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Sample records for cardiovascular adverse remodeling

  1. Adverse Remodeling and Reverse Remodeling After Myocardial Infarction.

    PubMed

    Bhatt, Ankeet S; Ambrosy, Andrew P; Velazquez, Eric J

    2017-08-01

    The purpose of this review it to summarize the current literature on remodeling after myocardial infarction, inclusive of pathophysiological considerations, imaging modalities, treatment strategies, and future directions. As patients continue to live longer after myocardial infarction (MI), the prevalence of post-MI heart failure continues to rise. Changes in the left ventricle (LV) after MI involve complex interactions between cellular and extracellular components, under neurohormonal regulation. Treatments to prevent adverse LV remodeling and promote reverse remodeling in the post-MI setting include early revascularization, pharmacotherapy aimed at neurohormonal blockade, and device-based therapies that address ventricular dyssynchrony. Despite varying definitions of adverse LV remodeling examined across multiple imaging modalities, the presence of an enlarged LV cavity and/or reduced ejection fraction is consistently associated with poor clinical outcomes. Advances in our knowledge of the neurohormonal regulation of adverse cardiac remodeling have been instrumental in generating therapies aimed at arresting adverse remodeling and promoting reserve remodeling. Further investigation into other specific mechanisms of adverse LV remodeling and pathways to disrupt these mechanisms is ongoing and may provide incremental benefit to current evidence-based therapies.

  2. Mitochondria, myocardial remodeling, and cardiovascular disease.

    PubMed

    Verdejo, Hugo E; del Campo, Andrea; Troncoso, Rodrigo; Gutierrez, Tomás; Toro, Barbra; Quiroga, Clara; Pedrozo, Zully; Munoz, Juan Pablo; Garcia, Lorena; Castro, Pablo F; Lavandero, Sergio

    2012-12-01

    The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca(2+) buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca(2+) handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease.

  3. [Remodeling of Cardiovascular System: Causes and Consequences].

    PubMed

    Lopatina, E V; Kipenko, A V; Penniyaynen, V A; Pasatetckaia, N A; Tsyrline, V A

    2016-01-01

    Literature and our data suggest the regulatory action of a number of biologically active substances (catecholamines, cardiac glycosides, β-blockers, angiotensin-converting-enzyme inhibitor) on the growth and proliferation of heart cells. By using of organotypic tissue culture has proved that the basis of this regulation is the ability of test substances, receptor- or transducer-mediated signaling to modulate the function of Na⁺, K⁺-ATPase. There is a delay in the development of vascular smooth muscle in the late postnatal period in rats with the blockade of the sympathetic nervous system in the prenatal period. The relationship between vascular remodeling and contractile activity is described. It seems that one of the causes of high blood pressure is a remodeling of the cardiovascular system, which precedes the development of hypertension.

  4. Air pollution and adverse cardiac remodeling: clinical effects and basic mechanisms

    PubMed Central

    Liu, Yonggang; Goodson, Jamie M.; Zhang, Bo; Chin, Michael T.

    2015-01-01

    Exposure to air pollution has long been known to trigger cardiovascular events, primarily through activation of local and systemic inflammatory pathways that affect the vasculature. Detrimental effects of air pollution exposure on heart failure and cardiac remodeling have also been described in human populations. Recent studies in both human subjects and animal models have provided insights into the basic physiological, cellular and molecular mechanisms that play a role in adverse cardiac remodeling. This review will give a brief overview of the relationship between air pollution and cardiovascular disease, describe the clinical effects of air pollution exposure on cardiac remodeling, describe the basic mechanisms that affect remodeling as described in human and animal systems and will discuss future areas of investigation. PMID:26042051

  5. Cardiovascular remodeling and the peripheral serotonergic system.

    PubMed

    Ayme-Dietrich, Estelle; Aubertin-Kirch, Gaëlle; Maroteaux, Luc; Monassier, Laurent

    2017-01-01

    Plasma 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, plays a major role in the human cardiovascular system. Besides the effect of endogenous serotonin, many drugs targeting serotonergic receptors are widely used in the general population (antiobesity agents, antidepressants, antipsychotics, antimigraine agents), and may enhance the cardiovascular risk. Depending on the type of serotonin receptor activated and its location, the use of these compounds triggers acute and chronic effects. The acute cardiovascular response to 5-HT, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT3, 5-HT1B/1D, 5-HT7 and 5-HT2A/2B receptors. The chronic contribution of 5-HT and its receptors (5-HT4 and 5-HT2A/2B) in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration, will be explored in this review. Finally, through the analysis of the effects of sarpogrelate, some new aspects of 5-HT2A receptor pharmacology in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells will also be discussed. The aim of this review is to emphasize the cardiac side effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system. Copyright © 2016. Published by Elsevier Masson SAS.

  6. [Cardiovascular pharmacotherapy. Risks and adverse effects].

    PubMed

    Voigt, N; Heijman, J; Dobrev, D

    2014-03-01

    Adverse side effects of drugs are a significantly underestimated problem in modern medicine. In this review article, we summarize common adverse side effects of cardiovascular drugs. In particular, we highlight the factors promoting these adverse side effects in patients, including reduced hepatic or renal clearance in elderly patients that often requires dosage adjustment. Pharmacodynamic and pharmacokinetic interactions between drugs (e.g. through the cytochrome P450 system or P-glycoproteins) can modify the plasma concentration of many compounds, thereby also increasing the likelihood of unwanted side effects. The most prominent cardiac side effects include arrhythmias, e.g. atrioventricular (AV) block, drug-induced long-QT syndrome and torsade de pointes and altered inotropy. Non-cardiac side effects are subsequently discussed grouped by drug class. A better understanding of the risks and side effects of cardiovascular drugs is expected to reduce the mortality and morbidity associated with adverse side effects.

  7. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia.

    PubMed

    Steed, Mesia M; Tyagi, Suresh C

    2011-10-01

    In hypertension, an increase in arterial wall thickness and loss of elasticity over time result in an increase in pulse wave velocity, a direct measure of arterial stiffness. This change is reflected in gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers in the media that occurs independently of atherosclerosis. Similar results are seen with an elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), which increases vascular thickness, elastin fragmentation, and arterial blood pressure. Studies from our laboratory have demonstrated a decrease in elasticity and an increase in pulse wave velocity in HHcy cystathionine β synthase heterozygote knockout (CBS(-/+)) mice. Nitric oxide (NO) is a potential regulator of matrix metalloproteinase (MMP) activity in MMP-NO-TIMP (tissue inhibitor of metalloproteinase) inhibitory tertiary complex. We have demonstrated the contribution of the NO synthase (NOS) isoforms, endothelial NOS and inducible NOS, in the activation of latent MMP. The differential production of NO contributes to oxidative stress and increased oxidative/nitrative activation of MMP resulting in vascular remodeling in response to HHcy. The contribution of the NOS isoforms, endothelial and inducible in the collagen/elastin switch, has been demonstrated. We have showed that an increase in inducible NOS activity is a key contributor to HHcy-mediated collagen/elastin switch and resulting decline in aortic compliance. In addition, increased levels of Hcy compete and suppress the γ-amino butyric acid-receptor, N-methyl-d-aspartate-receptor, and peroxisome proliferator-activated receptor. The HHcy causes oxidative stress by generating nitrotyrosine, activating the latent MMPs and decreasing the endothelial NO concentration. The HHcy causes elastinolysis and decrease elastic complicance of the vessel wall. The treatment with γ-amino butyric acid-receptor agonist (muscimol), N

  8. Adverse cardiovascular effects of air pollution.

    PubMed

    Mills, Nicholas L; Donaldson, Ken; Hadoke, Paddy W; Boon, Nicholas A; MacNee, William; Cassee, Flemming R; Sandström, Thomas; Blomberg, Anders; Newby, David E

    2009-01-01

    Air pollution is increasingly recognized as an important and modifiable determinant of cardiovascular disease in urban communities. Acute exposure has been linked to a range of adverse cardiovascular events including hospital admissions with angina, myocardial infarction, and heart failure. Long-term exposure increases an individual's lifetime risk of death from coronary heart disease. The main arbiter of these adverse health effects seems to be combustion-derived nanoparticles that incorporate reactive organic and transition metal components. Inhalation of this particulate matter leads to pulmonary inflammation with secondary systemic effects or, after translocation from the lung into the circulation, to direct toxic cardiovascular effects. Through the induction of cellular oxidative stress and proinflammatory pathways, particulate matter augments the development and progression of atherosclerosis via detrimental effects on platelets, vascular tissue, and the myocardium. These effects seem to underpin the atherothrombotic consequences of acute and chronic exposure to air pollution. An increased understanding of the mediators and mechanisms of these processes is necessary if we are to develop strategies to protect individuals at risk and reduce the effect of air pollution on cardiovascular disease.

