wang, Da-Zhi

2012-03-16

Mammalian heart has minimal regenerative capacity. In response to mechanical or pathological stress, the heart undergoes cardiac remodeling. Pressure and volume overload in the heart cause increased size (hypertrophic growth) of cardiomyocytes. Whereas the regulatory pathways that activate cardiac hypertrophy have been well-established, the molecular events that inhibit or repress cardiac hypertrophy are less known. To identify and investigate novel regulators that modulate cardiac hypertrophy. Here, we report the identification, characterization, and functional examination of a novel cardiac Isl1-interacting protein (CIP). CIP was identified from a bioinformatic search for novel cardiac-expressed genes in mouse embryonic hearts. CIP encodes a nuclear protein without recognizable motifs. Northern blotting, in situ hybridization, and reporter gene tracing demonstrated that CIP is highly expressed in cardiomyocytes of developing and adult hearts. Yeast two-hybrid screening identified Isl1, a LIM/homeodomain transcription factor essential for the specification of cardiac progenitor cells in the second heart field, as a cofactor of CIP. CIP directly interacted with Isl1, and we mapped the domains of these two proteins, which mediate their interaction. We show that CIP represses the transcriptional activity of Isl1 in the activation of the myocyte enhancer factor 2C. The expression of CIP was dramatically reduced in hypertrophic cardiomyocytes. Most importantly, overexpression of CIP repressed agonist-induced cardiomyocyte hypertrophy. Our studies therefore identify CIP as a novel regulator of cardiac hypertrophy.

Cardiac arrest: resuscitation and reperfusion.

PubMed

Patil, Kaustubha D; Halperin, Henry R; Becker, Lance B

2015-06-05

The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and

Molecular autopsy of sudden unexplained deaths reveals genetic predispositions for cardiac diseases among young forensic cases.

PubMed

Hellenthal, Nicole; Gaertner-Rommel, Anna; Klauke, Bärbel; Paluszkiewicz, Lech; Stuhr, Markus; Kerner, Thoralf; Farr, Martin; Püschel, Klaus; Milting, Hendrik

2017-11-01

Coronary artery disease accounts for the majority of sudden cardiac deaths (SCD) in the older population whereas cardiomyopathies and arrhythmogenic abnormalities predominate in younger SCD victims (<35 years) with a significant genetic component. The elucidation of the pathogenetic cause of death might be relevant for the prevention of further deaths within affected families. Aim of this study was to determine the portion of underlying genetic heart diseases among unexplained putative SCD cases from a large German forensic department. We included 10 forensic cases of sudden unexplained death (SUD) victims aged 19-40 years, who died by SCD due to forensic autopsy. DNA was analysed by next generation panel sequencing of 174 candidate genes for channelopathies and cardiomyopathies. Cardiological examinations, genetic counselling, and subsequent genetic testing were offered to all affected families. We identified within 1 year 10 cases of SUD among 172 forensic cases. Evidence for a genetic disposition was found in 8 of 10 (80%) cases, with pathogenic mutations in 3 and variants of uncertain significance in 5 of SCD cases. Subsequent selective screening of family members revealed two additional mutation carriers. The study provides strong evidence that molecular genetics improves the post mortem diagnosis of fatal genetic heart diseases among SUD victims. Molecular genetics should be integrated in forensic and pathological routine practice. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Syndecan-4 Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

PubMed Central

Xie, Jun; He, Guixin; Chen, Qinhua; Sun, Jiayin; Dai, Qin; Lu, Jianrong; Li, Guannan; Wu, Han; Li, Ran; Chen, Jianzhou; Xu, Wei; Xu, Biao

2016-01-01

Cardiac hypertrophy can be broadly classified as either physiological or pathological. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy and normal heart function. Pathological stimuli including hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Syndecan-4 (synd4) is a transmembrane proteoglycan identified as being involved in cardiac adaptation after injury, but whether it takes part in physiological cardiac hypertrophy is unclear. We observed upregulation of synd4 in exercise-induced hypertrophic myocardium. To evaluate the role of synd4 in the physiological form of cardiac hypertrophy, mice lacking synd4 (synd4–/–) were exercised by swimming for 4 wks. Ultrasonic cardiogram (UCG) and histological analysis revealed that swimming induced the hypertrophic phenotype but was blunted in synd4–/– compared with wild-type (WT) mice. The swimming-induced activation of Akt, a key molecule in physiological hypertrophy was also more decreased than in WT controls. In cultured cardiomyocytes, synd4 overexpression could induce cell enlargement, protein synthesis and distinct physiological molecular alternation. Akt activation also was observed in synd4-overexpressed cardiomyocytes. Furthermore, inhibition of protein kinase C (PKC) prevented the synd4-induced hypertrophic phenotype and Akt phosphorylation. This study identified an essential role of synd4 in mediation of physiological cardiac hypertrophy. PMID:26835698

Spatial distribution of specialized cardiac care units in the state of Santa Catarina

PubMed Central

Cirino, Silviana; Lima, Fabiana Santos; Gonçalves, Mirian Buss

2014-01-01

OBJECTIVE To analyze the methodology used for assessing the spatial distribution of specialized cardiac care units. METHODS A modeling and simulation method was adopted for the practical application of cardiac care service in the state of Santa Catarina, Southern Brazil, using the p-median model. As the state is divided into 21 health care regions, a methodology which suggests an arrangement of eight intermediate cardiac care units was analyzed, comparing the results obtained using data from 1996 and 2012. RESULTS Results obtained using data from 2012 indicated significant changes in the state, particularly in relation to the increased population density in the coastal regions. The current study provided a satisfactory response, indicated by the homogeneity of the results regarding the location of the intermediate cardiac care units and their respective regional administrations, thereby decreasing the average distance traveled by users to health care units, located in higher population density areas. The validity of the model was corroborated through the analysis of the allocation of the median vertices proposed in 1996 and 2012. CONCLUSIONS The current spatial distribution of specialized cardiac care units is more homogeneous and reflects the demographic changes that have occurred in the state over the last 17 years. The comparison between the two simulations and the current configuration showed the validity of the proposed model as an aid in decision making for system expansion. PMID:26039394

The Neural Crest in Cardiac Congenital Anomalies

PubMed Central

Keyte, Anna; Hutson, Mary Redmond

2012-01-01

This review discusses the function of neural crest as they relate to cardiovascular defects. The cardiac neural crest cells are a subpopulation of cranial neural crest discovered nearly 30 years ago by ablation of premigratory neural crest. The cardiac neural crest cells are necessary for normal cardiovascular development. We begin with a description of the crest cells in normal development, including their function in remodeling the pharyngeal arch arteries, outflow tract septation, valvulogenesis, and development of the cardiac conduction system. The cells are also responsible for modulating signaling in the caudal pharynx, including the second heart field. Many of the molecular pathways that are known to influence specification, migration, patterning and final targeting of the cardiac neural crest cells are reviewed. The cardiac neural crest cells play a critical role in the pathogenesis of various human cardiocraniofacial syndromes such as DiGeorge, Velocardiofacial, CHARGE, Fetal Alcohol, Alagille, LEOPARD, and Noonan syndromes, as well as Retinoic Acid Embryopathy. The loss of neural crest cells or their dysfunction may not always directly cause abnormal cardiovascular development, but are involved secondarily because crest cells represent a major component in the complex tissue interactions in the head, pharynx and outflow tract. Thus many of the human syndromes linking defects in the heart, face and brain can be better understood when considered within the context of a single cardiocraniofacial developmental module with the neural crest being a key cell type that interconnects the regions. PMID:22595346

Cardiac cell: a biological laser?

PubMed

Chorvat, D; Chorvatova, A

2008-04-01

We present a new concept of cardiac cells based on an analogy with lasers, practical implementations of quantum resonators. In this concept, each cardiac cell comprises a network of independent nodes, characterised by a set of discrete energy levels and certain transition probabilities between them. Interaction between the nodes is given by threshold-limited energy transfer, leading to quantum-like behaviour of the whole network. We propose that in cardiomyocytes, during each excitation-contraction coupling cycle, stochastic calcium release and the unitary properties of ionic channels constitute an analogue to laser active medium prone to "population inversion" and "spontaneous emission" phenomena. This medium, when powered by an incoming threshold-reaching voltage discharge in the form of an action potential, responds to the calcium influx through L-type calcium channels by stimulated emission of Ca2+ ions in a coherent, synchronised and amplified release process known as calcium-induced calcium release. In parallel, phosphorylation-stimulated molecular amplification in protein cascades adds tuneable features to the cells. In this framework, the heart can be viewed as a coherent network of synchronously firing cardiomyocytes behaving as pulsed laser-like amplifiers, coupled to pulse-generating pacemaker master-oscillators. The concept brings a new viewpoint on cardiac diseases as possible alterations of "cell lasing" properties.

Global cardiac risk assessment in the Registry Of Pregnancy And Cardiac disease: results of a registry from the European Society of Cardiology.

PubMed

van Hagen, Iris M; Boersma, Eric; Johnson, Mark R; Thorne, Sara A; Parsonage, William A; Escribano Subías, Pilar; Leśniak-Sobelga, Agata; Irtyuga, Olga; Sorour, Khaled A; Taha, Nasser; Maggioni, Aldo P; Hall, Roger; Roos-Hesselink, Jolien W

2016-05-01

To validate the modified World Health Organization (mWHO) risk classification in advanced and emerging countries, and to identify additional risk factors for cardiac events during pregnancy. The ongoing prospective worldwide Registry Of Pregnancy And Cardiac disease (ROPAC) included 2742 pregnant women (mean age ± standard deviation, 29.2 ± 5.5 years) with established cardiac disease: 1827 from advanced countries and 915 from emerging countries. In patients from advanced countries, congenital heart disease was the most prevalent diagnosis (70%) while in emerging countries valvular heart disease was more common (55%). A cardiac event occurred in 566 patients (20.6%) during pregnancy: 234 (12.8%) in advanced countries and 332 (36.3%) in emerging countries. The mWHO classification had a moderate performance to discriminate between women with and without cardiac events (c-statistic 0.711 and 95% confidence interval (CI) 0.686-0.735). However, its performance in advanced countries (0.726) was better than in emerging countries (0.633). The best performance was found in patients with acquired heart disease from developed countries (0.712). Pre-pregnancy signs of heart failure and, in advanced countries, atrial fibrillation and no previous cardiac intervention added prognostic value to the mWHO classification, with a c-statistic of 0.751 (95% CI 0.715-0.786) in advanced countries and of 0.724 (95% CI 0.691-0.758) in emerging countries. The mWHO risk classification is a useful tool for predicting cardiac events during pregnancy in women with established cardiac disease in advanced countries, but seems less effective in emerging countries. Data on pre-pregnancy cardiac condition including signs of heart failure and atrial fibrillation, may help to improve preconception counselling in advanced and emerging countries. © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.

[Chronic surplus of Japanese cardiac surgeon--ideal nurse practitioner for cardiac surgery, cardiac surgeon's attitude toward the future].

PubMed

Ikegami, Hirohisa

2014-03-01

It is chronically surplus of doctors in the world of cardiac surgery. There are too many cardiac surgeons because cardiac surgery requires a large amount of manpower resources to provide adequate medical services. Many Japanese cardiac surgeons do not have enough opportunity to perform cardiac surgery operations, and many Japanese cardiac surgery residents do not have enough opportunity to learn cardiac surgery operations. There are physician assistants and nurse practitioners in the US. Because they provide a part of medical care to cardiac surgery patients, American cardiac surgeons can focus more energy on operative procedures. Introduction of cardiac surgery specialized nurse practitioner is essential to deliver a high quality medical service as well as to solve chronic problems that Japanese cardiac surgery has had for a long time.

TRPV2 is critical for the maintenance of cardiac structure and function in mice

PubMed Central

Katanosaka, Yuki; Iwasaki, Keiichiro; Ujihara, Yoshihiro; Takatsu, Satomi; Nishitsuji, Koki; Kanagawa, Motoi; Sudo, Atsushi; Toda, Tatsushi; Katanosaka, Kimiaki; Mohri, Satoshi; Naruse, Keiji

2014-01-01

The heart has a dynamic compensatory mechanism for haemodynamic stress. However, the molecular details of how mechanical forces are transduced in the heart are unclear. Here we show that the transient receptor potential, vanilloid family type 2 (TRPV2) cation channel is critical for the maintenance of cardiac structure and function. Within 4 days of eliminating TRPV2 from hearts of the adult mice, cardiac function declines severely, with disorganization of the intercalated discs that support mechanical coupling with neighbouring myocytes and myocardial conduction defects. After 9 days, cell shortening and Ca2+ handling by single myocytes are impaired in TRPV2-deficient hearts. TRPV2-deficient neonatal cardiomyocytes form no intercalated discs and show no extracellular Ca2+-dependent intracellular Ca2+ increase and insulin-like growth factor (IGF-1) secretion in response to stretch stimulation. We further demonstrate that IGF-1 receptor/PI3K/Akt pathway signalling is significantly downregulated in TRPV2-deficient hearts, and that IGF-1 administration partially prevents chamber dilation and impairment in cardiac pump function in these hearts. Our results improve our understanding of the molecular processes underlying the maintenance of cardiac structure and function. PMID:24874017

TRPV2 is critical for the maintenance of cardiac structure and function in mice.

PubMed

Katanosaka, Yuki; Iwasaki, Keiichiro; Ujihara, Yoshihiro; Takatsu, Satomi; Nishitsuji, Koki; Kanagawa, Motoi; Sudo, Atsushi; Toda, Tatsushi; Katanosaka, Kimiaki; Mohri, Satoshi; Naruse, Keiji

2014-05-29

The heart has a dynamic compensatory mechanism for haemodynamic stress. However, the molecular details of how mechanical forces are transduced in the heart are unclear. Here we show that the transient receptor potential, vanilloid family type 2 (TRPV2) cation channel is critical for the maintenance of cardiac structure and function. Within 4 days of eliminating TRPV2 from hearts of the adult mice, cardiac function declines severely, with disorganization of the intercalated discs that support mechanical coupling with neighbouring myocytes and myocardial conduction defects. After 9 days, cell shortening and Ca(2+) handling by single myocytes are impaired in TRPV2-deficient hearts. TRPV2-deficient neonatal cardiomyocytes form no intercalated discs and show no extracellular Ca(2+)-dependent intracellular Ca(2+) increase and insulin-like growth factor (IGF-1) secretion in response to stretch stimulation. We further demonstrate that IGF-1 receptor/PI3K/Akt pathway signalling is significantly downregulated in TRPV2-deficient hearts, and that IGF-1 administration partially prevents chamber dilation and impairment in cardiac pump function in these hearts. Our results improve our understanding of the molecular processes underlying the maintenance of cardiac structure and function.

Effects of temperature acclimation on Pacific bluefin tuna (Thunnus orientalis) cardiac transcriptome.

PubMed

Jayasundara, Nishad; Gardner, Luke D; Block, Barbara A

2013-11-01

Little is known about the mechanisms underpinning thermal plasticity of vertebrate hearts. Bluefin tuna hearts offer a unique model to investigate processes underlying thermal acclimation. Their hearts, while supporting an endothermic physiology, operate at ambient temperature, and are presented with a thermal challenge when migrating to different thermal regimes. Here, we examined the molecular responses in atrial and ventricular tissues of Pacific bluefin tuna acclimated to 14°C, 20°C, and 25°C. Quantitative PCR studies showed an increase in sarcoplasmic reticulum Ca(2+) ATPase gene expression with cold acclimation and an induction of Na(+)/Ca(2+)-exchanger gene at both cold and warm temperatures. These data provide evidence for thermal plasticity of excitation-contraction coupling gene expression in bluefin tunas and indicate an increased capacity for internal Ca(2+) storage in cardiac myocytes at 14°C. Transcriptomic analysis showed profound changes in cardiac tissues with acclimation. A principal component analysis revealed that temperature effect was greatest on gene expression in warm-acclimated atrium. Overall data showed an increase in cardiac energy metabolism at 14°C, potentially compensating for cold temperature to optimize bluefin tuna performance in colder oceans. In contrast, metabolic enzyme activity and gene expression data suggest a decrease in ATP production at 25°C. Expression of genes involved in protein turnover and molecular chaperones was also decreased at 25°C. Expression of genes involved in oxidative stress response and programmed cell death suggest an increase in oxidative damage and apoptosis at 25°C, particularly in the atrium. These findings provide insights into molecular processes that may characterize cardiac phenotypes at upper thermal limits of teleosts.

Calcitriol attenuates cardiac remodeling and dysfunction in a murine model of polycystic ovary syndrome.

PubMed

Gao, Ling; Cao, Jia-Tian; Liang, Yan; Zhao, Yi-Chao; Lin, Xian-Hua; Li, Xiao-Cui; Tan, Ya-Jing; Li, Jing-Yi; Zhou, Cheng-Liang; Xu, Hai-Yan; Sheng, Jian-Zhong; Huang, He-Feng

2016-05-01

Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disorder affecting 10 % of reproductive-aged women, and is well associated with an increased prevalence of cardiovascular risk factors. However, there are few data concerning the direct association of PCOS with cardiac pathologies. The present study aims to investigate the changes in cardiac structure, function, and cardiomyocyte survival in a PCOS model, and explore the possible effect of calcitriol administration on these changes. PCOS was induced in C57BL/6J female mice by chronic dihydrotestosterone administration, as evidenced by irregular estrous cycles, obesity and dyslipidemia. PCOS mice progressively developed cardiac abnormalities including cardiac hypertrophy, interstitial fibrosis, myocardial apoptosis, and cardiac dysfunction. Conversely, concomitant administration of calcitriol significantly attenuated cardiac remodeling and cardiomyocyte apoptosis, and improved cardiac function. Molecular analysis revealed that the beneficial effect of calcitriol was associated with normalized autophagy function by increasing phosphorylation levels of AMP-activated protein kinase and inhibiting phosphorylation levels of mammalian target of rapamycin complex. Our findings provide the first evidence for the presence of cardiac remodeling in a PCOS model, and vitamin D supplementation may be a potential therapeutic strategy for the prevention and treatment of PCOS-related cardiac remodeling.

Validation and extraction of molecular-geometry information from small-molecule databases.

PubMed

Long, Fei; Nicholls, Robert A; Emsley, Paul; Graǽulis, Saulius; Merkys, Andrius; Vaitkus, Antanas; Murshudov, Garib N

2017-02-01

A freely available small-molecule structure database, the Crystallography Open Database (COD), is used for the extraction of molecular-geometry information on small-molecule compounds. The results are used for the generation of new ligand descriptions, which are subsequently used by macromolecular model-building and structure-refinement software. To increase the reliability of the derived data, and therefore the new ligand descriptions, the entries from this database were subjected to very strict validation. The selection criteria made sure that the crystal structures used to derive atom types, bond and angle classes are of sufficiently high quality. Any suspicious entries at a crystal or molecular level were removed from further consideration. The selection criteria included (i) the resolution of the data used for refinement (entries solved at 0.84 Å resolution or higher) and (ii) the structure-solution method (structures must be from a single-crystal experiment and all atoms of generated molecules must have full occupancies), as well as basic sanity checks such as (iii) consistency between the valences and the number of connections between atoms, (iv) acceptable bond-length deviations from the expected values and (v) detection of atomic collisions. The derived atom types and bond classes were then validated using high-order moment-based statistical techniques. The results of the statistical analyses were fed back to fine-tune the atom typing. The developed procedure was repeated four times, resulting in fine-grained atom typing, bond and angle classes. The procedure will be repeated in the future as and when new entries are deposited in the COD. The whole procedure can also be applied to any source of small-molecule structures, including the Cambridge Structural Database and the ZINC database.

Cardiac catheterization - discharge

MedlinePlus

Catheterization - cardiac - discharge; Heart catheterization - discharge: Catheterization - cardiac; Heart catheterization; Angina - cardiac catheterization discharge; CAD - cardiac catheterization discharge; Coronary artery disease - cardiac catheterization ...

Mechanisms of physiological and pathological cardiac hypertrophy.

PubMed

Nakamura, Michinari; Sadoshima, Junichi

2018-04-19

Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

The mechanical coupling of adult marrow stromal stem cells during cardiac regeneration assessed in a 2-D co-culture model

PubMed Central

Valarmathi, Mani T.; Fuseler, John W.; Goodwin, Richard L.; Davis, Jeffrey M.; Potts, Jay D.

2011-01-01

Postnatal cardiomyocytes undergo terminal differentiation and a restricted number of human cardiomyocytes retain the ability to divide and regenerate in response to ischemic injury. However, whether these neo-cardiomyocytes are derived from endogenous population of resident cardiac stem cells or from the exogenous double assurance population of resident bone marrow-derived stem cells that populate the damaged myocardium is unresolved and under intense investigation. The vital challenge is to ameliorate and/or regenerate the damaged myocardium. This can be achieved by stimulating proliferation of native quiescent cardiomyocytes and/or cardiac stem cell, or by recruiting exogenous autologous or allogeneic cells such as fetal or embryonic cardiomyocyte progenitors or bone marrow-derived stromal stem cells. The prerequisites are that these neo-cardiomyocytes must have the ability to integrate well within the native myocardium and must exhibit functional synchronization. Adult bone marrow stromal cells (BMSCs) have been shown to differentiate into cardiomyocyte-like cells both in vitro and in vivo. As a result, BMSCs may potentially play an essential role in cardiac repair and regeneration, but this concept requires further validation. In this report, we have provided compelling evidence that functioning cardiac tissue can be generated by the interaction of multipotent BMSCs with embryonic cardiac myocytes (ECMs) in two-dimensional (2-D) co-cultures. The differentiating BMSCs were induced to undergo cardiomyogenic differentiation pathway and were able to express unequivocal electromechanical coupling and functional synchronization with ECMs. Our 2-D co-culture system provides a useful in vitro model to elucidate various molecular mechanisms underpinning the integration and orderly maturation and differentiation of BMSCs into neo-cardiomyocytes during myocardial repair and regeneration. PMID:21288568

Cardiac Trauma.

PubMed

Gosavi, Sucheta; Tyroch, Alan H; Mukherjee, Debabrata

2016-11-01

Cardiac trauma is a leading cause of death in the United States and occurs mostly due to motor vehicle accidents. Blunt cardiac trauma and penetrating chest injuries are most common, and both can lead to aortic injuries. Timely diagnosis and early management are the key to improve mortality. Cardiac computed tomography and cardiac ultrasound are the 2 most important diagnostic modalities. Mortality related to cardiac trauma remains high despite improvement in diagnosis and management.

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.

ATP-Sensitive K+ Channel Knockout Induces Cardiac Proteome Remodeling Predictive of Heart Disease Susceptibility

PubMed Central

Arrell, D. Kent; Zlatkovic, Jelena; Kane, Garvan C.; Yamada, Satsuki; Terzic, Andre

2010-01-01

Forecasting disease susceptibility requires detection of maladaptive signatures prior to onset of overt symptoms. A case-in-point are cardiac ATP-sensitive K+ (KATP) channelopathies, for which the substrate underlying disease vulnerability remains to be identified. Resolving molecular pathobiology, even for single genetic defects, mandates a systems platform to reliably diagnose disease predisposition. High-throughput proteomic analysis was here integrated with network biology to decode consequences of Kir6.2 KATP channel pore deletion. Differential two-dimensional gel electrophoresis reproducibly resolved > 800 protein species from hearts of asymptomatic wild-type and Kir6.2-knockout counterparts. KATP channel ablation remodeled the cardiac proteome, significantly altering 71 protein spots, from which 102 unique identities were assigned following hybrid linear ion trap quadrupole-Orbitrap tandem mass spectrometry. Ontological annotation stratified the KATP channel-dependent protein cohort into a predominant bioenergetic module (63 resolved identities), with additional focused sets representing signaling molecules (6), oxidoreductases (8), chaperones (6), and proteins involved in catabolism (6), cytostructure (8), and transcription and translation (5). Protein interaction mapping, in conjunction with expression level changes, localized a KATP channel-associated subproteome within a nonstochastic scale-free network. Global assessment of the KATP channel deficient environment verified the primary impact on metabolic pathways and revealed overrepresentation of markers associated with cardiovascular disease. Experimental imposition of graded stress precipitated exaggerated structural and functional myocardial defects in the Kir6.2-knockout, decreasing survivorship and validating the forecast of disease susceptibility. Proteomic cartography thus provides an integral view of molecular remodeling in the heart induced by KATP channel deletion, establishing a systems

The heartbreak of depression: 'Psycho-cardiac' coupling in myocardial infarction.

PubMed

Headrick, John P; Peart, Jason N; Budiono, Boris P; Shum, David H K; Neumann, David L; Stapelberg, Nicolas J C

2017-05-01

Ample evidence identifies strong links between major depressive disorder (MDD) and both risk of ischemic or coronary heart disease (CHD) and resultant morbidity and mortality. The molecular mechanistic bases of these linkages are poorly defined. Systemic factors linked to MDD, including vascular dysfunction, atherosclerosis, obesity and diabetes, together with associated behavioral changes, all elevate CHD risk. Nonetheless, experimental evidence indicates the myocardium is also directly modified in depression, independently of these factors, impairing infarct tolerance and cardioprotection. It may be that MDD effectively breaks the heart's intrinsic defense mechanisms. Four extrinsic processes are implicated in this psycho-cardiac coupling, presenting potential targets for therapeutic intervention if causally involved: sympathetic over-activity vs. vagal under-activity, together with hypothalamic-pituitary-adrenal (HPA) axis and immuno-inflammatory dysfunctions. However, direct evidence of their involvement remains limited, and whether targeting these upstream mediators is effective (or practical) in limiting the cardiac consequences of MDD is unknown. Detailing myocardial phenotype in MDD can also inform approaches to cardioprotection, yet cardiac molecular changes are similarly ill defined. Studies support myocardial sensitization to ischemic insult in models of MDD, including worsened oxidative and nitrosative damage, apoptosis (with altered Bcl-2 family expression) and infarction. Moreover, depression may de-sensitize hearts to protective conditioning stimuli. The mechanistic underpinnings of these changes await delineation. Such information not only advances our fundamental understanding of psychological determinants of health, but also better informs management of the cardiac consequences of MDD and implementing cardioprotection in this cohort. Copyright © 2017 Elsevier Ltd. All rights reserved.

Complete cardiac regeneration in a mouse model of myocardial infarction.

PubMed

Haubner, Bernhard Johannes; Adamowicz-Brice, Martyna; Khadayate, Sanjay; Tiefenthaler, Viktoria; Metzler, Bernhard; Aitman, Tim; Penninger, Josef M

2012-12-01

Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, complete cardiac regeneration has been demonstrated in fish and newborn mice following resection of the cardiac apex. However, it remained entirely unclear whether the mammalian heart can also completely regenerate following a complex cardiac ischemic injury. We established a protocol to induce a severe heart attack in one-day-old mice using left anterior descending artery (LAD) ligation. LAD ligation triggered substantial cardiac injury in the left ventricle defined by Caspase 3 activation and massive cell death. Ischemia-induced cardiomyocyte death was also visible on day 4 after LAD ligation. Remarkably, 7 days after the initial ischemic insult, we observed complete cardiac regeneration without any signs of tissue damage or scarring. This tissue regeneration translated into long-term normal heart functions as assessed by echocardiography. In contrast, LAD ligations in 7-day-old mice resulted in extensive scarring comparable to adult mice, indicating that the regenerative capacity for complete cardiac healing after heart attacks can be traced to the first week after birth. RNAseq analyses of hearts on day 1, day 3, and day 10 and comparing LAD-ligated and sham-operated mice surprisingly revealed a transcriptional programme of major changes in genes mediating mitosis and cell division between days 1, 3 and 10 postnatally and a very limited set of genes, including genes regulating cell cycle and extracellular matrix synthesis, being differentially regulated in the regenerating hearts. We present for the first time a mammalian model of complete cardiac regeneration following a severe ischemic cardiac injury. This novel model system provides the unique opportunity to uncover molecular and cellular pathways that can induce cardiac regeneration after ischemic injury, findings that one day could be translated

Right ventricular involvement in cardiac sarcoidosis demonstrated with cardiac magnetic resonance

PubMed Central

van Geuns, Robert‐Jan; Ainslie, Gillian; Ector, Joris; Heidbuchel, Hein; Crijns, Harry J.G.M.

2017-01-01

Abstract Aims Cardiac involvement in sarcoidosis is reported in up to 30% of patients. Left ventricular involvement demonstrated by contrast‐enhanced cardiac magnetic resonance has been well validated. We sought to determine the prevalence and distribution of right ventricular late gadolinium enhancement in patients diagnosed with pulmonary sarcoidosis. Methods and results We prospectively evaluated 87 patients diagnosed with pulmonary sarcoidosis with contrast‐enhanced cardiac magnetic resonance for right ventricular involvement. Pulmonary artery pressures were non‐invasively evaluated with Doppler echocardiography. Patient characteristics were compared between the groups with and without right ventricular involvement, and right ventricular enhancement was correlated with pulmonary hypertension, ventricular mass, volume, and systolic function. Left ventricular late gadolinium enhancement was demonstrated in 30 patients (34%). Fourteen patients (16%) had right ventricular late gadolinium enhancement, with sole right ventricular enhancement in only two patients. The pattern of right ventricular enhancement consisted of right ventricular outflow tract enhancement in 1 patient, free wall enhancement in 8 patients, ventricular insertion point enhancement in 10 patients, and enhancement of the right side of the interventricular septum in 11 patients. Pulmonary arterial hypertension correlated with the presence of right ventricular enhancement (P < 0.001). Right ventricular enhancement correlated with systolic ventricular dysfunction (P < 0.001), hypertrophy (P = 0.001), and dilation (P < 0.001). Conclusions Right ventricular enhancement was present in 16% of patients diagnosed with pulmonary sarcoidosis and in 48% of patients with left ventricular enhancement. The presence of right ventricular enhancement correlated with pulmonary arterial hypertension, right ventricular systolic dysfunction, hypertrophy, and dilation. PMID:29154434

Aerobic exercise training rescues cardiac protein quality control and blunts endoplasmic reticulum stress in heart failure rats.

PubMed

Bozi, Luiz H M; Jannig, Paulo R; Rolim, Natale; Voltarelli, Vanessa A; Dourado, Paulo M M; Wisløff, Ulrik; Brum, Patricia C

2016-11-01

Cardiac endoplasmic reticulum (ER) stress through accumulation of misfolded proteins plays a pivotal role in cardiovascular diseases. In an attempt to reestablish ER homoeostasis, the unfolded protein response (UPR) is activated. However, if ER stress persists, sustained UPR activation leads to apoptosis. There is no available therapy for ER stress relief. Considering that aerobic exercise training (AET) attenuates oxidative stress, mitochondrial dysfunction and calcium imbalance, it may be a potential strategy to reestablish cardiac ER homoeostasis. We test the hypothesis that AET would attenuate impaired cardiac ER stress after myocardial infarction (MI). Wistar rats underwent to either MI or sham surgeries. Four weeks later, rats underwent to 8 weeks of moderate-intensity AET. Myocardial infarction rats displayed cardiac dysfunction and lung oedema, suggesting heart failure. Cardiac dysfunction in MI rats was paralleled by increased protein levels of UPR markers (GRP78, DERLIN-1 and CHOP), accumulation of misfolded and polyubiquitinated proteins, and reduced chymotrypsin-like proteasome activity. These results suggest an impaired cardiac protein quality control. Aerobic exercise training improved exercise capacity and cardiac function of MI animals. Interestingly, AET blunted MI-induced ER stress by reducing protein levels of UPR markers, and accumulation of both misfolded and polyubiquinated proteins, which was associated with restored proteasome activity. Taken together, our study provide evidence for AET attenuation of ER stress through the reestablishment of cardiac protein quality control, which contributes to better cardiac function in post-MI heart failure rats. These results reinforce the importance of AET as primary non-pharmacological therapy to cardiovascular disease. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Cardiac telomere length in heart development, function, and disease.

PubMed

Booth, S A; Charchar, F J

2017-07-01

Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury. Copyright © 2017 the American Physiological Society.

Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants

PubMed Central

Zhou, Zhiqun; Huang, Wenrui; Liang, Jingsheng; Szczesna-Cordary, Danuta

2016-01-01

The homozygous appearance of the intronic mutation (IVS6-1) in the MYL2 gene encoding for myosin ventricular/slow-twitch skeletal regulatory light chain (RLC) was recently linked to the development of slow skeletal muscle fiber type I hypotrophy and early cardiac death. The IVS6-1 (c403-1G>C) mutation resulted from a cryptic splice site in MYL2 causing a frameshift and replacement of the last 32 codons by 19 different amino acids in the RLC mutant protein. Infants who were IVS6-1+∕+-positive died between 4 and 6 months of age due to cardiomyopathy and heart failure. In this report we have investigated the molecular mechanism and functional consequences associated with the IVS6-1 mutation using recombinant human cardiac IVS6-1 and wild-type (WT) RLC proteins. Recombinant proteins were reconstituted into RLC-depleted porcine cardiac muscle preparations and subjected to enzymatic and functional assays. IVS6-1-RLC showed decreased binding to the myosin heavy chain (MHC) compared with WT, and IVS6-1-reconstituted myosin displayed reduced binding to actin in rigor. The IVS6-1 myosin demonstrated a significantly lower Vmax of the actin-activated myosin ATPase activity compared with WT. In stopped-flow experiments, IVS6-1 myosin showed slower kinetics of the ATP induced dissociation of the acto-myosin complex and a significantly reduced slope of the kobs-[MgATP] relationship compared to WT. In skinned porcine cardiac muscles, RLC-depleted and IVS6-1 reconstituted muscle strips displayed a significant decrease in maximal contractile force and a significantly increased Ca2+ sensitivity, both hallmarks of hypertrophic cardiomyopathy-associated mutations in MYL2. Our results showed that the amino-acid changes in IVS6-1 were sufficient to impose significant conformational alterations in the RLC protein and trigger a series of abnormal protein-protein interactions in the cardiac muscle sarcomere. Notably, the mutation disrupted the RLC-MHC interaction and the steady-state and

Implementation study of an analog spiking neural network for assisting cardiac delay prediction in a cardiac resynchronization therapy device.

PubMed

Sun, Qing; Schwartz, François; Michel, Jacques; Herve, Yannick; Dalmolin, Renzo

2011-06-01

In this paper, we aim at developing an analog spiking neural network (SNN) for reinforcing the performance of conventional cardiac resynchronization therapy (CRT) devices (also called biventricular pacemakers). Targeting an alternative analog solution in 0.13- μm CMOS technology, this paper proposes an approach to improve cardiac delay predictions in every cardiac period in order to assist the CRT device to provide real-time optimal heartbeats. The primary analog SNN architecture is proposed and its implementation is studied to fulfill the requirement of very low energy consumption. By using the Hebbian learning and reinforcement learning algorithms, the intended adaptive CRT device works with different functional modes. The simulations of both learning algorithms have been carried out, and they were shown to demonstrate the global functionalities. To improve the realism of the system, we introduce various heart behavior models (with constant/variable heart rates) that allow pathologic simulations with/without noise on the signals of the input sensors. The simulations of the global system (pacemaker models coupled with heart models) have been investigated and used to validate the analog spiking neural network implementation.

Hypoxia signaling controls postnatal changes in cardiac mitochondrial morphology and function

PubMed Central

Neary, Marianne T.; Ng, Keat-Eng; Ludtmann, Marthe H.R.; Hall, Andrew R.; Piotrowska, Izabela; Ong, Sang-Bing; Hausenloy, Derek J.; Mohun, Timothy J.; Abramov, Andrey Y.; Breckenridge, Ross A.