  9. Molecular Imaging of Angiogenesis and Vascular Remodeling in Cardiovascular Pathology

    PubMed Central

    Golestani, Reza; Jung, Jae-Joon; Sadeghi, Mehran M.

    2016-01-01

    Angiogenesis and vascular remodeling are involved in a wide array of cardiovascular diseases, from myocardial ischemia and peripheral arterial disease, to atherosclerosis and aortic aneurysm. Molecular imaging techniques to detect and quantify key molecular and cellular players in angiogenesis and vascular remodeling (e.g., vascular endothelial growth factor and its receptors, αvβ3 integrin, and matrix metalloproteinases) can advance vascular biology research and serve as clinical tools for early diagnosis, risk stratification, and selection of patients who would benefit most from therapeutic interventions. To target these key mediators, a number of molecular imaging techniques have been developed and evaluated in animal models of angiogenesis and vascular remodeling. This review of the state of the art molecular imaging of angiogenesis and vascular (and valvular) remodeling, will focus mostly on nuclear imaging techniques (positron emission tomography and single photon emission tomography) that offer high potential for clinical translation. PMID:27275836

  10. Galectin-3 Participates in Cardiovascular Remodeling Associated With Obesity.

    PubMed

    Martínez-Martínez, Ernesto; López-Ándres, Natalia; Jurado-López, Raquel; Rousseau, Elodie; Bartolomé, Mará Visitación; Fernández-Celis, Amaya; Rossignol, Patrick; Islas, Fabian; Antequera, Alfonso; Prieto, Santiago; Luaces, María; Cachofeiro, Victoria

    2015-11-01

    Remodeling, diastolic dysfunction, and arterial stiffness are some of the alterations through which obesity affects the cardiovascular system. Fibrosis and inflammation are important mechanisms underlying cardiovascular remodeling, although the precise promoters involved in these processes are still unclear. Galectin-3 (Gal-3) induces inflammation and fibrosis in the cardiovascular system. We have investigated the potential role of Gal-3 in cardiac damage in morbidly obese patients, and we have evaluated the protective effect of the Gal-3 inhibition in the occurrence of cardiovascular fibrosis and inflammation in an experimental model of obesity. Morbid obesity is associated with alterations in cardiac remodeling, mainly left ventricular hypertrophy and diastolic dysfunction. Obesity and hypertension are the main determinants of left ventricular hypertrophy. Insulin resistance, left ventricular hypertrophy, and circulating levels of C-reactive protein and Gal-3 are associated with a worsening of diastolic function in morbidly obese patients. Obesity upregulates Gal-3 production in the cardiovascular system in a normotensive animal model of diet-induced obesity by feeding for 6 weeks a high-fat diet (33.5% fat). Gal-3 inhibition with modified citrus pectin (100 mg/kg per day) reduced cardiovascular levels of Gal-3, total collagen, collagen I, transforming and connective growth factors, osteopontin, and monocyte chemoattractant protein-1 in the heart and aorta of obese animals without changes in body weight or blood pressure. In morbidly obese patients, Gal-3 levels are associated with diastolic dysfunction. In obese animals, Gal-3 blockade decreases cardiovascular fibrosis and inflammation. These data suggest that Gal-3 could be a novel therapeutic target in cardiac fibrosis and inflammation associated with obesity. © 2015 American Heart Association, Inc.

  11. Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse Remodeling.

    PubMed

    Kali, Avinash; Cokic, Ivan; Tang, Richard; Dohnalkova, Alice; Kovarik, Libor; Yang, Hsin-Jung; Kumar, Andreas; Prato, Frank S; Wood, John C; Underhill, David; Marbán, Eduardo; Dharmakumar, Rohan

    2016-11-01

    Emerging evidence indicates that persistent microvascular obstruction (PMO) is more predictive of major adverse cardiovascular events than myocardial infarct (MI) size. But it remains unclear how PMO, a phenomenon limited to the acute/subacute period of MI, drives adverse remodeling in chronic MI setting. We hypothesized that PMO resolves into chronic iron crystals within MI territories, which in turn are proinflammatory and favor adverse remodeling post-MI. Canines (n=40) were studied with cardiac magnetic resonance imaging to characterize the spatiotemporal relationships among PMO, iron deposition, infarct resorption, and left ventricular remodeling between day 7 (acute) and week 8 (chronic) post-MI. Histology was used to assess iron deposition and to examine relationships between iron content with macrophage infiltration, proinflammatory cytokine synthesis, and matrix metalloproteinase activation. Atomic resolution transmission electron microscopy was used to determine iron crystallinity, and energy-dispersive X-ray spectroscopy was used to identify the chemical composition of the iron composite. PMO with or without reperfusion hemorrhage led to chronic iron deposition, and the extent of this deposition was strongly related to PMO volume (r>0.8). Iron deposits were found within macrophages as aggregates of nanocrystals (≈2.5 nm diameter) in the ferric state. Extent of iron deposits was strongly correlated with proinflammatory burden, collagen-degrading enzyme activity, infarct resorption, and adverse structural remodeling (r>0.5). Crystallized iron deposition from PMO is directly related to proinflammatory burden, infarct resorption, and adverse left ventricular remodeling in the chronic phase of MI in canines. Therapeutic strategies to combat adverse remodeling could potentially benefit from taking into account the chronic iron-driven inflammatory process. © 2016 American Heart Association, Inc.

  12. Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy

    PubMed Central

    Thoonen, Robrecht; Ernande, Laura; Cheng, Juan; Nagasaka, Yasuko; Yao, Vincent; Miranda-Bezerra, Alexandre; Chen, Chan; Chao, Wei; Panagia, Marcello; Sosnovik, David E.; Puppala, Dheeraj; Armoundas, Antonis A.; Hindle, Allyson; Bloch, Kenneth D.; Buys, Emmanuel S.; Scherrer-Crosbie, Marielle

    2015-01-01

    Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1−/−) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1−/− mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1−/− mice. UCP1−/− mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1−/− mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1−/− BAT transplanted to either UCP1−/− or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1−/− mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1−/− mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy. PMID:25968336

  13. Adverse life events, cardiovascular responses, and sports performance under pressure.

    PubMed

    Moore, Lee J; Young, Tom; Freeman, Paul; Sarkar, Mustafa

    2017-06-05

    Research suggests that experiencing a moderate number of adverse life events can benefit future stress responses. This study explored the relationship between adverse life (ie, non-sport) events and cardiovascular responses to, and performance during, a pressurized sporting task. One hundred participants (64 men, 36 women; Mage =21.94 years, SDage =4.98) reported the number of adverse life events (eg, serious accident or injury) they had encountered before completing a pressurized dart-throwing task during which performance was recorded. Before the task, participants' demand and resource evaluations and cardiovascular reactivity were assessed. Adverse life events did not impact demand and resource evaluations. However, participants who reported 4-7 adverse life events displayed cardiovascular responses more reflective of a challenge state (relatively lower total peripheral resistance and/or higher cardiac output) compared to those who reported a lower (<4) or higher (>7) number of events. Furthermore, participants who reported 3-13 adverse life events outperformed those who reported a lower (<3) or higher (>13) number of events. Supplementary analyses suggested that this relationship might be due to a small number of extreme values. However, after outlier analyses, a significant linear relationship remained suggesting that a higher number of adverse life events facilitated performance. The results suggest that experiencing a moderate to high number of adverse life events might have beneficial effects on subsequent cardiovascular responses and performance under pressure. Practitioners should therefore consider prior brushes with adversity when identifying athletes who are likely to excel during stressful competition. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Failure of fertility therapy and subsequent adverse cardiovascular events

    PubMed Central

    Udell, Jacob A.; Lu, Hong; Redelmeier, Donald A.