2014-01-01

Fetal cardiomyocyte adaptation to low levels of oxygen in utero is incompletely understood, and is of interest as hypoxia tolerance is lost after birth, leading to vulnerability of adult cardiomyocytes. It is known that cardiac mitochondrial morphology, number and function change significantly following birth, although the underlying molecular mechanisms and physiological stimuli are undefined. Here we show that the decrease in cardiomyocyte HIF-signaling in cardiomyocytes immediately after birth acts as a physiological switch driving mitochondrial fusion and increased postnatal mitochondrial biogenesis. We also investigated mechanisms of ATP generation in embryonic cardiac mitochondria. We found that embryonic cardiac cardiomyocytes rely on both glycolysis and the tricarboxylic acid cycle to generate ATP, and that the balance between these two metabolic pathways in the heart is controlled around birth by the reduction in HIF signaling. We therefore propose that the increase in ambient oxygen encountered by the neonate at birth acts as a key physiological stimulus to cardiac mitochondrial adaptation. PMID:24984146

Pulsed electromagnetic field improves cardiac function in response to myocardial infarction.

PubMed

Hao, Chang-Ning; Huang, Jing-Juan; Shi, Yi-Qin; Cheng, Xian-Wu; Li, Hao-Yun; Zhou, Lin; Guo, Xin-Gui; Li, Rui-Lin; Lu, Wei; Zhu, Yi-Zhun; Duan, Jun-Li

2014-01-01

Extracorporeal pulsed electromagnetic field (PEMF) has been shown the ability to improve regeneration in various ischemic episodes. Here, we examined whether PEMF therapy facilitate cardiac recovery in rat myocardial infarction (MI), and the cellular/molecular mechanisms underlying PEMF-related therapy was further investigated. The MI rats were exposed to active PEMF for 4 cycles per day (8 minutes/cycle, 30 ± 3 Hz, 5 mT) after MI induction. The data demonstrated that PEMF treatment significantly inhibited cardiac apoptosis and improved cardiac systolic function. Moreover, PEMF treatment increased capillary density, the levels of vascular endothelial growth factor (VEGF) and hypoxic inducible factor-1α in infarct border zone. Furthermore, the number and function of circulating endothelial progenitor cells were advanced in PEMF treating rats. In vitro, PEMF induced the degree of human umbilical venous endothelial cells tubulization and increased soluble pro-angiogenic factor secretion (VEGF and nitric oxide). In conclusion, PEMF therapy preserves cardiac systolic function, inhibits apoptosis and trigger postnatal neovascularization in ischemic myocardium.

Responses of Cardiac Tissue to Simulated Weightlessness

NASA Technical Reports Server (NTRS)

Tahimic, Candice; Steczina, Sonette; Terada, Masahiro; Shirazi-Fard, Yasaman; Schreurs, Ann-Sofie; Goukassian, David; Globus, Ruth

2017-01-01

Our current study aims to determine the molecular mechanisms that underlie these cardiac changes in response to spaceflight. The central hypothesis of our study is that long duration simulated weightlessness and subsequent recovery causes select and persistent changes in gene expression and oxidative defense-related pathways. In this study, we will first conduct general analyses of three-month old male and female animals, focusing on two key long-duration time points, (i.e. after 90 days of simulated weightlessness (HU) and after 90 days recovery from 90 days of HU. Both rat-specific gene arrays and qPCR will be performed focusing on genes already implicated in oxidative stress responses and cardiac disease. Gene expression analyses will be complemented by biochemical tests of frozen tissue lysates for select markers of oxidative damage.

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis.

PubMed

Wu, Mei-Ping; Zhang, Yi-Shuai; Xu, Xiangbin; Zhou, Qian; Li, Jian-Dong; Yan, Chen

2017-04-01

Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.

Reptilian heart development and the molecular basis of cardiac chamber evolution.

PubMed

Koshiba-Takeuchi, Kazuko; Mori, Alessandro D; Kaynak, Bogac L; Cebra-Thomas, Judith; Sukonnik, Tatyana; Georges, Romain O; Latham, Stephany; Beck, Laurel; Beck, Laural; Henkelman, R Mark; Black, Brian L; Olson, Eric N; Wade, Juli; Takeuchi, Jun K; Nemer, Mona; Gilbert, Scott F; Bruneau, Benoit G

2009-09-03

The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals and crocodilians into complete septation of the heart into left and right sides, allowing separate pulmonary and systemic circulatory systems, a key requirement for the evolution of endothermy. However, the evolution of the amniote heart is poorly understood. Reptilian hearts have been the subject of debate in the context of the evolution of cardiac septation: do they possess a single ventricular chamber or two incompletely septated ventricles? Here we examine heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogenously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to left ventricle precursors. In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left-right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, we show that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus ventricular septation is established by a steep and correctly positioned Tbx5 gradient. Our findings provide a molecular mechanism for the evolution of the amniote ventricle, and support the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution.

Reptilian heart development and the molecular basis of cardiac chamber evolution

PubMed Central

Koshiba-Takeuchi, Kazuko; Mori, Alessandro D.; Kaynak, Bogac L.; Cebra-Thomas, Judith; Sukonnik, Tatyana; Georges, Romain O.; Latham, Stephany; Beck, Laural; Henkelman, R. Mark; Black, Brian L.; Olson, Eric N.; Wade, Juli; Takeuchi, Jun K.; Nemer, Mona; Gilbert, Scott F.; Bruneau, Benoit G.

2009-01-01

The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals, and crocodilians into complete septation of the heart into left and right sides, allowing separate pulmonary and systemic circulatory systems, a key requirement for the evolution of endothermy1–3. However, the evolution of the amniote heart is poorly understood. Reptilian hearts have been the subject of debate in the context of the evolution of cardiac septation: do they possess a single ventricular chamber or two incompletely septated ventricles4–7? We examined heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogenously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to left ventricle precursors8,9. In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left-right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, we show that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus, ventricular septation is established by a steep and correctly positioned Tbx5 gradient. Our findings provide a molecular mechanism for the evolution of the amniote ventricle, and support the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution. PMID:19727199

Comparative Proteome Profiling during Cardiac Hypertrophy and Myocardial Infarction Reveals Altered Glucose Oxidation by Differential Activation of Pyruvate Dehydrogenase E1 Component Subunit β.

PubMed

Mitra, Arkadeep; Basak, Trayambak; Ahmad, Shadab; Datta, Kaberi; Datta, Ritwik; Sengupta, Shantanu; Sarkar, Sagartirtha

2015-06-05

Cardiac hypertrophy and myocardial infarction (MI) are two etiologically different disease forms with varied pathological characteristics. However, the precise molecular mechanisms and specific causal proteins associated with these diseases are obscure to date. In this study, a comparative cardiac proteome profiling was performed in Wistar rat models for diseased and control (sham) groups using two-dimensional difference gel electrophoresis followed by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry. Proteins were identified using Protein Pilot™ software (version 4.0) and were subjected to stringent statistical analysis. Alteration of key proteins was validated by Western blot analysis. The differentially expressed protein sets identified in this study were associated with different functional groups, involving various metabolic pathways, stress responses, cytoskeletal organization, apoptotic signaling and other miscellaneous functions. It was further deciphered that altered energy metabolism during hypertrophy in comparison to MI may be predominantly attributed to induced glucose oxidation level, via reduced phosphorylation of pyruvate dehydrogenase E1 component subunit β (PDHE1-B) protein during hypertrophy. This study reports for the first time the global changes in rat cardiac proteome during two etiologically different cardiac diseases and identifies key signaling regulators modulating ontogeny of these two diseases culminating in heart failure. This study also pointed toward differential activation of PDHE1-B that accounts for upregulation of glucose oxidation during hypertrophy. Downstream analysis of altered proteome and the associated modulators would enhance our present knowledge regarding altered pathophysiology of these two etiologically different cardiac disease forms. Copyright © 2014 Elsevier Ltd. All rights reserved.

A practical approach for the validation of sterility, endotoxin and potency testing of bone marrow mononucleated cells used in cardiac regeneration in compliance with good manufacturing practice.

PubMed

Soncin, Sabrina; Lo Cicero, Viviana; Astori, Giuseppe; Soldati, Gianni; Gola, Mauro; Sürder, Daniel; Moccetti, Tiziano

2009-09-08

Main scope of the EU and FDA regulations is to establish a classification criterion for advanced therapy medicinal products (ATMP). Regulations require that ATMPs must be prepared under good manufacturing practice (GMP). We have validated a commercial system for the determination of bacterial endotoxins in compliance with EU Pharmacopoeia 2.6.14, the sterility testing in compliance with EU Pharmacopoeia 2.6.1 and a potency assay in an ATMP constituted of mononucleated cells used in cardiac regeneration. For the potency assay, cells were placed in the upper part of a modified Boyden chamber containing Endocult Basal Medium with supplements and transmigrated cells were scored. The invasion index was expressed as the ratio between the numbers of invading cells relative to cell migration through a control insert membrane. For endotoxins, we used a commercially available system based on the kinetic chromogenic LAL-test. Validation of sterility was performed by direct inoculation of TSB and FTM media with the cell product following Eu Ph 2.6.1 guideline. The calculated MVD and endotoxin limit were 780x and 39 EU/ml respectively. The 1:10 and 1:100 dilutions were selected for the validation. For sterility, all the FTM cultures were positive after 3 days. For TSB cultures, Mycetes and B. subtilis were positive after 5 and 3 days respectively. The detection limit was 1-10 colonies. A total of four invasion assay were performed: the calculated invasion index was 28.89 +/- 16.82% (mean +/- SD). We have validated a strategy for endotoxin, sterility and potency testing in an ATMP used in cardiac regeneration. Unlike pharmaceutical products, many stem-cell-based products may originate in hospitals where personnel are unfamiliar with the applicable regulations. As new ATMPs are developed, the regulatory framework is likely to evolve. Meanwhile, existing regulations provide an appropriate structure for ensuring the safety and efficacy of the next generation of ATMPs. Personnel

Chronomics of pressure overload-induced cardiac hypertrophy in mice reveals altered day/night gene expression and biomarkers of heart disease.

PubMed

Tsimakouridze, Elena V; Straume, Marty; Podobed, Peter S; Chin, Heather; LaMarre, Jonathan; Johnson, Ron; Antenos, Monica; Kirby, Gordon M; Mackay, Allison; Huether, Patsy; Simpson, Jeremy A; Sole, Michael; Gadal, Gerard; Martino, Tami A

2012-08-01

There is critical demand in contemporary medicine for gene expression markers in all areas of human disease, for early detection of disease, classification, prognosis, and response to therapy. The integrity of circadian gene expression underlies cardiovascular health and disease; however time-of-day profiling in heart disease has never been examined. We hypothesized that a time-of-day chronomic approach using samples collected across 24-h cycles and analyzed by microarrays and bioinformatics advances contemporary approaches, because it includes sleep-time and/or wake-time molecular responses. As proof of concept, we demonstrate the value of this approach in cardiovascular disease using a murine Transverse Aortic Constriction (TAC) model of pressure overload-induced cardiac hypertrophy in mice. First, microarrays and a novel algorithm termed DeltaGene were used to identify time-of-day differences in gene expression in cardiac hypertrophy 8 wks post-TAC. The top 300 candidates were further analyzed using knowledge-based platforms, paring the list to 20 candidates, which were then validated by real-time polymerase chain reaction (RTPCR). Next, we tested whether the time-of-day gene expression profiles could be indicative of disease progression by comparing the 1- vs. 8-wk TAC. Lastly, since protein expression is functionally relevant, we monitored time-of-day cycling for the analogous cardiac proteins. This approach is generally applicable and can lead to new understanding of disease.

Outcomes of cardiac surgery in the elderly.

PubMed

Drury, Nigel E; Nashef, Samer A M

2006-07-01

The elderly represent a rapidly growing and substantially under-treated sector in industrialized countries, with coronary artery disease and degenerative aortic stenosis rampant. The proportion of elderly patients undergoing cardiac surgery is rising steadily and outcomes continue to improve with the refinement of operative techniques and perioperative care. Advanced risk stratification models, such as the logistic European System for Cardiac Operative Risk Evaluation now offer validated prediction of operative mortality in these high-risk patients. Current trends towards off-pump coronary artery surgery, hybrid revascularization and mitral repair may have advantages in the elderly, who often have more diffuse cardiovascular disease and a lower tolerance to intervention. Recent advances may also provide surgical options for the emerging epidemics of cardiovascular disease affecting the elderly, atrial fibrillation and heart failure.

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis

PubMed Central

Wu, Mei-ping; Zhang, Yi-shuai; Xu, Xiangbin; Zhou, Qian

2017-01-01

Purpose Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Methods Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. Results We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Conclusions Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling. PMID:28321644

Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer?

PubMed

Beukema, Jannet C; van Luijk, Peter; Widder, Joachim; Langendijk, Johannes A; Muijs, Christina T

2015-01-01

In recent years several papers have been published on radiation-induced cardiac toxicity, especially in breast cancer patients. However, in esophageal cancer patients the radiation dose to the heart is usually markedly higher. To determine whether radiation-induced cardiac toxicity is also a relevant issue for this group, we conducted a review of the current literature. A literature search was performed in Medline for papers concerning cardiac toxicity in esophageal cancer patients treated with radiotherapy with or without chemotherapy. The overall crude incidence of symptomatic cardiac toxicity was as high as 10.8%. Toxicities corresponded with several dose-volume parameters of the heart. The most frequently reported complications were pericardial effusion, ischemic heart disease and heart failure. Cardiac toxicity is a relevant issue in the treatment of esophageal cancer. However, valid Normal Tissue Complication Probability models for esophageal cancer are not available at present. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cardiac Biomarkers: a Focus on Cardiac Regeneration

PubMed Central

Forough, Reza; Scarcello, Catherine; Perkins, Matthew

2011-01-01

Historically, biomarkers have been used in two major ways to maintain and improve better health status: first, for diagnostic purposes, and second, as specific targets to treat various diseases. A new era in treatment and even cure for the some diseases using reprograming of somatic cells is about to be born. In this approach, scientists are successfully taking human skin cells (previously considered terminally-differentiated cells) and re-programming them into functional cardiac myocytes and other cell types in vitro. A cell reprograming approach for treatment of cardiovascular diseases will revolutionize the field of medicine and significantly expand the human lifetime. Availability of a comprehensive catalogue for cardiac biomarkers is necessary for developing cell reprograming modalities to treat cardiac diseases, as well as for determining the progress of reprogrammed cells as they become cardiac cells. In this review, we present a comprehensive survey of the cardiac biomarkers currently known. PMID:23074366

Cardiac Ca2+ signalling in zebrafish: Translation of findings to man.

PubMed

van Opbergen, Chantal J M; van der Voorn, Stephanie M; Vos, Marc A; de Boer, Teun P; van Veen, Toon A B

2018-05-07

Sudden cardiac death is a leading cause of death worldwide, mainly caused by highly disturbed electrical activation patterns in the heart. Currently, murine models are the most popular model to study underlying molecular mechanisms of inherited or acquired cardiac electrical abnormalities, although the numerous electrophysiological discrepancies between mouse and human raise the question whether mice are the optimal model to study cardiac rhythm disorders. Recently it has been uncovered that the zebrafish cardiac electrophysiology seems surprisingly similar to the human heart, mainly because the zebrafish AP contains a clear plateau phase and ECG characteristics show alignment with the human ECG. Although, before using zebrafish as a model to study cardiac arrhythmogenesis, however, it is very important to gain a better insight into the electrophysiological characteristics of the zebrafish heart. In this review we outline the electrophysiological machinery of the zebrafish cardiomyocytes, with a special focus on the intracellular Ca 2+ dynamics and excitation-contraction coupling. We debate the potential of zebrafish as a model to study human cardiovascular diseases and postulate steps to employ zebrafish into a more 'humanized' model. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Molecular Basis of Cardiac Mechanics: Regulation of Motor Unit Recruitment

DTIC Science & Technology

2001-10-25

sensitivity, Cooperativity. I. INTRODUCTION The biological linear motor, that produces cardiac and skeletal muscle contraction , is by far smaller than...who have described the role of the mechanical initial loading condition (Preload) on muscle contraction and by Fenn (1923) who has showed that the...2437, 1982. [4] E. Eisenberg, and T. L. Hill. Muscle contraction and energy transduction in biological system. Science 227: 999-1006, 1985. [5

Library of molecular associations: curating the complex molecular basis of liver diseases.

PubMed

Buchkremer, Stefan; Hendel, Jasmin; Krupp, Markus; Weinmann, Arndt; Schlamp, Kai; Maass, Thorsten; Staib, Frank; Galle, Peter R; Teufel, Andreas

2010-03-20

Systems biology approaches offer novel insights into the development of chronic liver diseases. Current genomic databases supporting systems biology analyses are mostly based on microarray data. Although these data often cover genome wide expression, the validity of single microarray experiments remains questionable. However, for systems biology approaches addressing the interactions of molecular networks comprehensive but also highly validated data are necessary. We have therefore generated the first comprehensive database for published molecular associations in human liver diseases. It is based on PubMed published abstracts and aimed to close the gap between genome wide coverage of low validity from microarray data and individual highly validated data from PubMed. After an initial text mining process, the extracted abstracts were all manually validated to confirm content and potential genetic associations and may therefore be highly trusted. All data were stored in a publicly available database, Library of Molecular Associations http://www.medicalgenomics.org/databases/loma/news, currently holding approximately 1260 confirmed molecular associations for chronic liver diseases such as HCC, CCC, liver fibrosis, NASH/fatty liver disease, AIH, PBC, and PSC. We furthermore transformed these data into a powerful resource for molecular liver research by connecting them to multiple biomedical information resources. Together, this database is the first available database providing a comprehensive view and analysis options for published molecular associations on multiple liver diseases.

Molecular biology based assessment of green tea effects on oxidative stress and cardiac remodelling in dialysis patients.

PubMed

Calo, Lorenzo A; Vertolli, Ugo; Davis, Paul A; Maso, Lucia Dal; Pagnin, Elisa; Ravarotto, Verdiana; Maiolino, Giuseppe; Lupia, Mario; Seccia, Teresa M; Rossi, Gian Paolo

2014-06-01

Cardiovascular disease, the most common cause for morbidity and mortality in end-stage renal disease (ESRD), has prompted the exploration of multiple approaches to improve outcomes. Cardiovascular risk factors such as oxidative stress (OxSt) and cardiac remodelling are common in ESRD and dialysis patients. Green tea (GT) is well recognized as reducing OxSt. This 6 months study evaluated in 20 ESRD patients under chronic dialysis, the effect of GT treatment (1 g/day as commercially available capsule) on cellular and plasma OxSt and proliferation related markers using a molecular biology approach. Mononuclear cell p22(phox), Haeme Oxygenase (HO)-1 protein expression, and phosphorylated ERK1/2 status were evaluated in dialysis patients at baseline, after 3 and 6 months of GT treatment by Western blot analysis and plasma oxLDL by ELISA. Cardiac remodelling was assessed by echocardiographic left ventricular (LV) mass determination at baseline and at the end of the study. GT treatment reduced p22(phox) and pERK1/2 from baseline while HO-1 increased. At baseline, LV mass correlated with both p22(phox) and oxLDL. GT treatment decreased LV mass from baseline, which correlated with oxLDL. 9 patients had LV hypertrophy at baseline, which, at 6 months, was normalized in 5 and reduced in 3, showing a parallel decrease of p22(phox), pERK1/2, oxLDL and increase of HO-1. Treatment with GT decreased the expression of OxSt-related proteins tightly associated with cardiovascular disease and decreased LV mass. It appears highly likely that the addition of GT can provide a benefit in terms of cardiovascular protection in dialysis patients. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Right ventricular involvement in cardiac sarcoidosis demonstrated with cardiac magnetic resonance.

PubMed

Smedema, Jan-Peter; van Geuns, Robert-Jan; Ainslie, Gillian; Ector, Joris; Heidbuchel, Hein; Crijns, Harry J G M

2017-11-01

Cardiac involvement in sarcoidosis is reported in up to 30% of patients. Left ventricular involvement demonstrated by contrast-enhanced cardiac magnetic resonance has been well validated. We sought to determine the prevalence and distribution of right ventricular late gadolinium enhancement in patients diagnosed with pulmonary sarcoidosis. We prospectively evaluated 87 patients diagnosed with pulmonary sarcoidosis with contrast-enhanced cardiac magnetic resonance for right ventricular involvement. Pulmonary artery pressures were non-invasively evaluated with Doppler echocardiography. Patient characteristics were compared between the groups with and without right ventricular involvement, and right ventricular enhancement was correlated with pulmonary hypertension, ventricular mass, volume, and systolic function. Left ventricular late gadolinium enhancement was demonstrated in 30 patients (34%). Fourteen patients (16%) had right ventricular late gadolinium enhancement, with sole right ventricular enhancement in only two patients. The pattern of right ventricular enhancement consisted of right ventricular outflow tract enhancement in 1 patient, free wall enhancement in 8 patients, ventricular insertion point enhancement in 10 patients, and enhancement of the right side of the interventricular septum in 11 patients. Pulmonary arterial hypertension correlated with the presence of right ventricular enhancement (P < 0.001). Right ventricular enhancement correlated with systolic ventricular dysfunction (P < 0.001), hypertrophy (P = 0.001), and dilation (P < 0.001). Right ventricular enhancement was present in 16% of patients diagnosed with pulmonary sarcoidosis and in 48% of patients with left ventricular enhancement. The presence of right ventricular enhancement correlated with pulmonary arterial hypertension, right ventricular systolic dysfunction, hypertrophy, and dilation. © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of

High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss.

PubMed

Zeng, Heng; Vaka, Venkata Ramana; He, Xiaochen; Booz, George W; Chen, Jian-Xiong

2015-08-01

Mitochondrial dysfunction plays an important role in obesity-induced cardiac impairment. SIRT3 is a mitochondrial protein associated with increased human life span and metabolism. This study investigated the functional role of SIRT3 in obesity-induced cardiac dysfunction. Wild-type (WT) and SIRT3 knockout (KO) mice were fed a normal diet (ND) or high-fat diet (HFD) for 16 weeks. Body weight, fasting glucose levels, reactive oxygen species (ROS) levels, myocardial capillary density, cardiac function and expression of hypoxia-inducible factor (HIF)-1α/-2α were assessed. HFD resulted in a significant reduction in SIRT3 expression in the heart. Both HFD and SIRT3 KO mice showed increased ROS formation, impaired HIF signalling and reduced capillary density in the heart. HFD induced cardiac hypertrophy and impaired cardiac function. SIRT3 KO mice fed HFD showed greater ROS production and a further reduction in cardiac function compared to SIRT3 KO mice on ND. Thus, the adverse effects of HFD on cardiac function were not attributable to SIRT3 loss alone. However, HFD did not further reduce capillary density in SIRT3 KO hearts, implicating SIRT3 loss in HFD-induced capillary rarefaction. Our study demonstrates the importance of SIRT3 in preserving heart function and capillary density in the setting of obesity. Thus, SIRT3 may be a potential therapeutic target for obesity-induced heart failure. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Development of a diagnosis- and procedure-based risk model for 30-day outcome after pediatric cardiac surgery.

PubMed

Crowe, Sonya; Brown, Kate L; Pagel, Christina; Muthialu, Nagarajan; Cunningham, David; Gibbs, John; Bull, Catherine; Franklin, Rodney; Utley, Martin; Tsang, Victor T

2013-05-01

The study objective was to develop a risk model incorporating diagnostic information to adjust for case-mix severity during routine monitoring of outcomes for pediatric cardiac surgery. Data from the Central Cardiac Audit Database for all pediatric cardiac surgery procedures performed in the United Kingdom between 2000 and 2010 were included: 70% for model development and 30% for validation. Units of analysis were 30-day episodes after the first surgical procedure. We used logistic regression for 30-day mortality. Risk factors considered included procedural information based on Central Cardiac Audit Database "specific procedures," diagnostic information defined by 24 "primary" cardiac diagnoses and "univentricular" status, and other patient characteristics. Of the 27,140 30-day episodes in the development set, 25,613 were survivals, 834 were deaths, and 693 were of unknown status (mortality, 3.2%). The risk model includes procedure, cardiac diagnosis, univentricular status, age band (neonate, infant, child), continuous age, continuous weight, presence of non-Down syndrome comorbidity, bypass, and year of operation 2007 or later (because of decreasing mortality). A risk score was calculated for 95% of cases in the validation set (weight missing in 5%). The model discriminated well; the C-index for validation set was 0.77 (0.81 for post-2007 data). Removal of all but procedural information gave a reduced C-index of 0.72. The model performed well across the spectrum of predicted risk, but there was evidence of underestimation of mortality risk in neonates undergoing operation from 2007. The risk model performs well. Diagnostic information added useful discriminatory power. A future application is risk adjustment during routine monitoring of outcomes in the United Kingdom to assist quality assurance. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Local sympathetic denervation attenuates myocardial inflammation and improves cardiac function after myocardial infarction in mice

PubMed Central

Ziegler, Karin A; Ahles, Andrea; Wille, Timo; Kerler, Julia; Ramanujam, Deepak; Engelhardt, Stefan

2018-01-01

Abstract Aims Cardiac inflammation has been suggested to be regulated by the sympathetic nervous system (SNS). However, due to the lack of methodology to surgically eliminate the myocardial SNS in mice, neuronal control of cardiac inflammation remains ill-defined. Here, we report a procedure for local cardiac sympathetic denervation in mice and tested its effect in a mouse model of heart failure post-myocardial infarction. Methods and results Upon preparation of the carotid bifurcation, the right and the left superior cervical ganglia were localized and their pre- and postganglionic branches dissected before removal of the ganglion. Ganglionectomy led to an almost entire loss of myocardial sympathetic innervation in the left ventricular anterior wall. When applied at the time of myocardial infarction (MI), cardiac sympathetic denervation did not affect acute myocardial damage and infarct size. In contrast, cardiac sympathetic denervation significantly attenuated chronic consequences of MI, including myocardial inflammation, myocyte hypertrophy, and overall cardiac dysfunction. Conclusion These data suggest a critical role for local sympathetic control of cardiac inflammation. Our model of myocardial sympathetic denervation in mice should prove useful to further dissect the molecular mechanisms underlying cardiac neural control. PMID:29186414

THE INCIDENCE OF SUDDEN CARDIAC DEATH IN AUSTRIA

PubMed Central

Halberg, F.; Cornélissen, G.; Schnaiter, D.; Mitsutake, G.; Otsuka, K.; Fišer, B.; Siegelová, J.; Olah, A.; Bakken, E. E.; Chibisov, S.

2008-01-01

The aim of the study was to assess the time structure (chronome) of sudden cardiac death (SCD) in Austria. The daily incidence of SCD (ICD-10 I46.1) in Austria was obtained for the 4-year span from Jan 2002 to Dec 2005. Data were available separately for men and women. This data series was analyzed by linear-nonlinear rhythmometry. The major feature is the detection of a cis-half-year that is validated nonlinearly, the estimated period of the cis-half-year is 0.408 year (95% CI: 0.389, 0.426). It is concluded that the chronobiological analysis of sudden cardiac death in Austria showed the variability of total incidence with the period of a cis-half-year. PMID:19129929

Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing

NASA Astrophysics Data System (ADS)

Lind, Johan U.; Busbee, Travis A.; Valentine, Alexander D.; Pasqualini, Francesco S.; Yuan, Hongyan; Yadid, Moran; Park, Sung-Jin; Kotikian, Arda; Nesmith, Alexander P.; Campbell, Patrick H.; Vlassak, Joost J.; Lewis, Jennifer A.; Parker, Kevin K.

2017-03-01

Biomedical research has relied on animal studies and conventional cell cultures for decades. Recently, microphysiological systems (MPS), also known as organs-on-chips, that recapitulate the structure and function of native tissues in vitro, have emerged as a promising alternative. However, current MPS typically lack integrated sensors and their fabrication requires multi-step lithographic processes. Here, we introduce a facile route for fabricating a new class of instrumented cardiac microphysiological devices via multimaterial three-dimensional (3D) printing. Specifically, we designed six functional inks, based on piezo-resistive, high-conductance, and biocompatible soft materials that enable integration of soft strain gauge sensors within micro-architectures that guide the self-assembly of physio-mimetic laminar cardiac tissues. We validated that these embedded sensors provide non-invasive, electronic readouts of tissue contractile stresses inside cell incubator environments. We further applied these devices to study drug responses, as well as the contractile development of human stem cell-derived laminar cardiac tissues over four weeks.

Noninvasive quantification of left ventricular mass by cardiac magnetic resonance imaging: Development of the method and experimental validation

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

Maddahi, J.; Crues, J.; Berman, D.S.

1985-05-01

Determination of left ventricular myocardial (LV) mass may aid evaluation of hypertrophic cardiomyopathies as well as percent viable myocardium in ischemic heart disease. The validity of cardiac NMR for determination of LV mass was evaluated in 9 dogs using a superconducting magnet operating at 0.35 Tesla. In-vivo gated spin echo pulsing sequences were used obtaining 0.7 cm thick slices of the heart, spaced by 1 cm, in three orthogonal planes. After sacrifice, the nonbeating hearts were imaged in-situ without gating. On each NMR slice, the LV surface area was planimetered and multiplied by slice spacing (1) and myocardial specific gravitymore » (1.05) to obtain slice mass. For total LV mass, slice masses were added on coronal (Method (Meth) 1), transaxial (Meth 2), and sagittal (Meth 3) planes. Mass of the LV portions subject to partial volume effect were derived from an orthogonal plane. Excised LV weight ranged from 27 to 134 grams. The intra- and inter-observer agreement for planimetry of the NMR slices was high (r=.99 and r=.97, respectively). For in-situ imaging, r values of all methods were high (r=.99, .99, and .98); however, the slope and intercept of the regression line were closes to the line of identity with Meth 1 (y=0.94x+0.52). For in-vivo beating heart images, Meth 1 also had the best results (r=.99, y= 0.99x+8.3). Failure to correct for partial volume effect resulted in underestimation of in-situ and in-vivo LV masses as indicated by slope of <1 (r=,.98, y=0.77x+3.9; r=.98, y= 0.88x+0.98, respectively, Meth 1). Thus, cardiac NMR is a reproducible and accurate method for noninvasive determination of LV myocardial mass.« less

Living cardiac patch: the elixir for cardiac regeneration.

PubMed

Lakshmanan, Rajesh; Krishnan, Uma Maheswari; Sethuraman, Swaminathan

2012-12-01

A thorough understanding of the cellular and muscle fiber orientation in left ventricular cardiac tissue is of paramount importance for the generation of artificial cardiac patches to treat the ischemic myocardium. The major challenge faced during cardiac patch engineering is to choose a perfect combination of three entities; cells, scaffolds and signaling molecules comprising the tissue engineering triad for repair and regeneration. This review provides an overview of various scaffold materials, their mechanical properties and fabrication methods utilized in cardiac patch engineering. Stem cell therapies in clinical trials and the commercially available cardiac patch materials were summarized in an attempt to provide a recent perspective in the treatment of heart failure. Various tissue engineering strategies employed thus far to construct viable thick cardiac patches is schematically illustrated. Though many strategies have been proposed for fabrication of various cardiac scaffold materials, the stage and severity of the disease condition demands the incorporation of additional cues in a suitable scaffold material. The scaffold may be nanofibrous patch, hydrogel or custom designed films. Integration of stem cells and biomolecular cues along with the scaffold may provide the right microenvironment for the repair of unhealthy left ventricular tissue as well as promote its regeneration.

[Image processing applying in analysis of motion features of cultured cardiac myocyte in rat].

PubMed

Teng, Qizhi; He, Xiaohai; Luo, Daisheng; Wang, Zhengrong; Zhou, Beiyi; Yuan, Zhirun; Tao, Dachang

2007-02-01

Study of mechanism of medicine actions, by quantitative analysis of cultured cardiac myocyte, is one of the cutting edge researches in myocyte dynamics and molecular biology. The characteristics of cardiac myocyte auto-beating without external stimulation make the research sense. Research of the morphology and cardiac myocyte motion using image analysis can reveal the fundamental mechanism of medical actions, increase the accuracy of medicine filtering, and design the optimal formula of medicine for best medical treatments. A system of hardware and software has been built with complete sets of functions including living cardiac myocyte image acquisition, image processing, motion image analysis, and image recognition. In this paper, theories and approaches are introduced for analysis of living cardiac myocyte motion images and implementing quantitative analysis of cardiac myocyte features. A motion estimation algorithm is used for motion vector detection of particular points and amplitude and frequency detection of a cardiac myocyte. Beatings of cardiac myocytes are sometimes very small. In such case, it is difficult to detect the motion vectors from the particular points in a time sequence of images. For this reason, an image correlation theory is employed to detect the beating frequencies. Active contour algorithm in terms of energy function is proposed to approximate the boundary and detect the changes of edge of myocyte.

In Vitro Hepatic Trans-Differentiation of Human Mesenchymal Stem Cells Using Sera from Congestive/Ischemic Liver during Cardiac Failure

PubMed Central

Bishi, Dillip Kumar; Mathapati, Santosh; Cherian, Kotturathu Mammen; Guhathakurta, Soma; Verma, Rama Shanker

2014-01-01

Cellular therapy for end-stage liver failures using human mesenchymal stem cells (hMSCs)-derived hepatocytes is a potential alternative to liver transplantation. Hepatic trans-differentiation of hMSCs is routinely accomplished by induction with commercially available recombinant growth factors, which is of limited clinical applications. In the present study, we have evaluated the potential of sera from cardiac-failure-associated congestive/ischemic liver patients for hepatic trans-differentiation of hMSCs. Results from such experiments were confirmed through morphological changes and expression of hepatocyte-specific markers at molecular and cellular level. Furthermore, the process of mesenchymal-to-epithelial transition during hepatic trans-differentiation of hMSCs was confirmed by elevated expression of E-Cadherin and down-regulation of Snail. The functionality of hMSCs-derived hepatocytes was validated by various liver function tests such as albumin synthesis, urea release, glycogen accumulation and presence of a drug inducible cytochrome P450 system. Based on these findings, we conclude that sera from congestive/ischemic liver during cardiac failure support a liver specific microenvironment for effective hepatic trans-differentiation of hMSCs in vitro. PMID:24642599

Real-Time MRI-Guided Cardiac Cryo-Ablation: A Feasibility Study.

PubMed

Kholmovski, Eugene G; Coulombe, Nicolas; Silvernagel, Joshua; Angel, Nathan; Parker, Dennis; Macleod, Rob; Marrouche, Nassir; Ranjan, Ravi

2016-05-01

MRI-based ablation provides an attractive capability of seeing ablation-related tissue changes in real time. Here we describe a real-time MRI-based cardiac cryo-ablation system. Studies were performed in canine model (n = 4) using MR-compatible cryo-ablation devices built for animal use: focal cryo-catheter with 8 mm tip and 28 mm diameter cryo-balloon. The main steps of MRI-guided cardiac cryo-ablation procedure (real-time navigation, confirmation of tip-tissue contact, confirmation of vessel occlusion, real-time monitoring of a freeze zone formation, and intra-procedural assessment of lesions) were validated in a 3 Tesla clinical MRI scanner. The MRI compatible cryo-devices were advanced to the right atrium (RA) and right ventricle (RV) and their position was confirmed by real-time MRI. Specifically, contact between catheter tip and myocardium and occlusion of superior vena cava (SVC) by the balloon was visually validated. Focal cryo-lesions were created in the RV septum. Circumferential ablation of SVC-RA junction with no gaps was achieved using the cryo-balloon. Real-time visualization of freeze zone formation was achieved in all studies when lesions were successfully created. The ablations and presence of collateral damage were confirmed by T1-weighted and late gadolinium enhancement MRI and gross pathological examination. This study confirms the feasibility of a MRI-based cryo-ablation system in performing cardiac ablation procedures. The system allows real-time catheter navigation, confirmation of catheter tip-tissue contact, validation of vessel occlusion by cryo-balloon, real-time monitoring of a freeze zone formation, and intra-procedural assessment of ablations including collateral damage. © 2016 Wiley Periodicals, Inc.

MiR-130a inhibition protects rat cardiac myocytes from hypoxia-triggered apoptosis by targeting Smad4.