    2017-01-01

    BACKGROUND: Infertility may indicate an underlying predisposition toward premature cardiovascular disease, yet little is known about potential long-term cardiovascular events following fertility therapy. We investigated whether failure of fertility therapy is associated with subsequent adverse cardiovascular events. METHODS: We performed a population-based cohort analysis of women who received gonadotropin-based fertility therapy between Apr. 1, 1993, and Mar. 31, 2011, distinguishing those who subsequently gave birth and those who did not. Using multivariable Poisson regression models, we estimated the relative rate ratio of adverse cardiovascular events associated with fertility therapy failure, accounting for age, year, baseline risk factors, health care history and number of fertility cycles. The primary outcome was subsequent treatment for nonfatal coronary ischemia, stroke, transient ischemic attack, heart failure or thromboembolism. RESULTS: Of 28 442 women who received fertility therapy, 9349 (32.9%) subsequently gave birth and 19 093 (67.1%) did not. The median number of fertility treatments was 3 (interquartile range 1–5). We identified 2686 cardiovascular events over a median 8.4 years of follow-up. The annual rate of cardiovascular events was 19% higher among women who did not give birth after fertility therapy than among those who did (1.08 v. 0.91 per 100 patient-years, p < 0.001), equivalent to a 21% relative increase in the annual rate (95% confidence interval 13%–30%). We observed no association between event rates and number of treatment cycles. INTERPRETATION: Fertility therapy failure was associated with an increased risk of long-term adverse cardiovascular events. These women merit surveillance for subsequent cardiovascular events. PMID:28385819

  15. Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium

    PubMed Central

    Weber, Karl T.; Weglicki, William B.; Simpson, Robert U.

    2009-01-01

    Hypertension and heart failure are worldwide health problems of ever-increasing proportions. A failure of the heart, during either systolic and/or diastolic phases of the cardiac cycle, has its origins rooted in an adverse structural, biochemical, and molecular remodelling of myocardium that involves its cellular constituents, extracellular matrix, and intramural coronary vasculature. Herein we focus on the pathogenic role of a dyshomeostasis of several macro- (i.e. Ca2+ and Mg2+) and micronutrients (i.e. Zn2+, Se2+, and vitamin D) in contributing to adverse remodelling of the myocardium and its failure as a pulsatile muscular pump. An improved understanding of how these macro- and micronutrients account for the causes and consequences of adverse myocardial remodelling carries with it the potential of identifying new biomarkers predictive of risk, onset and progression, and response to intervention(s), which could be monitored non-invasively and serially over time. Moreover, such incremental knowledge will serve as the underpinning to the development of novel strategies aimed at preventing and/or regressing the ongoing adverse remodelling of myocardium. The time is at hand to recognize the importance of macro- and micronutrient dyshomeostasis in the evaluation and management of hypertension and heart failure. PMID:18835843

  16. Protective effects of grape seed proanthocyanidins on cardiovascular remodeling in DOCA-salt hypertension rats.

    PubMed

    Huang, Ling-ling; Pan, Chen; Wang, Li; Ding, Ling; Guo, Kun; Wang, Hong-zhi; Xu, A-Man; Gao, Shan

    2015-08-01

    Cardiovascular remodeling, as a hallmark of hypertension-induced pathophysiology, causes substantial cardiovascular morbidity and mortality. There is increasing evidence that has demonstrated a broad spectrum of pharmacological and therapeutic benefits of grape seed proanthocyanidins (GSP) against oxidative stress and cardiovascular diseases. In this study, 180- to 200-g SD rats treated with DOCA (120 mg/week sc with 1% NaCl and 0.2% KCl in drinking water) and GSP (150, 240, 384 mg/kg) or amlodipine (ALM) (5 mg/kg) for 4 weeks were recruited. The protective effects of GSP on blood pressure and cardiovascular remodeling in rats with DOCA-salt-induced hypertension were investigated. Our results indicated that DOCA-salt could induce hypertension, cardiovascular remodeling and dysfunction, oxidative stress and the release of endothelin-1 (ET-1) and could increase JNK1/2 and p38MAPK phosphorylation. GSP or ALM treatments significantly improved hypertension, cardiovascular remodeling and dysfunction and oxidative stress, restrained the release of ET-1 and down-regulated the JNK1/2 and p38MAPK phosphorylation. These findings demonstrate that GSP has protective effects against increase of blood pressure induced by DOCA-salt hypertension and cardiovascular remodeling by inhibiting the reactive oxygen species/mitogen-activated protein kinase pathway via restraining the release of ET-1. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Apelin Is a Negative Regulator of Angiotensin II-Mediated Adverse Myocardial Remodeling and Dysfunction.

    PubMed

    Zhang, Zhen-Zhou; Wang, Wang; Jin, Hai-Yan; Chen, Xueyi; Cheng, Yu-Wen; Xu, Ying-Le; Song, Bei; Penninger, Josef M; Oudit, Gavin Y; Zhong, Jiu-Chang

    2017-10-03

    The apelin pathway has emerged as a critical regulator of cardiovascular homeostasis and disease. However, the exact role of pyr1-apelin-13 in angiotensin (Ang) II-mediated heart disease remains unclear. We used apelin-deficient (APLN(-)(/y)) and apolipoprotein E knockout mice to evaluate the regulatory roles of pyr1-apelin-13. The 1-year aged APLN(-)(/y) mice developed myocardial hypertrophy and dysfunction with reduced angiotensin-converting enzyme 2 levels. Ang II infusion (1.5 mg kg(-)(1) d(-)(1)) for 4 weeks potentiated oxidative stress, pathological hypertrophy, and myocardial fibrosis in young APLN(-)(/y) hearts resulting in exacerbation of cardiac dysfunction. Importantly, daily administration of 100 μg/kg pyr1-apelin-13 resulted in upregulated angiotensin-converting enzyme 2 levels, decreased superoxide production and expression of hypertrophy- and fibrosis-related genes leading to attenuated myocardial hypertrophy, fibrosis, and dysfunction in the Ang II-infused apolipoprotein E knockout mice. In addition, pyr1-apelin-13 treatment largely attenuated Ang II-induced apoptosis and ultrastructural injury in the apolipoprotein E knockout mice by activating Akt and endothelial nitric oxide synthase phosphorylation signaling. In cultured neonatal rat cardiomyocytes and cardiofibroblasts, exposure of Ang II decreased angiotensin-converting enzyme 2 protein and increased superoxide generation, cellular proliferation, and migration, which were rescued by pyr1-apelin-13, and Akt and endothelial nitric oxide synthase agonist stimulation. The increased superoxide generation and apoptosis in cultured cardiofibroblasts in response to Ang II were strikingly prevented by pyr1-apelin-13 which was partially reversed by cotreatment with the Akt inhibitor MK2206. In conclusion, pyr1-apelin-13 peptide pathway is a negative regulator of aging-mediated and Ang II-mediated adverse myocardial remodeling and dysfunction and represents a potential candidate to prevent and treat

  18. Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling.