PubMed

Li, Yuanshi; Du, Yingrong; Cao, Junxian; Gao, Qianping; Li, Hongjuan; Chen, Yangjun; Lu, Nihong

2018-02-05

Cardiomyocyte death facilitates the pathological process underlying ischemic heart diseases, such as myocardial infarction. Emerging evidence suggests that microRNAs play a critical role in the pathological process underlying myocardial infarction by regulating cardiomyocyte apoptosis. However, the relevance of miR-130a in regulating cardiomyocyte apoptosis and the mechanism of regulation is still uncertain. This study aimed to explore the regulatory effect of miR-130a on hypoxic cardiomyocyte apoptosis. The expression of miR-130a was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell survival was determined by the MTT assay. The lactate dehydrogenase (LDH) assay was performed to determine the severity of hypoxia-induced cell injury. Apoptosis was assessed via caspase-3 analysis. Protein expression level was determined by Western blotting. The genes targeted by miR-130a were predicted using bioinformatics and were validated via the dual-luciferase reporter assay. We found that miR-130a expression was greatly increased in hypoxic cardiac myocytes, and that the downregulation of miR-130a effectively shielded cardiac myocytes from hypoxia-triggered apoptosis. The results of our bioinformatic analysis predicted the Smad4 gene to be the target of miR-130a. This finding was validated through the Western blot assay, dual-luciferase reporter gene assay, and qRT-PCR. MiR-130a inhibition significantly promoted the activation of Smad4 in hypoxic cardiomyocytes. Interestingly, knockdown of Smad4 markedly reversed the protective effects induced by miR-130a inhibition. Moreover, we found that the inhibition of miR-130a promoted the activation of TGF-β signaling. Blocking Smad4 signaling significantly abrogated the protective effects of miR-130a inhibition. Overall, these findings indicate that inhibition of miR-130a, which targets the Smad4 gene, shields cardiac myocytes from hypoxic apoptosis. This study offers a novel perspective of the

Risk-adjusted outcome prediction with initial post-cardiac arrest illness severity: implications for cardiac arrest survivors being considered for early invasive strategy.

PubMed

Reynolds, Joshua C; Rittenberger, Jon C; Toma, Catalin; Callaway, Clifton W

2014-09-01

Early CATH is recommended for cardiac arrest survivors with STEMI or suspicion for coronary ischemia. Comatose patients are at risk of death from neurologic injury irrespective of CATH, but post-procedural mortality data do not distinguish between causes of death. Pittsburgh Post Cardiac Arrest Category (PCAC) is a validated, early post-cardiac arrest illness severity score based on initial cardiopulmonary dysfunction and neurologic examination. We evaluated the association between early coronary angiography (CATH) and patient outcome after adjusting for initial post-cardiac arrest illness severity. Retrospective study of a prospective cardiac arrest database at a single site. We included 1011 adult survivors of non-traumatic in-hospital or out-of-hospital cardiac arrest from 2005 to 2012, then stratified by PCAC and immediate CATH. Logistic regression tested the association between immediate CATH and patient outcomes, adjusting for PCAC. Overall, 273 (27%) received immediate CATH. Patients with immediate CATH had higher proportions of good outcome in all but the most severe stratum of illness severity (11% vs. 6%; p=0.11). The primary mode of death was neurologic for all but the least severe stratum. Adjusting for PCAC, immediate CATH was associated with favorable discharge disposition (OR 1.92; 95%CI 1.20, 3.07; p=0.006) and modified Rankin scale (OR 1.95; 95%CI 1.12, 3.38; p=0.02). The benefit of CATH is less clear in the most severe stratum of illness, in which the high risk of mortality is primarily from neurologic causes. PCAC is a risk-stratification tool that provides pre-procedural risk-adjusted outcome prediction for post-cardiac arrest patients being evaluated for immediate CATH. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

[New aspects of the molecular effect of anti-arrhythmia agents].

PubMed

Honerjäger, P

1990-04-01

Excitation propagation is mediated by the brief opening of voltage-dependent Na-channels in the plasma membranes of cells of the conduction system and working myocardium. The refractory period is a function of the re-availability of the Na-channel for renewed opening. Most antiarrhythmic agents block cardiac Na-channels and, consequently, affect the desired refractory period prolongation. At the same time, however, dependent on the concentration and the substance, they slow conduction; an effect which can facilitate reentry excitation in the injured heart. The Na-channel blocking drugs, class I antiarrhythmic agents, are distinguished from the beta-receptor blockers, class II, repolarizing prolonging drugs, class III, and the cardiac Ca-channel blocking drugs (class IV) (Table 1). MOLECULAR STRUCTURE OF THE CARDIAC NA-CHANNEL: Voltage-dependent Na-channels which have been structurally elucidated to date are glycoprotein macromolecules of about 2000 amino acids with a molecular weight of about 260,000. Beginning at the amino terminal, four consecutive homologous domains can be differentiated which are composed of six transmembranous segments each. The terminal portion of the chain as well as the connecting segments between the domains appear intracellular. There are important relationships between the molecular structure and the function of the Na-channel (Figure 1). On comparison of the primary structures of neuronal and cardiac Na-channels, domains I to IV as well as the connecting segment between domains III and IV, are nearly identical. Homology in all of the remaining molecular regions, in contrast, is less than 70%. These segments as well as the differing structure of the four S5-S6 connecting chains may be responsible for the varying functional response of the cardiac Na-channels. MOLECULAR SITE OF ACTION OF ANTIARRHYTHMIC AGENTS AT THE CARDIAC NA-CHANNEL: Since most antiarrhythmic agents are weak bases with pK values between 7.5 and 9.5, in the physiologic

Mapping cardiac fiber orientations from high-resolution DTI to high-frequency 3D ultrasound

NASA Astrophysics Data System (ADS)

Qin, Xulei; Wang, Silun; Shen, Ming; Zhang, Xiaodong; Wagner, Mary B.; Fei, Baowei

2014-03-01

The orientation of cardiac fibers affects the anatomical, mechanical, and electrophysiological properties of the heart. Although echocardiography is the most common imaging modality in clinical cardiac examination, it can only provide the cardiac geometry or motion information without cardiac fiber orientations. If the patient's cardiac fiber orientations can be mapped to his/her echocardiography images in clinical examinations, it may provide quantitative measures for diagnosis, personalized modeling, and image-guided cardiac therapies. Therefore, this project addresses the feasibility of mapping personalized cardiac fiber orientations to three-dimensional (3D) ultrasound image volumes. First, the geometry of the heart extracted from the MRI is translated to 3D ultrasound by rigid and deformable registration. Deformation fields between both geometries from MRI and ultrasound are obtained after registration. Three different deformable registration methods were utilized for the MRI-ultrasound registration. Finally, the cardiac fiber orientations imaged by DTI are mapped to ultrasound volumes based on the extracted deformation fields. Moreover, this study also demonstrated the ability to simulate electricity activations during the cardiac resynchronization therapy (CRT) process. The proposed method has been validated in two rat hearts and three canine hearts. After MRI/ultrasound image registration, the Dice similarity scores were more than 90% and the corresponding target errors were less than 0.25 mm. This proposed approach can provide cardiac fiber orientations to ultrasound images and can have a variety of potential applications in cardiac imaging.

Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.

PubMed

Kommoss, S; McConechy, M K; Kommoss, F; Leung, S; Bunz, A; Magrill, J; Britton, H; Kommoss, F; Grevenkamp, F; Karnezis, A; Yang, W; Lum, A; Krämer, B; Taran, F; Staebler, A; Lax, S; Brucker, S Y; Huntsman, D G; Gilks, C B; McAlpine, J N; Talhouk, A

2018-05-01

We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application. We assessed a retrospective cohort of women from the Tübingen University Women's Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features. Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB [89 (19.7%)], stage II [26 (5.8%)], and stage III/IV [61 (13.5%)]. ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P = 0.001) and disease-specific (P = 0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88. We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy

Initial Efficacy of a Cardiac Rehabilitation Transition Program: Cardiac TRUST

PubMed Central

Zullo, Melissa; Boxer, Rebecca; Moore, Shirley M.

2012-01-01

Patients recovering from cardiac events are increasingly using postacute care, such as home health care and skilled nursing facility services. The purpose of this pilot study was to test the initial efficacy, feasibility, and safety of a specially designed postacute care transitional rehabilitation intervention for cardiac patients. Cardiac Transitional Rehabilitation Using Self- Management Techniques (Cardiac TRUST) is a family-focused intervention that includes progressive low-intensity walking and education in self-management skills to facilitate recovery following a cardiac event. Using a randomized two-group design, exercise self-efficacy, steps walked, and participation in an outpatient cardiac rehabilitation program were compared in a sample of 38 older adults; 17 who received the Cardiac TRUST program and 21 who received usual care only. At discharge from postacute care, the intervention group had a trend for higher levels of self-efficacy for exercise outcomes (X=39.1, SD=7.4) than the usual care group (X=34.5; SD=7.0) (t-test 1.9, p=.06). During the 6 weeks following discharge, compared with the usual care group, the intervention group had more attendance in out-patient cardiac rehabilitation (33% compared to 11.8%, F=7.1, p=.03) and a trend toward more steps walked during the first week (X=1,307, SD=652 compared to X=782, SD=544, t-test 1.8, p=.07). The feasibility of the intervention was better for the home health participants than for those in the skilled nursing facility and there were no safety concerns. The provision of cardiac-focused rehabilitation during postacute care has the potential to bridge the gap in transitional services from hospitalization to outpatient cardiac rehabilitation for these patients at high risk for future cardiac events. Further evidence of the efficacy of Cardiac TRUST is warranted. PMID:22084960

Exercise-based cardiac rehabilitation for coronary heart disease

PubMed Central

Heran, Balraj S; Chen, Jenny MH; Ebrahim, Shah; Moxham, Tiffany; Oldridge, Neil; Rees, Karen; Thompson, David R; Taylor, Rod S

2014-01-01

-related quality of life using validated measures was there evidence of a significantly higher level of quality of life with exercise-based cardiac rehabilitation than usual care. Authors’ conclusions Exercise-based cardiac rehabilitation is effective in reducing total and cardiovascular mortality (in medium to longer term studies) and hospital admissions (in shorter term studies) but not total MI or revascularisation (CABG or PTCA). Despite inclusion of more recent trials, the population studied in this review is still predominantly male, middle aged and low risk. Therefore, well-designed, and adequately reported RCTs in groups of CHD patients more representative of usual clinical practice are still needed. These trials should include validated health-related quality of life outcome measures, need to explicitly report clinical events including hospital admission, and assess costs and cost-effectiveness. PMID:21735386

HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development.

PubMed

Laurent, Frédéric; Girdziusaite, Ausra; Gamart, Julie; Barozzi, Iros; Osterwalder, Marco; Akiyama, Jennifer A; Lincoln, Joy; Lopez-Rios, Javier; Visel, Axel; Zuniga, Aimée; Zeller, Rolf

2017-05-23

The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development

DOE PAGES

Laurent, Frédéric; Girdziusaite, Ausra; Gamart, Julie; ...

2017-05-23

The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost frommore » Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development.« less

HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development

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

Laurent, Frédéric; Girdziusaite, Ausra; Gamart, Julie

The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost frommore » Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development.« less

Validation of nonlinear interferometric vibrational imaging as a molecular OCT technique by the use of Raman microscopy

NASA Astrophysics Data System (ADS)

Benalcazar, Wladimir A.; Jiang, Zhi; Marks, Daniel L.; Geddes, Joseph B.; Boppart, Stephen A.

2009-02-01

We validate a molecular imaging technique called Nonlinear Interferometric Vibrational Imaging (NIVI) by comparing vibrational spectra with those acquired from Raman microscopy. This broadband coherent anti-Stokes Raman scattering (CARS) technique uses heterodyne detection and OCT acquisition and design principles to interfere a CARS signal generated by a sample with a local oscillator signal generated separately by a four-wave mixing process. These are mixed and demodulated by spectral interferometry. Its confocal configuration allows the acquisition of 3D images based on endogenous molecular signatures. Images from both phantom and mammary tissues have been acquired by this instrument and its spectrum is compared with its spontaneous Raman signatures.

Multiple Roles of Pitx2 in Cardiac Development and Disease

PubMed Central

2017-01-01

Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases. PMID:29367545

Polarization-resolved SHG microscopy in cardiac hypertrophy study (Conference Presentation)

NASA Astrophysics Data System (ADS)

Wang, Zhonghai; Yuan, Cai; Shao, Yonghong; Bradshaw, Amy D.; Borg, Thomas K.; Gao, Bruce Z.

2017-02-01

Cardiac hypertrophy, a process initiated by mechanical alterations, is hypothesized to cause long-term molecular-level alteration in the sarcomere lattice, which is the main force-generating component in the heart muscle. This molecular-level alteration is beyond the resolving capacity of common light microscopy. Second harmonic generation (SHG) microscopy has unique capability for visualizing ordered molecular structures in biological tissues without labeling. Combined with polarization imaging technique, SHG microscopy is able to extract structural details of myosin at the molecular level so as to reveal molecular-level alterations that occur during hypertrophy. The myosin filaments are believed to possess C6 symmetry; thus, the nonlinear polarization response relationship between generated second harmonic light I^2ωand incident fundamental light I^ω is determined by nonlinear coefficients, χ_15, χ_31 and χ_33. χ_31/χ_15 is believed to be an indicator of the molecular symmetry of myosin filament, whileχ_33/χ_15represents the intramyosin orientation angle of the double helix. By changing the polarization of the incident light and evaluating the corresponding SHG signals, the molecular structure of the myosin, reflected by the χ coefficients, can be revealed. With this method, we studied the structural properties of heart tissues in different conditions, including those in normal, physiologically hypertrophic (heart tissue from postpartum female rats), and pathologically hypertrophic (heart tissue from transverse-aorta constricted rats) conditions. We found that ratios of χ_31/χ_15 showed no significant difference between heart tissues from different conditions; their values were all close to 1, which demonstrated that Kleinman symmetry held for all conditions. Ratios of χ_33/χ_15 from physiologically or pathologically hypertrophic heart tissues were raised and showed significant difference from those from normal heart tissues, which indicated that

Characterization of cocaine-induced block of cardiac sodium channels.

PubMed

Crumb, W J; Clarkson, C W

1990-03-01

Recent evidence suggests that cocaine can produce marked cardiac arrhythmias and sudden death. A possible mechanism for this effect is slowing of impulse conduction due to block of cardiac Na channels. We therefore investigated its effects on Na channels in isolated guinea pig ventricular myocytes using the whole-cell variant of the patch clamp technique. Cocaine (10-50 microM) was found to reduce Na current in a use-dependent manner. The time course for block development and recovery were characterized. At 30 microM cocaine, two phases of block development were defined: a rapid phase (tau = 5.7 +/- 4.9 ms) and a slower phase (tau = 2.3 +/- 0.7 s). Recovery from block at -140 mV was also defined by two phases: (tau f = 136 +/- 61 ms, tau s = 8.5 +/- 1.7 s) (n = 6). To further clarify the molecular mechanisms of cocaine action on cardiac Na channels, we characterized its effects using the guarded receptor model, obtaining estimated Kd values of 328, 19, and 8 microM for channels predominantly in the rested, activated, and inactivated states. These data indicate that cocaine can block cardiac Na channels in a use-dependent manner and provides a possible cellular explanation for its cardiotoxic effects.

Early neuroprotection after cardiac arrest.

PubMed

Dell'anna, Antonio M; Scolletta, Sabino; Donadello, Katia; Taccone, Fabio S

2014-06-01

Many efforts have been made in the last decades to improve outcome in patients who are successfully resuscitated from sudden cardiac arrest. Despite some advances, postanoxic encephalopathy remains the most common cause of death among those patients and several investigations have focused on early neuroprotection in this setting. Therapeutic hypothermia is the only strategy able to provide effective neuroprotection in clinical practice. Experimental studies showed that therapeutic hypothermia was even more effective when it was started immediately after the ischemic event. In human studies, the use of prehospital hypothermia was able to reduce the time to target temperature but did not result in higher survival rate or neurological recovery in patients with out-of-hospital cardiac arrest, when compared with standard in-hospital therapeutic hypothermia. Thus, intra-arrest hypothermia (i.e., initiated during cardiopulmonary resuscitation) may be a valid alternative to improve the effectiveness of therapeutic hypothermia in this setting; however, more clinical data are needed to demonstrate any potential benefit of such intervention on neurological outcome. Together with cooling, early hemodynamic optimization should be considered to improve cerebral perfusion in cardiac arrest patients and minimize any secondary brain injury. Nevertheless, only scarce data are available on the impact of early hemodynamic optimization on the development of organ dysfunction and neurological recovery in such patients. Some new protective strategies, including inhaled gases (i.e., xenon, argon, nitric oxide) and intravenous drugs (i.e., erythropoietin) are emerging in experimental studies as promising tools to improve neuroprotection, especially when combined with therapeutic hypothermia. Early cooling may contribute to enhance neuroprotection after cardiac arrest. Hemodynamic optimization is mandatory to avoid cerebral hypoperfusion in this setting. The combination of such

Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization.

PubMed

Bhattacharya, Sayanti; Granger, Christopher B; Craig, Damian; Haynes, Carol; Bain, James; Stevens, Robert D; Hauser, Elizabeth R; Newgard, Christopher B; Kraus, William E; Newby, L Kristin; Shah, Svati H

2014-01-01

To validate independent associations between branched-chain amino acids (BCAA) and other metabolites with coronary artery disease (CAD). We conducted mass-spectrometry-based profiling of 63 metabolites in fasting plasma from 1983 sequential patients undergoing cardiac catheterization. Significant CAD was defined as CADindex ≥ 32 (at least one vessel with ≥ 95% stenosis; N = 995) and no CAD as CADindex ≤ 23 and no previous cardiac events (N = 610). Individuals (N = 378) with CAD severity between these extremes were excluded. Principal components analysis (PCA) reduced large numbers of correlated metabolites into uncorrelated factors. Association between metabolite factors and significant CAD vs. no CAD was tested using logistic regression; and between metabolite factors and severity of CAD was tested using linear regression. Of twelve PCA-derived metabolite factors, two were associated with CAD in multivariable models: factor 10, composed of BCAA (adjusted odds ratio, OR, 1.20; 95% CI 1.05-1.35, p = 0.005) and factor 7, composed of short-chain acylcarnitines, which include byproducts of BCAA metabolism (adjusted OR 1.30; 95% CI 1.14-1.48, p = 0.001). After adjustment for glycated albumin (marker of insulin resistance [IR]) both factors 7 (p = 0.0001) and 10 (p = 0.004) remained associated with CAD. Severity of CAD as a continuous variable (including patients with non-obstructive disease) was associated with metabolite factors 2, 3, 6, 7, 8 and 9; only factors 7 and 10 were associated in multivariable models. We validated the independent association of metabolites involved in BCAA metabolism with CAD extremes. These metabolites may be reporting on novel mechanisms of CAD pathogenesis that are independent of IR and diabetes. Copyright © 2013. Published by Elsevier Ireland Ltd.

Interaction of cardiac troponin with cardiotonic drugs: a structural perspective.

PubMed

Li, Monica X; Robertson, Ian M; Sykes, Brian D

2008-04-25

Over the 40 years since its discovery, many studies have focused on understanding the role of troponin as a myofilament based molecular switch in regulating the Ca(2+)-dependent activation of striated muscle contraction. Recently, studies have explored the role of cardiac troponin as a target for cardiotonic agents. These drugs are clinically useful for treating heart failure, a condition in which the heart is no longer able to pump enough blood to other organs. These agents act via a mechanism that modulates the Ca(2+)-sensitivity of troponin; such a mode of action is therapeutically desirable because intracellular Ca(2+) concentration is not perturbed, preserving the regulation of other Ca(2+)-based signaling pathways. This review describes molecular details of the interaction of cardiac troponin with a variety of cardiotonic drugs. We present recent structural work that has identified the docking sites of several cardiotonic drugs in the troponin C-troponin I interface and discuss their relevance in the design of troponin based drugs for the treatment of heart disease.

Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging.

PubMed

Hariharan, Nirmala; Quijada, Pearl; Mohsin, Sadia; Joyo, Anya; Samse, Kaitlen; Monsanto, Megan; De La Torre, Andrea; Avitabile, Daniele; Ormachea, Lucia; McGregor, Michael J; Tsai, Emily J; Sussman, Mark A

2015-01-20

Functional decline in stem cell-mediated regeneration contributes to aging associated with cellular senescence in c-kit+ cardiac progenitor cells (CPCs). Clinical implementation of CPC-based therapy in elderly patients would benefit tremendously from understanding molecular characteristics of senescence to antagonize aging. Nucleostemin (NS) is a nucleolar protein regulating stem cell proliferation and pluripotency. This study sought to demonstrate that NS preserves characteristics associated with "stemness" in CPCs and antagonizes myocardial senescence and aging. CPCs isolated from human fetal (fetal human cardiac progenitor cell [FhCPC]) and adult failing (adult human cardiac progenitor cell [AhCPC]) hearts, as well as young (young cardiac progenitor cell [YCPC]) and old mice (old cardiac progenitor cell [OCPC]), were studied for senescence characteristics and NS expression. Heterozygous knockout mice with 1 functional allele of NS (NS+/-) were used to demonstrate that NS preserves myocardial structure and function and slows characteristics of aging. NS expression is decreased in AhCPCs relative to FhCPCs, correlating with lowered proliferation potential and shortened telomere length. AhCPC characteristics resemble those of OCPCs, which have a phenotype induced by NS silencing, resulting in cell flattening, senescence, multinucleated cells, decreased S-phase progression, diminished expression of stemness markers, and up-regulation of p53 and p16. CPC senescence resulting from NS loss is partially p53 dependent and is rescued by concurrent silencing of p53. Mechanistically, NS induction correlates with Pim-1 kinase-mediated stabilization of c-Myc. Engineering OCPCs and AhCPCs to overexpress NS decreases senescent and multinucleated cells, restores morphology, and antagonizes senescence, thereby preserving phenotypic properties of "stemness." Early cardiac aging with a decline in cardiac function, an increase in senescence markers p53 and p16, telomere attrition

Rapid Rule-Out of Acute Myocardial Injury Using a Single High-Sensitivity Cardiac Troponin I Measurement.

PubMed

Sandoval, Yader; Smith, Stephen W; Shah, Anoop S V; Anand, Atul; Chapman, Andrew R; Love, Sara A; Schulz, Karen; Cao, Jing; Mills, Nicholas L; Apple, Fred S

2017-01-01

Rapid rule-out strategies using high-sensitivity cardiac troponin assays are largely supported by studies performed outside the US in selected cohorts of patients with chest pain that are atypical of US practice, and focused exclusively on ruling out acute myocardial infarction (AMI), rather than acute myocardial injury, which is more common and associated with a poor prognosis. Prospective, observational study of consecutive patients presenting to emergency departments [derivation (n = 1647) and validation (n = 2198) cohorts], where high-sensitivity cardiac troponin I (hs-cTnI) was measured on clinical indication. The negative predictive value (NPV) and diagnostic sensitivity of an hs-cTnI concentration cardiac death at 30 days. In patients with hs-cTnI concentrations <99th percentile at presentation, acute myocardial injury occurred in 8.3% and 11.0% in the derivation and validation cohorts, respectively. In the derivation cohort, 27% had hs-cTnI < LoD, with NPV and diagnostic sensitivity for acute myocardial injury of 99.1% (95% CI, 97.7-99.8) and 99.0% (97.5-99.7) and an NPV for AMI or cardiac death at 30 days of 99.6% (98.4-100). In the validation cohort, 22% had hs-cTnI cardiac death at 30 days of 99.1% (98.2-99.8). A single hs-cTnI concentration cardiac death at 30 days. ClinicalTrials.gov Identifier: NCT02060760. © 2016 American Association for Clinical Chemistry.

Validating clustering of molecular dynamics simulations using polymer models.

PubMed

Phillips, Joshua L; Colvin, Michael E; Newsam, Shawn

2011-11-14

Molecular dynamics (MD) simulation is a powerful technique for sampling the meta-stable and transitional conformations of proteins and other biomolecules. Computational data clustering has emerged as a useful, automated technique for extracting conformational states from MD simulation data. Despite extensive application, relatively little work has been done to determine if the clustering algorithms are actually extracting useful information. A primary goal of this paper therefore is to provide such an understanding through a detailed analysis of data clustering applied to a series of increasingly complex biopolymer models. We develop a novel series of models using basic polymer theory that have intuitive, clearly-defined dynamics and exhibit the essential properties that we are seeking to identify in MD simulations of real biomolecules. We then apply spectral clustering, an algorithm particularly well-suited for clustering polymer structures, to our models and MD simulations of several intrinsically disordered proteins. Clustering results for the polymer models provide clear evidence that the meta-stable and transitional conformations are detected by the algorithm. The results for the polymer models also help guide the analysis of the disordered protein simulations by comparing and contrasting the statistical properties of the extracted clusters. We have developed a framework for validating the performance and utility of clustering algorithms for studying molecular biopolymer simulations that utilizes several analytic and dynamic polymer models which exhibit well-behaved dynamics including: meta-stable states, transition states, helical structures, and stochastic dynamics. We show that spectral clustering is robust to anomalies introduced by structural alignment and that different structural classes of intrinsically disordered proteins can be reliably discriminated from the clustering results. To our knowledge, our framework is the first to utilize model polymers

Validating clustering of molecular dynamics simulations using polymer models

PubMed Central

2011-01-01

Background Molecular dynamics (MD) simulation is a powerful technique for sampling the meta-stable and transitional conformations of proteins and other biomolecules. Computational data clustering has emerged as a useful, automated technique for extracting conformational states from MD simulation data. Despite extensive application, relatively little work has been done to determine if the clustering algorithms are actually extracting useful information. A primary goal of this paper therefore is to provide such an understanding through a detailed analysis of data clustering applied to a series of increasingly complex biopolymer models. Results We develop a novel series of models using basic polymer theory that have intuitive, clearly-defined dynamics and exhibit the essential properties that we are seeking to identify in MD simulations of real biomolecules. We then apply spectral clustering, an algorithm particularly well-suited for clustering polymer structures, to our models and MD simulations of several intrinsically disordered proteins. Clustering results for the polymer models provide clear evidence that the meta-stable and transitional conformations are detected by the algorithm. The results for the polymer models also help guide the analysis of the disordered protein simulations by comparing and contrasting the statistical properties of the extracted clusters. Conclusions We have developed a framework for validating the performance and utility of clustering algorithms for studying molecular biopolymer simulations that utilizes several analytic and dynamic polymer models which exhibit well-behaved dynamics including: meta-stable states, transition states, helical structures, and stochastic dynamics. We show that spectral clustering is robust to anomalies introduced by structural alignment and that different structural classes of intrinsically disordered proteins can be reliably discriminated from the clustering results. To our knowledge, our framework is the

Molecular Pathogenesis of Familial Wolff-Parkinson-White Syndrome.

PubMed

Licht, Miyamotoa

2018-01-01

Familial Wolff-Parkinson-White (WPW) syndrome is an autosomal dominant inherited disease and consists of a small percentage of WPW syndrome which exhibits ventricular pre-excitation by development of accessory atrioventricular pathway. A series of mutations in PRKAG2 gene encoding gamma2 subunit of 5'AMP-activated protein kinase (AMPK) has been identified as the cause of familial WPW syndrome. AMPK is one of the most important metabolic regulators of carbohydrates and lipids in many types of tissues including cardiac and skeletal muscles. Patients and animals with the mutation in PRKAG2 gene exhibit aberrant atrioventricular conduction associated with cardiac glycogen overload. Recent studies have revealed "novel" significance of canonical pathways leading to glycogen synthesis and provided us profound insights into molecular mechanism of the regulation of glycogen metabolism by AMPK. This review focuses on the molecular basis of the pathogenesis of cardiac abnormality due to PRKAG2 mutation and will provide current overviews of the mechanism of glycogen regulation by AMPK. J. Med. Invest. 65:1-8, February, 2018.

Validation of systems biology derived molecular markers of renal donor organ status associated with long term allograft function.

PubMed

Perco, Paul; Heinzel, Andreas; Leierer, Johannes; Schneeberger, Stefan; Bösmüller, Claudia; Oberhuber, Rupert; Wagner, Silvia; Engler, Franziska; Mayer, Gert

2018-05-03

Donor organ quality affects long term outcome after renal transplantation. A variety of prognostic molecular markers is available, yet their validity often remains undetermined. A network-based molecular model reflecting donor kidney status based on transcriptomics data and molecular features reported in scientific literature to be associated with chronic allograft nephropathy was created. Significantly enriched biological processes were identified and representative markers were selected. An independent kidney pre-implantation transcriptomics dataset of 76 organs was used to predict estimated glomerular filtration rate (eGFR) values twelve months after transplantation using available clinical data and marker expression values. The best-performing regression model solely based on the clinical parameters donor age, donor gender, and recipient gender explained 17% of variance in post-transplant eGFR values. The five molecular markers EGF, CD2BP2, RALBP1, SF3B1, and DDX19B representing key molecular processes of the constructed renal donor organ status molecular model in addition to the clinical parameters significantly improved model performance (p-value = 0.0007) explaining around 33% of the variability of eGFR values twelve months after transplantation. Collectively, molecular markers reflecting donor organ status significantly add to prediction of post-transplant renal function when added to the clinical parameters donor age and gender.

Cardiac remodeling in response to chronic iron deficiency: role of the erythropoietin receptor.

PubMed

Naito, Yoshiro; Sawada, Hisashi; Oboshi, Makiko; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Eguchi, Akiyo; Hirotani, Shinichi; Mano, Toshiaki; Tsujino, Takeshi; Masuyama, Tohru

2015-06-01

Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency. Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated. Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron-restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency. These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency.

New Knowledge About Old Drugs: The Anti-Inflammatory Properties of Cardiac Glycosides.

PubMed

Fürst, Robert; Zündorf, Ilse; Dingermann, Theo

2017-08-01

In the 19th century, cardio-active steroid glycosides, shortly cardiac glycosides, were scientifically established as drugs against heart failure. Their in vivo , cellular, and molecular actions as well as their predominant target, Na + -K + -ATPase, have been comprehensively investigated in the 20th century and the discovery of endogenous cardiac glycosides has fostered this research field. In the last years, however, results from clinical trials and meta-analyses have questioned their therapeutic value due to efficacy and safety issues. This has led to a considerable decline of their usage. Beyond the cardiovascular system, cardiac glycosides have been increasingly recognized as antitumor compounds and Na + -K + -ATPase has evolved into a promising drug target in oncology. A wealth of review articles exists that intensively discuss these topics. Surprisingly, the anti-inflammatory actions of cardiac glycosides, which were discovered in the 1960s, have so far hardly been perceived and have not yet been summarized. This review provides an overview of the in vivo and in vitro actions of cardiac glycosides on inflammatory processes and of the signaling mechanisms responsible for these effects: cardiac glycosides have been found to decrease inflammatory symptoms in different animal models of acute and chronic inflammation. Regarding the underlying mechanisms most research has focused on leukocytes. In these cells, cardiac glycosides primarily inhibit cell proliferation and the secretion of proinflammatory cytokines. Georg Thieme Verlag KG Stuttgart · New York.

Hybrid automata models of cardiac ventricular electrophysiology for real-time computational applications.

PubMed

Andalam, Sidharta; Ramanna, Harshavardhan; Malik, Avinash; Roop, Parthasarathi; Patel, Nitish; Trew, Mark L

2016-08-01

Virtual heart models have been proposed for closed loop validation of safety-critical embedded medical devices, such as pacemakers. These models must react in real-time to off-the-shelf medical devices. Real-time performance can be obtained by implementing models in computer hardware, and methods of compiling classes of Hybrid Automata (HA) onto FPGA have been developed. Models of ventricular cardiac cell electrophysiology have been described using HA which capture the complex nonlinear behavior of biological systems. However, many models that have been used for closed-loop validation of pacemakers are highly abstract and do not capture important characteristics of the dynamic rate response. We developed a new HA model of cardiac cells which captures dynamic behavior and we implemented the model in hardware. This potentially enables modeling the heart with over 1 million dynamic cells, making the approach ideal for closed loop testing of medical devices.

Measure of synchrony in the activity of intrinsic cardiac neurons

PubMed Central

Longpré, Jean-Philippe; Salavatian, Siamak; Beaumont, Eric; Armour, J. Andrew; Ardell, Jeffrey L.; Jacquemet, Vincent

2014-01-01

Recent multielectrode array recordings in ganglionated plexi of canine atria have opened the way to the study of population dynamics of intrinsic cardiac neurons. These data provide critical insights into the role of local processing that these ganglia play in the regulation of cardiac function. Low firing rates, marked non-stationarity, interplay with the cardiovascular and pulmonary systems and artifacts generated by myocardial activity create new constraints not present in brain recordings for which almost all neuronal analysis techniques have been developed. We adapted and extended the jitter-based synchrony index (SI) to (1) provide a robust and computationally-efficient tool for assessing the level and statistical significance of SI between cardiac neurons, (2) estimate the bias on SI resulting from neuronal activity possibly hidden in myocardial artifacts, (3) quantify the synchrony or anti-synchrony between neuronal activity and the phase in the cardiac and respiratory cycles. The method was validated on firing time series from a total of 98 individual neurons identified in 8 dog experiments. SI ranged from −0.14 to 0.66, with 23 pairs of neurons with SI>0.1. The estimated bias due to artifacts was typically < 1%. Strongly cardiovascular- and pulmonary-related neurons (SI>0.5) were found. Results support the use of jitter-based synchrony index in the context of intrinsic cardiac neurons. PMID:24621585

Cardiac function and cognition in older community-dwelling cardiac patients.

PubMed

Eggermont, Laura H P; Aly, Mohamed F A; Vuijk, Pieter J; de Boer, Karin; Kamp, Otto; van Rossum, Albert C; Scherder, Erik J A

2017-11-01

Cognitive deficits have been reported in older cardiac patients. An underlying mechanism for these findings may be reduced cardiac function. The relationship between cardiac function as represented by different echocardiographic measures and different cognitive function domains in older cardiac patients remains unknown. An older (≥70 years) heterogeneous group of 117 community-dwelling cardiac patients under medical supervision by a cardiologist underwent thorough echocardiographic assessment including left ventricular ejection fraction, cardiac index, left atrial volume index, left ventricular mass index, left ventricular diastolic function, and valvular calcification. During a home visit, a neuropsychological assessment was performed within 7.1 ± 3.8 months after echocardiographic assessment; the neuropsychological assessment included three subtests of a word-learning test (encoding, recall, recognition) to examine one memory function domain and three executive function tests, including digit span backwards, Trail Making Test B minus A, and the Stroop colour-word test. Regression analyses showed no significant linear or quadratic associations between any of the echocardiographic functions and the cognitive function measures. None of the echocardiographic measures as representative of cardiac function was correlated with memory or executive function in this group of community-dwelling older cardiac patients. These findings contrast with those of previous studies. © 2017 Japanese Psychogeriatric Society.

The challenge of cardiac modeling--interaction and integration.

PubMed

Sideman, Samuel

2006-10-01

The goal of clinical cardiology is to obtain an integrated picture of the interacting parameters of muscle and vessel mechanics, blood circulation and myocardial perfusion, oxygen consumption and energy metabolism, and electrical activation and heart rate, thus relating to the true physiological and pathophysiological characteristics of the heart. Scientific insight into the cardiac physiology and performance is achieved by utilizing life sciences, for example, molecular biology, genetics and related intra- and intercellular phenomena, as well as the exact sciences, for example, mathematics, computer science, and related imaging and visualization techniques. The tools to achieve these goals are based on the intimate interactions between engineering science and medicine and the developments of modern, medically oriented technology. Most significant is the beneficiary effect of the globalization of science, the Internet, and the unprecedented international interaction and scientific cooperation in facing difficult multidisciplined challenges. This meeting aims to explore some important interactions in the cardiac system and relate to the integration of spatial and temporal interacting system parameters, so as to gain better insight into the structure and function of the cardiac system, thus leading to better therapeutic modalities.

Characterizing cardiac arrest in children undergoing cardiac surgery: A single-center study.

PubMed

Gupta, Punkaj; Wilcox, Andrew; Noel, Tommy R; Gossett, Jeffrey M; Rockett, Stephanie R; Eble, Brian K; Rettiganti, Mallikarjuna

2017-02-01

To characterize cardiac arrest in children undergoing cardiac surgery using single-center data from the Society of Thoracic Surgeons and Pediatric Advanced Life Support Utstein-Style Guidelines. Patients aged 18 years or less having a cardiac arrest for 1 minute or more during the same hospital stay as heart operation qualified for inclusion (2002-2014). Patients having a cardiac arrest both before or after heart operation were included. Heart operations were classified on the basis of the first cardiovascular operation of each hospital admission (the index operation). The primary outcome was survival to hospital discharge. A total of 3437 children undergoing at least 1 heart operation were included. Overall rate of cardiac arrest among these patients was 4.5% (n = 154) with survival to hospital discharge of 84 patients (66.6%). Presurgery cardiac arrest was noted among 28 patients, with survival of 21 patients (75%). Among the 126 patients with postsurgery cardiac arrest, survival was noted among 84 patients (66.6%). Regardless of surgical case complexity, the median days between heart operation and cardiac arrest, duration of cardiac arrest, and survival after cardiac arrest were similar. The independent risk factors associated with improved chances of survival included shorter duration of cardiac arrest (odds ratio, 1.12; 95% confidence interval, 1.05-1.20; P = .01) and use of defibrillator (odds ratio, 4.51; 95% confidence interval, 1.08-18.87; P = .03). This single-center study demonstrates that characterizing cardiac arrest in children undergoing cardiac surgery using definitions from 2 societies helps to increase data granularity and understand the relationship between cardiac arrest and heart operation in a better way. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Sarcomeric protein modification during adrenergic stress enhances cross-bridge kinetics and cardiac output

PubMed Central

Gresham, Kenneth S.; Mamidi, Ranganath; Li, Jiayang; Kwak, Hyerin

2017-01-01

Molecular adaptations to chronic neurohormonal stress, including sarcomeric protein cleavage and phosphorylation, provide a mechanism to increase ventricular contractility and enhance cardiac output, yet the link between sarcomeric protein modifications and changes in myocardial function remains unclear. To examine the effects of neurohormonal stress on posttranslational modifications of sarcomeric proteins, mice were administered combined α- and β-adrenergic receptor agonists (isoproterenol and phenylephrine, IPE) for 14 days using implantable osmotic pumps. In addition to significant cardiac hypertrophy and increased maximal ventricular pressure, IPE treatment accelerated pressure development and relaxation (74% increase in dP/dtmax and 14% decrease in τ), resulting in a 52% increase in cardiac output compared with saline (SAL)-treated mice. Accelerated pressure development was maintained when accounting for changes in heart rate and preload, suggesting that myocardial adaptations contribute to enhanced ventricular contractility. Ventricular myocardium isolated from IPE-treated mice displayed a significant reduction in troponin I (TnI) and myosin-binding protein C (MyBP-C) expression and a concomitant increase in the phosphorylation levels of the remaining TnI and MyBP-C protein compared with myocardium isolated from saline-treated control mice. Skinned myocardium isolated from IPE-treated mice displayed a significant acceleration in the rate of cross-bridge (XB) detachment (46% increase) and an enhanced magnitude of XB recruitment (43% increase) at submaximal Ca2+ activation compared with SAL-treated mice but unaltered myofilament Ca2+ sensitivity of force generation. These findings demonstrate that sarcomeric protein modifications during neurohormonal stress are molecular adaptations that enhance in vivo ventricular contractility through accelerated XB kinetics to increase cardiac output. NEW & NOTEWORTHY Posttranslational modifications to sarcomeric

Sarcomeric protein modification during adrenergic stress enhances cross-bridge kinetics and cardiac output.

PubMed

Gresham, Kenneth S; Mamidi, Ranganath; Li, Jiayang; Kwak, Hyerin; Stelzer, Julian E

2017-03-01

Molecular adaptations to chronic neurohormonal stress, including sarcomeric protein cleavage and phosphorylation, provide a mechanism to increase ventricular contractility and enhance cardiac output, yet the link between sarcomeric protein modifications and changes in myocardial function remains unclear. To examine the effects of neurohormonal stress on posttranslational modifications of sarcomeric proteins, mice were administered combined α- and β-adrenergic receptor agonists (isoproterenol and phenylephrine, IPE) for 14 days using implantable osmotic pumps. In addition to significant cardiac hypertrophy and increased maximal ventricular pressure, IPE treatment accelerated pressure development and relaxation (74% increase in dP/d t max and 14% decrease in τ), resulting in a 52% increase in cardiac output compared with saline (SAL)-treated mice. Accelerated pressure development was maintained when accounting for changes in heart rate and preload, suggesting that myocardial adaptations contribute to enhanced ventricular contractility. Ventricular myocardium isolated from IPE-treated mice displayed a significant reduction in troponin I (TnI) and myosin-binding protein C (MyBP-C) expression and a concomitant increase in the phosphorylation levels of the remaining TnI and MyBP-C protein compared with myocardium isolated from saline-treated control mice. Skinned myocardium isolated from IPE-treated mice displayed a significant acceleration in the rate of cross-bridge (XB) detachment (46% increase) and an enhanced magnitude of XB recruitment (43% increase) at submaximal Ca 2+ activation compared with SAL-treated mice but unaltered myofilament Ca 2+ sensitivity of force generation. These findings demonstrate that sarcomeric protein modifications during neurohormonal stress are molecular adaptations that enhance in vivo ventricular contractility through accelerated XB kinetics to increase cardiac output. NEW & NOTEWORTHY Posttranslational modifications to sarcomeric

Methods of assessment of the post-exercise cardiac autonomic recovery: A methodological review.

PubMed

Peçanha, Tiago; Bartels, Rhenan; Brito, Leandro C; Paula-Ribeiro, Marcelle; Oliveira, Ricardo S; Goldberger, Jeffrey J

2017-01-15

The analysis of post-exercise cardiac autonomic recovery is a practical clinical tool for the assessment of cardiovascular health. A reduced heart rate recovery - an indicator of autonomic dysfunction - has been found in a broad range of cardiovascular diseases and has been associated with increased risks of both cardiac and all-cause mortality. For this reason, over the last several years, non-invasive methods for the assessment of cardiac autonomic recovery after exercise - either based on heart rate recovery or heart rate variability indices - have been proposed. However, for the proper implementation of such methods in daily clinical practice, the discussion of their clinical validity, physiologic meaning, mathematical formulation and reproducibility should be better addressed. Therefore, the aim of this methodological review is to present some of the most employed methods of post-exercise cardiac autonomic recovery in the literature and comprehensively discuss their strengths and weaknesses. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Measurement of cardiac output using improved chromatographic analysis of sulfur hexafluoride (SF6).

PubMed

Klocke, F J; Roberts, D L; Farhi, E R; Naughton, B J; Sekovski, B; Klocke, R A

1977-06-01

A constant current variable frequency pulsed electron capture detector has been incorporated into the gas chromatographic analysis of trace amounts of sulfur hexafluoride (SF6) in water and blood. The resulting system offers a broader effective operating range than more conventional electron capture units and has been utilized for measurements of cardiac output employing constant-rate infusion of dissolved SF6. The SF6 technique has been validated against direct volumetric measurements of cardiac output in a canine right-heart bypass preparation and used subsequently for rapidly repeated measurements in conscious animals and man.

Cardiac ion channels

PubMed Central

Priest, Birgit T; McDermott, Jeff S

2015-01-01

Ion channels are critical for all aspects of cardiac function, including rhythmicity and contractility. Consequently, ion channels are key targets for therapeutics aimed at cardiac pathophysiologies such as atrial fibrillation or angina. At the same time, off-target interactions of drugs with cardiac ion channels can be the cause of unwanted side effects. This manuscript aims to review the physiology and pharmacology of key cardiac ion channels. The intent is to highlight recent developments for therapeutic development, as well as elucidate potential mechanisms for drug-induced cardiac side effects, rather than present an in-depth review of each channel subtype. PMID:26556552

Echocardiography and cardiac resynchronisation therapy, friends or foes?

PubMed

van Everdingen, W M; Schipper, J C; van 't Sant, J; Ramdat Misier, K; Meine, M; Cramer, M J

2016-01-01

Echocardiography is used in cardiac resynchronisation therapy (CRT) to assess cardiac function, and in particular left ventricular (LV) volumetric status, and prediction of response. Despite its widespread applicability, LV volumes determined by echocardiography have inherent measurement errors, interobserver and intraobserver variability, and discrepancies with the gold standard magnetic resonance imaging. Echocardiographic predictors of CRT response are based on mechanical dyssynchrony. However, parameters are mainly tested in single-centre studies or lack feasibility. Speckle tracking echocardiography can guide LV lead placement, improving volumetric response and clinical outcome by guiding lead positioning towards the latest contracting segment. Results on optimisation of CRT device settings using echocardiographic indices have so far been rather disappointing, as results suffer from noise. Defining response by echocardiography seems valid, although re-assessment after 6 months is advisable, as patients can show both continuous improvement as well as deterioration after the initial response. Three-dimensional echocardiography is interesting for future implications, as it can determine volume, dyssynchrony and viability in a single recording, although image quality needs to be adequate. Deformation patterns from the septum and the derived parameters are promising, although validation in a multicentre trial is required. We conclude that echocardiography has a pivotal role in CRT, although clinicians should know its shortcomings.

Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway

PubMed Central

Yang, Hao; Luo, Fangbo; Chen, Lihong; Cai, Huawei; Li, Yajiao; You, Guiying; Long, Dan; Li, Shengfu; Zhang, Qiuping; Rao, Li

2016-01-01

Aims Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy. Methods and Results In an in vitro model of PE-induced cardiac hypertrophy, Selumetinib significantly inhibited the ERK activation and prevented enlargement of cardiomyocytes or reactivation of certain fetal genes. In the pathologic cardiac hypertrophy model of ascending aortic constriction, Selumetinib provided significant ERK inhibition in the stressed heart but not in the other organs. This selective ERK inhibition prevented left ventricular (LV) wall thickening, LV mass increase, fetal gene reactivation and cardiac fibrosis. In another distinct physiologic cardiac hypertrophy model of a swimming rat, Selumetinib provided a similar anti-hypertrophy effect, except that no significant fetal gene reactivation or cardiac fibrosis was observed. Conclusions Selumetinib, a novel oral anti-cancer drug with good safety records in a number of Phase II clinical trials, can inhibit ERK activity in the heart and prevent cardiac hypertrophy. These promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy. However, this hypothesis needs to be validated in human clinical trials. PMID:27438013

Validation of periodontitis screening model using sociodemographic, systemic, and molecular information in a Korean population.

PubMed

Kim, Hyun-Duck; Sukhbaatar, Munkhzaya; Shin, Myungseop; Ahn, Yoo-Been; Yoo, Wook-Sung

2014-12-01

This study aims to evaluate and validate a periodontitis screening model that includes sociodemographic, metabolic syndrome (MetS), and molecular information, including gingival crevicular fluid (GCF), matrix metalloproteinase (MMP), and blood cytokines. The authors selected 506 participants from the Shiwha-Banwol cohort: 322 participants from the 2005 cohort for deriving the screening model and 184 participants from the 2007 cohort for its validation. Periodontitis was assessed by dentists using the community periodontal index. Interleukin (IL)-6, IL-8, and tumor necrosis factor-α in blood and MMP-8, -9, and -13 in GCF were assayed using enzyme-linked immunosorbent assay. MetS was assessed by physicians using physical examination and blood laboratory data. Information about age, sex, income, smoking, and drinking was obtained by interview. Logistic regression analysis was applied to finalize the best-fitting model and validate the model using sensitivity, specificity, and c-statistics. The derived model for periodontitis screening had a sensitivity of 0.73, specificity of 0.85, and c-statistic of 0.86 (P <0.001); those of the validated model were 0.64, 0.91, and 0.83 (P <0.001), respectively. The model that included age, sex, income, smoking, drinking, and blood and GCF biomarkers could be useful in screening for periodontitis. A future prospective study is indicated for evaluating this model's ability to predict the occurrence of periodontitis.

Cardiac resynchronization therapy for patients with cardiac sarcoidosis.

PubMed

Sairaku, Akinori; Yoshida, Yukihiko; Nakano, Yukiko; Hirayama, Haruo; Maeda, Mayuho; Hashimoto, Haruki; Kihara, Yasuki

2017-05-01

Sarcoidosis with cardiac involvement is a rare pathological condition, and therefore cardiac resynchronization therapy (CRT) for patients with cardiac sarcoidosis is even further rare. We aimed to clarify the clinical features of patients with cardiac sarcoidosis who received CRT. We retrospectively reviewed the clinical data on CRT at three cardiovascular centres to detect cardiac sarcoidosis patients. We identified 18 (8.9%) patients with cardiac sarcoidosis who met the inclusion criteria out of 202 with systolic heart failure who received CRT based on the guidelines. The majority of the patients were female [15 (83.3%)] and underwent an upgrade from a pacemaker or implantable cardioverter defibrillator [13 (72.2%)]. We found 1 (5.6%) cardiovascular death during the follow-up period (mean ± SD, 4.7 ± 3.0 years). Seven (38.9%) patients had a composite outcome of cardiovascular death or hospitalization from worsening heart failure within 5 years after the CRT. Twelve (66.7%) patients had a history of sustained ventricular arrhythmias or those occurring after the CRT. Among the overall patients, no significant improvement was found in either the end-systolic volume or left ventricular ejection fraction (LVEF) 6 months after the CRT. A worsening LVEF was, however, more likely to be seen in 5 (27.8%) patients with ventricular arrhythmias after the CRT than in those without (P = 0.04). An improved clinical composite score was seen in 10 (55.6%) patients. Cardiac sarcoidosis patients receiving CRT may have poor LV reverse remodelling and a high incidence of ventricular arrhythmias. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

Chemical genetics and its potential in cardiac stem cell therapy

PubMed Central

Vieira, Joaquim M; Riley, Paul R

2013-01-01

Over the last decade or so, intensive research in cardiac stem cell biology has led to significant discoveries towards a potential therapy for cardiovascular disease; the main cause of morbidity and mortality in humans. The major goal within the field of cardiovascular regenerative medicine is to replace lost or damaged cardiac muscle and coronaries following ischaemic disease. At present, de novo cardiomyocytes can be generated either in vitro, for cell transplantation or disease modelling using directed differentiation of embryonic stem cells or induced pluripotent stem cells, or in vivo via direct reprogramming of resident adult cardiac fibroblast or ectopic stimulation of resident cardiac stem or progenitor cells. A major bottleneck with all of these approaches is the low efficiency of cardiomyocyte differentiation alongside their relative functional immaturity. Chemical genetics, and the application of phenotypic screening with small molecule libraries, represent a means to enhance understanding of the molecular pathways controlling cardiovascular cell differentiation and, moreover, offer the potential for discovery of new drugs to invoke heart repair and regeneration. Here, we review the potential of chemical genetics in cardiac stem cell therapy, highlighting not only the major contributions to the field so far, but also the future challenges. LINKED ARTICLES This article is part of a themed section on Regenerative Medicine and Pharmacology: A Look to the Future. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-2 PMID:22385148

State of the art in forensic investigation of sudden cardiac death.

PubMed

Oliva, Antonio; Brugada, Ramon; D'Aloja, Ernesto; Boschi, Ilaria; Partemi, Sara; Brugada, Josep; Pascali, Vincenzo L

2011-03-01

The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death. Many of the causes of sudden death are due to genetic heart disorders, which can lead to both structural (eg, hypertrophic cardiomyopathy) and arrhythmogenic abnormalities (eg, familial long QT syndrome, Brugada syndrome). Most commonly, sudden cardiac death can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is this a tragic event for those involved, but it also presents a great challenge to the forensic pathologist involved in the management of the surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist, a genetic counselor, and the forensic pathologist directly involved in the sudden death case. This multifaceted cardiac genetic service is crucial in the evaluation and management of the clinical, genetic, psychological, and social complexities observed in families in which there has been a young sudden cardiac death. The present study will address the spectrum of structural substrates of cardiac sudden death with particular emphasis given to the possible role of forensic molecular biology techniques in identifying subtle or even merely functional disorders accounting for electrical instability.

Elevated Cardiac Troponin T in Patients With Skeletal Myopathies.

PubMed

Schmid, Johannes; Liesinger, Laura; Birner-Gruenberger, Ruth; Stojakovic, Tatjana; Scharnagl, Hubert; Dieplinger, Benjamin; Asslaber, Martin; Radl, Roman; Beer, Meinrad; Polacin, Malgorzata; Mair, Johannes; Szolar, Dieter; Berghold, Andrea; Quasthoff, Stefan; Binder, Josepha S; Rainer, Peter P

2018-04-10

Cardiac troponins are often elevated in patients with skeletal muscle disease who have no evidence of cardiac disease. The goal of this study was to characterize cardiac troponin concentrations in patients with myopathies and derive insights regarding the source of elevated troponin T measurements. Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) concentrations were determined by using high sensitivity assays in 74 patients with hereditary and acquired skeletal myopathies. Patients underwent comprehensive cardiac evaluation, including 12-lead electrocardiogram, 24-h electrocardiogram, cardiac magnetic resonance imaging, and coronary artery computed tomography. cTnT and cTnI protein expression was determined in skeletal muscle samples of 9 patients and in control tissues derived from autopsy using antibodies that are used in commercial assays. Relevant Western blot bands were subjected to liquid chromatography tandem mass spectrometry for protein identification. Levels of cTnT (median: 24 ng/l; interquartile range: 11 to 54 ng/l) were elevated (>14 ng/l) in 68.9% of patients; cTnI was elevated (>26 ng/l) in 4.1% of patients. Serum cTnT levels significantly correlated with creatine kinase and myoglobin (r = 0.679 and 0.786, respectively; both p < 0.001). Based on cTnT serial testing, 30.1% would have fulfilled current rule-in criteria for myocardial infarction. Noncoronary cardiac disease was present in 23%. Using cTnT antibodies, positive bands were found in both diseased and healthy skeletal muscle at molecular weights approximately 5 kDa below cTnT. Liquid chromatography tandem mass spectrometry identified the presence of skeletal troponin T isoforms in these bands. Measured cTnT concentrations were chronically elevated in the majority of patients with skeletal myopathies, whereas cTnI elevation was rare. Our data indicate that cross-reaction of the cTnT immunoassay with skeletal muscle troponin isoforms was the likely cause. Copyright © 2018 The

64Cu-CTS: A Promising Radiopharmaceutical for the Identification of Low-Grade Cardiac Hypoxia by PET.

PubMed

Medina, Rodolfo A; Mariotti, Erika; Pavlovic, Davor; Shaw, Karen P; Eykyn, Thomas R; Blower, Philip J; Southworth, Richard

2015-06-01

The subtle hypoxia underlying chronic cardiovascular disease is an attractive target for PET imaging, but the lead hypoxia imaging agents (64)Cu-2,3-butanedione bis(N4-methylthiosemicarbazone) (ATSM) and (18)F-fluoromisonidazole are trapped only at extreme levels of hypoxia and hence are insufficiently sensitive for this purpose. We have therefore sought an analog of (64)Cu-ATSM better suited to identify compromised but salvageable myocardium, and we validated it using parallel biomarkers of cardiac energetics comparable to those observed in chronic cardiac ischemic syndromes. Rat hearts were perfused with aerobic buffer for 20 min, followed by a range of hypoxic buffers (using a computer-controlled gas mixer) for 45 min. Contractility was monitored by intraventricular balloon, energetics by (31)P nuclear MR spectroscopy, lactate and creatine kinase release spectrophotometrically, and hypoxia-inducible factor 1-α by Western blotting. We identified a key hypoxia threshold at a 30% buffer O2 saturation that induces a stable and potentially survivable functional and energetic compromise: left ventricular developed pressure was depressed by 20%, and cardiac phosphocreatine was depleted by 65.5% ± 14% (P < 0.05 vs. control), but adenosine triphosphate levels were maintained. Lactate release was elevated (0.21 ± 0.067 mmol/L/min vs. 0.056 ± 0.01 mmol/L/min, P < 0.05) but not maximal (0.46 ± 0.117 mmol/L/min), indicating residual oxidative metabolic capacity. Hypoxia-inducible factor 1-α was elevated but not maximal. At this key threshold, (64)Cu-2,3-pentanedione bis(thiosemicarbazone) (CTS) selectively deposited significantly more (64)Cu than any other tracer we examined (61.8% ± 9.6% injected dose vs. 29.4% ± 9.5% for (64)Cu-ATSM, P < 0.05). The hypoxic threshold that induced survivable metabolic and functional compromise was 30% O2. At this threshold, only (64)Cu-CTS delivered a hypoxic-to-normoxic contrast of 3:1, and it therefore warrants in vivo evaluation

Genetic modification of embryonic stem cells with VEGF enhances cell survival and improves cardiac function.

PubMed

Xie, Xiaoyan; Cao, Feng; Sheikh, Ahmad Y; Li, Zongjin; Connolly, Andrew J; Pei, Xuetao; Li, Ren-Ke; Robbins, Robert C; Wu, Joseph C

2007-01-01

Cardiac stem cell therapy remains hampered by acute donor cell death posttransplantation and the lack of reliable methods for tracking cell survival in vivo. We hypothesize that cells transfected with inducible vascular endothelial growth factor 165 (VEGF(165)) can improve their survival as monitored by novel molecular imaging techniques. Mouse embryonic stem (ES) cells were transfected with an inducible, bidirectional tetracycline (Bi-Tet) promoter driving VEGF(165) and renilla luciferase (Rluc). Addition of doxycycline induced Bi-Tet expression of VEGF(165) and Rluc significantly compared to baseline (p<0.05). Expression of VEGF(165) enhanced ES cell proliferation and inhibited apoptosis as determined by Annexin-V staining. For noninvasive imaging, ES cells were transduced with a double fusion (DF) reporter gene consisting of firefly luciferase and enhanced green fluorescence protein (Fluc-eGFP). There was a robust correlation between cell number and Fluc activity (R(2)=0.99). Analysis by immunostaining, histology, and RT-PCR confirmed that expression of Bi-Tet and DF systems did not affect ES cell self-renewal or pluripotency. ES cells were differentiated into beating embryoid bodies expressing cardiac markers such as troponin, Nkx2.5, and beta-MHC. Afterward, 5 x 10(5) cells obtained from these beating embryoid bodies or saline were injected into the myocardium of SV129 mice (n=36) following ligation of the left anterior descending (LAD) artery. Bioluminescence imaging (BLI) and echocardiography showed that VEGF(165) induction led to significant improvements in both transplanted cell survival and cardiac function (p<0.05). This is the first study to demonstrate imaging of embryonic stem cell-mediated gene therapy targeting cardiovascular disease. With further validation, this platform may have broad applications for current basic research and further clinical studies.

Single-item measures for depression and anxiety: Validation of the Screening Tool for Psychological Distress in an inpatient cardiology setting.

PubMed

Young, Quincy-Robyn; Nguyen, Michelle; Roth, Susan; Broadberry, Ann; Mackay, Martha H

2015-12-01

Depression and anxiety are common among patients with cardiovascular disease (CVD) and confer significant cardiac risk, contributing to CVD morbidity and mortality. Unfortunately, due to the lack of screening tools that address the specific needs of hospitalized patients, few cardiac inpatient programs offer routine screening for these forms of psychological distress, despite recommendations to do so. The purpose of this study was to validate single-item measures for depression and anxiety among cardiac inpatients. Consecutive inpatients were recruited from the cardiology and cardiac surgery step-down units at a university-affiliated, quaternary-care hospital. Subjects completed a questionnaire that included: (a) demographics, (b) single-item-measures for depression and anxiety (from the Screening Tool for Psychological Distress (STOP-D)), and (c) Hospital Anxiety and Depression Scale (HADS). One hundred and five participants were recruited with a wide variety of cardiac diagnoses, having a mean age of 66 years, and 28% were women. Both STOP-D items were highly correlated with their corresponding validated measures and demonstrated robust receiver-operator characteristic curves. Severity scores on both items correlated well with established severity cut-off scores on the corresponding subscales of the HADS. The STOP-D is a self-administered, self-report measure using two independent items that provide severity scores for depression and anxiety. The tool performs very well compared with other previously validated measures. Requiring no additional scoring and being free, STOP-D offers a simple and valid method for identifying hospitalized cardiac patients who are experiencing psychological distress. This crucial first step triggers initiation of appropriate monitoring and intervention, thus reducing the likelihood of the adverse cardiac outcomes associated with psychological distress. © The European Society of Cardiology 2014.

Mechanistic Insights from Vascular and Cardiac Impairments in Rats Inhaling Diesel Exhaust Particles and Ozone

EPA Science Inventory

Although the causality has been established between air pollution and cardiovascular impairments, the molecular mechanisms are unknown. Moreover, cardiovascular effects of ozone have not been studied until recently. We hypothesize that vasculature and cardiac tissues are targets ...

2D/3D fetal cardiac dataset segmentation using a deformable model.

PubMed

Dindoyal, Irving; Lambrou, Tryphon; Deng, Jing; Todd-Pokropek, Andrew

2011-07-01

To segment the fetal heart in order to facilitate the 3D assessment of the cardiac function and structure. Ultrasound acquisition typically results in drop-out artifacts of the chamber walls. The authors outline a level set deformable model to automatically delineate the small fetal cardiac chambers. The level set is penalized from growing into an adjacent cardiac compartment using a novel collision detection term. The region based model allows simultaneous segmentation of all four cardiac chambers from a user defined seed point placed in each chamber. The segmented boundaries are automatically penalized from intersecting at walls with signal dropout. Root mean square errors of the perpendicular distances between the algorithm's delineation and manual tracings are within 2 mm which is less than 10% of the length of a typical fetal heart. The ejection fractions were determined from the 3D datasets. We validate the algorithm using a physical phantom and obtain volumes that are comparable to those from physically determined means. The algorithm segments volumes with an error of within 13% as determined using a physical phantom. Our original work in fetal cardiac segmentation compares automatic and manual tracings to a physical phantom and also measures inter observer variation.

Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming

PubMed Central

Spitler, Kathryn M.; Ponce, Jessica M.; Oudit, Gavin Y.; Hall, Duane D.

2017-01-01

The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function. NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac

Epidemiology and Outcomes After In-Hospital Cardiac Arrest After Pediatric Cardiac Surgery

PubMed Central

Gupta, Punkaj; Jacobs, Jeffrey P.; Pasquali, Sara K.; Hill, Kevin D.; Gaynor, J. William; O’Brien, Sean M.; He, Max; Sheng, Shubin; Schexnayder, Stephen M.; Berg, Robert A.; Nadkarni, Vinay M.; Imamura, Michiaki; Jacobs, Marshall L.

2014-01-01

Background Multicenter data regarding cardiac arrest in children undergoing heart operations are limited. We describe epidemiology and outcomes associated with postoperative cardiac arrest in a large multiinstitutional cohort. Methods Patients younger than 18 years in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2007 through 2012) were included. Patient factors, operative characteristics, and outcomes were described for patients with and without postoperative cardiac arrest. Multivariable models were used to evaluate the association of center volume with cardiac arrest rate and mortality after cardiac arrest, adjusting for patient and procedural factors. Results Of 70,270 patients (97 centers), 1,843 (2.6%) had postoperative cardiac arrest. Younger age, lower weight, and presence of preoperative morbidities (all p < 0.0001) were associated with cardiac arrest. Arrest rate increased with procedural complexity across common benchmark operations, ranging from 0.7% (ventricular septal defect repair) to 12.7% (Norwood operation). Cardiac arrest was associated with significant mortality risk across procedures, ranging from 15.4% to 62.3% (all p < 0.0001). In multivariable analysis, arrest rate was not associated with center volume (odds ratio, 1.06; 95% confidence interval, 0.71 to 1.57 in low- versus high-volume centers). However, mortality after cardiac arrest was higher in low-volume centers (odds ratio, 2.00; 95% confidence interval, 1.52 to 2.63). This association was present for both high- and low-complexity operations. Conclusions Cardiac arrest carries a significant mortality risk across the stratum of procedural complexity. Although arrest rates are not associated with center volume, lower-volume centers have increased mortality after cardiac arrest. Further study of mechanisms to prevent cardiac arrest and to reduce mortality in those with an arrest is warranted. PMID:25443018

Molecular and Subcellular-Scale Modeling of Nucleotide Diffusion in the Cardiac Myofilament Lattice

PubMed Central

Kekenes-Huskey, Peter M.; Liao, Tao; Gillette, Andrew K.; Hake, Johan E.; Zhang, Yongjie; Michailova, Anushka P.; McCulloch, Andrew D.; McCammon, J. Andrew

2013-01-01

Contractile function of cardiac cells is driven by the sliding displacement of myofilaments powered by the cycling myosin crossbridges. Critical to this process is the availability of ATP, which myosin hydrolyzes during the cross-bridge cycle. The diffusion of adenine nucleotides through the myofilament lattice has been shown to be anisotropic, with slower radial diffusion perpendicular to the filament axis relative to parallel, and is attributed to the periodic hexagonal arrangement of the thin (actin) and thick (myosin) filaments. We investigated whether atomistic-resolution details of myofilament proteins can refine coarse-grain estimates of diffusional anisotropy for adenine nucleotides in the cardiac myofibril, using homogenization theory and atomistic thin filament models from the Protein Data Bank. Our results demonstrate considerable anisotropy in ATP and ADP diffusion constants that is consistent with experimental measurements and dependent on lattice spacing and myofilament overlap. A reaction-diffusion model of the half-sarcomere further suggests that diffusional anisotropy may lead to modest adenine nucleotide gradients in the myoplasm under physiological conditions. PMID:24209858

Dual-Gated Motion-Frozen Cardiac PET with Flurpiridaz F 18.

PubMed

Slomka, Piotr J; Rubeaux, Mathieu; Le Meunier, Ludovic; Dey, Damini; Lazewatsky, Joel L; Pan, Tinsu; Dweck, Marc R; Newby, David E; Germano, Guido; Berman, Daniel S

2015-12-01

A novel PET radiotracer, Flurpiridaz F 18, has undergone phase II clinical trial evaluation as a high-resolution PET cardiac perfusion imaging agent. In a subgroup of patients imaged with this agent, we assessed the feasibility and benefit of simultaneous correction of respiratory and cardiac motion. In 16 patients, PET imaging was performed on a 4-ring scanner in dual cardiac and respiratory gating mode. Four sets of data were reconstructed with high-definition reconstruction (HD•PET): ungated and 8-bin electrocardiography-gated images using 5-min acquisition, optimal respiratory gating (ORG)-as developed for oncologic imaging-using a narrow range of breathing amplitude around end-expiration level with 35% of the counts in a 7-min acquisition, and 4-bin respiration-gated and 8-bin electrocardiography-gated images (32 bins in total) using the 7-min acquisition (dual-gating, using all data). Motion-frozen (MF) registration algorithms were applied to electrocardiography-gated and dual-gated data, creating cardiac-MF and dual-MF images. We computed wall thickness, wall/cavity contrast, and contrast-to-noise ratio for standard, ORG, cardiac-MF, and dual-MF images to assess image quality. The wall/cavity contrast was similar for ungated (9.3 ± 2.9) and ORG (9.5 ± 3.2) images and improved for cardiac-MF (10.8 ± 3.6) and dual-MF images (14.8 ± 8.0) (P < 0.05). The contrast-to-noise ratio was 22.2 ± 9.1 with ungated, 24.7 ± 12.2 with ORG, 35.5 ± 12.8 with cardiac-MF, and 42.1 ± 13.2 with dual-MF images (all P < 0.05). The wall thickness was significantly decreased (P < 0.05) with dual-MF (11.6 ± 1.9 mm) compared with ungated (13.9 ± 2.8 mm), ORG (13.1 ± 2.9 mm), and cardiac-MF images (12.1 ± 2.7 mm). Dual (respiratory/cardiac)-gated perfusion imaging with Flurpiridaz F 18 is feasible and improves image resolution, contrast, and contrast-to-noise ratio when MF registration methods are applied. © 2015 by the Society of Nuclear Medicine and Molecular Imaging

Cardiac rehabilitation

MedlinePlus

... page: //medlineplus.gov/ency/patientinstructions/000791.htm Cardiac rehabilitation To use the sharing features on this page, please enable JavaScript. Cardiac rehabilitation (rehab) is a program that helps you live ...

The new criterion for cardiac resynchronization therapy treatment assessed by two channels impedance cardiography

NASA Astrophysics Data System (ADS)

Peczalski, K.; Palko, T.; Wojciechowski, D.; Dunajski, Z.; Kowalewski, M.

2013-04-01

The cardiac resynchronization therapy is an effective treatment for systolic failure patients. Independent electrical stimulation of left and right ventricle corrects mechanical ventricular dyssynchrony. About 30-40% treated patients do not respond to therapy. In order to improve clinical outcome authors propose the two channels impedance cardiography for assessment of ventricular dyssynchrony. The proposed method is intended for validation of patients diagnosis and optimization of pacemaker settings for cardiac resynchronization therapy. The preliminary study has showed that bichannel impedance cardiography is a promising tool for assessment of ventricular dyssynchrony.

Chronic Intermittent Hypobaric Hypoxia Improves Cardiac Function through Inhibition of Endoplasmic Reticulum Stress.

PubMed

Yuan, Fang; Zhang, Li; Li, Yan-Qing; Teng, Xu; Tian, Si-Yu; Wang, Xiao-Ran; Zhang, Yi

2017-08-11

We investigated the role of endoplasmic reticulum stress (ERS) in chronic intermittent hypobaric hypoxia (CIHH)-induced cardiac protection. Adult male Sprague-Dawley rats were exposed to CIHH treatment simulating 5000 m altitude for 28 days, 6 hours per day. The heart was isolated and perfused with Langendorff apparatus and subjected to 30-min ischemia followed by 60-min reperfusion. Cardiac function, infarct size, and lactate dehydrogenase (LDH) activity were assessed. Expression of ERS molecular chaperones (GRP78, CHOP and caspase-12) was assayed by western blot analysis. CIHH treatment improved the recovery of left ventricular function and decreased cardiac infarct size and activity of LDH after I/R compared to control rats. Furthermore, CIHH treatment inhibited over-expression of ERS-related factors including GRP78, CHOP and caspase-12. CIHH-induced cardioprotection and inhibition of ERS were eliminated by application of dithiothreitol, an ERS inducer, and chelerythrine, a protein kinase C (PKC) inhibitor. In conclusion CIHH treatment exerts cardiac protection against I/R injury through inhibition of ERS via PKC signaling pathway.

Cumulative Burden of Myocardial Dysfunction in Cardiac Amyloidosis Assessed Using Four-Chamber Cardiac Strain.

PubMed

Kado, Yuichiro; Obokata, Masaru; Nagata, Yasufumi; Ishizu, Tomoko; Addetia, Karima; Aonuma, Kazutaka; Kurabayashi, Masahiko; Lang, Roberto M; Takeuchi, Masaaki; Otsuji, Yutaka

2016-11-01

The aim of this study was to test the hypothesis that prognosis in patients with cardiac amyloidosis is closely coupled with amyloid burden in all four cardiac chambers. The goal was to evaluate longitudinal strain (LS) in each cardiac chamber and to determine whether LS in specific cardiac chambers is preferentially associated with prognosis over conventional two-dimensional echocardiographic parameters in patients with cardiac amyloidosis. Patients with two phenotypes of left ventricular (LV) hypertrophy (cardiac amyloidosis in 55 patients and nonobstructive hypertrophic cardiomyopathy in 40 patients) and 55 healthy subjects were retrospectively enrolled for the simultaneous assessment of LS of all four cardiac chambers in the apical four-chamber view. Patients with cardiac amyloidosis were followed up to record major adverse cardiovascular events, including cardiac death, heart transplantation, nonfatal myocardial infarction, ventricular tachyarrhythmia, and exacerbation of heart failure requiring hospitalization. LS in each chamber was significantly depressed in patients with both LV hypertrophy phenotypes compared with healthy subjects. Right atrial LS was significantly lower in patients with cardiac amyloidosis than those with nonobstructive hypertrophic cardiomyopathy after adjusting for LV ejection fraction and LV mass index. During a median follow-up period of 10 months, major adverse cardiovascular events developed in 22 patients with cardiac amyloidosis. Four-chamber LS were significantly associated with major adverse cardiovascular events, with incremental value over traditional echocardiographic parameters. Cardiac amyloidosis involves all cardiac chambers, and thus, chamber-specific strain analysis may be useful to assess the total cumulative burden of cardiac dysfunction. Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

Circulating microRNAs as emerging cardiac biomarkers responsive to acute exercise.