    PubMed

    Medzikovic, Lejla; Schumacher, Cees A; Verkerk, Arie O; van Deel, Elza D; Wolswinkel, Rianne; van der Made, Ingeborg; Bleeker, Natascha; Cakici, Daniella; van den Hoogenhof, Maarten M G; Meggouh, Farid; Creemers, Esther E; Remme, Carol Ann; Baartscheer, Antonius; de Winter, Robbert J; de Vries, Carlie J M; Arkenbout, E Karin; de Waard, Vivian

    2015-10-21

    Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca(2+) ([Ca(2+)]i). However, chronic β-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by β-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with β-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca(2+)]i and prolonged action potentials compared to wild type (WT). In vivo, these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes, and more cardiac fibrosis in Nur77-KO mice upon chronic isoproterenol stimulation. In line with the observed elevated [Ca(2+)]i, Ca(2+)-activated phosphatase calcineurin was more active in Nur77-KO mice compared to WT. In contrast, after cardiac pressure overload by aortic constriction, Nur77-KO mice exhibited attenuated remodelling compared to WT. Concluding, Nur77-deficiency results in significantly altered cardiac Ca(2+) homeostasis and distinct remodelling outcome depending on the type of insult. Detailed knowledge on the role of Nur77 in maintaining cardiomyocyte Ca(2+) homeostasis and the dual role Nur77 plays in cardiac remodelling will aid in developing personalized therapies against heart failure.

  19. [Are there cardiovascular adverse effects of inhaled anticholinergics?].

    PubMed

    Nagy, László Béla

    2015-08-02

    The purpose of this review is to discuss the cardiovascular risk associated with inhaled anticholinergics in chronic obstructive pulmonary disease. Several meta-analyses of data for tiotropium raised the possibility of an increased risk for arrhythmia, angina, myocardial infarction, etc. This review includes the data of retrospective studies of databases using databases, randomized controlled trials, and meta-analyses of clinical trials. The conclusions of studies were inconsistent. In most clinical trials the incidence of cardiovascular adverse events was similar in active treatment and placebo groups, especially in patients with previous cardiovascular diseases. Considering meta-analyses, there is little, if any, evidence for the association between anticholinergics and the development of cardiovascular symptoms. The author discusses the presence and function of cholinergic receptor subtypes in human heart, and cardiac functions controlled by the autonomic nervous system via these receptors, their possible role, and pharmacokinetic properties of inhaled anticholinergics. The author concludes that it is not possible to find evidence of increased cardiovascular harm of inhaled anticholinergics.

  20. Improving the adverse cardiovascular prognosis of type 2 diabetes.

    PubMed

    O'Keefe, J H; Miles, J M; Harris, W H; Moe, R M; McCallister, B D

    1999-02-01

    Approximately 80% of all patients with diabetes die of cardiovascular disease. The traditional management of type 2 diabetes has been ineffective in altering this dismal prognosis. Insulin resistance is the fundamental defect of type 2 diabetes. Insulin resistance often leads to hyperinsulinemia, which is associated with hypertension, atherogenic dyslipidemia, left ventricular hypertrophy, impaired fibrinolysis, visceral obesity, and sedentary lifestyle. Although all these conditions are associated with atherosclerosis and adverse cardiovascular events, the therapeutic efforts in patients with diabetes have focused predominantly on normalizing glucose levels. Improved insulin sensitivity through lifestyle modifications or pharmacologic therapy (troglitazone and metformin) will lower both insulin and glucose levels as well as diminish dyslipidemia and hypertension. In contrast, sulfonylurea agents lower glucose by increasing insulin levels and may increase the risk of cardiovascular events. Therapy including aspirin, lipid agents (for example, statins), angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, postmenopausal estrogen replacement, and vitamin E should be considered for patients with type 2 diabetes. In most patients with diabetes who have multivessel coronary artery disease, coronary artery bypass grafting is superior to coronary angioplasty for improving long-term cardiovascular prognosis. This superiority is mediated in part by the use of a left internal mammary graft to the left anterior descending coronary artery. Urgent coronary angioplasty or thrombolytic therapy should be considered for all patients with diabetes who have acute myocardial infarction.

  1. Delayed, oral pharmacological inhibition of calpains attenuates adverse post-infarction remodelling.

    PubMed

    Poncelas, Marcos; Inserte, Javier; Aluja, David; Hernando, Victor; Vilardosa, Ursula; Garcia-Dorado, David

    2017-07-01

    Calpains activate during myocardial ischemia-reperfusion and contribute to reperfusion injury. Studies in transgenic animals with altered calpain/calpastatin system subjected to permanent ischemia suggest that calpains are also involved in post-infarction remodelling and heart failure. To determine whether delayed oral administration of the calpain inhibitor SNJ-1945 reduces adverse myocardial remodelling and dysfunction following transient coronary occlusion. Male Sprague-Dawley rats were subjected to 30 min of ischemia followed by 21 days of reperfusion and received the calpain inhibitor SNJ-1945 intraperitoneally at the onset of reperfusion (Acute group), orally starting after 24 h of reperfusion and for 14 days (Chronic group), or the combination of both treatments. Calpain-1 and calpain-2 protein content increased and correlated with higher calpain activity in control hearts. Administration of SNJ-1945 attenuated calpain activation, and reduced scar expansion, ventricular dilation and dysfunction in both acute and chronic groups. Acute treatment reduced infarct size in hearts reperfused for 24 h and inflammation measured after 3 days. Delayed, chronic oral administration of SNJ-1945 attenuated inflammation, cardiomyocyte hypertrophy and collagen infiltration in the non-infarcted myocardium at 21 days in correlation with increased levels of IĸB and reduced NF-ĸB activation. In cultured fibroblasts, SNJ-1945 attenuated TGF-β1-induced fibroblast activation. Our data demonstrate for the first time that long-term calpain inhibition is possible with delayed oral treatment, attenuates adverse post-infarction remodelling, likely through prevention of NF-ĸB activation, and may be a promising therapeutic intervention to prevent adverse remodelling and heart failure in patients with acute myocardial infarction.

  2. UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine.

    PubMed

    Uitterdijk, André; Hermans, Kevin C M; de Wijs-Meijler, Daphne P M; Daskalopoulos, Evangelos P; Reiss, Irwin K; Duncker, Dirk J; Matthijs Blankesteijn, W; Merkus, Daphne

    2016-02-01

    Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (-41±10%), whereas infarct mass remained stable in the Control-MI group (+3±17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53±0.43% vs 3.38±0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling.

  3. Analysis of post-infarction salvaged myocardium by cardiac magnetic resonance. Predictors and influence on adverse ventricular remodeling.

    PubMed

    Monmeneu, José V; Bodí, Vicente; López-Lereu, María P; Sanchis, Juan; Núñez, Julio; Chaustre, Fabián; Husser, Oliver; Merlos, Pilar; Bonanad, Clara; Miñana, Gema; Chorro, Francisco J; Llácer, Angel

    2012-07-01

    To evaluate by cardiovascular magnetic resonance those factors related to the amount of salvaged myocardium after a myocardial infarction and its value in predicting adverse ventricular remodeling. One hundred eighteen patients admitted for a first ST elevation myocardial infarction (primary angioplasty, 65 patients; a pharmacoinvasive strategy, 53 patients) underwent magnetic resonance (6 [5-8] days and 6 months; n=83). The myocardial salvage index was quantitatively assessed as the percentage of area at risk (T2-weighted sequences) not showing late enhancement. Myocardial salvage index >31% (median) was associated with a shorter time to reperfusion (153 min vs 258 min), a lower rate of diabetes (12% vs 32%), shorter time to magnetic resonance, and better cardiovascular parameters (P<.05 for all analyses). There were no significant differences depending on the reperfusion method. In a logistic regression analysis, delayed reperfusion (odds ratio=0.42 [0.29-0.63]; P<.0001), diabetes (odds ratio=0.32 [0.11-0.99]; P<.05) and a longer time to the performance of magnetic resonance (odds ratio=0.86 [0.76-0.97]; P<.05) were independently related to a lower probability of a myocardial salvage index >31%. Predictors of increased left ventricular end-systolic volume at 6 months were the number of segments showing an extent of transmural necrosis >50% (odds ratio =1.51 [1.21-1.90]; P<.0001) and left ventricular end-systolic volume at one week (odds ratio=1.12 [1.06-1.18]; P<.0001). Cardiovascular magnetic resonance enables the quantification of the salvaged myocardium after myocardial infarction. The celerity with which reperfusion therapy is administered constitutes its most important predictor. The possible effect of a delay in the performance of magnetic resonance on myocardial salvage needs to be confirmed. Salvaged myocardium does not improve the value of magnetic resonance for predicting adverse remodeling. Copyright © 2012 Sociedad Española de Cardiolog