PubMed

de Gonzalo-Calvo, David; Dávalos, Alberto; Fernández-Sanjurjo, Manuel; Amado-Rodríguez, Laura; Díaz-Coto, Susana; Tomás-Zapico, Cristina; Montero, Ana; García-González, Ángela; Llorente-Cortés, Vicenta; Heras, Maria Eugenia; Boraita Pérez, Araceli; Díaz-Martínez, Ángel E; Úbeda, Natalia; Iglesias-Gutiérrez, Eduardo

2018-08-01

Circulating microRNAs (c-miRNAs) are mediators of intercellular communication with great potential as cardiac biomarkers. The analysis of c-miRNAs in response to physiological stress, such as exercise, would provide valuable information for clinical practice and a deeper understanding of the molecular response to physical activity. Here, we analysed for the first time the acute exercise response of c-miRNAs reported as biomarkers of cardiac disease in a well-characterized cohort of healthy active adults. Blood samples were collected immediately before and after (0 h, 24 h, 72 h) a 10-km race, a half-marathon (HM) and a marathon (M). Serum RNA from 10-km and M samples was extracted and a panel of 74 miRNAs analysed using RT-qPCR. c-miRNA response was compared with a panel of nine cardiac biomarkers. Functional enrichment analysis was performed. Pre- and post-M echocardiographic analyses were carried out. Serum levels of all cardiac biomarkers were upregulated in a dose-dependent manner in response to exercise, even in the absence of symptoms or signs of cardiac injury. A deregulation in the profiles of 5 and 19 c-miRNAs was observed for 10-km and M, respectively. Each race induced a specific qualitative and quantitative alteration of c-miRNAs implicated in cardiac adaptions. Supporting their discriminative potential, a number of c-miRNAs previously associated with cardiac disease were undetectable or stable in response to exercise. Conversely, "pseudo-disease" signatures were also observed. c-miRNAs may be useful for the management of cardiac conditions in the context of acute aerobic exercise. Circulating microRNAs could offer incremental diagnostic value to established and emerging cardiac biomarkers, such as hs-cTnT or NT-proBNP, in those patients with cardiac dysfunction symptoms after an acute bout of endurance exercise. Furthermore, circulating miRNAs could also show "pseudo-disease" signatures in response to acute exercise. Clinical practitioners should

Cardiac arrest

MedlinePlus

... it does not necessarily cause death. Sometimes a heart attack can trigger a cardiac arrest, however. Cardiac arrest is caused by a problem with the heart's electrical system, such as: Ventricular fibrillation (VF) . When ...

Remote controlled robot assisted cardiac navigation: feasibility assessment and validation in a porcine model.

PubMed

Ganji, Yusof; Janabi-Sharifi, Farrokh; Cheema, Asim N

2011-12-01

Despite the recent advances in catheter design and technology, intra-cardiac navigation during electrophysiology procedures remains challenging. Incorporation of imaging along with magnetic or robotic guidance may improve navigation accuracy and procedural safety. In the present study, the in vivo performance of a novel remote controlled Robot Assisted Cardiac Navigation System (RACN) was evaluated in a porcine model. The navigation catheter and target sensor were advanced to the right atrium using fluoroscopic and intra-cardiac echo guidance. The target sensor was positioned at three target locations in the right atrium (RA) and the navigation task was completed by an experienced physician using both manual and RACN guidance. The navigation time, final distance between the catheter tip and target sensor, and variability in final catheter tip position were determined and compared for manual and RACN guided navigation. The experiments were completed in three animals and five measurements recorded for each target location. The mean distance (mm) between catheter tip and target sensor at the end of the navigation task was significantly less using RACN guidance compared with manual navigation (5.02 ± 0.31 vs. 9.66 ± 2.88, p = 0.050 for high RA, 9.19 ± 1.13 vs. 13.0 ± 1.00, p = 0.011 for low RA and 6.77 ± 0.59 vs. 15.66 ± 2.51, p = 0.003 for tricuspid valve annulus). The average time (s) needed to complete the navigation task was significantly longer by RACN guided navigation compared with manual navigation (43.31 ± 18.19 vs. 13.54 ± 1.36, p = 0.047 for high RA, 43.71 ± 11.93 vs. 22.71 ± 3.79, p = 0.043 for low RA and 37.84 ± 3.71 vs. 16.13 ± 4.92, p = 0.003 for tricuspid valve annulus. RACN guided navigation resulted in greater consistency in performance compared with manual navigation as evidenced by lower variability in final distance measurements (0.41 vs. 0.99 mm, p = 0

A closer look at the relationships between panic attacks, emergency department visits and non-cardiac chest pain.

PubMed

Foldes-Busque, Guillaume; Denis, Isabelle; Poitras, Julien; Fleet, Richard P; Archambault, Patrick; Dionne, Clermont E

2017-01-01

This study examined the prevalence of emergency department visits prompted by panic attacks in patients with non-cardiac chest pain. A validated structured telephone interview was used to assess panic attacks and their association with the emergency department consultation in 1327 emergency department patients with non-cardiac chest pain. Patients reported at least one panic attack in the past 6 months in 34.5 per cent (95% confidence interval: 32.0%-37.1%) of cases, and 77.1 per cent (95% confidence interval: 73.0%-80.7%) of patients who reported panic attacks had visited the emergency department with non-cardiac chest pain following a panic attack. These results indicate that panic attacks may explain a significant proportion of emergency department visits for non-cardiac chest pain.

Recent advances in the Laboratory of Molecular and Cellular Cardiology.

PubMed

Breitbart, R E; London, B; Nguyen, H T; Satler, C A

1995-12-01

This article highlights some of the research in cardiac molecular biology in progress in the Department of Cardiology at Children's Hospital. It provides a sampling of investigative approaches to key questions in cardiovascular development and function and, as such, is intended as an overview rather than a comprehensive treatment of these problems. The featured projects, encompassing four different "model" systems, include (1) genetic analysis of the mef2 gene required for fruit fly cardial cell differentiation, (2) cardiac-specific homeobox factors in zebrafish cardiovascular development, (3) mouse transgenic and gene knockout models of cardiac potassium ion channel function, and (4) mapping and identification of human gene mutations causing long QT syndrome.

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

PubMed Central

O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

2014-01-01

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

Cardiac fatty acid uptake and metabolism in the rat model of polycystic ovary syndrome.

PubMed

Tepavčević, Snežana; Milutinović, Danijela Vojnović; Macut, Djuro; Stojiljković, Mojca; Nikolić, Marina; Božić-Antić, Ivana; Ćulafić, Tijana; Bjekić-Macut, Jelica; Matić, Gordana; Korićanac, Goran

2015-09-01

Polycystic ovary syndrome (PCOS) is associated with an altered plasma lipid profile and increased risk for cardiovascular diseases. We hypothesized that molecular mechanisms underlying cardiac pathology in PCOS involve changes in expression and subcellular localization of several key proteins involved in cardiac lipid transport and metabolism, such as fatty acid transporter CD36, lipin 1, peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ coactivator-1 (PGC1), and carnitine palmitoyltransferase 1 (CPT1). We used the animal model of PCOS obtained by treating female rats with dihydrotestosterone (DHT). Protein levels of CD36, lipin 1, PPARα, PGC1, and antioxidative enzymes were assessed by Western blot in different cardiac cell compartments. Cardiac triglycerides (TG) and lipid peroxidation were also measured. The content of CD36 was decreased in both the cardiac plasma membranes and intracellular pool. On the other hand, total content of cardiac lipin 1 in DHT-treated rats was elevated, in contrast to decreased microsomal lipin 1 content. An increase in nuclear content of lipin 1 was observed together with elevation of nuclear PPARα and PGC1, and an increase in CPT1 expression. However, lipid peroxidation was reduced in the heart, without alterations in antioxidative enzymes expression and cardiac TG content. The results indicate that treatment of female rats with DHT is accompanied by a decrease of fatty acid uptake and a reduction of lipid peroxidation in the heart. The observed elevation of lipin 1, PPARα, PGC1, and CPT1 expression suggests that cardiac fatty acid metabolism is shifted toward mitochondrial beta oxidation.

A Novel Human Tissue-Engineered 3-D Functional Vascularized Cardiac Muscle Construct

PubMed Central

Valarmathi, Mani T.; Fuseler, John W.; Davis, Jeffrey M.; Price, Robert L.

2017-01-01

Organ tissue engineering, including cardiovascular tissues, has been an area of intense investigation. The major challenge to these approaches has been the inability to vascularize and perfuse the in vitro engineered tissue constructs. Attempts to provide oxygen and nutrients to the cells contained in the biomaterial constructs have had varying degrees of success. The aim of this current study is to develop a three-dimensional (3-D) model of vascularized cardiac tissue to examine the concurrent temporal and spatial regulation of cardiomyogenesis in the context of postnatal de novo vasculogenesis during stem cell cardiac regeneration. In order to achieve the above aim, we have developed an in vitro 3-D functional vascularized cardiac muscle construct using human induced pluripotent stem cell-derived embryonic cardiac myocytes (hiPSC-ECMs) and human mesenchymal stem cells (hMSCs). First, to generate the prevascularized scaffold, human cardiac microvascular endothelial cells (hCMVECs) and hMSCs were co-cultured onto a 3-D collagen cell carrier (CCC) for 7 days under vasculogenic culture conditions. In this milieu, hCMVECs/hMSCs underwent maturation, differentiation, and morphogenesis characteristic of microvessels, and formed extensive plexuses of vascular networks. Next, the hiPSC-ECMs and hMSCs were co-cultured onto this generated prevascularized CCCs for further 7 or 14 days in myogenic culture conditions. Finally, the vascular and cardiac phenotypic inductions were analyzed at the morphological, immunological, biochemical, molecular, and functional levels. Expression and functional analyses of the differentiated cells revealed neo-angiogenesis and neo-cardiomyogenesis. Thus, our unique 3-D co-culture system provided us the apt in vitro functional vascularized 3-D cardiac patch that can be utilized for cellular cardiomyoplasty. PMID:28194397

Defining the Intrinsic Cardiac Risks of Operations to Improve Preoperative Cardiac Risk Assessments.

PubMed

Liu, Jason B; Liu, Yaoming; Cohen, Mark E; Ko, Clifford Y; Sweitzer, Bobbie J

2018-02-01

Current preoperative cardiac risk stratification practices group operations into broad categories, which might inadequately consider the intrinsic cardiac risks of individual operations. We sought to define the intrinsic cardiac risks of individual operations and to demonstrate how grouping operations might lead to imprecise estimates of perioperative cardiac risk. Elective operations (based on Common Procedural Terminology codes) performed from January 1, 2010 to December 31, 2015 at hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program were studied. A composite measure of perioperative adverse cardiac events was defined as either cardiac arrest requiring cardiopulmonary resuscitation or acute myocardial infarction. Operations' intrinsic cardiac risks were derived from mixed-effects models while controlling for patient mix. Resultant risks were sorted into low-, intermediate-, and high-risk categories, and the most commonly performed operations within each category were identified. Intrinsic operative risks were also examined using a representative grouping of operations to portray within-group variation. Sixty-six low, 30 intermediate, and 106 high intrinsic cardiac risk operations were identified. Excisional breast biopsy had the lowest intrinsic cardiac risk (overall rate, 0.01%; odds ratio, 0.11; 95% CI, 0.02 to 0.25) relative to the average, whereas aorto-bifemoral bypass grafting had the highest (overall rate, 4.1%; odds ratio, 6.61; 95% CI, 5.54 to 7.90). There was wide variation in the intrinsic cardiac risks of operations within the representative grouping (median odds ratio, 1.40; interquartile range, 0.88 to 2.17). A continuum of intrinsic cardiac risk exists among operations. Grouping operations into broad categories inadequately accounts for the intrinsic cardiac risk of individual operations.

Early rise in postoperative creatinine for identification of acute kidney injury after cardiac surgery.

PubMed

Karkouti, Keyvan; Rao, Vivek; Chan, Christopher T; Wijeysundera, Duminda N

2017-08-01

Acute kidney injury (AKI) is a potentially serious complication of cardiac surgery. Treatment strategies are unlikely to prove efficacious unless patients are identified and treated soon after the onset of injury. In this observational study, we determined and validated the ability of an early rise in postoperative serum creatinine to identify patients who suffer AKI during cardiac surgery. The relationship between an early rise in creatinine (immediate postoperative / preoperative creatinine) and AKI (> 50% increase in creatinine by postoperative calendar days 1or 2) was determined by logistic regression modelling. Existing databases were used for model development (n = 4,820; one institution) and validation (n = 6,553; 12 institutions). Acute kidney injury occurred in 9.1% (n = 437) and 9.8% (n = 645) of patients in the development and validation sets, respectively. An early rise in creatinine was related to AKI (P < 0.001), with an area under the receiver operating characteristic curve of 0.78 (95% confidence interval [CI], 0.75 to 0.80) in the development set and 0.77 (95% CI, 0.75 to 0.79) in the validation set. Using a threshold ratio of > 1.30 (n = 127), the sensitivity, specificity, positive, and negative predictive values for AKI in the development set were 20% (95% CI, 16 to 24), 99% (95% CI, 99 to 99), 68% (95% CI, 59 to 76), and 93% (95% CI, 92 to 93), respectively. In patients undergoing cardiac surgery with cardiopulmonary bypass, an early rise in postoperative creatinine is a useful marker for the early identification of AKI patients. This could allow inclusion of such patients in clinical trials of promising therapeutic strategies that need to be initiated soon after the onset of injury.

Inhibition of cardiac inward rectifier currents by cationic amphiphilic drugs.

PubMed

van der Heyden, M A G; Stary-Weinzinger, A; Sanchez-Chapula, J A

2013-09-01

Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. Here, we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships.

[Cardiac Anaesthesia: Anaesthesiological Management].

PubMed

Renner, Jochen; Bein, Berthold; Broch, Ole

2018-05-01

The anaesthesiological management of patients scheduled for cardiac surgery has been refined distinctively over the last decade due to different reasons. The continuing growth of the elderly patient population and the increasing number of combined cardiac surgery procedures in octogenarians on the one hand are one aspect. The rapid development of minimally invasive cardiac surgery and the enhancements in mechanical, artificial heart assist devices on the other hand can be seen as additional decisive factors. All of these innovations in the field of cardiac surgery implicate further enhancements regarding the anaesthesiological management. This review article addresses the following subareas of cardiac anaesthesia: significance of pharmacological myocardial protection, anaesthetic management during cardiopulmonary bypass, importance of "Enhanced Recovery After Cardiac Surgery"-protocols as well as innovations in the field of minimally invasive cardiac surgery like transcatheter aortic valve implantation. Georg Thieme Verlag KG Stuttgart · New York.

Accurate reconstruction of 3D cardiac geometry from coarsely-sliced MRI.

PubMed

Ringenberg, Jordan; Deo, Makarand; Devabhaktuni, Vijay; Berenfeld, Omer; Snyder, Brett; Boyers, Pamela; Gold, Jeffrey

2014-02-01

We present a comprehensive validation analysis to assess the geometric impact of using coarsely-sliced short-axis images to reconstruct patient-specific cardiac geometry. The methods utilize high-resolution diffusion tensor MRI (DTMRI) datasets as reference geometries from which synthesized coarsely-sliced datasets simulating in vivo MRI were produced. 3D models are reconstructed from the coarse data using variational implicit surfaces through a commonly used modeling tool, CardioViz3D. The resulting geometries were then compared to the reference DTMRI models from which they were derived to analyze how well the synthesized geometries approximate the reference anatomy. Averaged over seven hearts, 95% spatial overlap, less than 3% volume variability, and normal-to-surface distance of 0.32 mm was observed between the synthesized myocardial geometries reconstructed from 8 mm sliced images and the reference data. The results provide strong supportive evidence to validate the hypothesis that coarsely-sliced MRI may be used to accurately reconstruct geometric ventricular models. Furthermore, the use of DTMRI for validation of in vivo MRI presents a novel benchmark procedure for studies which aim to substantiate their modeling and simulation methods using coarsely-sliced cardiac data. In addition, the paper outlines a suggested original procedure for deriving image-based ventricular models using the CardioViz3D software. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Forward Programming of Cardiac Stem Cells by Homogeneous Transduction with MYOCD plus TBX5

PubMed Central

Belian, Elisa; Noseda, Michela; Abreu Paiva, Marta S.; Leja, Thomas; Sampson, Robert; Schneider, Michael D.

2015-01-01

Adult cardiac stem cells (CSCs) express many endogenous cardiogenic transcription factors including members of the Gata, Hand, Mef2, and T-box family. Unlike its DNA-binding targets, Myocardin (Myocd)—a co-activator not only for serum response factor, but also for Gata4 and Tbx5—is not expressed in CSCs. We hypothesised that its absence was a limiting factor for reprogramming. Here, we sought to investigate the susceptibility of adult mouse Sca1+ side population CSCs to reprogramming by supplementing the triad of GATA4, MEF2C, and TBX5 (GMT), and more specifically by testing the effect of the missing co-activator, Myocd. Exogenous factors were expressed via doxycycline-inducible lentiviral vectors in various combinations. High throughput quantitative RT-PCR was used to test expression of 29 cardiac lineage markers two weeks post-induction. GMT induced more than half the analysed cardiac transcripts. However, no protein was detected for the induced sarcomeric genes Actc1, Myh6, and Myl2. Adding MYOCD to GMT affected only slightly the breadth and level of gene induction, but, importantly, triggered expression of all three proteins examined (α-cardiac actin, atrial natriuretic peptide, sarcomeric myosin heavy chains). MYOCD + TBX was the most effective pairwise combination in this system. In clonal derivatives homogenously expressing MYOCD + TBX at high levels, 93% of cardiac transcripts were up-regulated and all five proteins tested were visualized. In summary: (1) GMT induced cardiac genes in CSCs, but not cardiac proteins under the conditions used. (2) Complementing GMT with MYOCD induced cardiac protein expression, indicating a more complete cardiac differentiation program. (3) Homogeneous transduction with MYOCD + TBX5 facilitated the identification of differentiating cells and the validation of this combinatorial reprogramming strategy. Together, these results highlight the pivotal importance of MYOCD in driving CSCs toward a cardiac muscle fate. PMID

Forward Programming of Cardiac Stem Cells by Homogeneous Transduction with MYOCD plus TBX5.

PubMed

Belian, Elisa; Noseda, Michela; Abreu Paiva, Marta S; Leja, Thomas; Sampson, Robert; Schneider, Michael D

2015-01-01

Adult cardiac stem cells (CSCs) express many endogenous cardiogenic transcription factors including members of the Gata, Hand, Mef2, and T-box family. Unlike its DNA-binding targets, Myocardin (Myocd)-a co-activator not only for serum response factor, but also for Gata4 and Tbx5-is not expressed in CSCs. We hypothesised that its absence was a limiting factor for reprogramming. Here, we sought to investigate the susceptibility of adult mouse Sca1+ side population CSCs to reprogramming by supplementing the triad of GATA4, MEF2C, and TBX5 (GMT), and more specifically by testing the effect of the missing co-activator, Myocd. Exogenous factors were expressed via doxycycline-inducible lentiviral vectors in various combinations. High throughput quantitative RT-PCR was used to test expression of 29 cardiac lineage markers two weeks post-induction. GMT induced more than half the analysed cardiac transcripts. However, no protein was detected for the induced sarcomeric genes Actc1, Myh6, and Myl2. Adding MYOCD to GMT affected only slightly the breadth and level of gene induction, but, importantly, triggered expression of all three proteins examined (α-cardiac actin, atrial natriuretic peptide, sarcomeric myosin heavy chains). MYOCD + TBX was the most effective pairwise combination in this system. In clonal derivatives homogenously expressing MYOCD + TBX at high levels, 93% of cardiac transcripts were up-regulated and all five proteins tested were visualized. (1) GMT induced cardiac genes in CSCs, but not cardiac proteins under the conditions used. (2) Complementing GMT with MYOCD induced cardiac protein expression, indicating a more complete cardiac differentiation program. (3) Homogeneous transduction with MYOCD + TBX5 facilitated the identification of differentiating cells and the validation of this combinatorial reprogramming strategy. Together, these results highlight the pivotal importance of MYOCD in driving CSCs toward a cardiac muscle fate.

Dual function of the UNC-45b chaperone with myosin and GATA4 in cardiac development

PubMed Central

Chen, Daisi; Li, Shumin; Singh, Ram; Spinette, Sarah; Sedlmeier, Reinhard; Epstein, Henry F.

2012-01-01

Summary Cardiac development requires interplay between the regulation of gene expression and the assembly of functional sarcomeric proteins. We report that UNC-45b recessive loss-of-function mutations in C3H and C57BL/6 inbred mouse strains cause arrest of cardiac morphogenesis at the formation of right heart structures and failure of contractile function. Wild-type C3H and C57BL/6 embryos at the same stage, E9.5, form actively contracting right and left atria and ventricles. The known interactions of UNC-45b as a molecular chaperone are consistent with diminished accumulation of the sarcomeric myosins, but not their mRNAs, and the resulting decreased contraction of homozygous mutant embryonic hearts. The novel finding that GATA4 accumulation is similarly decreased at the protein but not mRNA levels is also consistent with the function of UNC-45b as a chaperone. The mRNAs of known downstream targets of GATA4 during secondary cardiac field development, the cardiogenic factors Hand1, Hand2 and Nkx-2.5, are also decreased, consistent with the reduced GATA4 protein accumulation. Direct binding studies show that the UNC-45b chaperone forms physical complexes with both the alpha and beta cardiac myosins and the cardiogenic transcription factor GATA4. Co-expression of UNC-45b with GATA4 led to enhanced transcription from GATA promoters in naïve cells. These novel results suggest that the heart-specific UNC-45b isoform functions as a molecular chaperone mediating contractile function of the sarcomere and gene expression in cardiac development. PMID:22553207

Novel insights into cardiac remodelling revealed by proteomic analysis of the trout heart during exercise training.

PubMed

Dindia, Laura A; Alderman, Sarah L; Gillis, Todd E

2017-05-24

The changes in the cardiac proteome of rainbow trout (Oncorhynchus mykiss) were quantified during the early phases (4, 7, and 14d) of a typical exercise-training regime to provide a comprehensive overview of the cellular changes responsible for developing a trained heart phenotype. Enhanced somatic growth during the 14d experiment was paralleled by cardiac growth to maintain relative ventricular mass. This was reflected in the cardiac proteome by the increased abundance of contractile proteins and cellular integrity proteins as early as Day 4, including a pronounced and sustained increase in blood vessel epicardial substance - an intercellular adhesion protein expressed in the vertebrate heart. An unexpected finding was that proteins involved in energy pathways, including glycolysis, β-oxidation, the TCA cycle, and the electron transport chain, were generally present at lower levels relative to Day 0 levels, suggesting a reduced investment in the maintenance of energy production pathways. However, as the fish demonstrated somatic and cardiac growth during the exercise-training program, this change did not appear to influence cardiac function. The in-depth analysis of temporal changes in the cardiac proteome of trout during the early stages of exercise training reveals novel insights into cardiac remodelling in an important model species. Rainbow trout hearts have a remarkable ability for molecular, structural, and functional plasticity, and the inherent athleticism of these fish makes them ideal models for studies in comparative exercise physiology. Indeed, several decades of research using exercise-trained trout has shown both conserved and unique aspects of cardiac plasticity induced by a sustained increase in the workload of the heart. Despite a strong appreciation for the outcome of exercise training, however, the temporal events that generate this phenotype are not known. This study interrogates the early stages of exercise training using in-depth proteomic

Development and validation of a dual sensing scheme to improve accuracy of bradycardia and pause detection in an insertable cardiac monitor.

PubMed

Passman, Rod S; Rogers, John D; Sarkar, Shantanu; Reiland, Jerry; Reisfeld, Erin; Koehler, Jodi; Mittal, Suneet

2017-07-01

Undersensing of premature ventricular beats and low-amplitude R waves are primary causes for inappropriate bradycardia and pause detections in insertable cardiac monitors (ICMs). The purpose of this study was to develop and validate an enhanced algorithm to reduce inappropriately detected bradycardia and pause episodes. Independent data sets to develop and validate the enhanced algorithm were derived from a database of ICM-detected bradycardia and pause episodes in de-identified patients monitored for unexplained syncope. The original algorithm uses an auto-adjusting sensitivity threshold for R-wave sensing to detect tachycardia and avoid T-wave oversensing. In the enhanced algorithm, a second sensing threshold is used with a long blanking and fixed lower sensitivity threshold, looking for evidence of undersensed signals. Data reported includes percent change in appropriate and inappropriate bradycardia and pause detections as well as changes in episode detection sensitivity and positive predictive value with the enhanced algorithm. The validation data set, from 663 consecutive patients, consisted of 4904 (161 patients) bradycardia and 2582 (133 patients) pause episodes, of which 2976 (61%) and 996 (39%) were appropriately detected bradycardia and pause episodes. The enhanced algorithm reduced inappropriate bradycardia and pause episodes by 95% and 47%, respectively, with 1.7% and 0.6% reduction in appropriate episodes, respectively. The average episode positive predictive value improved by 62% (P < .001) for bradycardia detection and by 26% (P < .001) for pause detection, with an average relative sensitivity of 95% (P < .001) and 99% (P = .5), respectively. The enhanced dual sense algorithm for bradycardia and pause detection in ICMs substantially reduced inappropriate episode detection with a minimal reduction in true episode detection. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes.

PubMed

Adam, B A; Smith, R N; Rosales, I A; Matsunami, M; Afzali, B; Oura, T; Cosimi, A B; Kawai, T; Colvin, R B; Mengel, M

2017-11-01

Molecular testing represents a promising adjunct for the diagnosis of antibody-mediated rejection (AMR). Here, we apply a novel gene expression platform in sequential formalin-fixed paraffin-embedded samples from nonhuman primate (NHP) renal transplants. We analyzed 34 previously described gene transcripts related to AMR in humans in 197 archival NHP samples, including 102 from recipients that developed chronic AMR, 80 from recipients without AMR, and 15 normal native nephrectomies. Three endothelial genes (VWF, DARC, and CAV1), derived from 10-fold cross-validation receiver operating characteristic curve analysis, demonstrated excellent discrimination between AMR and non-AMR samples (area under the curve = 0.92). This three-gene set correlated with classic features of AMR, including glomerulitis, capillaritis, glomerulopathy, C4d deposition, and DSAs (r = 0.39-0.63, p < 0.001). Principal component analysis confirmed the association between three-gene set expression and AMR and highlighted the ambiguity of v lesions and ptc lesions between AMR and T cell-mediated rejection (TCMR). Elevated three-gene set expression corresponded with the development of immunopathological evidence of rejection and often preceded it. Many recipients demonstrated mixed AMR and TCMR, suggesting that this represents the natural pattern of rejection. These data provide NHP animal model validation of recent updates to the Banff classification including the assessment of molecular markers for diagnosing AMR. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Ursolic acid promotes robust tolerance to cardiac allografts in mice

PubMed Central

Liu, Y; Huang, X; Li, Y; Li, C; Hu, X; Xue, C; Meng, F; Zhou, P

2011-01-01

Nuclear factor (NF)-κB is an important molecule in T cell activation. Our previous work has found that T cell-restricted NF-κB super-repressor (IκBαΔN-Tg) mice, expressing an inhibitor of NF-κB restricted to the T cell compartment, can permanently accept fully allogeneic cardiac grafts and secondary donor skin grafts. In this study, we explore if transient NF-κB inhibition by a small molecular inhibitor could induce permanent graft survival. Ursolic acid, a small molecular compound, dose-dependently inhibited T cell receptor (TCR)-triggered NF-κB nuclear translocation and T cell activation in vitro. In vivo, ursolic acid monotherapy prolonged significantly the survival of cardiac allograft in mice. Assisted with donor-specific transfusion (DST) on day 0, ursolic acid promoted 84·6% of first cardiac grafts to survive for more than 150 days. While the mice with long-term surviving grafts (LTS) did not reject the second donor strain hearts for more than 100 days without any treatment, they all promptly rejected the third-party strain hearts within 14 days. Interestingly, this protocol did not result in an increased proportion of CD4+CD25+forkhead box P3+ regulatory T cells in splenocytes. That adoptive transfer experiments also did not support regulation was the main mechanism in this model. Splenocytes from LTS showed reduced alloreactivity to donor antigen. However, depletion of CD4+CD25+ regulatory T cells did not alter the donor-reactivity of LTS splenocytes. These data suggest that depletion of donor-reactive T cells may play an important role in this protocol. PMID:21391985

Quantifying the influence of respiration and cardiac pulsations on cerebrospinal fluid dynamics using real-time phase-contrast MRI.

PubMed

Yildiz, Selda; Thyagaraj, Suraj; Jin, Ning; Zhong, Xiaodong; Heidari Pahlavian, Soroush; Martin, Bryn A; Loth, Francis; Oshinski, John; Sabra, Karim G

2017-08-01

To validate a real-time phase contrast magnetic resonance imaging (RT-PCMRI) sequence in a controlled phantom model, and to quantify the relative contributions of respiration and cardiac pulsations on cerebrospinal fluid (CSF) velocity at the level of the foramen magnum (FM). To validate the 3T MRI techniques, in vitro studies used a realistic model of the spinal subarachnoid space driven by pulsatile flow waveforms mimicking the respiratory and cardiac components of CSF flow. Subsequently, CSF flow was measured continuously during 1-minute RT-PCMRI acquisitions at the FM while healthy subjects (N = 20) performed natural breathing, deep breathing, breath-holding, and coughing. Conventional cardiac-gated PCMRI was obtained for comparison. A frequency domain power ratio analysis determined the relative contribution of respiration versus cardiac ([r/c]) components of CSF velocity. In vitro studies demonstrating the accuracy of RT-PCMRI within 5% of input values showed that conventional PCMRI measures only the cardiac component of CSF velocity (0.42 ± 0.02 cm/s), averages out respiratory effects, and underestimates the magnitude of CSF velocity (0.96 ± 0.07 cm/s). In vivo RT-PCMRI measurements indicated the ratio of respiratory to cardiac velocity pulsations averaged over all subjects as [r/c = 0.14 ± 0.27] and [r/c = 0.40 ± 0.47] for natural and deep breathing, respectively. During coughing, the peak CSF velocity increased by a factor of 2.27 ± 1.40. RT-PCMRI can noninvasively measure instantaneous CSF velocity driven by cardiac pulsations, respiration, and coughing in real time. A comparable contribution of respiration and cardiac pulsations on CSF velocity was found during deep breathing but not during natural breathing. 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:431-439. © 2017 International Society for Magnetic Resonance in Medicine.

Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity.

PubMed

Sun, Dongdong; Li, Shuang; Wu, Hao; Zhang, Mingming; Zhang, Xiaotian; Wei, Liping; Qin, Xing; Gao, Erhe

2015-06-01

Oncostatin M (OSM) exhibits many unique biological activities by activating Oβ receptor. However, its role in myocardial I/R injury in diabetic mice remains unknown. The involvement of OSM was assessed in diabetic mice which underwent myocardial I/R injury by OSM treatment or genetic deficiency of OSM receptor Oβ. Its mechanism on cardiomyocyte apoptosis, mitochondrial biogenesis and insulin sensitivity were further studied. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through inhibition of inositol pyrophosphate 7 (IP7) production, thus activating PI3K/Akt/BAD pathway, decreasing Bax expression while up-regulating Bcl-2 expression and decreasing the ratio of Bax to Bcl-2 in db/db mice. OSM enhanced mitochondrial biogenesis and mitochondrial function in db/db mice subjected to cardiac I/R injury. On the contrary, OSM receptor Oβ knockout exacerbated cardiac I/R injury, increased IP7 production, enhanced cardiomyocyte apoptosis, impaired mitochondrial biogenesis, glucose homoeostasis and insulin sensitivity in cardiac I/R injured diabetic mice. Inhibition of IP7 production by TNP (IP6K inhibitor) exerted similar effects of OSM. The mechanism of OSM on cardiac I/R injury in diabetic mice is partly associated with IP7/Akt and adenine mononucleotide protein kinase/PGC-1α pathway. OSM protects against cardiac I/R Injury by regulating apoptosis, insulin sensitivity and mitochondrial biogenesis in diabetic mice through inhibition of IP7 production. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Influenza epidemics, seasonality, and the effects of cold weather on cardiac mortality

PubMed Central

2012-01-01

Background More people die in the winter from cardiac disease, and there are competing hypotheses to explain this. The authors conducted a study in 48 US cities to determine how much of the seasonal pattern in cardiac deaths could be explained by influenza epidemics, whether that allowed a more parsimonious control for season than traditional spline models, and whether such control changed the short term association with temperature. Methods The authors obtained counts of daily cardiac deaths and of emergency hospital admissions of the elderly for influenza during 1992–2000. Quasi-Poisson regression models were conducted estimating the association between daily cardiac mortality, and temperature. Results Controlling for influenza admissions provided a more parsimonious model with better Generalized Cross-Validation, lower residual serial correlation, and better captured Winter peaks. The temperature-response function was not greatly affected by adjusting for influenza. The pooled estimated increase in risk for a temperature decrease from 0 to −5°C was 1.6% (95% confidence interval (CI) 1.1-2.1%). Influenza accounted for 2.3% of cardiac deaths over this period. Conclusions The results suggest that including epidemic data explained most of the irregular seasonal pattern (about 18% of the total seasonal variation), allowing more parsimonious models than when adjusting for seasonality only with smooth functions of time. The effect of cold temperature is not confounded by epidemics. PMID:23025494

Using Simulation to Implement an OR Cardiac Arrest Crisis Checklist.

PubMed

Dagey, Darleen

2017-01-01

Crisis checklists are cognitive aids used to coordinate care during critical events. Simulation training is a method to validate process improvement initiatives such as checklist implementation. In response to concerns staff members expressed regarding their comfort level when responding to infrequent occurrences such as cardiac arrest and other OR emergencies, the OR Comprehensive Unit-based Safety Program team at our facility decided to institute the use of crisis checklists in the OR during critical events. We provided 90-minute education sessions, simulation opportunities, and debriefings to help staff members become more comfortable using these checklists. Based on program evaluations, 80% of staff members who participated in the training expressed an increased comfort level when caring for a patient in cardiac arrest. Copyright © 2017 AORN, Inc. Published by Elsevier Inc. All rights reserved.

Engineered Three-Dimensional Cardiac Fibrotic Tissue to Study Fibrotic Remodeling

PubMed Central

Sadeghi, Amir Hossein; Shin, Su Ryon; Deddens, Janine C.; Fratta, Giuseppe; Mandla, Serena; Yazdi, Iman K.; Prakash, Gyan; Antona, Silvia; Demarchi, Danilo; Buijsrogge, Marc P.; Sluijter, Joost P.G.; Hjortnaes, Jesper

2017-01-01

Activation of cardiac fibroblasts (CF) into myofibroblasts is considered to play an essential role in cardiac remodeling and fibrosis. A limiting factor in studying this process is the spontaneous activation of CFs when cultured on two-dimensional (2D) culture plates. Here, a simplified 3D hydrogel platform of contractile cardiac tissue, stimulated by transforming growth factor-β1 (TGF-β1), is presented to recapitulate a fibrogenic micro-environment. It was hypothesized that the quiescent state of CFs can be maintained by mimicking the mechanical stiffness of native heart tissue. To test this hypothesis, a 3D cell culture model consisting of cardiomyocytes and CFs encapsulated within mechanically engineered gelatin methacryloyl (GelMA) hydrogel, was developed. The study shows that CFs maintain their quiescent phenotype in mechanically tuned hydrogels. Additionally, treatment with a beta-adrenergic agonist increased beating frequency, demonstrating physiologic-like behavior of the heart constructs. Subsequently, quiescent CFs within the constructs were activated by the exogenous addition of TGF-β1. The expression of fibrotic protein markers (and the functional changes in mechanical stiffness) in the fibrotic-like tissues were analyzed to validate the model. Overall, this 3D engineered culture model of contractile cardiac tissue enabled controlled activation of CFs, demonstrating the usability of this platform to study fibrotic remodeling. PMID:28498548

Cardiac Endothelial Cell Transcriptome.