  4. Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance

    PubMed Central

    Kurtz, Baptiste; Thibault, Helene B.; Raher, Michael J.; Popovich, John R.; Cawley, Sharon; Atochin, Dmitriy N.; Hayton, Sarah; Shakartzi, Hannah R.; Huang, Paul L.; Bloch, Kenneth D.; Buys, Emmanuel

    2011-01-01

    Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3−/−) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2′,7′-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3−/− mice than in SD-fed WT mice. In contrast, HFD-fed NOS3−/− developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3−/− than in those from HFD-fed WT. Nω-nitro-l-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3−/− mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts. PMID:21856905

  5. Residual Myocardial Iron Following Intramyocardial Hemorrhage During the Convalescent Phase of Reperfused ST-Segment-Elevation Myocardial Infarction and Adverse Left Ventricular Remodeling.

    PubMed

    Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; White, Steven K; Bhuva, Anish N; Treibel, Thomas A; Fontana, Marianna; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Herrey, Anna S; Manisty, Charlotte; Yellon, Derek M; Kellman, Peter; Moon, James C; Hausenloy, Derek J

    2016-10-01

    The presence of intramyocardial hemorrhage (IMH) in ST-segment-elevation myocardial infarction patients reperfused by primary percutaneous coronary intervention has been associated with residual myocardial iron at follow-up, and its impact on adverse left ventricular (LV) remodeling is incompletely understood and is investigated here. Forty-eight ST-segment-elevation myocardial infarction patients underwent cardiovascular magnetic resonance at 4±2 days post primary percutaneous coronary intervention, of whom 40 had a follow-up scan at 5±2 months. Native T1, T2, and T2* maps were acquired. Eight out of 40 (20%) patients developed adverse LV remodeling. A subset of 28 patients had matching T2* maps, of which 15/28 patients (54%) had IMH. Eighteen of 28 (64%) patients had microvascular obstruction on the acute scan, of whom 15/18 (83%) patients had microvascular obstruction with IMH. On the follow-up scan, 13/15 patients (87%) had evidence of residual iron within the infarct zone. Patients with residual iron had higher T2 in the infarct zone surrounding the residual iron when compared with those without. In patients with adverse LV remodeling, T2 in the infarct zone surrounding the residual iron was also higher than in those without (60 [54-64] ms versus 53 [51-56] ms; P=0.025). Acute myocardial infarct size, extent of microvascular obstruction, and IMH correlated with the change in LV end-diastolic volume (Pearson's rho of 0.64, 0.59, and 0.66, respectively; P=0.18 and 0.62, respectively, for correlation coefficient comparison) and performed equally well on receiver operating characteristic curve for predicting adverse LV remodeling (area under the curve: 0.99, 0.94, and 0.95, respectively; P=0.19 for receiver operating characteristic curve comparison). The majority of ST-segment-elevation myocardial infarction patients with IMH had residual myocardial iron at follow-up. This was associated with persistently elevated T2 values in the surrounding infarct tissue and

  6. Residual Myocardial Iron Following Intramyocardial Hemorrhage During the Convalescent Phase of Reperfused ST-Segment–Elevation Myocardial Infarction and Adverse Left Ventricular Remodeling

    PubMed Central

    Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; White, Steven K.; Bhuva, Anish N.; Treibel, Thomas A.; Fontana, Marianna; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Herrey, Anna S.; Manisty, Charlotte; Yellon, Derek M.; Kellman, Peter; Moon, James C.

    2016-01-01

    Background— The presence of intramyocardial hemorrhage (IMH) in ST-segment–elevation myocardial infarction patients reperfused by primary percutaneous coronary intervention has been associated with residual myocardial iron at follow-up, and its impact on adverse left ventricular (LV) remodeling is incompletely understood and is investigated here. Methods and Results— Forty-eight ST-segment–elevation myocardial infarction patients underwent cardiovascular magnetic resonance at 4±2 days post primary percutaneous coronary intervention, of whom 40 had a follow-up scan at 5±2 months. Native T1, T2, and T2* maps were acquired. Eight out of 40 (20%) patients developed adverse LV remodeling. A subset of 28 patients had matching T2* maps, of which 15/28 patients (54%) had IMH. Eighteen of 28 (64%) patients had microvascular obstruction on the acute scan, of whom 15/18 (83%) patients had microvascular obstruction with IMH. On the follow-up scan, 13/15 patients (87%) had evidence of residual iron within the infarct zone. Patients with residual iron had higher T2 in the infarct zone surrounding the residual iron when compared with those without. In patients with adverse LV remodeling, T2 in the infarct zone surrounding the residual iron was also higher than in those without (60 [54–64] ms versus 53 [51–56] ms; P=0.025). Acute myocardial infarct size, extent of microvascular obstruction, and IMH correlated with the change in LV end-diastolic volume (Pearson’s rho of 0.64, 0.59, and 0.66, respectively; P=0.18 and 0.62, respectively, for correlation coefficient comparison) and performed equally well on receiver operating characteristic curve for predicting adverse LV remodeling (area under the curve: 0.99, 0.94, and 0.95, respectively; P=0.19 for receiver operating characteristic curve comparison). Conclusions— The majority of ST-segment–elevation myocardial infarction patients with IMH had residual myocardial iron at follow-up. This was associated with

  7. Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse RemodelingCLINICAL PERSPECTIVE

    SciTech Connect

    Kali, Avinash; Cokic, Ivan; Tang, Richard; Dohnalkova, Alice; Kovarik, Libor; Yang, Hsin-Jung; Kumar, Andreas; Prato, Frank S.; Wood, John C.; Underhill, David; Marbán, Eduardo; Dharmakumar, Rohan

    2016-11-01

    Emerging evidence now supports the notion that persistent microvascular obstruction (PMO) may be more predictive of major adverse cardiovascular events than MI size itself. But, how PMO, a phenomenon limited to the acute/sub-acute period of MI, imparts adverse remodeling throughout the post MI period, particularly after its resolution, is incompletely understood. We hypothesized that PMOs resolve into chronic iron crystals within MI territories and actively impart a proinflammatory burden and adverse remodeling of infarction and LV in the chronic phase of MI. Canine models reperfused (n=20) and non-reperfused (n=20) with and without PMO were studied with serial cardiac MRI to characterize the spatiotemporal relationships between PMO, iron deposition, and infarct and LV remodeling indices between acute (day 7, post MI) and chronic (week 8, post MI). Histopathology and immunohistochemistry were used to validate the iron deposition, microscopically map and quantify the relationship between iron-rich chronic MI regions against pro-inflammatory macrophages, proinflammatory cytokines and matrix metalloproteinase. Atomic resolution transmission electron microscopy (TEM) was used to determine the crystallinity of iron and assess the physical effects of iron on lysosomes within macrophages, and energy-dispersive X-ray spectroscopy (EDS) to identify the chemical composition of the iron composite. Results showed that PMOs lead to iron deposition within chronic MI and that the extent of chronic iron deposition is strongly related to PMO Volume (r>0.6, p<0.001). TEM and EDS analysis showed that iron within chronic MI is found within macrophages as aggregates of nanocrystals of ~2.5 nm diameter in ferric state. Correlative histological studies showed that iron content, proinflammatory burden and collagen degrading enzyme were highly correlated (r >0.7, p<0.001). Iron within chronic MI was significantly associated with infarct resorption (r>0.5, p<0.001) and adverse structural (r

  8. Cardiovascular Adaptation and Remodeling to Rigorous Athletic Training.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2015-07-01

    Exercise-induced cardiac remodeling is a complex process by which the cardinal hemodynamic stresses of pressure and volume lead to a host of structural or functional adaptations. In aggregate, the constellation of changes that accompany this process serve to facilitate athletic performance by minimizing the cardiac work inherent in athletic activity. Although several key determinants of athletic cardiac adaptation have been described, observed variability across athlete cohorts remains an incompletely understood area. Ongoing and future work are required to further understand this process and ultimately to determine where the boundary lies between adaptive physiology and maladaptive disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. LATE GADOLINIUM ENHANCEMENT BY CARDIOVASCULAR MAGNETIC RESONANCE HERALDS AN ADVERSE PROGNOSIS IN NONISCHEMIC CARDIOMYOPATHY

    PubMed Central

    Wu, Katherine C.; Weiss, Robert G.; Thiemann, David R.; Kitagawa, Kakuya; Schmidt, André; Dalal, Darshan; Lai, Shenghan; Bluemke, David A.; Gerstenblith, Gary; Marbán, Eduardo; Tomaselli, Gordon F.; Lima, João A.C.

    2008-01-01

    Structured Abstract Objectives We examined whether the presence and extent of late gadolinium enhancement (LGE) by CMR predict adverse outcomes in nonischemic cardiomyopathy (NICM) patients. Background Morbidity and mortality is high in NICM patients. However, the clinical course of an individual patient is unpredictable and current risk stratification approaches are limited. Cardiovascular magnetic resonance (CMR) detects myocardial fibrosis, which appears as LGE after contrast administration and may convey prognostic importance. Methods In a prospective cohort study, 65 NICM patients with LVEF ≤35% underwent CMR before placement of an internal cardioverter defibrillator (ICD) for primary prevention of sudden cardiac death. CMRs were analyzed for the presence and extent of LGE, and for LV function, volumes, and mass. Patients were followed for an index composite endpoint of three cardiac events: hospitalization for heart failure, appropriate ICD firing, and cardiac death. Results 42% (n=27) of patients had CMR LGE, averaging 10±13% of LV mass. During a 17 month median follow-up, 44% (n=12) of patients with LGE had an index composite outcome event, versus only 8% (n=3) of those without LGE (p<0.001 for Kaplan-Meier survival curves). After adjustment for LV volume index and functional class, patients with LGE had an eight-fold higher risk of experiencing the primary outcome (hazard ratio 8.2, 95% CI 2.2–30.9, p=0.002). Conclusions CMR LGE in NICM patients strongly predicts adverse cardiac outcomes. CMR LGE may represent the end-organ consequences of sustained adrenergic activation and adverse LV remodeling, and its identification may significantly improve risk stratification strategies in this high risk population. Condensed Abstract Predicting prognosis in nonischemic cardiomyopathy patients is challenging and current risk stratification approaches are limited. Cardiovascular magnetic resonance (CMR) detects myocardial fibrosis, which appears as late

  10. Peroxisome proliferator-activated receptors and cardiovascular remodeling.

    PubMed

    Schiffrin, Ernesto L

    2005-03-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate the function of many target genes. Three PPARs are known: alpha, beta/delta, and gamma. The better known are PPAR-alpha and PPAR-gamma, which may be activated by different synthetic agonists, although the endogenous ligands are unknown. PPAR-alpha is involved in fatty acid oxidation and expressed in the liver, kidney, and skeletal muscle, whereas PPAR-gamma is involved in fat cell differentiation, lipid storage, and insulin sensitivity. However, both have been shown to be present in variable amounts in cardiovascular tissues, including endothelium, smooth muscle cells, macrophages, and the heart. The activators of PPAR-alpha (fibrates) and PPAR-gamma (thiazolidinediones or glitazones) antagonized the actions of angiotensin II in vivo and in vitro and exerted cardiovascular antioxidant and anti-inflammatory effects. PPAR activators lowered blood pressure, induced favorable effects on the heart, and corrected vascular structure and endothelial dysfunction in several rodent models of hypertension. Activators of PPARs may become therapeutic agents useful in the prevention of cardiovascular disease beyond their effects on carbohydrate and lipid metabolism. Some side effects, such as weight gain, as well as documented aggravation of advanced heart failure through fluid retention by glitazones, may, however, limit their therapeutic application in prevention of cardiovascular disease.

  11. Pulmonary function and adverse cardiovascular outcomes: Can cardiac function explain the link?

    PubMed

    Burroughs Peña, Melissa S; Dunning, Allison; Schulte, Phillip J; Durheim, Michael T; Kussin, Peter; Checkley, William; Velazquez, Eric J

    2016-12-01

    The complex interaction between pulmonary function, cardiac function and adverse cardiovascular events has only been partially described. We sought to describe the association between pulmonary function with left heart structure and function, all-cause mortality and incident cardiovascular hospitalization. This study is a retrospective analysis of patients evaluated in a single tertiary care medical center. We used multivariable linear regression analyses to examine the relationship between FVC and FEV1 with left ventricular ejection fraction (LVEF), left ventricular internal dimension in systole and diastole (LVIDS, LVIDD) and left atrial diameter, adjusting for baseline characteristics, right ventricular function and lung hyperinflation. We also used Cox proportional hazards models to examine the relationship between FVC and FEV1 with all-cause mortality and cardiac hospitalization. A total of 1807 patients were included in this analysis with a median age of 61 years and 50% were female. Decreased FVC and FEV1 were both associated with decreased LVEF. In individuals with FVC less than 2.75 L, decreased FVC was associated with increased all-cause mortality after adjusting for left and right heart echocardiographic variables (hazard ratio [HR] 0.49, 95% CI 0.29, 0.82, respectively). Decreased FVC was associated with increased cardiac hospitalization after adjusting for left heart size (HR 0.80, 95% CI 0.67, 0.96), even in patients with normal LVEF (HR 0.75, 95% CI 0.57, 0.97). In a tertiary care center reduced pulmonary function was associated with adverse cardiovascular events, a relationship that is not fully explained by left heart remodeling or right heart dysfunction. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Nobiletin attenuates adverse cardiac remodeling after acute myocardial infarction in rats via restoring autophagy flux.

    PubMed

    Wu, Xiaoqian; Zheng, Dechong; Qin, Yuyan; Liu, Zumei; Zhang, Guiping; Zhu, Xiaoyan; Zeng, Lihuan; Liang, Zhenye

    2017-10-14

    Our previous study showed that autophagy flux was impaired with sustained heart ischemia, which exacerbated adverse cardiac remodeling after acute myocardial infarction (AMI). Here we investigated whether Nobiletin, a citrus polymethoxylated flavonoids, could restore the autophagy flux and improve cardiac prognosis after AMI. AMI was induced by ligating left anterior descending (LAD) coronary artery in rats. Nobiletin improved the post-infarct cardiac dysfunction significantly and attenuated adverse cardiac remodeling. Meanwhile, Nobiletin protected H9C2 cells against oxygen glucose deprivation (OGD) in vitro. The impaired autophagy flux due to ischemia was ameliorated after Nobiletin treatment by testing the autophagy substrate, LC3BⅡ and P62 protein level both in vivo and in vitro. GFP-mRFP-LC3 adenovirus transfection also supported that Nobiletin restored the impaired autophagy flux. Specifically, the autophagy flux inhibitor, chloroquine, but not 3 MA, alleviated Nobiletin-mediated protection against OGD. Notably, Nobiletin does not affect the activation of classical upstream autophagy signaling pathways. However, Nobiletin increased the lysosome acidation which also supported that Nobiletin accelerated autophagy flux. Taken together, our findings suggested that Nobiletin restored impaired autophagy flux and protected against acute myocardial infarction, suggesting a potential role of autophagy flux in Nobiletin-mediated myocardial protection. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Cardiac restricted overexpression of membrane type-1 matrix metalloproteinase causes adverse myocardial remodeling following myocardial infarction.

    PubMed

    Spinale, Francis G; Mukherjee, Rupak; Zavadzkas, Juozas A; Koval, Christine N; Bouges, Shenikqua; Stroud, Robert E; Dobrucki, Lawrence W; Sinusas, Albert J

    2010-09-24

    The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.