PubMed

Lother, Achim; Bergemann, Stella; Deng, Lisa; Moser, Martin; Bode, Christoph; Hein, Lutz

2018-03-01

Endothelial cells (ECs) are a highly specialized cell type with marked diversity between different organs or vascular beds. Cardiac ECs are an important player in cardiac physiology and pathophysiology but are not sufficiently characterized yet. Thus, the aim of the present study was to analyze the cardiac EC transcriptome. We applied fluorescence-assisted cell sorting to isolate pure ECs from adult mouse hearts. RNAseq revealed 1288 genes predominantly expressed in cardiac ECs versus heart tissue including several transcription factors. We found an overrepresentation of corresponding transcription factor binding motifs within the promotor region of EC-enriched genes, suggesting that they control the EC transcriptome. Cardiac ECs exhibit a distinct gene expression profile when compared with renal, cerebral, or pulmonary ECs. For example, we found the Meox2 / Tcf15, Fabp4 , and Cd36 signaling cascade higher expressed in cardiac ECs which is a key regulator of fatty acid uptake and involved in the development of atherosclerosis. The results from this study provide a comprehensive resource of gene expression and transcriptional control in cardiac ECs. The cardiac EC transcriptome exhibits distinct differences in gene expression compared with other cardiac cell types and ECs from other organs. We identified new candidate genes that have not been investigated in ECs yet as promising targets for future evaluation. © 2018 American Heart Association, Inc.

Temporal and Molecular Analyses of Cardiac Extracellular Matrix Remodeling following Pressure Overload in Adiponectin Deficient Mice

PubMed Central

Dadson, Keith; Turdi, Subat; Boo, Stellar; Hinz, Boris; Sweeney, Gary

2015-01-01

Adiponectin, circulating levels of which are reduced in obesity and diabetes, mediates cardiac extracellular matrix (ECM) remodeling in response to pressure overload (PO). Here, we performed a detailed temporal analysis of progressive cardiac ECM remodelling in adiponectin knockout (AdKO) and wild-type (WT) mice at 3 days and 1, 2, 3 and 4 weeks following the induction of mild PO via minimally invasive transverse aortic banding. We first observed that myocardial adiponectin gene expression was reduced after 4 weeks of PO, whereas increased adiponectin levels were detected in cardiac homogenates at this time despite decreased circulating levels of adiponectin. Scanning electron microscopy and Masson’s trichrome staining showed collagen accumulation increased in response to 2 and 4 weeks of PO in WT mice, while fibrosis in AdKO mice was notably absent after 2 weeks but highly apparent after 4 weeks of PO. Time and intensity of fibroblast appearance after PO was not significantly different between AdKO and WT animals. Gene array analysis indicated that MMP2, TIMP2, collagen 1α1 and collagen 1α3 were induced after 2 weeks of PO in WT but not AdKO mice. After 4 weeks MMP8 was induced in both genotypes, MMP9 only in WT mice and MMP1α only in AdKO mice. Direct stimulation of primary cardiac fibroblasts with adiponectin induced a transient increase in total collagen detected by picrosirius red staining and collagen III levels synthesis, as well as enhanced MMP2 activity detected via gelatin zymography. Adiponectin also enhanced fibroblast migration and attenuated angiotensin-II induced differentiation to a myofibroblast phenotype. In conclusion, these data indicate that increased myocardial bioavailability of adiponectin mediates ECM remodeling following PO and that adiponectin deficiency delays these effects. PMID:25910275

Association between dental caries and out-of-hospital cardiac arrests of cardiac origin in Japan.

PubMed

Suematsu, Yasunori; Miura, Shin-Ichiro; Zhang, Bo; Uehara, Yoshinari; Ogawa, Masahiro; Yonemoto, Naohiro; Nonogi, Hiroshi; Nagao, Ken; Kimura, Takeshi; Saku, Keijiro

2016-04-01

Oral infection contributes to atherosclerosis and coronary heart disease. We hypothesized that dental caries may be associated with out-of-hospital cardiac arrests (OHCA) of cardiac origin, but not non-cardiac origin. We compared the age-adjusted incidence of OHCA (785,591 cases of OHCA: 55.4% of cardiac origin and 44.6% of non-cardiac origin) to the age-adjusted prevalence of dental caries between 2005 and 2011 in the 47 prefectures of Japan. In both the total population and males over 65 years, the number of cases of dental caries was significantly associated with the number of OHCA of total and cardiac origin from 2005 to 2011, but not those of non-cardiac origin. In the total population, the age-adjusted prevalence of dental caries was not significantly associated with the age-adjusted incidence of OHCA (total OHCA: r correlation coefficient=0.22, p=0.14; OHCA of cardiac origin: r=0.25, p=0.09; OHCA of non-cardiac origin: r=-0.002, p=0.99). Among male patients over 65 years, the age-adjusted prevalence of dental caries was significantly associated with OHCA of total and cardiac origin, but not non-cardiac origin (total OHCA: r=0.47, p<0.001; OHCA of cardiac origin: r=0.37, p=0.01; OHCA of non-cardiac origin: r=0.28, p=0.054). While oral hygiene is important in all age groups, it may be particularly associated with OHCAs of cardiac origin in males over 65 years. Copyright © 2015. Published by Elsevier Ltd.

Cardiac Metastasis from Invasive Thymoma Via the Superior Vena Cava: Cardiac MRI Findings

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

Dursun, Memduh, E-mail: memduhdursun@yahoo.com; Sarvar, Sadik; Cekrezi, Bledi

2008-07-15

Cardiac tumors are rare, and metastatic deposits are more common than primary cardiac tumors. We present cardiac magnetic resonance imaging (MRI) findings of a 50-year-old woman with invasive thymoma. Cardiac MRI revealed a heterogeneous, lobulated anterior mediastinal mass invading the superior vena cava and extending to the right atrium. In cine images there was no invasion to the right atrial wall.

Transthyretin Cardiac Amyloidosis.

PubMed

Mankad, Anit K; Shah, Keyur B

2017-08-24

Transthyretin (TTR)-related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive, hypertrophic heart disease and may go undiagnosed. Transthyretin-derived amyloidosis accounts for 18% of all cases of cardiac amyloidosis. Thus, the study's purpose is to provide a comprehensive review of transthyretin cardiac amyloidosis. Wild-type transthyretin (ATTRwt) protein causes cardiac amyloidosis sporadically, with 25 to 36% of the population older than 80 years of age are at risk to develop a slowly progressive, infiltrative amyloid cardiomyopathy secondary to ATTRwt. In contrast, hereditary amyloidosis (ATTRm) is an autosomal dominant inherited disease associated with more than 100 point mutations in the transthyretin gene and has a tendency to affect the heart and nervous system. Up to 4% of African-Americans carry the Val122Ile mutation in the transthyretin gene, the most prevalent cause of hereditary cardiac amyloidosis in the USA. Identifying transthyretin cardiac amyloidosis requires increased awareness of the prevalence, signs and symptoms, and diagnostic tools available for discrimination of this progressive form of cardiomyopathy associated with left ventricular hypertrophy. While there are no FDA-approved medical treatments, investigation is underway on agents to reduce circulating mutated transthyretin.

Comparison of Bruce treadmill exercise test protocols: is ramped Bruce equal or superior to standard bruce in producing clinically valid studies for patients presenting for evaluation of cardiac ischemia or arrhythmia with body mass index equal to or greater than 30?

PubMed

Bires, Angela Macci; Lawson, Dori; Wasser, Thomas E; Raber-Baer, Donna

2013-12-01

Clinically valid cardiac evaluation via treadmill stress testing requires patients to achieve specific target heart rates and to successfully complete the cardiac examination. A comparison of the standard Bruce protocol and the ramped Bruce protocol was performed using data collected over a 1-y period from a targeted patient population with a body mass index (BMI) equal to or greater than 30 to determine which treadmill protocol provided more successful examination results. The functional capacity, metabolic equivalent units achieved, pressure rate product, and total time on the treadmill as measured for the obese patients were clinically valid and comparable to normal-weight and overweight patients (P < 0.001). Data gathered from each protocol demonstrated that the usage of the ramped Bruce protocol achieved more consistent results in comparison across all BMI groups in achieving 80%-85% of their age-predicted maximum heart rate. This study did not adequately establish that the ramped Bruce protocol was superior to the standard Bruce protocol for the examination of patients with a BMI equal to or greater than 30.

Cardiac rhabdomyosarcoma

PubMed Central

Chlumský, Jaromír; Holá, Dana; Hlaváček, Karel; Michal, Michal; Švec, Alexander; Špatenka, Jaroslav; Dušek, Jan

2001-01-01

Cardiac sarcoma is a very rare neoplasm and is difficult to diagnose. The case of a 51-year-old man with a left atrial tumour, locally recurrent three months after its surgical removal, is presented. Computed tomography showed metastatic spread to the lung parenchyma. On revised histology, the mass extirpated was a sarcoma. Because of the metastatic spread, further therapy was symptomatic only; the patient died 15 months after the first manifestation of his problems. Immunohistochemical staining confirmed cardiac rhabdomyosarcoma with metastatic spread to the lungs. Difficulty in diagnosing and treating cardiac tumours is discussed. PMID:20428274

Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events.

PubMed

Hanchard, Neil A; Umana, Luis A; D'Alessandro, Lisa; Azamian, Mahshid; Poopola, Mojisola; Morris, Shaine A; Fernbach, Susan; Lalani, Seema R; Towbin, Jeffrey A; Zender, Gloria A; Fitzgerald-Butt, Sara; Garg, Vidu; Bowman, Jessica; Zapata, Gladys; Hernandez, Patricia; Arrington, Cammon B; Furthner, Dieter; Prakash, Siddharth K; Bowles, Neil E; McBride, Kim L; Belmont, John W

2017-08-01

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals. © 2017 Wiley Periodicals, Inc.

Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment

PubMed Central

Kim, Yong Sook; Jeong, Hye-yun; Kim, Ah Ra; Kim, Woong-Hee; Cho, Haaglim; Um, JungIn; Seo, Youngha; Kang, Wan Seok; Jin, Suk-Won; Kim, Min Chul; Kim, Yong-Chul; Jung, Da-Woon; Williams, Darren R.; Ahn, Youngkeun

2016-01-01

The cardiac microenvironment includes cardiomyocytes, fibroblasts and macrophages, which regulate remodeling after myocardial infarction (MI). Targeting this microenvironment is a novel therapeutic approach for MI. We found that the natural compound derivative, BIO ((2′Z,3′E)-6-Bromoindirubin-3′-oxime) modulated the cardiac microenvironment to exert a therapeutic effect on MI. Using a series of co-culture studies, BIO induced proliferation in cardiomyocytes and inhibited proliferation in cardiac fibroblasts. BIO produced multiple anti-fibrotic effects in cardiac fibroblasts. In macrophages, BIO inhibited the expression of pro-inflammatory factors. Significantly, BIO modulated the molecular crosstalk between cardiac fibroblasts and differentiating macrophages to induce polarization to the anti-inflammatory M2 phenotype. In the optically transparent zebrafish-based heart failure model, BIO induced cardiomyocyte proliferation and completely recovered survival rate. BIO is a known glycogen synthase kinase-3β inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel therapeutic effects of BIO. We identified the mechanism of BIO as differential modulation of p27 protein expression and potent induction of anti-inflammatory interleukin-10. In a rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed modulation of the cardiac microenvironment by BIO, with increased presence of anti-inflammatory M2 macrophages. Our results demonstrate that BIO produces unique effects in the cardiac microenvironment to promote recovery post-MI. PMID:27510556

Loss of P53 regresses cardiac remodeling induced by pressure overload partially through inhibiting HIF1α signaling in mice.

PubMed

Li, Jiming; Zeng, Jingjing; Wu, Lianpin; Tao, Luyuan; Liao, Zhiyong; Chu, Maoping; Li, Lei

2018-06-22

The tumor suppressor p53 is recognized as the guardian of the genome in cell cycle and cell death. P53 expression increases as cardiac hypertrophy worsens to heart failure, suggesting that p53 may play important role in cardiac remodeling. In the present study, deletion of p53 in the mice heart would ameliorate cardiac hypertrophy induced by pressure overload. The role of p53 on heart was investigated using in vivo models. Cardiac hypertrophy in mice was induced by transverse aortic banding surgery. The extent of cardiac hypertrophy was examined by echocardiography, as well as pathological and molecular analyses of heart tissue. Global knockout of p53 in the mice reduced the hypertrophic response and markedly reduced cardiac apoptosis, and fibrosis. Ejection fraction of heart was also improved in hearts without p53 in response to pressure overload. Protein determination further suggested loss of p53 expression markedly increased Hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) expression. The study indicated p53 deteriorated cardiac functions and cardiac hypertrophy, apoptosis, and fibrosis by partially inhibition of HIF1α and VEGF. Copyright © 2018 Elsevier Inc. All rights reserved.

Lentiviral Vectors Bearing the Cardiac Promoter of the Na+-Ca2+ Exchanger Report Cardiogenic Differentiation in Stem Cells

PubMed Central

Barth, Andreas S; Kizana, Eddy; Smith, Rachel R; Terrovitis, John; Dong, Peihong; Leppo, Michelle K; Zhang, Yiqiang; Miake, Junichiro; Olson, Eric N; Schneider, Jay W; Abraham, M Roselle; Marbán, Eduardo

2009-01-01

Cardiosphere-derived resident cardiac stem cells (CDCs) are readily isolated from adult hearts and confer functional benefit in animal models of heart failure. To study cardiogenic differentiation in CDCs, we developed a method to genetically label and selectively enrich for cells that have acquired a cardiac phenotype. Lentiviral vectors achieved significantly higher transduction efficiencies in CDCs than any of the nine adeno-associated viral (AAV) serotypes tested. To define the most suitable vector system for reporting cardiogenic differentiation, we compared the cell specificity of five commonly-used cardiac-specific promoters in the context of lentiviral vectors. The promoter of the cardiac sodium-calcium exchanger (NCX1) conveyed the highest degree of cardiac specificity, as assessed by transducing seven cell types with each vector and measuring fluorescence intensity by flow cytometry. NCX1-GFP-positive CDC subpopulations, demonstrating prolonged expression of a variety of cardiac markers, could be isolated and expanded in vitro. Finally, we used chemical biology to validate that lentiviral vectors bearing the cardiac NCX1-promoter can serve as a highly accurate biosensor of cardiogenic small molecules in stem cells. The ability to accurately report cardiac fate and selectively enrich for cardiomyocytes and their precursors has important implications for drug discovery and the development of cell-based therapies. PMID:18388932

An integrated platform for image-guided cardiac resynchronization therapy

NASA Astrophysics Data System (ADS)

Ma, Ying Liang; Shetty, Anoop K.; Duckett, Simon; Etyngier, Patrick; Gijsbers, Geert; Bullens, Roland; Schaeffter, Tobias; Razavi, Reza; Rinaldi, Christopher A.; Rhode, Kawal S.

2012-05-01

Cardiac resynchronization therapy (CRT) is an effective procedure for patients with heart failure but 30% of patients do not respond. This may be due to sub-optimal placement of the left ventricular (LV) lead. It is hypothesized that the use of cardiac anatomy, myocardial scar distribution and dyssynchrony information, derived from cardiac magnetic resonance imaging (MRI), may improve outcome by guiding the physician for optimal LV lead positioning. Whole heart MR data can be processed to yield detailed anatomical models including the coronary veins. Cine MR data can be used to measure the motion of the LV to determine which regions are late-activating. Finally, delayed Gadolinium enhancement imaging can be used to detect regions of scarring. This paper presents a complete platform for the guidance of CRT using pre-procedural MR data combined with live x-ray fluoroscopy. The platform was used for 21 patients undergoing CRT in a standard catheterization laboratory. The patients underwent cardiac MRI prior to their procedure. For each patient, a MRI-derived cardiac model, showing the LV lead targets, was registered to x-ray fluoroscopy using multiple views of a catheter looped in the right atrium. Registration was maintained throughout the procedure by a combination of C-arm/x-ray table tracking and respiratory motion compensation. Validation of the registration between the three-dimensional (3D) roadmap and the 2D x-ray images was performed using balloon occlusion coronary venograms. A 2D registration error of 1.2 ± 0.7 mm was achieved. In addition, a novel navigation technique was developed, called Cardiac Unfold, where an entire cardiac chamber is unfolded from 3D to 2D along with all relevant anatomical and functional information and coupled to real-time device detection. This allowed more intuitive navigation as the entire 3D scene was displayed simultaneously on a 2D plot. The accuracy of the unfold navigation was assessed off-line using 13 patient data sets

Resolution of abnormal cardiac MRI T2 signal following immune suppression for cardiac sarcoidosis.

PubMed

Crouser, Elliott D; Ruden, Emily; Julian, Mark W; Raman, Subha V

2016-08-01

Cardiac MR (CMR) with late gadolinium enhancement is commonly used to detect cardiac damage in the setting of cardiac sarcoidosis. The addition of T2 mapping to CMR was recently shown to enhance cardiac sarcoidosis detection and correlates with increased cardiac arrhythmia risk. This study was conducted to determine if CMR T2 abnormalities and related arrhythmias are reversible following immune suppression therapy. A retrospective study of subjects with cardiac sarcoidosis with abnormal T2 signal on baseline CMR and a follow-up CMR study at least 4 months later was conducted at The Ohio State University from 2011 to 2015. Immune suppression treated participants had a significant reduction in peak myocardial T2 value (70.0±5.5 vs 59.2±6.1 ms, pretreatment vs post-treatment; p=0.017), and 83% of immune suppression treated subjects had objective improvement in cardiac arrhythmias. Two subjects who had received inadequate immune suppression treatment experienced progression of cardiac sarcoidosis. This report indicates that abnormal CMR T2 signal represents an acute inflammatory manifestation of cardiac sarcoidosis that is potentially reversible with adequate immune suppression therapy. Copyright © 2016 American Federation for Medical Research.

Estimated glomerular filtration rate is an early biomarker of cardiac surgery-associated acute kidney injury.

PubMed

Candela-Toha, Ángel; Pardo, María Carmen; Pérez, Teresa; Muriel, Alfonso; Zamora, Javier

2018-04-20

and objective Acute kidney injury (AKI) diagnosis is still based on serum creatinine and diuresis. However, increases in creatinine are typically delayed 48h or longer after injury. Our aim was to determine the utility of routine postoperative renal function blood tests, to predict AKI one or 2days in advance in a cohort of cardiac surgery patients. Using a prospective database, we selected a sample of patients who had undergone major cardiac surgery between January 2002 and December 2013. The ability of the parameters to predict AKI was based on Acute Kidney Injury Network serum creatinine criteria. A cohort of 3,962 cases was divided into 2groups of similar size, one being exploratory and the other a validation sample. The exploratory group was used to show primary objectives and the validation group to confirm results. The ability to predict AKI of several kidney function parameters measured in routine postoperative blood tests, was measured with time-dependent ROC curves. The primary endpoint was time from measurement to AKI diagnosis. AKI developed in 610 (30.8%) and 623 (31.4%) patients in the exploratory and validation samples, respectively. Estimated glomerular filtration rate using the MDRD-4 equation showed the best AKI prediction capacity, with values for the AUC ROC curves between 0.700 and 0.946. We obtained different cut-off values for estimated glomerular filtration rate depending on the degree of AKI severity and on the time elapsed between surgery and parameter measurement. Results were confirmed in the validation sample. Postoperative estimated glomerular filtration rate using the MDRD-4 equation showed good ability to predict AKI following cardiac surgery one or 2days in advance. Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

The Role of Nrf2-Mediated Pathway in Cardiac Remodeling and Heart Failure

PubMed Central

Sun, Wanqing; Zhang, Zhiguo; Zheng, Yang

2014-01-01

Heart failure (HF) is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS) in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2-) related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF. PMID:25101151

A coarse-grained model to study calcium activation of the cardiac thin filament

NASA Astrophysics Data System (ADS)

Zhang, Jing; Schwartz, Steven

2015-03-01

Familial hypertrophic cardiomyopathy (FHC) is one of the most common heart disease caused by genetic mutations. Cardiac muscle contraction and relaxation involve regulation of crossbridge binding to the cardiac thin filament, which regulates actomyosin interactions through calcium-dependent alterations in the dynamics of cardiac troponin (cTn) and tropomyosin (Tm). An atomistic model of cTn complex interacting with Tm has been studied by our group. A more realistic model requires the inclusion of the dynamics of actin filament, which is almost 6 times larger than cTn and Tm in terms of atom numbers, and extensive sampling of the model becomes very resource-demanding. By using physics-based protein united-residue force field, we introduce a coarse-grained model to study the calcium activation of the thin filament resulting from cTn's allosteric regulation of Tm dynamics on actin. The time scale is much longer than that of all-atom molecular dynamics simulation because of the reduction of the degrees of freedom. The coarse-grained model is a good template for studying cardiac thin filament mutations that cause FHC, and reduces the cost of computational resources.

[Cardiac failure in endocrine diseases].

PubMed

Hashizume, K

1993-05-01

Several endocrine diseases show the symptoms of cardiac failure. Among them, patients with acromegaly show a specific cardiomyopathy which results in a severe left-sided cardiac failure. Hypoparathyroidism also induces cardiac failure, which is resulted from hypocalcemia and low levels of serum parathyroid hormone. In the cases of hypothyroidism, the patients with myxedemal coma show a severe cardiac failure, which is characterized by disturbance of central nervous system, renal function, and cardiac function. In the patients with thyroid crisis (storm), the cardiac failure comes from the great reduction of cardiac output with dehydration. The reduction of circulation volume, observed in the patients with pheochromocytoma easily induces cardiac failure (shock) just after the removal of adrenal tumor. In patients with malignant carcinoid syndrome, right-sided ventricular failure which may be occurred through the actions of biogenic amines is observed.

Cardiac Aging - Benefits of Exercise, Nrf2 Activation and Antioxidant Signaling.

PubMed

Narasimhan, Madhusudhanan; Rajasekaran, Namakkal-Soorappan

2017-01-01

Cardiovascular dysfunction and heart failure associated with aging not only impairs the cardiac function but also the quality of life eventually decreasing the life expectancy of the elderly. Notably, cardiac tissue can prematurely age under certain conditions such as genetic mutation, persistent redox stress and overload, aberrant molecular signaling, DNA damage, telomere attrition, and other pathological insults. While cardiovascular-related morbidity and mortality is on the rise and remains a global health threat, there has been only little to moderate improvements in its medical management. This is due to the fact that the lifestyle changes to molecular mechanisms underlying age-related myocardial structure and functional remodeling are multifactorial and intricately operate at different levels. Along these lines, the intrinsic redox mechanisms and oxidative stress (OS) are widely studied in the myocardium. The accumulation of reactive oxygen species (ROS) with age and the resultant oxidative damage has been shown to increase the susceptibility of the myocardium to multiple complications such as atherosclerosis, hypertension, ischemic heart disease, cardiac myopathy, and heart failure. There has been growing interest in trying to enhance the mechanisms that neutralize the ROS and curtailing OS as a possible anti-aging intervention and as a treatment for age-related disorders. Natural defense system to fight against OS involves a master transcription factor named nuclear erythroid-2-p45-related factor-2 (Nrf2) that regulates several antioxidant genes. Compelling evidence exists on the Nrf2 gain of function through pharmacological interventions in counteracting the oxidative damage and affords cytoprotection in several organs including but not limited to lung, liver, kidney, brain, etc. Nevertheless, thus far, only a few studies have described the potential role of Nrf2 and its non-pharmacological induction in cardiac aging. This chapter explores the effects of

Thermal adaptation of the crucian carp (Carassius carassius) cardiac delayed rectifier current, IKs, by homomeric assembly of Kv7.1 subunits without MinK.

PubMed

Hassinen, Minna; Laulaja, Salla; Paajanen, Vesa; Haverinen, Jaakko; Vornanen, Matti

2011-07-01

Ectothermic vertebrates experience acute and chronic temperature changes which affect cardiac excitability and may threaten electrical stability of the heart. Nevertheless, ectothermic hearts function over wide range of temperatures without cardiac arrhythmias, probably due to special molecular adaptations. We examine function and molecular basis of the slow delayed rectifier K(+) current (I(Ks)) in cardiac myocytes of a eurythermic fish (Carassius carassius L.). I(Ks) is an important repolarizing current that prevents excessive prolongation of cardiac action potential, but it is extremely slowly activating when expressed in typical molecular composition of the endothermic animals. Comparison of the I(Ks) of the crucian carp atrial myocytes with the currents produced by homomeric K(v)7.1 and heteromeric K(v)7.1/MinK channels in Chinese hamster ovary cells indicates that activation kinetics and pharmacological properties of the I(Ks) are similar to those of the homomeric K(v)7.1 channels. Consistently with electrophysiological properties and homomeric K(v)7.1 channel composition, atrial transcript expression of the MinK subunit is only 1.6-1.9% of the expression level of the K(v)7.1 subunit. Since activation kinetics of the homomeric K(v)7.1 channels is much faster than activation of the heteromeric K(v)7.1/MinK channels, the homomeric K(v)7.1 composition of the crucian carp cardiac I(Ks) is thermally adaptive: the slow delayed rectifier channels can open despite low body temperatures and curtail the duration of cardiac action potential in ectothermic crucian carp. We suggest that the homomeric K(v)7.1 channel assembly is an evolutionary thermal adaptation of ectothermic hearts and the heteromeric K(v)7.1/MinK channels evolved later to adapt I(Ks) to high body temperature of endotherms.

Genetic analysis of sudden cardiac death victims: a survey of current forensic autopsy practices.

PubMed

Michaud, Katarzyna; Mangin, Patrice; Elger, Bernice S

2011-05-01

Autopsy-negative sudden cardiac deaths (SCD) seen in forensic practice are most often thought to be the result of sudden arrhythmic death syndrome. Postmortem genetic analysis is recommended in such cases, but is currently performed in only a few academic centers. In order to determine actual current practice, an on-line questionnaire was sent by e-mail to members of various forensic medical associations. The questions addressed routine procedures employed in cases of sudden cardiac death (autopsy ordering, macroscopic and microscopic cardiac examination, conduction tissue examination, immunohistochemistry and electron microscopy, biochemical markers, sampling and storage of material for genetic analyses, toxicological analyses, and molecular autopsy). Some questions concerned the legal and ethical aspects of genetic analyses in postmortem examinations, as well as any existing multidisciplinary collaborations in SCD cases. There were 97 respondents, mostly from European countries. Genetic testing in cases of sudden cardiac death is rarely practiced in routine forensic investigation. Approximately 60% of respondents reported not having the means to perform genetic postmortem testing and 40% do not collect adequate material to perform these investigations at a later date, despite working at university hospitals. The survey demonstrated that many of the problems involved in the adequate investigation of SCD cases are often financial in origin, due to the fact that activities in forensic medicine are often paid by and dependent on the judicial authorities. Problems also exist concerning the contact with family members and/or the family doctor, as well as the often-nonexistent collaboration with others clinicians with special expertise beneficial in the investigation of SCD cases, such as cardiologists and geneticists. This study highlights the importance in establishing guidelines for molecular autopsies in forensic medicine.

Characterization of Epicardial-Derived Cardiac Interstitial Cells: Differentiation and Mobilization of Heart Fibroblast Progenitors

PubMed Central

Ehrbar, Martin; Pérez-Pomares, José M.

2013-01-01

The non-muscular cells that populate the space found between cardiomyocyte fibers are known as ‘cardiac interstitial cells’ (CICs). CICs are heterogeneous in nature and include different cardiac progenitor/stem cells, cardiac fibroblasts and other cell types. Upon heart damage CICs soon respond by initiating a reparative response that transforms with time into extensive fibrosis and heart failure. Despite the biomedical relevance of CICs, controversy remains on the ontogenetic relationship existing between the different cell kinds homing at the cardiac interstitium, as well as on the molecular signals that regulate their differentiation, maturation, mutual interaction and role in adult cardiac homeostasis and disease. Our work focuses on the analysis of epicardial-derived cells, the first cell type that colonizes the cardiac interstitium. We present here a characterization and an experimental analysis of the differentiation potential and mobilization properties of a new cell line derived from mouse embryonic epicardium (EPIC). Our results indicate that these cells express some markers associated with cardiovascular stemness and retain part of the multipotent properties of embryonic epicardial derivatives, spontaneously differentiating into smooth muscle, and fibroblast/myofibroblast-like cells. Epicardium-derived cells are also shown to initiate a characteristic response to different growth factors, to display a characteristic proteolytic expression profile and to degrade biological matrices in 3D in vitro assays. Taken together, these data indicate that EPICs are relevant to the analysis of epicardial-derived CICs, and are a god model for the research on cardiac fibroblasts and the role these cells play in ventricular remodeling in both ischemic or non/ischemic myocardial disease. PMID:23349729

Role of the Lebanese family caregivers in cardiac self-care: a collective approach.

PubMed

Dumit, Nuhad Y; Abboud, Sarah; Massouh, Angela; Magilvy, Joan K

2015-11-01

The purpose of this study was to explore perceptions of cardiac self-care among Lebanese family caregivers of cardiac patients. The specific aims were to describe the cultural context of cardiac care-giving in Lebanon and to explore the roles of family caregivers in enhancing self-care practices in patients with cardiac diseases. The role of family caregivers in Lebanon, a country in the Middle East, is assumed to extend beyond care-giving to making decisions on behalf of the patient and assuming responsibility for patient care. To date, there has been no study done to empirically validate this impression. The design of the study is qualitative descriptive that used semi-structured individual interviews with family caregivers of Lebanese cardiac patients. Thirteen family caregivers of cardiac patients were recruited from a referral medical centre in Lebanon. The participants were designated by their patients and interviewed in a place of their choice. One overarching and three themes emerged from data analysis describing roles of family care givers in cardiac self-care. The overarching theme was: Family caregivers of Lebanese cardiac patients were unfamiliar with the term, concept and meaning of Self-Care. The moral and emotional duty to care for the family member stemmed from obligation and responsibility towards patients (theme I). Interdependent care (theme II) between cardiac patients and their families emerged as a significant cultural role. Family members play multiple supportive roles in care-giving namely emotional, informational and instrumental role (theme III). In this study, family caregiver role is shown to be based in the sense of obligation and duty towards the sick family member who collectively provide different types of supportive care. Nurses have to give significant importance to the family caregiver role as an integral part of any culturally sensitive patient/family intervention. © 2015 John Wiley & Sons Ltd.

Cardiac c-Kit Biology Revealed by Inducible Transgenesis.

PubMed

Gude, Natalie A; Firouzi, Fareheh; Broughton, Kathleen M; Ilves, Kelli; Nguyen, Kristine P; Payne, Christina R; Sacchi, Veronica; Monsanto, Megan M; Casillas, Alexandria R; Khalafalla, Farid G; Wang, Bingyan J; Ebeid, David E; Alvarez, Roberto; Dembitsky, Walter P; Bailey, Barbara A; van Berlo, Jop; Sussman, Mark A

2018-06-22

Biological significance of c-Kit as a cardiac stem cell marker and role(s) of c-Kit+ cells in myocardial development or response to pathological injury remain unresolved because of varied and discrepant findings. Alternative experimental models are required to contextualize and reconcile discordant published observations of cardiac c-Kit myocardial biology and provide meaningful insights regarding clinical relevance of c-Kit signaling for translational cell therapy. The main objectives of this study are as follows: demonstrating c-Kit myocardial biology through combined studies of both human and murine cardiac cells; advancing understanding of c-Kit myocardial biology through creation and characterization of a novel, inducible transgenic c-Kit reporter mouse model that overcomes limitations inherent to knock-in reporter models; and providing perspective to reconcile disparate viewpoints on c-Kit biology in the myocardium. In vitro studies confirm a critical role for c-Kit signaling in both cardiomyocytes and cardiac stem cells. Activation of c-Kit receptor promotes cell survival and proliferation in stem cells and cardiomyocytes of either human or murine origin. For creation of the mouse model, the cloned mouse c-Kit promoter drives Histone2B-EGFP (enhanced green fluorescent protein; H2BEGFP) expression in a doxycycline-inducible transgenic reporter line. The combination of c-Kit transgenesis coupled to H2BEGFP readout provides sensitive, specific, inducible, and persistent tracking of c-Kit promoter activation. Tagging efficiency for EGFP+/c-Kit+ cells is similar between our transgenic versus a c-Kit knock-in mouse line, but frequency of c-Kit+ cells in cardiac tissue from the knock-in model is 55% lower than that from our transgenic line. The c-Kit transgenic reporter model reveals intimate association of c-Kit expression with adult myocardial biology. Both cardiac stem cells and a subpopulation of cardiomyocytes express c-Kit in uninjured adult heart

The ACTA PORT-score for predicting perioperative risk of blood transfusion for adult cardiac surgery.

PubMed

Klein, A A; Collier, T; Yeates, J; Miles, L F; Fletcher, S N; Evans, C; Richards, T

2017-09-01

A simple and accurate scoring system to predict risk of transfusion for patients undergoing cardiac surgery is lacking. We identified independent risk factors associated with transfusion by performing univariate analysis, followed by logistic regression. We then simplified the score to an integer-based system and tested it using the area under the receiver operator characteristic (AUC) statistic with a Hosmer-Lemeshow goodness-of-fit test. Finally, the scoring system was applied to the external validation dataset and the same statistical methods applied to test the accuracy of the ACTA-PORT score. Several factors were independently associated with risk of transfusion, including age, sex, body surface area, logistic EuroSCORE, preoperative haemoglobin and creatinine, and type of surgery. In our primary dataset, the score accurately predicted risk of perioperative transfusion in cardiac surgery patients with an AUC of 0.76. The external validation confirmed accuracy of the scoring method with an AUC of 0.84 and good agreement across all scores, with a minor tendency to under-estimate transfusion risk in very high-risk patients. The ACTA-PORT score is a reliable, validated tool for predicting risk of transfusion for patients undergoing cardiac surgery. This and other scores can be used in research studies for risk adjustment when assessing outcomes, and might also be incorporated into a Patient Blood Management programme. © The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Clinical usefulness of the definitions for defining characteristics of activity intolerance, excess fluid volume and decreased cardiac output in decompensated heart failure: a descriptive exploratory study.

PubMed

de Souza, Vanessa; Zeitoun, Sandra Salloum; Lopes, Camila Takao; de Oliveira, Ana Paula Dias; Lopes, Juliana de Lima; de Barros, Alba Lucia Bottura Leite

2015-09-01

To assess the clinical usefulness of the operational definitions for the defining characteristics of the NANDA International nursing diagnoses, activity intolerance, decreased cardiac output and excess fluid volume, and the concomitant presence of those diagnoses in patients with decompensated heart failure. Content validity of the operational definitions for the defining characteristics of activity intolerance, excess fluid volume and decreased cardiac output have been previously validated by experts. Their clinical usefulness requires clinical validation. This was a descriptive exploratory study. Two expert nurses independently assessed 25 patients with decompensated heart failure for the presence or absence of 29 defining characteristics. Interrater reliability was analysed using the Kappa coefficient as a measure of clinical usefulness. The Fisher's exact test was used to test the association of the defining characteristics of activity intolerance and excess fluid volume in the presence of decreased cardiac output, and the correlation between the three diagnoses. Assessments regarding the presence of all defining characteristics reached 100% agreement, except with anxiety. Five defining characteristics of excess fluid volume were significantly associated with the presence of decreased cardiac output. Concomitant presence of the three diagnoses occurred in 80% of the patients. However, there was no significant correlation between the three diagnoses. The operational definitions for the diagnoses had strong interrater reliability, therefore they were considered clinically useful. Only five defining characteristics were representative of the association between excess fluid volume and decreased cardiac output. Therefore, excess fluid volume is related to decreased cardiac output, although these diagnoses are not necessarily associated with activity intolerance. The operational definitions may favour early recognition of the sequence of responses to decompensation

A simplified method for identification of human cardiac myosin heavy-chain isoforms.