  14. Estrogen inhibits mast cell chymase release to prevent pressure overload-induced adverse cardiac remodeling.

    PubMed

    Li, Jianping; Jubair, Shaiban; Janicki, Joseph S

    2015-02-01

    Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload-induced adverse cardiac remodeling by inhibiting mast cell (MC) chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized (OVX) rats. Three days before creating the constriction, additional groups of OVX rats began receiving 17β-estradiol, a chymase inhibitor, or a MC stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, MC density and degranulation, and myocardial and plasma chymase levels were assessed 18 days postsurgery. Aortic constriction resulted in ventricular hypertrophy in intact and OVX groups, whereas collagen volume fraction was increased only in OVX rats. Chymase protein content was increased by aortic constriction in the intact and OVX groups, with the magnitude of the increase being greater in OVX rats. MC density and degranulation, plasma chymase levels, and myocardial active transforming growth factor-β1 levels were increased by aortic constriction only in OVX rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, MC density and degranulation, plasma chymase, and myocardial active transforming growth factor-β1, as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction-induced ventricular hypertrophy and collagen volume fraction in the OVX rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects, except for the reduction of chymase content. We conclude that the estrogen-inhibited release of MC chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling.

  15. Mast Cell Inhibition Attenuates Myocardial Damage, Adverse Remodeling and Dysfunction during Fulminant Myocarditis in Rat

    PubMed Central

    Mina, Yair; Rinkevich-Shop, Shunit; Konen, Eli; Goitein, Orly; Kushnir, Tammar; Epstein, Frederick H.; Feinberg, Micha S.; Leor, Jonathan; Landa-Rouben, Natalie

    2013-01-01

    Background Myocarditis is a life-threatening heart disease characterized by myocardial inflammation, necrosis and chronic fibrosis. While mast cell inhibition has been suggested to prevents fibrosis in rat myocarditis, little is known about its effectiveness in attenuating cardiac remodeling and dysfunction in myocarditis. Thus, we sought to test the hypothesis that mast cell inhibition will attenuate the inflammatory reaction and associated left ventricular (LV) remodeling and dysfunction after fulminant autoimmune myocarditis. Methods and Results To induce experimental autoimmune myocarditis, we immunized 30 rats with porcine cardiac myosin twice at a 7-day interval. On day 8 animals were randomized into treatment either with an intraperitoneal (IP) injection of 25mg/kg of cromolyn sodium (n=13), or an equivalent volume (~0.5ml IP) of normal saline (n=11). All animals were scanned by serial echocardiography studies before treatment (baseline echocardiogram) and after 20 days of cromolyn sodium (28 days after immunization). Furthermore, serial cardiac magnetic resonance was performed in a subgroup of 12 animals. After 20 days of treatment (28 days from first immunization), hearts were harvested for histopathological analysis. By echocardiography, cromolyn sodium prevented LV dilatation and attenuated LV dysfunction, compared with controls. Postmortem analysis of hearts showed that cromolyn sodium reduced myocardial fibrosis, as well as the number and size of cardiac mast cells in the inflamed myocardium, compared with controls. Conclusions Our study suggests that mast cell inhibition with cromolyn sodium attenuates adverse LV remodeling and dysfunction in myocarditis. This mechanism-based therapy is clinically relevant and could improve the outcome of patients at risk for inflammatory cardiomyopathy and heart failure. PMID:23172937

  16. Basic mechanisms for adverse cardiovascular events associated with air pollution

    PubMed Central

    Chin, Michael T.

    2015-01-01

    Air pollution is a significant cause of cardiovascular morbidity and mortality worldwide. Although the epidemiologic association between air pollution exposures and exacerbation of cardiovascular disease is well established, the mechanisms by which these exposures promote cardiovascular disease are incompletely understood. In this review I will give an overview of the components of air pollution, an overview of the cardiovascular effects of air pollution exposure and a review of the basic mechanisms that are activated by exposure to promote cardiovascular disease. PMID:25552258

  17. ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension.

    PubMed

    Mendoza-Torres, Evelyn; Oyarzún, Alejandra; Mondaca-Ruff, David; Azocar, Andrés; Castro, Pablo F; Jalil, Jorge E; Chiong, Mario; Lavandero, Sergio; Ocaranza, María Paz

    2015-08-01

    The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling. © The Author(s), 2015.

  18. Overexpression of TIMP-1 in embryonic stem cells attenuates adverse cardiac remodeling following myocardial infarction.

    PubMed

    Glass, Carley; Singla, Dinender K

    2012-01-01

    Transplanted embryonic stem (ES) cells, following myocardial infarction (MI), contribute to limited cardiac repair and regeneration with improved function. Therefore, novel strategies are still needed to understand the effects of genetically modified transplanted stem cells on cardiac remodeling. The present study evaluates whether transplanted mouse ES cells overexpressing TIMP-1, an antiapoptotic and antifibrotic protein, can enhance cardiac myocyte differentiation, inhibit native cardiac myocyte apoptosis, reduce fibrosis, and improve cardiac function in the infarcted myocardium. MI was produced in C57BL/6 mice by coronary artery ligation. TIMP-1-ES cells, ES cells, or culture medium (control) were transplanted into the peri-infarct region of the heart. Immunofluorescence, TUNEL staining, caspase-3 activity, ELISAs, histology, and echocardiography were used to identify newly differentiated cardiac myocytes and assess apoptosis, fibrosis, and heart function. Two weeks post-MI, significantly (p < 0.05) enhanced engraftment and cardiac myocyte differentiation was observed in TIMP-1-ES cell-transplanted hearts compared with hearts transplanted with ES cells and control. Hearts transplanted with TIMP-1-ES cells demonstrated a reduction in apoptosis as well as an increase (p< 0.05) in p-Akt activity compared with ES cells or culture media controls. Infarct size and interstitial and vascular fibrosis were significantly (p< 0.05) decreased in the TIMP-1-ES cell group compared to controls. Furthermore, MMP-9, a key profibrotic protein, was significantly (p < 0.01) reduced following TIMP-1-ES cell transplantation. Echocardiography data showed fractional shortening and ejection fraction were significantly (p< 0.05) improved in the TIMP-1-ES cell group compared with respective controls. Our data suggest that transplanted ES cells overexpressing TIMP-1 attenuate adverse myocardial remodeling and improve cardiac function compared with ES cells that may have therapeutic

  19. Qiliqiangxin Attenuates Adverse Cardiac Remodeling after Myocardial Infarction in Ovariectomized Mice via Activation of PPARγ.

    PubMed

    Shen, Shutong; Jiang, Huimin; Bei, Yihua; Zhang, Jialiang; Zhang, Haifeng; Zhu, Hongsheng; Zhang, Chenlin; Yao, Wenming; Wei, Cong; Shang, Hongcai; Li, Xinli

    2017-06-23

    This study was designed to investigate the therapeutic effect of traditional Chinese medication Qiliqiangxin (QLQX) on adverse cardiac remodeling after myocardial infarction (MI) in bilateral ovariectomized (OVX) female mice. Eight-week old female C57BL/6 mice were operated to ligate the left anterior descending coronary artery seven days after bilateral ovariectomy and were orally administered either QLQX or vehicle. 21 days after ligation, echocardiography was performed to evaluate the heart function of all mice. Masson's Trichrome staining was applied to evaluate myocardial fibrosis. Collagen deposition was determined by the mRNA level of Collagen I, Collagen III and α-SMA using real-time quantitative polymerase chain reaction (qPCR). Myocardial apoptosis was examined by the protein level of Bax, Bcl2 and the Bcl2/Bax ratio using western blotting. These mice displayed a significant reduction in heart function, increased myocardial fibrosis and apoptosis, and decreased expression of peroxisome proliferator activated receptor γ (PPARγ) in the heart tissue, which could be reversed by QLQX treatment. Inhibition of PPAR reduced QLQX-mediated cardio-protective effects, while PPARγ activation did not further enhance the beneficial effect of QLQX. Furthermore, QLQX upregulated 9 genes (Cd36, Fatp, Pdk4, Acadm, Acadl, Acadvl, Cpt1a, Cpt1b and Cpt2) facilitating energy metabolism in the MI hearts of the OVX mice and 5 (Acadm, Acadl, Cpt1a, Cpt1b, Cpt2) of the 9 genes were the downstream targets of PPARγ. The present study indicates that QLQX has a treatment effect on pathological remodeling post MI in bilateral OVX female mice via activation of PPARγ, suggesting that QLQX may be a promising prescription for the treatment of postmenopausal women suffering from MI. © 2017 The Author(s). Published by S. Karger AG, Basel.