PubMed

Piao, Shengfu; Yu, Fushun; Mihm, Michael J; Reiser, Peter J; McCarthy, Patrick M; Van Wagoner, David R; Bauer, John Anthony

2003-02-01

Cardiac myosin is a central participant in the cross-bridge cycling that mediates myocyte contraction and consists of multiple subunits that mediate both hydrolysis of ATP and mechanical production of contractile force Two isoforms of myosin heavy chain (MHC- alpha and MHC- beta ) are known to exist in mammalian cardiac tissue, and it is within this myosin subunit that ATPase activity resides. These isoforms differ by less than 0.2% in total molecular mass and amino acid sequence, but, strikingly, influence the rate and efficiency of energy utilization for generation of contractile force. Changes in the MHC- alpha /MHC- beta ratio has been classically viewed as an adaptation of a failing myocyte in both animal models and humans; however, their measurement has traditionally required specialized preparations and materials for sufficient resolution. Here we describe a greatly simplified method for routine assessments of myosin isoform composition in human cardiac tissues. The primary advantages of our approach include higher throughput and reduced supply costs with no apparent loss of statistical power, reproducibility or achieved results. Use of this more convenient method may provide enhanced access to an otherwise specialized technique and could provide additional opportunity for investigation of cardiac myocyte adaptive changes.

Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration

PubMed Central

Wang, ER; Jarrah, AA; Benard, L; Chen, J; Schwarzkopf, M; Hadri, L; Tarzami, ST

2014-01-01

Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its down stream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases while fibrosis increases. Additionally, CXCR4 expression was rescued with the use of cardiotropic Adeno-associated viral-9 (AAV9) vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo. PMID:24646609

Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology.

PubMed

Wu, Wei; Sanguinetti, Michael C

2016-06-01

Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity. Copyright © 2016 Elsevier Inc. All rights reserved.

Neurological Complications of Cardiac Disease.

PubMed

Madan, Nandini; Carvalho, Karen S

2017-02-01

This article focuses on the complex interactions between the cardiovascular and neurologic systems. Initially, we focus on neurological complications in children with congenital heart disease both secondary to the underlying cardiac disease and complications of interventions. We later discuss diagnosis and management of common syncope syndromes with emphasis on vasovagal syncope. We also review the diagnosis, classification, and management of children and adolescents with postural orthostatic tachycardia syndrome. Lastly, we discuss long QT syndrome and sudden unexpected death in epilepsy (SUDEP), reviewing advances in genetics and current knowledge of pathophysiology of these conditions. This article attempts to provide an overview of these disorders with focus on pathophysiology, advances in molecular genetics, and current medical interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

PREVALENCE OF POST-THROMBOTIC SYNDROME AFTER CARDIAC CATHETERIZATION

PubMed Central

Luceri, Michael J.; Tala, Joana A.; Weismann, Constance G.; Silva, Cicero T.; Faustino, E. Vincent S.

2015-01-01

BACKGROUND As the survival of children with cardiac disease increases, chronic complications of deep venous thrombosis from cardiac catheterization, particularly post-thrombotic syndrome, may be important to monitor for and treat, if needed. We aimed to determine the prevalence of this syndrome in children who underwent cardiac catheterization. PROCEDURE We conducted a cross-sectional study of children <18 years old at least 1 year from first catheterization through the femoral vein. We used the Manco-Johnson instrument, the only tool validated in children, to diagnose post-thrombotic syndrome. We defined the syndrome as a score ≥1. It was considered physically and functionally significant if the score was ≥1 in both physical and functional domains of the instrument. We also conducted ultrasonography to assess for thrombosis and valvular insufficiency. RESULTS We enrolled 62 children with a median age of 4 months during catheterization and a median of 5.4 years since catheterization. A total of 40 children had post-thrombotic syndrome (prevalence: 64.5%; 95% confidence interval: 51.3%–76.3%), the majority of which were mild. Presence of cyanotic congenital heart disease, total number of catheterizations, use of antithrombotic agents at any time after the first catheterization, age at first catheterization, or time since first catheterization was not associated with the syndrome. A total of 7 children (prevalence: 11.3%; 95% confidence interval: 3.2%–19.4%) had physically and functionally significant syndrome. None of the children had abnormalities on ultrasonography at the time of enrollment. CONCLUSIONS Post-thrombotic syndrome is a common complication after cardiac catheterization. Manifestations are usually mild and unlikely to require treatment. PMID:25663038

The cost-effectiveness of cardiac computed tomography for patients with stable chest pain.

PubMed

Agus, A M; McKavanagh, P; Lusk, L; Verghis, R M; Walls, G M; Ball, P A; Trinick, T R; Harbinson, M T; Donnelly, P M

2016-03-01

To assess the cost-effectiveness of cardiac CT compared with exercise stress testing (EST) in improving the health-related quality of life of patients with stable chest pain. A cost-utility analysis alongside a single-centre randomised controlled trial carried out in Northern Ireland. Patients with stable chest pain were randomised to undergo either cardiac CT assessment or EST (standard care). The main outcome measure was cost per quality adjusted life year (QALY) gained at 1 year. Of the 500 patients recruited, 250 were randomised to cardiac CT and 250 were randomised to EST. Cardiac CT was the dominant strategy as it was both less costly (incremental total costs -£50.45; 95% CI -£672.26 to £571.36) and more effective (incremental QALYs 0.02; 95% CI -0.02 to 0.05) than EST. At a willingness-to-pay threshold of £20 000 per QALY the probability of cardiac CT being cost-effective was 83%. Subgroup analyses indicated that cardiac CT appears to be most cost-effective in patients with a likelihood of coronary artery disease (CAD) of <30%, followed by 30%-60% and then >60%. Cardiac CT is cost-effective compared with EST and cost-effectiveness was observed to vary with likelihood of CAD. This finding could have major implications for how patients with chest pain in the UK are assessed, however it would need to be validated in other healthcare systems. (ISRCTN52480460); 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/

Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis.

PubMed

Treibel, Thomas A; Bandula, Steve; Fontana, Marianna; White, Steven K; Gilbertson, Janet A; Herrey, Anna S; Gillmore, Julian D; Punwani, Shonit; Hawkins, Philip N; Taylor, Stuart A; Moon, James C

2015-01-01

Cardiac involvement determines outcome in patients with systemic amyloidosis. There is major unmet need for quantification of cardiac amyloid burden, which is currently only met in part through semi-quantitative bone scintigraphy or Cardiovascular Magnetic Resonance (CMR), which measures ECVCMR. Other accessible tests are needed. To develop cardiac computed tomography to diagnose and quantify cardiac amyloidosis by measuring the myocardial Extracellular Volume, ECVCT. Twenty-six patients (21 male, 64 ± 14 years) with a biopsy-proven systemic amyloidosis (ATTR n = 18; AL n = 8) were compared with twenty-seven patients (19 male, 68 ± 8 years) with severe aortic stenosis (AS). All patients had undergone echocardiography, bone scintigraphy, NT-pro-BNP measurement and EQ-CMR. Dynamic Equilibrium CT (DynEQ-CT) was performed using a prospectively gated cardiac scan prior to and after (5 and 15 minutes) a standard Iodixanol (1 ml/kg) bolus to measure ECVCT. ECVCT was compared to the reference ECVCMR and conventional amyloid measures: bone scintigraphy and clinical markers of cardiac amyloid severity (NT-pro-BNP, Troponin, LVEF, LV mass, LA and RA area). ECVCT and ECVCMR results were well correlated (r(2) = 0.85 vs r(2) = 0.74 for 5 and 15 minutes post bolus respectively). ECVCT was higher in amyloidosis than AS (0.54 ± 0.11 vs 0.28 ± 0.04, p<0.001) with no overlap. ECVCT tracked clinical markers of cardiac amyloid severity (NT-pro-BNP, Troponin, LVEF, LV mass, LA and RA area), and bone scintigraphy amyloid burden (p<0.001). Dynamic Equilibrium CT, a 5 minute contrast-enhanced gated cardiac CT, has potential for non-invasive diagnosis and quantification of cardiac amyloidosis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis

PubMed Central

Treibel, Thomas A.; Bandula, Steve; Fontana, Marianna; White, Steven K.; Gilbertson, Janet A.; Herrey, Anna S.; Gillmore, Julian D.; Punwani, Shonit; Hawkins, Philip N.; Taylor, Stuart A.; Moon, James C.

2015-01-01

Background Cardiac involvement determines outcome in patients with systemic amyloidosis. There is major unmet need for quantification of cardiac amyloid burden, which is currently only met in part through semi-quantitative bone scintigraphy or Cardiovascular Magnetic Resonance (CMR), which measures ECVCMR. Other accessible tests are needed. Objectives To develop cardiac computed tomography to diagnose and quantify cardiac amyloidosis by measuring the myocardial Extracellular Volume, ECVCT. Methods Twenty-six patients (21 male, 64 ± 14 years) with a biopsy-proven systemic amyloidosis (ATTR n = 18; AL n = 8) were compared with twenty-seven patients (19 male, 68 ± 8 years) with severe aortic stenosis (AS). All patients had undergone echocardiography, bone scintigraphy, NT-pro-BNP measurement and EQ-CMR. Dynamic Equilibrium CT (DynEQ-CT) was performed using a prospectively gated cardiac scan prior to and after (5 and 15 minutes) a standard Iodixanol (1 ml/kg) bolus to measure ECVCT. ECVCT was compared to the reference ECVCMR and conventional amyloid measures: bone scintigraphy and clinical markers of cardiac amyloid severity (NT-pro-BNP, Troponin, LVEF, LV mass, LA and RA area). Results ECVCT and ECVCMR results were well correlated (r2 = 0.85 vs r2 = 0.74 for 5 and 15 minutes post bolus respectively). ECVCT was higher in amyloidosis than AS (0.54 ± 0.11 vs 0.28 ± 0.04, p<0.001) with no overlap. ECVCT tracked clinical markers of cardiac amyloid severity (NT-pro-BNP, Troponin, LVEF, LV mass, LA and RA area), and bone scintigraphy amyloid burden (p<0.001). Conclusion Dynamic Equilibrium CT, a 5 minute contrast-enhanced gated cardiac CT, has potential for non-invasive diagnosis and quantification of cardiac amyloidosis. PMID:26209459

Functional TRPV2 and TRPV4 channels in human cardiac c-kit(+) progenitor cells.

PubMed

Che, Hui; Xiao, Guo-Sheng; Sun, Hai-Ying; Wang, Yan; Li, Gui-Rong

2016-06-01

The cellular physiology and biology of human cardiac c-kit(+) progenitor cells has not been extensively characterized and remains an area of active research. This study investigates the functional expression of transient receptor potential vanilloid (TRPV) and possible roles for this ion channel in regulating proliferation and migration of human cardiac c-kit(+) progenitor cells. We found that genes coding for TRPV2 and TRPV4 channels and their proteins are significantly expressed in human c-kit(+) cardiac stem cells. Probenecid, an activator of TRPV2, induced an increase in intracellular Ca(2+) (Ca(2+) i ), an effect that may be attenuated or abolished by the TRPV2 blocker ruthenium red. The TRPV4 channel activator 4α-phorbol 12-13-dicaprinate induced Ca(2+) i oscillations, which can be inhibited by the TRPV4 blocker RN-1734. The alteration of Ca(2+) i by probenecid or 4α-phorbol 12-13-dicprinate was dramatically inhibited in cells infected with TRPV2 short hairpin RNA (shRNA) or TRPV4 shRNA. Silencing TRPV2, but not TRPV4, significantly reduced cell proliferation by arresting cells at the G0/G1 boundary of the cell cycle. Cell migration was reduced by silencing TRPV2 or TRPV4. Western blot revealed that silencing TRPV2 decreased expression of cyclin D1, cyclin E, pERK1/2 and pAkt, whereas silencing TRPV4 only reduced pAkt expression. Our results demonstrate for the first time that functional TRPV2 and TRPV4 channels are abundantly expressed in human cardiac c-kit(+) progenitor cells. TRPV2 channels, but not TRPV4 channels, participate in regulating cell cycle progression; moreover, both TRPV2 and TRPV4 are involved in migration of human cardiac c-kit(+) progenitor cells. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Recurrent myocardial infarction: Mechanisms of free-floating adaptation and autonomic derangement in networked cardiac neural control.

PubMed

Kember, Guy; Ardell, Jeffrey L; Shivkumar, Kalyanam; Armour, J Andrew

2017-01-01

The cardiac nervous system continuously controls cardiac function whether or not pathology is present. While myocardial infarction typically has a major and catastrophic impact, population studies have shown that longer-term risk for recurrent myocardial infarction and the related potential for sudden cardiac death depends mainly upon standard atherosclerotic variables and autonomic nervous system maladaptations. Investigative neurocardiology has demonstrated that autonomic control of cardiac function includes local circuit neurons for networked control within the peripheral nervous system. The structural and adaptive characteristics of such networked interactions define the dynamics and a new normal for cardiac control that results in the aftermath of recurrent myocardial infarction and/or unstable angina that may or may not precipitate autonomic derangement. These features are explored here via a mathematical model of cardiac regulation. A main observation is that the control environment during pathology is an extrapolation to a setting outside prior experience. Although global bounds guarantee stability, the resulting closed-loop dynamics exhibited while the network adapts during pathology are aptly described as 'free-floating' in order to emphasize their dependence upon details of the network structure. The totality of the results provide a mechanistic reasoning that validates the clinical practice of reducing sympathetic efferent neuronal tone while aggressively targeting autonomic derangement in the treatment of ischemic heart disease.

A multimodal spatiotemporal cardiac motion atlas from MR and ultrasound data.

PubMed

Puyol-Antón, Esther; Sinclair, Matthew; Gerber, Bernhard; Amzulescu, Mihaela Silvia; Langet, Hélène; Craene, Mathieu De; Aljabar, Paul; Piro, Paolo; King, Andrew P

2017-08-01

Cardiac motion atlases provide a space of reference in which the motions of a cohort of subjects can be directly compared. Motion atlases can be used to learn descriptors that are linked to different pathologies and which can subsequently be used for diagnosis. To date, all such atlases have been formed and applied using data from the same modality. In this work we propose a framework to build a multimodal cardiac motion atlas from 3D magnetic resonance (MR) and 3D ultrasound (US) data. Such an atlas will benefit from the complementary motion features derived from the two modalities, and furthermore, it could be applied in clinics to detect cardiovascular disease using US data alone. The processing pipeline for the formation of the multimodal motion atlas initially involves spatial and temporal normalisation of subjects' cardiac geometry and motion. This step was accomplished following a similar pipeline to that proposed for single modality atlas formation. The main novelty of this paper lies in the use of a multi-view algorithm to simultaneously reduce the dimensionality of both the MR and US derived motion data in order to find a common space between both modalities to model their variability. Three different dimensionality reduction algorithms were investigated: principal component analysis, canonical correlation analysis and partial least squares regression (PLS). A leave-one-out cross validation on a multimodal data set of 50 volunteers was employed to quantify the accuracy of the three algorithms. Results show that PLS resulted in the lowest errors, with a reconstruction error of less than 2.3 mm for MR-derived motion data, and less than 2.5  mm for US-derived motion data. In addition, 1000 subjects from the UK Biobank database were used to build a large scale monomodal data set for a systematic validation of the proposed algorithms. Our results demonstrate the feasibility of using US data alone to analyse cardiac function based on a multimodal motion atlas

β-Adrenergic Receptor-Mediated Cardiac Contractility is Inhibited via Vasopressin Type 1A-Receptor-Dependent Signaling

PubMed Central

Tilley, Douglas G.; Zhu, Weizhong; Myers, Valerie D.; Barr, Larry A.; Gao, Erhe; Li, Xue; Song, Jianliang; Carter, Rhonda L.; Makarewich, Catherine A.; Yu, Daohai; Troupes, Constantine D.; Grisanti, Laurel A.; Coleman, Ryan C.; Koch, Walter J.; Houser, Steven R.; Cheung, Joseph Y.; Feldman, Arthur M.

2014-01-01

Background Enhanced arginine vasopressin (AVP) levels are associated with increased mortality during end-stage human heart failure (HF), and cardiac AVP type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulated βAR responsiveness and in doing so contributes to HF development. Methods and Results Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca2+ mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/GRK-dependent manner. Conclusions This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated HF and elevated AVP. PMID:25205804

Improving validation methods for molecular diagnostics: application of Bland-Altman, Deming and simple linear regression analyses in assay comparison and evaluation for next-generation sequencing

PubMed Central

Misyura, Maksym; Sukhai, Mahadeo A; Kulasignam, Vathany; Zhang, Tong; Kamel-Reid, Suzanne; Stockley, Tracy L

2018-01-01

Aims A standard approach in test evaluation is to compare results of the assay in validation to results from previously validated methods. For quantitative molecular diagnostic assays, comparison of test values is often performed using simple linear regression and the coefficient of determination (R2), using R2 as the primary metric of assay agreement. However, the use of R2 alone does not adequately quantify constant or proportional errors required for optimal test evaluation. More extensive statistical approaches, such as Bland-Altman and expanded interpretation of linear regression methods, can be used to more thoroughly compare data from quantitative molecular assays. Methods We present the application of Bland-Altman and linear regression statistical methods to evaluate quantitative outputs from next-generation sequencing assays (NGS). NGS-derived data sets from assay validation experiments were used to demonstrate the utility of the statistical methods. Results Both Bland-Altman and linear regression were able to detect the presence and magnitude of constant and proportional error in quantitative values of NGS data. Deming linear regression was used in the context of assay comparison studies, while simple linear regression was used to analyse serial dilution data. Bland-Altman statistical approach was also adapted to quantify assay accuracy, including constant and proportional errors, and precision where theoretical and empirical values were known. Conclusions The complementary application of the statistical methods described in this manuscript enables more extensive evaluation of performance characteristics of quantitative molecular assays, prior to implementation in the clinical molecular laboratory. PMID:28747393

Cardiac Autonomic Balance vs. Cardiac Regulatory Capacity

PubMed Central

Berntson, Gary G.; Norman, Greg J.; Hawkley, Louise C.; Cacioppo, John T.

2013-01-01

The concept of autonomic balance views autonomic states along a bipolar continuum from sympathetic (S) to parasympathetic (P) dominance, whereas regulatory capacity models emphasize overall autonomic flexibility as a marker of the capacity for regulation. These two concepts were evaluated for their utility in characterizing patterns of autonomic control. Measures of P (high frequency heart rate variability, HF) and S (pre-ejection period, PEP) cardiac control were obtained. A measure of cardiac autonomic balance (CAB) was derived as the difference in the normalized P index minus the S index, and a measure of cardiac autonomic regulation (CAR) was derived as the normalized P index plus the S index. Results reveal that CAR, but not CAB, was a significant predictor of the prior occurrence of a myocardial infarction, net of demographic and other variables, whereas CAB, but not CAR, was a significant predictor of concurrent diabetes. PMID:18282204

ERBB2 Deficiency Alters an E2F-1-Dependent Adaptive Stress Response and Leads to Cardiac Dysfunction

PubMed Central

Perry, Marie-Claude; Dufour, Catherine R.; Eichner, Lillian J.; Tsang, David W. K.; Deblois, Geneviève; Muller, William J.

2014-01-01

The tyrosine kinase receptor ERBB2 is required for normal development of the heart and is a potent oncogene in breast epithelium. Trastuzumab, a monoclonal antibody targeting ERBB2, improves the survival of breast cancer patients, but cardiac dysfunction is a major side effect of the drug. The molecular mechanisms underlying how ERBB2 regulates cardiac function and why trastuzumab is cardiotoxic remain poorly understood. We show here that ERBB2 hypomorphic mice develop cardiac dysfunction that mimics the side effects observed in patients treated with trastuzumab. We demonstrate that this phenotype is related to the critical role played by ERBB2 in cardiac homeostasis and physiological hypertrophy. Importantly, genetic and therapeutic reduction of ERBB2 activity in mice, as well as ablation of ERBB2 signaling by trastuzumab or siRNAs in human cardiomyocytes, led to the identification of an impaired E2F-1-dependent genetic program critical for the cardiac adaptive stress response. These findings demonstrate the existence of a previously unknown mechanistic link between ERBB2 and E2F-1 transcriptional activity in heart physiology and trastuzumab-induced cardiac dysfunction. PMID:25246633

The effect of Cardiac Arrhythmias Simulation Software on the nurses' learning and professional development.

PubMed

Bazrafkan, Leila; Hemmati, Mehdi

2018-04-01

One of the important tasks of nurses in intensive care unit is interpretation of ECG. The use of training simulator is a new paradigm in the age of computers. This study was performed to evaluate the impact of cardiac arrhythmias simulator software on nurses' learning in the subspecialty Vali-Asr Hospital in 2016. This study was conducted by quasi-experimental randomized Salomon four group design with the participation of 120 nurses in subspecialty Vali-Asr Hospital in Tehran, Iran in 2016 that were selected purposefully and allocated in 4 groups. By this design other confounding factors such as the prior information, maturation and the role of sex and age were controlled by Solomon 4 design. The valid and reliable multiple choice test tools were used to gather information; the validity of the test was approved by experts and its reliability was obtained by Cronbach's alpha coefficient 0.89. At first, the knowledge and skills of the participants were assessed by a pre-test; following the educational intervention with cardiac arrhythmias simulator software during 14 days in ICUs, the mentioned factors were measured for the two groups again by a post-test in the four groups. Data were analyzed using the two way ANOVA. The significance level was considered as p<0.05. Based on randomized four-group Solomon designs and our test results, using cardiac arrhythmias simulator software as an intervention was effective in the nurses' learning since a significant difference was found between pre-test and post-test in the first group (p<0.05). Also, other comparisons by ANOVA test showed that there was no interaction between pre-test and intervention in all of the three knowledge areas of cardiac arrhythmias, their treatments and their diagnosis (P>0.05). The use of software-based simulator for cardiac arrhythmias was effective in nurses' learning in light of its attractive components and interactive method. This intervention increased the knowledge of the nurses in cognitive

Molecular simulation and experimental validation of resorcinol adsorption on Ordered Mesoporous Carbon (OMC).

PubMed

Ahmad, Zaki Uddin; Chao, Bing; Konggidinata, Mas Iwan; Lian, Qiyu; Zappi, Mark E; Gang, Daniel Dianchen

2018-04-27

Numerous research works have been devoted in the adsorption area using experimental approaches. All these approaches are based on trial and error process and extremely time consuming. Molecular simulation technique is a new tool that can be used to design and predict the performance of an adsorbent. This research proposed a simulation technique that can greatly reduce the time in designing the adsorbent. In this study, a new Rhombic ordered mesoporous carbon (OMC) model is proposed and constructed with various pore sizes and oxygen contents using Materials Visualizer Module to optimize the structure of OMC for resorcinol adsorption. The specific surface area, pore volume, small angle X-ray diffraction pattern, and resorcinol adsorption capacity were calculated by Forcite and Sorption module in Materials Studio Package. The simulation results were validated experimentally through synthesizing OMC with different pore sizes and oxygen contents prepared via hard template method employing SBA-15 silica scaffold. Boric acid was used as the pore expanding reagent to synthesize OMC with different pore sizes (from 4.6 to 11.3 nm) and varying oxygen contents (from 11.9% to 17.8%). Based on the simulation and experimental validation, the optimal pore size was found to be 6 nm for maximum adsorption of resorcinol. Copyright © 2018 Elsevier B.V. All rights reserved.

19-Hydroxyeicosatetraenoic acid and isoniazid protect against angiotensin II-induced cardiac hypertrophy

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

Elkhatali, Samya; El-Sherbeni, Ahmed A.; Elshenawy, Osama H.

We have recently demonstrated that 19-hydroxyeicosatetraenoic acid (19-HETE) is the major subterminal-HETE formed in the heart tissue, and its formation was decreased during cardiac hypertrophy. In the current study, we examined whether 19-HETE confers cardioprotection against angiotensin II (Ang II)-induced cardiac hypertrophy. The effect of Ang II, with and without 19-HETE (20 μM), on the development of cellular hypertrophy in cardiomyocyte RL-14 cells was assessed by real-time PCR. Also, cardiac hypertrophy was induced in Sprague–Dawley rats by Ang II, and the effect of increasing 19-HETE by isoniazid (INH; 200 mg/kg/day) was assessed by heart weight and echocardiography. Also, alterations inmore » cardiac cytochrome P450 (CYP) and their associated arachidonic acid (AA) metabolites were determined by real-time PCR, Western blotting and liquid-chromatography–mass-spectrometry. Our results demonstrated that 19-HETE conferred a cardioprotective effect against Ang II-induced cellular hypertrophy in vitro, as indicated by the significant reduction in β/α-myosin heavy chain ratio. In vivo, INH improved heart dimensions, and reversed the increase in heart weight to tibia length ratio caused by Ang II. We found a significant increase in cardiac 19-HETE, as well as a significant reduction in AA and its metabolite, 20-HETE. In conclusion, 19-HETE, incubated with cardiomyocytes in vitro or induced in the heart by INH in vivo, provides cardioprotection against Ang II-induced hypertrophy. This further confirms the role of CYP, and their associated AA metabolites in the development of cardiac hypertrophy. - Highlights: • We found 19-hydroxy arachidonic acid to protect cardiomyocytes from hypertrophy. • We validated the use of isoniazid as a cardiac 19-hydroxy arachidonic acid inducer. • We found isoniazid to increase protective and inhibit toxic eicosanoides. • We found isoniazid to protect against angiotensin-induced cardiac hypertrophy. • This will help

Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention.

PubMed

Goldman, Alica M; Behr, Elijah R; Semsarian, Christopher; Bagnall, Richard D; Sisodiya, Sanjay; Cooper, Paul N

2016-01-01

Epidemiologic studies clearly document the public health burden of sudden unexpected death in epilepsy (SUDEP). Clinical and experimental studies have uncovered dynamic cardiorespiratory dysfunction, both interictally and at the time of sudden death due to epilepsy. Genetic analyses in humans and in model systems have facilitated our current molecular understanding of SUDEP. Many discoveries have been informed by progress in the field of sudden cardiac death and sudden infant death syndrome. It is becoming apparent that SUDEP genomic complexity parallels that of sudden cardiac death, and that there is a pauci1ty of analytically useful postmortem material. Because many challenges remain, future progress in SUDEP research, molecular diagnostics, and prevention rests in international, collaborative, and transdisciplinary dialogue in human and experimental translational research of sudden death. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Role of plasma membrane-associated AKAPs for the regulation of cardiac IK1 current by protein kinase A.

PubMed

Seyler, Claudia; Scherer, Daniel; Köpple, Christoph; Kulzer, Martin; Korkmaz, Sevil; Xynogalos, Panagiotis; Thomas, Dierk; Kaya, Ziya; Scholz, Eberhard; Backs, Johannes; Karle, Christoph; Katus, Hugo A; Zitron, Edgar

2017-05-01

The cardiac I K1 current stabilizes the resting membrane potential of cardiomyocytes. Protein kinase A (PKA) induces an inhibition of I K1 current which strongly promotes focal arrhythmogenesis. The molecular mechanisms underlying this regulation have only partially been elucidated yet. Furthermore, the role of A-kinase anchoring proteins (AKAPs) in this regulation has not been examined to date. The objective of this project was to elucidate the molecular mechanisms underlying the inhibition of I K1 by PKA and to identify novel molecular targets for antiarrhythmic therapy downstream β-adrenoreceptors. Patch clamp and voltage clamp experiments were used to record currents and co-immunoprecipitation, and co-localization experiments were performed to show spatial and functional coupling. Activation of PKA inhibited I K1 current in rat cardiomyocytes. This regulation was markedly attenuated by disrupting PKA-binding to AKAPs with the peptide inhibitor AKAP-IS. We observed functional and spatial coupling of the plasma membrane-associated AKAP15 and AKAP79 to Kir2.1 and Kir2.2 channel subunits, but not to Kir2.3 channels. In contrast, AKAPyotiao had no functional effect on the PKA regulation of Kir channels. AKAP15 and AKAP79 co-immunoprecipitated with and co-localized to Kir2.1 and Kir2.2 channel subunits in ventricular cardiomyocytes. In this study, we provide evidence for coupling of cardiac Kir2.1 and Kir2.2 subunits with the plasma membrane-bound AKAPs 15 and 79. Cardiac membrane-associated AKAPs are a functionally essential part of the regulatory cascade determining I K1 current function and may be novel molecular targets for antiarrhythmic therapy downstream from β-adrenoreceptors.

Cardiac conduction system

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... cardiac muscle cells in the walls of the heart that send signals to the heart muscle causing it to contract. The main components ... the cardiac conduction system's electrical activity in the heart.

Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation.

PubMed

Ali, Shah R; Ranjbarvaziri, Sara; Talkhabi, Mahmood; Zhao, Peng; Subat, Ali; Hojjat, Armin; Kamran, Paniz; Müller, Antonia M S; Volz, Katharina S; Tang, Zhaoyi; Red-Horse, Kristy; Ardehali, Reza

2014-09-12

Fibrosis is mediated partly by extracellular matrix-depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. We showed that Thy1(+)CD45(-)CD31(-)CD11b(-)Ter119(-) cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response. © 2014 American Heart Association, Inc.

Association between a Hospital’s Rate of Cardiac Arrest Incidence and Cardiac Arrest Survival

PubMed Central

Chen, Lena M.; Nallamothu, Brahmajee K.; Spertus, John A.; Li, Yan; Chan, Paul S.

2014-01-01

Context National efforts to measure hospital performance for cardiac arrest have focused on case survival, with the hope of improving survival after cardiac arrest. However, it is plausible that hospitals with high case-survival rates do a poor job of preventing cardiac arrests in the first place. Objective To describe the association between inpatient cardiac arrest incidence and survival rates. Design, Setting, and Patients Within a large, national registry, we identified hospitals with at least 50 adult in-hospital cardiac arrest cases between January 1, 2000 and November 30, 2009. We used multivariable hierarchical regression to evaluate the correlation between a hospital’s cardiac arrest incidence rate and its case-survival rate after adjusting for patient and hospital characteristics. Main Outcome Measure The correlation between a hospital’s incidence rate and case-survival rate for cardiac arrest. Results Of 102,153 cases at 358 hospitals, the median hospital cardiac arrest incidence rate was 4.02 per 1000 admissions (IQR: 2.95 to 5.65 per 1000 admissions), and the median hospital case-survival rate was 18.8% (IQR: 14.5% to 22.6%). In crude analyses, hospitals with higher case-survival rates also had lower cardiac arrest incidence (correlation of -0.16; P=0.003). This relationship persisted after adjusting for patient characteristics (correlation of -0.15; P=0.004). After adjusting for potential mediators of this relationship (i.e., hospital characteristics), the relationship between incidence and case-survival was attenuated (correlation of -0.07; P=0.18). The one modifiable hospital factor that most attenuated this relationship was a hospital’s nurse-to-bed ratio (correlation of -0.12; P=0.03). Conclusions Hospitals with exceptional rates of survival for in-hospital cardiac arrest are also better at preventing cardiac arrests, even after adjusting for patient case-mix. This relationship is partially mediated by measured hospital attributes

Validation of the prognostic gene portfolio, ClinicoMolecular Triad Classification, using an independent prospective breast cancer cohort and external patient populations.

PubMed

Wang, Dong-Yu; Done, Susan J; Mc Cready, David R; Leong, Wey L

2014-07-04

Using genome-wide expression profiles of a prospective training cohort of breast cancer patients, ClinicoMolecular Triad Classification (CMTC) was recently developed to classify breast cancers into three clinically relevant groups to aid treatment decisions. CMTC was found to be both prognostic and predictive in a large external breast cancer cohort in that study. This study serves to validate the reproducibility of CMTC and its prognostic value using independent patient cohorts. An independent internal cohort (n = 284) and a new external cohort (n = 2,181) were used to validate the association of CMTC between clinicopathological factors, 12 known gene signatures, two molecular subtype classifiers, and 19 oncogenic signalling pathway activities, and to reproduce the abilities of CMTC to predict clinical outcomes of breast cancer. In addition, we also updated the outcome data of the original training cohort (n = 147). The original training cohort reached a statistically significant difference (p < 0.05) in disease-free survivals between the three CMTC groups after an additional two years of follow-up (median = 55 months). The prognostic value of the triad classification was reproduced in the second independent internal cohort and the new external validation cohort. CMTC achieved even higher prognostic significance when all available patients were analyzed (n = 4,851). Oncogenic pathways Myc, E2F1, Ras and β-catenin were again implicated in the high-risk groups. Both prospective internal cohorts and the independent external cohorts reproduced the triad classification of CMTC and its prognostic significance. CMTC is an independent prognostic predictor, and it outperformed 12 other known prognostic gene signatures, molecular subtype classifications, and all other standard prognostic clinicopathological factors. Our results support further development of CMTC portfolio into a guide for personalized breast cancer treatments.

Validation of the prognostic gene portfolio, ClinicoMolecular Triad Classification, using an independent prospective breast cancer cohort and external patient populations

PubMed Central

2014-01-01

Introduction Using genome-wide expression profiles of a prospective training cohort of breast cancer patients, ClinicoMolecular Triad Classification (CMTC) was recently developed to classify breast cancers into three clinically relevant groups to aid treatment decisions. CMTC was found to be both prognostic and predictive in a large external breast cancer cohort in that study. This study serves to validate the reproducibility of CMTC and its prognostic value using independent patient cohorts. Methods An independent internal cohort (n = 284) and a new external cohort (n = 2,181) were used to validate the association of CMTC between clinicopathological factors, 12 known gene signatures, two molecular subtype classifiers, and 19 oncogenic signalling pathway activities, and to reproduce the abilities of CMTC to predict clinical outcomes of breast cancer. In addition, we also updated the outcome data of the original training cohort (n = 147). Results The original training cohort reached a statistically significant difference (p < 0.05) in disease-free survivals between the three CMTC groups after an additional two years of follow-up (median = 55 months). The prognostic value of the triad classification was reproduced in the second independent internal cohort and the new external validation cohort. CMTC achieved even higher prognostic significance when all available patients were analyzed (n = 4,851). Oncogenic pathways Myc, E2F1, Ras and β-catenin were again implicated in the high-risk groups. Conclusions Both prospective internal cohorts and the independent external cohorts reproduced the triad classification of CMTC and its prognostic significance. CMTC is an independent prognostic predictor, and it outperformed 12 other known prognostic gene signatures, molecular subtype classifications, and all other standard prognostic clinicopathological factors. Our results support further development of CMTC portfolio into a guide for personalized breast cancer treatments. PMID

Empirical Refinements of a Molecular Genetics Learning Progression: The Molecular Constructs

ERIC Educational Resources Information Center

Todd, Amber; Kenyon, Lisa

2016-01-01

This article describes revisions to four of the eight constructs of the Duncan molecular genetics learning progression [Duncan, Rogat, & Yarden, (2009)]. As learning progressions remain hypothetical models until validated by multiple rounds of empirical studies, these revisions are an important step toward validating the progression. Our…

Management of Cardiac Involvement in NeuroMuscular Diseases: Review

PubMed Central

Bouhouch, Rachida; Elhouari, Tarik; Oukerraj, Latifa; Fellat, Ibtissam; Zarzur, Jamila; Bennani, Rajaa; Arharbi, Mhamed

2008-01-01

Neuromuscular Diseases are a heterogeneous molecular, clinical and prognosis group. Progress has been achieved in the understanding and classification of these diseases. Cardiac involvement in neuromuscular diseases namely conduction disorders, ventricular dilatation and dilated cardiomyopathy with its impact on prognosis, is often dissociated from the peripheral myopathy. Therefore, close surveillance is mandatory in the affected patients. In this context, preventive therapy (beta-blockers and angiotensin converting enzyme inhibitors) has been recently recommended in the most common Neuromuscular Diseases, Duchenne Muscular Dystrophy and Myotonic Dystrophy. PMID:19337361

Large-scale molecular dynamics simulation of DNA: implementation and validation of the AMBER98 force field in LAMMPS.

PubMed

Grindon, Christina; Harris, Sarah; Evans, Tom; Novik, Keir; Coveney, Peter; Laughton, Charles

2004-07-15

Molecular modelling played a central role in the discovery of the structure of DNA by Watson and Crick. Today, such modelling is done on computers: the more powerful these computers are, the more detailed and extensive can be the study of the dynamics of such biological macromolecules. To fully harness the power of modern massively parallel computers, however, we need to develop and deploy algorithms which can exploit the structure of such hardware. The Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) is a scalable molecular dynamics code including long-range Coulomb interactions, which has been specifically designed to function efficiently on parallel platforms. Here we describe the implementation of the AMBER98 force field in LAMMPS and its validation for molecular dynamics investigations of DNA structure and flexibility against the benchmark of results obtained with the long-established code AMBER6 (Assisted Model Building with Energy Refinement, version 6). Extended molecular dynamics simulations on the hydrated DNA dodecamer d(CTTTTGCAAAAG)(2), which has previously been the subject of extensive dynamical analysis using AMBER6, show that it is possible to obtain excellent agreement in terms of static, dynamic and thermodynamic parameters between AMBER6 and LAMMPS. In comparison with AMBER6, LAMMPS shows greatly improved scalability in massively parallel environments, opening up the possibility of efficient simulations of order-of-magnitude larger systems and/or for order-of-magnitude greater simulation times.

Comparative effects of torasemide and furosemide on gap junction proteins and cardiac fibrosis in a rat model of dilated cardiomyopathy.

PubMed

Watanabe, Kenichi; Sreedhar, Remya; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Giridharan, Vijayasree V; Antony, Shanish; Harima, Meilei; Nakamura, Masahiko; Suzuki, Kenji; Suzuki, Hiroshi; Sone, Hirohito; Arumugam, Somasundaram

2017-03-01

Cardiac fibrosis is the major hallmark of adverse cardiac remodeling in chronic heart failure (CHF) and its therapeutic targeting might help against cardiac dysfunction during chronic conditions. Diuretic agents are potentially useful in these cases, but their effects on the cardiac fibrosis pathogenesis are yet to be identified. This study was designed to identify and compare the effects of diuretic drugs torasemide and furosemide on cardiac fibrosis in a rat model of dilated cardiomyopathy induced by porcine cardiac myosin mediated experimental autoimmune myocarditis. Gap junction proteins, connexin-43 and N-cadherin, expressions were downregulated in the hearts of CHF rats, while torasemide treatment has upregulated their expression. Western blotting and immunohistochemical analysis for various cardiac fibrosis related proteins as well as histopathological studies have shown that both drugs have potential anti-fibrotic effects. Among them, torasemide has superior efficacy in offering protection against adverse cardiac remodeling in the selected rat model of dilated cardiomyopathy. In conclusion, torasemide treatment has potential anti-fibrotic effect in the hearts of CHF rats, possibly via improving the gap junction proteins expression and thereby improving the cell-cell interaction in the heart. © 2016 BioFactors, 43(2):187-194, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

Pathological presentation of cardiac mitochondria in a rat model for chronic kidney disease.

PubMed

Bigelman, Einat; Cohen, Lena; Aharon-Hananel, Genya; Levy, Ran; Rozenbaum, Zach; Saada, Ann; Keren, Gad; Entin-Meer, Michal

2018-01-01

cardiac hypertrophy. Chronic administration of ARB may improve the pathological appearance of the heart. Further recognition of the molecular pathways leading to mitochondrial insult and appropriate intervention is of crucial importance.

Role of the immune system in cardiac tissue damage and repair following myocardial infarction.

PubMed

Saparov, Arman; Ogay, Vyacheslav; Nurgozhin, Talgat; Chen, William C W; Mansurov, Nurlan; Issabekova, Assel; Zhakupova, Jamilya

2017-09-01

The immune system plays a crucial role in the initiation, development, and resolution of inflammation following myocardial infarction (MI). The lack of oxygen and nutrients causes the death of cardiomyocytes and leads to the exposure of danger-associated molecular patterns that are recognized by the immune system to initiate inflammation. At the initial stage of post-MI inflammation, the immune system further damages cardiac tissue to clear cell debris. The excessive production of reactive oxygen species (ROS) by immune cells and the inability of the anti-oxidant system to neutralize ROS cause oxidative stress that further aggravates inflammation. On the other hand, the cells of both innate and adaptive immune system and their secreted factors are critically instrumental in the very dynamic and complex processes of regulating inflammation and mediating cardiac repair. It is important to decipher the balance between detrimental and beneficial effects of the immune system in MI. This enables us to identify better therapeutic targets for reducing the infarct size, sustaining the cardiac function, and minimizing the likelihood of heart failure. This review discusses the role of both innate and adaptive immune systems in cardiac tissue damage and repair in experimental models of MI.

BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy

PubMed Central

Spagnolli, Ester; Ernande, Laura; Thoonen, Robrecht; Kolodziej, Starsha A.; Leyton, Patricio A.; Cheng, Juan; Tainsh, Robert E. T.; Mayeur, Claire; Rhee, David K.; Wu, Mei. X.; Scherrer-Crosbie, Marielle; Buys, Emmanuel S.; Zapol, Warren M.; Bloch, Kenneth D.; Bloch, Donald B.

2016-01-01

Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. PMID:26873969

Validation of On-Orbit Methodology for the Assessment of Cardiac Function and Changes in the Circulating Volume Using "Braslet-M" Occlusion Cuffs

NASA Technical Reports Server (NTRS)

Hamilton, D. R.; Sargsyan, A. E.; Garcia, K. M.; Ebert, D.; Feiveson, A. H.; Alferova, I. V.; Dulchavsky, S. A.; Matveev, V. P.; Bogomolov, V. V.; Duncan, J. M.

2011-01-01

BACKGROUND: The transition to microgravity eliminates the hydrostatic gradients in the vascular system. The resulting fluid redistribution commonly manifests as facial edema, engorgement of the external neck veins, nasal congestion, and headache. This experiment examined the responses to modified Valsalva and Mueller maneuvers as measured by cardiac and vascular ultrasound in a baseline microgravity steady state, and under the influence of thigh occlusion cuffs (Braslet cuffs). METHODS: Nine International Space Station crewmember subjects (Expeditions 16 - 20) were examined in 15 experiment sessions 101 46 days after launch (mean SD; 33 - 185). 27 cardiac and vascular parameters were obtained under three respiratory conditions (baseline, Valsalva, and Mueller) before and after tightening of the Braslet cuffs for a total of 162 data points per session. The quality of cardiac and vascular ultrasound examinations was assured through remote monitoring and guidance by Investigators from the NASA Telescience Center in Houston, TX, USA. RESULTS: Fourteen of the 81 measured conditions were significantly different with Braslet application and were apparently related to cardiac preload reduction or increase in the venous volume sequestered in the lower extremity. These changes represented 10 of the 27 parameters measured. In secondary analysis, 7 of the 27 parameters were found to respond differently to respiratory maneuvers depending on the presence or absence of thigh compression, with a total of 11 differences. CONCLUSIONS: Acute application of Braslet occlusion cuffs causes lower extremity fluid sequestration and exerts proportionate measurable effects on cardiac performance in microgravity. Ultrasound techniques measuring the hemodynamic effects of thigh cuffs in combination with respiratory maneuvers may serve as an effective tool in determining the volume status of a cardiac or hemodynamically compromised patient in microgravity.

Prediction of acute kidney injury within 30 days of cardiac surgery.

PubMed

Ng, Shu Yi; Sanagou, Masoumeh; Wolfe, Rory; Cochrane, Andrew; Smith, Julian A; Reid, Christopher Michael

2014-06-01

To predict acute kidney injury after cardiac surgery. The study included 28,422 cardiac surgery patients who had had no preoperative renal dialysis from June 2001 to June 2009 in 18 hospitals. Logistic regression analyses were undertaken to identify the best combination of risk factors for predicting acute kidney injury. Two models were developed, one including the preoperative risk factors and another including the pre-, peri-, and early postoperative risk factors. The area under the receiver operating characteristic curve was calculated, using split-sample internal validation, to assess model discrimination. The incidence of acute kidney injury was 5.8% (1642 patients). The mortality for patients who experienced acute kidney injury was 17.4% versus 1.6% for patients who did not. On validation, the area under the curve for the preoperative model was 0.77, and the Hosmer-Lemeshow goodness-of-fit P value was .06. For the postoperative model area under the curve was 0.81 and the Hosmer-Lemeshow P value was .6. Both models had good discrimination and acceptable calibration. Acute kidney injury after cardiac surgery can be predicted using preoperative risk factors alone or, with greater accuracy, using pre-, peri-, and early postoperative risk factors. The ability to identify high-risk individuals can be useful in preoperative patient management and for recruitment of appropriate patients to clinical trials. Prediction in the early stages of postoperative care can guide subsequent intensive care of patients and could also be the basis of a retrospective performance audit tool. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Large-deflection statics analysis of active cardiac catheters through co-rotational modelling.

PubMed

Peng Qi; Chen Qiu; Mehndiratta, Aadarsh; I-Ming Chen; Haoyong Yu

2016-08-01

This paper presents a co-rotational concept for large-deflection formulation of cardiac catheters. Using this approach, the catheter is first discretized with a number of equal length beam elements and nodes, and the rigid body motions of an individual beam element are separated from its deformations. Therefore, it is adequate for modelling arbitrarily large deflections of a catheter with linear elastic analysis at the local element level. A novel design of active cardiac catheter of 9 Fr in diameter at the beginning of the paper is proposed, which is based on the contra-rotating double helix patterns and is improved from the previous prototypes. The modelling section is followed by MATLAB simulations of various deflections when the catheter is exerted different types of loads. This proves the feasibility of the presented modelling approach. To the best knowledge of the authors, it is the first to utilize this methodology for large-deflection static analysis of the catheter, which will enable more accurate control of robot-assisted cardiac catheterization procedures. Future work would include further experimental validations.

Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil

PubMed Central

Tiberti, Matteo

2017-01-01

New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations. PMID:29108014

About Cardiac Arrest

MedlinePlus

... Options for Heart Failure Living With HF and Advanced HF High Blood Pressure ... Updated:Mar 10,2017 What is cardiac arrest? Cardiac arrest is the abrupt loss of heart function in a person who may or may not ...

Marketing cardiac CT programs.

PubMed

Scott, Jason

2010-01-01

There are two components of cardiac CT discussed in this article: coronary artery calcium scoring (CACS) and coronary computed tomography angiography (CCTA).The distinctive advantages of each CT examination are outlined. In order to ensure a successful cardiac CT program, it is imperative that imaging facilities market their cardiac CT practices effectively in order to gain a competitive advantage in this valuable market share. If patients receive quality care by competent individuals, they are more likely to recommend the facility's cardiac CT program. Satisfied patients will also be more willing to come back for any further testing.

[Validation of taking arterial pulse in Primary Care for the detection of atrial fibrillation and other cardiac rhythm disorders in patients over 65 years old].

PubMed

Pérula-de Torres, L A; González-Blanco V, V; Luque-Montilla, R; Martín-Rioboó, E; Martínez-Adell, M A; Ruiz-de Castroviejo, J

2017-09-01

Atrial fibrillation (AF) is the most frequent arrhythmia in clinical practice and has important prognostic implications. The objective of this study was to demonstrate the validity and the reliability of taking the arterial pulse (TAP) in patients over 65 years for detecting in AF and other rhythm disorders. A descriptive, observational, multicentre study to validate a diagnostic test within in a controlled clinical trial. 39 Primary Care Centres in the Spanish National Health Service. A total of 318 physicians and nurses took part in the analysis of validity, and 166 of them took part in the analysis of reliability. The professionals were previously called to a meeting in which they took the arterial pulses, and were given 4 ECGs to interpret. The participants TAP of 864 patients followed by an ECG to confirm the cardiac rhythm. Sensitivity, specificity and predictive values were estimated to assess the criterial validity and the simple concordance index to check reproducibility. The sensitivity of pulse measurement for detecting AF detection was 99.4% (95% CI: 97.9-100.0), with a specificity of 30.7% (95% CI: 26.1-35.3), a positive predictive value of 36.6% (95% CI 32.0-41.2), and negative predictive value of 99.2% (97.3-100.0). The simple concordance between the researchers and the cardiologist for the ECG diagnosis of AF ranged between 84.9% and 91.6%. The TAP has a high sensitivity but a low specificity to detect AF. It is a reliable test for the opportunistic screening of arrhythmias in patients aged over 65 years. Copyright © 2016 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

MyoR Modulates Cardiac Conduction by Repressing Gata4

PubMed Central

Harris, John P.; Bhakta, Minoti; Bezprozvannaya, Svetlana; Wang, Lin; Lubczyk, Christina; Olson, Eric N.

2014-01-01

The cardiac conduction system coordinates electrical activation through a series of interconnected structures, including the atrioventricular node (AVN), the central connection point that delays impulse propagation to optimize cardiac performance. Although recent studies have uncovered important molecular details of AVN formation, relatively little is known about the transcriptional mechanisms that regulate AV delay, the primary function of the mature AVN. We identify here MyoR as a novel transcription factor expressed in Cx30.2+ cells of the AVN. We show that MyoR specifically inhibits a Cx30.2 enhancer required for AVN-specific gene expression. Furthermore, we demonstrate that MyoR interacts directly with Gata4 to mediate transcriptional repression. Our studies reveal that MyoR contains two nonequivalent repression domains. While the MyoR C-terminal repression domain inhibits transcription in a context-dependent manner, the N-terminal repression domain can function in a heterologous context to convert the Hand2 activator into a repressor. In addition, we show that genetic deletion of MyoR in mice increases Cx30.2 expression by 50% and prolongs AV delay by 13%. Taken together, we conclude that MyoR modulates a Gata4-dependent regulatory circuit that establishes proper AV delay, and these findings may have wider implications for the variability of cardiac rhythm observed in the general population. PMID:25487574

The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes.

PubMed

Xie, Yuan; Bergström, Tobias; Jiang, Yiwen; Johansson, Patrik; Marinescu, Voichita Dana; Lindberg, Nanna; Segerman, Anna; Wicher, Grzegorz; Niklasson, Mia; Baskaran, Sathishkumar; Sreedharan, Smitha; Everlien, Isabelle; Kastemar, Marianne; Hermansson, Annika; Elfineh, Lioudmila; Libard, Sylwia; Holland, Eric Charles; Hesselager, Göran; Alafuzoff, Irina; Westermark, Bengt; Nelander, Sven; Forsberg-Nilsson, Karin; Uhrbom, Lene

2015-10-01

Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

Improving validation methods for molecular diagnostics: application of Bland-Altman, Deming and simple linear regression analyses in assay comparison and evaluation for next-generation sequencing.

PubMed

Misyura, Maksym; Sukhai, Mahadeo A; Kulasignam, Vathany; Zhang, Tong; Kamel-Reid, Suzanne; Stockley, Tracy L

2018-02-01

A standard approach in test evaluation is to compare results of the assay in validation to results from previously validated methods. For quantitative molecular diagnostic assays, comparison of test values is often performed using simple linear regression and the coefficient of determination (R 2 ), using R 2 as the primary metric of assay agreement. However, the use of R 2 alone does not adequately quantify constant or proportional errors required for optimal test evaluation. More extensive statistical approaches, such as Bland-Altman and expanded interpretation of linear regression methods, can be used to more thoroughly compare data from quantitative molecular assays. We present the application of Bland-Altman and linear regression statistical methods to evaluate quantitative outputs from next-generation sequencing assays (NGS). NGS-derived data sets from assay validation experiments were used to demonstrate the utility of the statistical methods. Both Bland-Altman and linear regression were able to detect the presence and magnitude of constant and proportional error in quantitative values of NGS data. Deming linear regression was used in the context of assay comparison studies, while simple linear regression was used to analyse serial dilution data. Bland-Altman statistical approach was also adapted to quantify assay accuracy, including constant and proportional errors, and precision where theoretical and empirical values were known. The complementary application of the statistical methods described in this manuscript enables more extensive evaluation of performance characteristics of quantitative molecular assays, prior to implementation in the clinical molecular laboratory. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Cardiac Fibroblast: The Renaissance Cell

PubMed Central

Souders, Colby A.; Bowers, Stephanie L.K.; Baudino, Troy A.

2012-01-01

The permanent cellular constituents of the heart include cardiac fibroblasts, myocytes, endothelial cells and vascular smooth muscle cells. Previous studies have demonstrated that there are undulating changes in cardiac cell populations during embryonic development, through neonatal development and into the adult. Transient cell populations include lymphocytes, mast cells and macrophages, which can interact with these permanent cell types to affect cardiac function. It has also been observed that there are marked differences in the makeup of the cardiac cell populations depending on the species, which may be important when examining myocardial remodeling. Current dogma states that the fibroblast makes up the largest cell population of the heart; however, this appears to vary for different species, especially mice. Cardiac fibroblasts play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as myocardial infarct and hypertension. These cells have numerous functions, including synthesis and deposition of extracellular matrix, cell-cell communication with myocytes, cell-cell signaling with other fibroblasts, as well as with endothelial cells. These contacts affect the electrophysiological properties, secretion of growth factors and cytokines, as well as potentiating blood vessel formation. While a plethora of information is known about several of these processes, relatively little is understood about fibroblasts and their role in angiogenesis during development or cardiac remodeling. In this review we provide insight into the various properties of cardiac fibroblasts that helps illustrate their importance in maintaining proper cardiac function, as well as their critical role in the remodeling heart. PMID:19959782

The first Latin-American risk stratification system for cardiac surgery: can be used as a graphic pocket-card score.

PubMed

Carosella, Victorio C; Navia, Jose L; Al-Ruzzeh, Sharif; Grancelli, Hugo; Rodriguez, Walter; Cardenas, Cesar; Bilbao, Jorge; Nojek, Carlos

2009-08-01

This study aims to develop the first Latin-American risk model that can be used as a simple, pocket-card graphic score at bedside. The risk model was developed on 2903 patients who underwent cardiac surgery at the Spanish Hospital of Buenos Aires, Argentina, between June 1994 and December 1999. Internal validation was performed on 708 patients between January 2000 and June 2001 at the same center. External validation was performed on 1087 patients between February 2000 and January 2007 at three other centers in Argentina. In the development dataset the area under receiver operating characteristics (ROC) curve was 0.73 and the Hosmer-Lemeshow (HL) test was P=0.88. In the internal validation ROC curve was 0.77. In the external validation ROC curve was 0.81, but imperfect calibration was detected because the observed in-hospital mortality (3.96%) was significantly lower than the development dataset (8.20%) (P<0.0001). Recalibration was done in 2007, showing excellent level of agreement between the observed and predicted mortality rates on all patients (P=0.92). This is the first risk model for cardiac surgery developed in a population of Latin-America with both internal and external validation. A simple graphic pocket-card score allows an easy bedside application with acceptable statistic precision.

Polymer microfiber meshes facilitate cardiac differentiation of c-kit{sup +} human cardiac stem cells

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

Kan, Lijuan; Thayer, Patrick; Fan, Huimin

Electrospun microfiber meshes have been shown to support the proliferation and differentiation of many types of stem cells, but the phenotypic fate of c-kit{sup +} human cardiac stem cells (hCSCs) have not been explored. To this end, we utilized thin (~5 µm) elastomeric meshes consisting of aligned 1.7 µm diameter poly (ester-urethane urea) microfibers as substrates to examine their effect on hCSC viability, morphology, proliferation, and differentiation relative to cells cultured on tissue culture polystyrene (TCPS). The results showed that cells on microfiber meshes displayed an elongated morphology aligned in the direction of fiber orientation, lower proliferation rates, but increasedmore » expressions of genes and proteins majorly associated with cardiomyocyte phenotype. The early (NK2 homeobox 5, Nkx2.5) and late (cardiac troponin I, cTnI) cardiomyocyte genes were significantly increased on meshes (Nkx=2.5 56.2±13.0, cTnl=2.9±0.56,) over TCPS (Nkx2.5=4.2±0.9, cTnl=1.6±0.5, n=9, p<0.05 for both groups) after differentiation. In contrast, expressions of smooth muscle markers, Gata6 and myosin heavy chain (SM-MHC), were decreased on meshes. Immunocytochemical analysis with cardiac antibody exhibited the similar pattern of above cardiac differentiation. We conclude that aligned microfiber meshes are suitable for guiding cardiac differentiation of hCSCs and may facilitate stem cell-based therapies for treatment of cardiac diseases. - Highlights: • First study to characterize c-kit{sup +} human cardiac stem cells on microfiber meshes. • Microfiber meshes seem reducing cell proliferation, but no effect on cell viability. • Microfiber meshes facilitate the elongation of human cardiac stem cells in culture. • Cardiac but not smooth muscle differentiation were enhanced on microfiber meshes. • Microfiber meshes may be used as cardiac patches in cell-based cardiac therapy.« less

Sacral neuromodulation and cardiac pacemakers.

PubMed

Roth, Ted M

2010-08-01

Potential for cross-talk between cardiac pacemakers and sacral neuromodulation remains speculative. We present a case series of patients with cardiac pacemakers who underwent staged Interstim (Medtronic, Minneapolis, MN) implantation and patients who had pulse generator implantation who later required cardiac pacemakers. No cross-talk was demonstrated in either group. Sacral neuromodulation appears to be safe in the setting of cardiac pacemakers without cardioversion/defibrillation technology.

Cardiac perioperative complications in noncardiac surgery.

PubMed

Radovanović, Dragana; Kolak, Radmila; Stokić, Aleksandar; Radovanović, Zoran; Jovanović, Gordana

2008-01-01

Anesthesiologists are confronted with an increasing population of patients undergoing noncardiac surgery who are at risk for cardiac complications in the perioperative period. Perioperative cardiac complications are responsible for significant mortality and morbidity. The aim of the present study was to determine the incidence of perioperative (operative and postoperative) cardiac complications and correlations between the incidence of perioperative cardiac complications and type of surgical procedure, age, presence of concurrent deseases. A total of 100 patients with cardiac diseases undergoing noncardiac surgery were included in the prospective study (Group A 50 patients undergoing intraperitoneal surgery and Group B 50 patients undergoing breast and thyroid surgery). The patients were followed up during the perioperative period and after surgery until leaving hospital to assess the occurrence of cardiac events. Cardiac complications (systemic arterial hypertension, systemic arterial hypotension, abnormalities of cardiac conduction and cardiac rhythm, perioperative myocardial ischemia and acute myocardial infarction) occurred in 64% of the patients. One of the 100 patients (1%) had postoperative myocardial infarction which was fatal. Systemic arterial hypertension occured in 57% of patients intraoperatively and 33% postoperatively, abnormalities of cardiac rhythm in 31% of patients intraoperatively and 17% postoperatively, perioperative myocardial ischemia in 23% of patients intraoperatively and 11% of postoperatively. The most often cardiac complications were systemic arterial hypertension, abnormalities of cardiac rhythm and perioperative mvocardial ischemia. Factors independently associated with the incidence of cardiac complications included the type of surgical procedure, advanced age, duration of anaesthesia and surgery, abnormal preoperative electrocardiogram, abnormal preoperative chest radiography and diabetes.

Calreticulin reveals a critical Ca2+ checkpoint in cardiac myofibrillogenesis

PubMed Central

Li, Jian; Pucéat, Michel; Perez-Terzic, Carmen; Mery, Annabelle; Nakamura, Kimitoshi; Michalak, Marek; Krause, Karl-Heinz; Jaconi, Marisa E.

2002-01-01

Calreticulin (crt) is an ubiquitously expressed and multifunctional Ca2+-binding protein that regulates diverse vital cell functions, including Ca2+ storage in the ER and protein folding. Calreticulin deficiency in mice is lethal in utero due to defects in heart development and function. Herein, we used crt − / − embryonic stem (ES) cells differentiated in vitro into cardiac cells to investigate the molecular mechanisms underlying heart failure of knockout embryos. After 8 d of differentiation, beating areas were prominent in ES-derived wild-type (wt) embryoid bodies (EBs), but not in ES-derived crt − / − EBs, despite normal expression levels of cardiac transcription factors. Crt − / − EBs exhibited a severe decrease in expression and a lack of phosphorylation of ventricular myosin light chain 2 (MLC2v), resulting in an impaired organization of myofibrils. Crt − / − phenotype could be recreated in wt cells by chelating extracellular or cytoplasmic Ca2+ with EGTA or BAPTA, or by inhibiting Ca2+/calmodulin-dependent kinases (CaMKs). An imposed ionomycin-triggered cystolic-free Ca2+ concentration ([Ca2+]c) elevation restored the expression, phosphorylation, and insertion of MLC2v into sarcomeric structures and in turn the myofibrillogenesis. The transcription factor myocyte enhancer factor C2 failed to accumulate into nuclei of crt − / − cardiac cells in the absence of ionomycin-triggered [Ca2+]c increase. We conclude that the absence of calreticulin interferes with myofibril formation. Most importantly, calreticulin deficiency revealed the importance of a Ca2+-dependent checkpoint critical for early events during cardiac myofibrillogenesis. PMID:12105184

Associations of baseline depressed mood and happiness with subsequent well-being in cardiac patients.

PubMed

Craner, Julia; Douglas, Kristin Vickers; Dierkhising, Ross; Hathaway, Julie; Goel, Kashish; Thomas, Randal J

2017-02-01

The relationship between depressive symptoms and adverse outcomes for patients with cardiac problems has been well established for several decades. However, less is known about other factors that may influence psychosocial outcomes for cardiac patients. To evaluate the association between baseline happiness and depressed mood on later psychosocial functioning among cardiac patients. Participants (N = 250) were patients who had received medical treatment at an academic medical center for a cardiac event. Participants completed questionnaires at two time points: Approximately 2 weeks after they had been discharged from the hospital (baseline) and again 12 weeks later. Participants completed validated measures of depressed mood, happiness, health distress, expectations about health, and quality of life. Baseline depressed mood and happiness both significantly predicted health-related distress and depressive symptoms at follow up. Happiness ratings were associated with lower distress and depressed mood, whereas scores for depressive symptoms showed the opposite pattern. Happiness, but not depressed mood, was a significant predictor of more positive quality of life ratings. Conversely, only depressed mood was a significant predictor of less positive expectations about health. The results of this study suggest that investigating positive baseline affect in addition to depressed mood provides additional useful information that may help explain why some patients have more negative outcomes following cardiac events. Copyright © 2016 Elsevier Ltd. All rights reserved.

Novel approaches to determine contractile function of the isolated adult zebrafish ventricular cardiac myocyte.

PubMed

Dvornikov, Alexey V; Dewan, Sukriti; Alekhina, Olga V; Pickett, F Bryan; de Tombe, Pieter P

2014-05-01

The zebrafish (Danio rerio) has been used extensively in cardiovascular biology, but mainly in the study of heart development. The relative ease of its genetic manipulation may indicate the suitability of this species as a cost-effective model system for the study of cardiac contractile biology. However, whether the zebrafish heart is an appropriate model system for investigations pertaining to mammalian cardiac contractile structure-function relationships remains to be resolved. Myocytes were isolated from adult zebrafish hearts by enzymatic digestion, attached to carbon rods, and twitch force and intracellular Ca(2+) were measured. We observed the modulation of twitch force, but not of intracellular Ca(2+), by both extracellular [Ca(2+)] and sarcomere length. In permeabilized cells/myofibrils, we found robust myofilament length-dependent activation. Moreover, modulation of myofilament activation-relaxation and force redevelopment kinetics by varied Ca(2+) activation levels resembled that found previously in mammalian myofilaments. We conclude that the zebrafish is a valid model system for the study of cardiac contractile structure-function relationships.

Circulating Pneumolysin Is a Potent Inducer of Cardiac Injury during Pneumococcal Infection.

PubMed

Alhamdi, Yasir; Neill, Daniel R; Abrams, Simon T; Malak, Hesham A; Yahya, Reham; Barrett-Jolley, Richard; Wang, Guozheng; Kadioglu, Aras; Toh, Cheng-Hock

2015-05-01

dysfunction in clinical and experimental sepsis and ultimately resulted in depressed cardiomyocyte contractile performance along with rhythm disturbance. Our study proposes a detailed molecular mechanism of pneumococcal toxin-induced cardiac injury and highlights the major translational potential of targeting circulating PLY to protect against cardiac complications during pneumococcal infections.

Circulating Pneumolysin Is a Potent Inducer of Cardiac Injury during Pneumococcal Infection

PubMed Central

Alhamdi, Yasir; Neill, Daniel R.; Abrams, Simon T.; Malak, Hesham A.; Yahya, Reham; Barrett-Jolley, Richard; Wang, Guozheng; Kadioglu, Aras; Toh, Cheng-Hock

2015-01-01

dysfunction in clinical and experimental sepsis and ultimately resulted in depressed cardiomyocyte contractile performance along with rhythm disturbance. Our study proposes a detailed molecular mechanism of pneumococcal toxin-induced cardiac injury and highlights the major translational potential of targeting circulating PLY to protect against cardiac complications during pneumococcal infections. PMID:25973949

Recurrent myocardial infarction: Mechanisms of free-floating adaptation and autonomic derangement in networked cardiac neural control

PubMed Central

Ardell, Jeffrey L.; Shivkumar, Kalyanam; Armour, J. Andrew

2017-01-01

The cardiac nervous system continuously controls cardiac function whether or not pathology is present. While myocardial infarction typically has a major and catastrophic impact, population studies have shown that longer-term risk for recurrent myocardial infarction and the related potential for sudden cardiac death depends mainly upon standard atherosclerotic variables and autonomic nervous system maladaptations. Investigative neurocardiology has demonstrated that autonomic control of cardiac function includes local circuit neurons for networked control within the peripheral nervous system. The structural and adaptive characteristics of such networked interactions define the dynamics and a new normal for cardiac control that results in the aftermath of recurrent myocardial infarction and/or unstable angina that may or may not precipitate autonomic derangement. These features are explored here via a mathematical model of cardiac regulation. A main observation is that the control environment during pathology is an extrapolation to a setting outside prior experience. Although global bounds guarantee stability, the resulting closed-loop dynamics exhibited while the network adapts during pathology are aptly described as ‘free-floating’ in order to emphasize their dependence upon details of the network structure. The totality of the results provide a mechanistic reasoning that validates the clinical practice of reducing sympathetic efferent neuronal tone while aggressively targeting autonomic derangement in the treatment of ischemic heart disease. PMID:28692680

Hybrid options for treating cardiac disease.

PubMed

Umakanthan, Ramanan; Leacche, Marzia; Zhao, David X; Gallion, Anna H; Mishra, Prabodh C; Byrne, John G

2011-01-01

The options for treating heart disease have greatly expanded during the course of the last 2 1/2 decades with the advent of hybrid technology. The hybrid option for treating cardiac disease implies using the technology of both interventional cardiology and cardiac surgery to treat cardiac disease. This rapidly developing technology has given rise to new and creative techniques to treat cardiac disease involving coronary artery disease, coronary artery disease and cardiac valve disease, and atrial fibrillation. It has also led to the establishment of new procedural suites called hybrid operating rooms that facilitate the integration of technologies of interventional cardiology catheterization laboratories with those of cardiac surgery operating rooms. The development of hybrid options for treating cardiac disease has also greatly augmented teamwork and collaboration between interventional cardiologists and cardiac surgeons. Copyright © 2011 Elsevier Inc. All rights reserved.

Cardiac differentiation of cardiosphere-derived cells in scaffolds mimicking morphology of the cardiac extracellular matrix.

PubMed

Xu, Yanyi; Patnaik, Sourav; Guo, Xiaolei; Li, Zhenqing; Lo, Wilson; Butler, Ryan; Claude, Andrew; Liu, Zhenguo; Zhang, Ge; Liao, Jun; Anderson, Peter M; Guan, Jianjun

2014-08-01

Stem cell therapy has the potential to regenerate heart tissue after myocardial infarction (MI). The regeneration is dependent upon cardiac differentiation of the delivered stem cells. We hypothesized that timing of the stem cell delivery determines the extent of cardiac differentiation as cell differentiation is dependent on matrix properties such as biomechanics, structure and morphology, and these properties in cardiac extracellular matrix (ECM) continuously vary with time after MI. In order to elucidate the relationship between ECM properties and cardiac differentiation, we created an in vitro model based on ECM-mimicking fibers and a type of cardiac progenitor cell, cardiosphere-derived cells (CDCs). A simultaneous fiber electrospinning and cell electrospraying technique was utilized to fabricate constructs. By blending a highly soft hydrogel with a relatively stiff polyurethane and modulating fabrication parameters, tissue constructs with similar cell adhesion property but different global modulus, single fiber modulus, fiber density and fiber alignment were achieved. The CDCs remained alive within the constructs during a 1week culture period. CDC cardiac differentiation was dependent on the scaffold modulus, fiber volume fraction and fiber alignment. Two constructs with relatively low scaffold modulus, ∼50-60kPa, most significantly directed the CDC differentiation into mature cardiomyocytes as evidenced by gene expressions of cardiac troponin T (cTnT), calcium channel (CACNA1c) and cardiac myosin heavy chain (MYH6), and protein expressions of cardiac troponin I (cTnI) and connexin 43 (CX43). Of these two low-modulus constructs, the extent of differentiation was greater for lower fiber alignment and higher fiber volume fraction. These results suggest that cardiac ECM properties may have an effect on cardiac differentiation of delivered stem cells. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Novel echocardiographic prediction of non-response to cardiac resynchronization therapy

NASA Astrophysics Data System (ADS)

Chan, R.; Tournoux, F.; Tournoux, A. C.; Nandigam, V.; Manzke, R.; Dalal, S.; Solis-Martin, J.; McCarty, D.; Ruskin, J. N.; Picard, M. H.; Weyman, A. E.; Singh, J. P.

2009-02-01

Imaging techniques try to identify patients who may respond to cardiac resynchronization therapy (CRT). However, it may be clinically more useful to identify patients for whom CRT would not be beneficial as the procedure would not be indicated for this group. We developed a novel, clinically feasible and technically-simple echocardiographic dyssynchrony index and tested its negative predictive value. Subjects with standard indications for CRT had echo preand post-device implantation. Atrial-ventricular dyssynchrony was defined as a left ventricular (LV) filling time of <40% of the cardiac cycle. Intra-ventricular dyssynchrony was quantified as the magnitude of LV apical rocking. The apical rocking was measured using tissue displacement estimates from echo data. In a 4-chamber view, a region of interest was positioned within the apical end of the middle segment within each wall. Tissue displacement curves were analyzed with custom software in MATLAB. Rocking was quantified as a percentage of the cardiac cycle over which the displacement curves showed discordant behavior and classified as non-significant for values <35%. Validation in 50 patients showed that absence of significant LV apical rocking or atrial-ventricular dyssynchrony was associated with non-response to CRT. This measure may therefore be useful in screening to avoid non-therapeutic CRT procedures.

Cardiac rhythm management devices

PubMed

Stevenson, Irene; Voskoboinik, Alex

2018-05-01

The last decade has seen ongoing evolution and use of cardiac rhythm management devices, including pacemakers, cardiac resynchronisation therapy, implantable cardioverter defibrillators and loop recorders. General practitioners are increasingly involved in follow-up and management of patients with these devices. The aim of this article is to provide an overview of different cardiac rhythm management devices, including their role, implant procedure, post-procedural care, potential complications and follow‑up. We also include practical advice for patients regarding driving, exercise, sexual intimacy and precautions with regards to electromagnetic interference. Cardiac rhythm management devices perform many functions, including bradycardia pacing, monitoring for arrhythmias, cardiac resynchronisation for heart failure, defibrillation and anti-tachycardia pacing for tachyarrhythmias. Concerns regarding potential device-related complications should be discussed with the implanting physician. In the post-implant period, patients with cardiac rhythm management devices can expect to lead normal, active lives. However, caution must occasionally be exercised in certain situations, such as near appliances with electromagnetic interference. Future innovations will move away from transvenous leads to leadless designs with combinations of different components on a 'modular' basis according to the function required.