  20. Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: role of autophagy.

    PubMed

    Zhang, Yao-Jun; Yang, Shao-Hua; Li, Ming-Hui; Iqbal, Javaid; Bourantas, Christos V; Mi, Qiong-Yu; Yu, Yi-Hui; Li, Jing-Jing; Zhao, Shu-Li; Tian, Nai-Liang; Chen, Shao-Liang

    2014-12-01

    The present study aimed to test the hypothesis that berberine, a plant-derived anti-oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction (MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague-Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC-3B, Beclin-1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high-dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post-MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC-3B II and Beclin-1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho-Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho-Akt signalling pathways.

  1. Intermittent Hypoxia-Induced Cardiovascular Remodeling Is Reversed by Normoxia in a Mouse Model of Sleep Apnea.

    PubMed

    Castro-Grattoni, Anabel L; Alvarez-Buvé, Roger; Torres, Marta; Farré, Ramon; Montserrat, Josep M; Dalmases, Mireia; Almendros, Isaac; Barbé, Ferran; Sánchez-de-la-Torre, Manuel

    2016-06-01

    Intermittent hypoxia (IH) is the principal injurious factor involved in the cardiovascular morbidity and mortality associated with OSA. The gold standard for treatment is CPAP, which eliminates IH and appears to reduce cardiovascular risk. There is no experimental evidence on the reversibility of cardiovascular remodeling after IH withdrawal. The objective of the present study is to assess the reversibility of early cardiovascular structural remodeling induced by IH after resumption of normoxic breathing in a novel recovery animal model mimicking OSA treatment. We investigated cardiovascular remodeling in C57BL/6 mice exposed to IH for 6 weeks vs the normoxia group and its spontaneous recovery after 6 subsequent weeks under normoxia. Aortic expansive remodeling was induced by IH, with intima-media thickening and without lumen perimeter changes. Elastic fiber network disorganization, fragmentation, and estrangement between the end points of disrupted fibers were increased by IH. Extracellular matrix turnover was altered, as visualized by collagen and mucoid interlaminar accumulation. Furthermore, left ventricular perivascular fibrosis was increased by IH, whereas cardiomyocytes size was unaffected. These cardiovascular remodeling events induced by IH were normalized after recovery in normoxia, mimicking CPAP treatment. The early structural cardiovascular remodeling induced by IH was normalized after IH removal, revealing a novel recovery model for studying the effects of OSA treatment. Our findings suggest the clinical relevance of early detection and effective treatment of OSA in patients to prevent the natural course of cardiovascular diseases. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  2. Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activity.

    PubMed

    Kuwahara, Koichiro; Teg Pipes, Gordon C; McAnally, John; Richardson, James A; Hill, Joseph A; Bassel-Duby, Rhonda; Olson, Eric N

    2007-05-01

    Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor-dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor-2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.

  3. Pathological Role of Serum- and Glucocorticoid-Regulated Kinase 1 in Adverse Ventricular Remodeling

    PubMed Central

    Das, Saumya; Aiba, Takeshi; Rosenberg, Michael; Hessler, Katherine; Xiao, Chunyang; Quintero, Pablo A.; Ottaviano, Filomena G.; Knight, Ashley C.; Graham, Evan L.; Boström, Pontus; Morissette, Michael R.; del Monte, Federica; Begley, Michael J.; Cantley, Lewis C.; Ellinor, Patrick T.; Tomaselli, Gordon F.; Rosenzweig, Anthony

    2012-01-01

    Background Heart failure is a growing cause of morbidity and mortality. Cardiac PI3-kinase signaling promotes cardiomyocyte survival and function but is paradoxically activated in heart failure, suggesting chronic activation of this pathway may become maladaptive. Here we investigated the downstream PI3-kinase effector, SGK1 (serum- and glucocorticoid-regulated kinase-1), in heart failure and its complications. Methods and Results We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart using cardiac-specific expression of constitutively-active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The pro-arrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations. Conclusions SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease. PMID:23019294

  4. Basic mechanisms for adverse cardiovascular events associated with air pollution.

    PubMed

    Chin, Michael T

    2015-02-01

    Air pollution is a significant cause of cardiovascular morbidity and mortality worldwide. Although the epidemiologic association between air pollution exposures and exacerbation of cardiovascular disease (CVD) is well established, the mechanisms by which these exposures promote CVD are incompletely understood. This review provides an overview of the components of air pollution, an overview of the cardiovascular effects of air pollution exposure, and a review of the basic mechanisms that are activated by exposure to promote CVD. 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.

  5. Endothelial progenitor cell transplantation decreases lymphangiogenesis and adverse myocardial remodeling in a mouse model of acute myocardial infarction.

    PubMed

    Park, Jae-Hyeong; Yoon, Jung Yeon; Ko, Seon Mi; Jin, Seon Ah; Kim, Jun Hyung; Cho, Chung-Hyun; Kim, Jin-Man; Lee, Jae-Hwan; Choi, Si Wan; Seong, In-Whan; Jeong, Jin Ok

    2011-08-31

    Cardiac lymphatic system in the remodeling after acute myocardial infarction (AMI) has been overlooked. We wanted to investigate the role of bone marrow-derived endothelial progenitor cells (EPCs) and their contribution to lymphatic distribution in myocardial remodeling after AMI. Mouse (C57bl/6J) MI models were created by ligation of the left anterior descending coronary artery and were treated with phosphate buffered saline (PBS) or EPCs. Real-time RT-PCR with 2- to 4-week myocardial tissue samples revealed that lymphangiogenetic factors such as vascular endothelial growth factor (VEGF)-C (8.5 fold, P < 0.05), VEGF-D (6.1 fold, P < 0.05), Lyve-1 (15 fold, P < 0.05), and Prox-1 (11 fold, P < 0.05) were expressed at significantly higher levels in the PBS group than the EPC group. The PBS group also showed a significantly higher density of lymphatic vessels in the peri-infarction area. Echocardiography showed that from 2 weeks after the treatment, left ventricle (LV) dimensions at both systole and diastole were significantly smaller in the EPC group than in the PBS group (P < 0.01) and LV fractional shortening was higher in the EPC group accordingly (P < 0.01). Lymphangiogenic markers increased in a mouse MI model. EPC transplantation decreased lymphangiogenesis and adverse ventricular remodeling after AMI. These novel findings suggest that new lymphatic vessels may be formed in severely damaged myocardium, and may be involved in adverse myocardial remodeling after AMI.

  6. Silencing salusin-β attenuates cardiovascular remodeling and hypertension in spontaneously hypertensive rats

    PubMed Central

    Ren, Xing-Sheng; Ling, Li; Zhou, Bing; Han, Ying; Zhou, Ye-Bo; Chen, Qi; Li, Yue-Hua; Kang, Yu-Ming; Zhu, Guo-Qing

    2017-01-01

    Salusin-β is a bioactive peptide involved in vascular smooth muscle cell proliferation, vascular fibrosis and hypertension. The present study was designed to determine the effects of silencing salusin-β on hypertension and cardiovascular remodeling in spontaneously hypertensive rats (SHR). Thirteen-week-old male SHR and normotensive Wistar-Kyoto rats (WKY) were subjected to intravenous injection of PBS, adenoviral vectors encoding salusin-β shRNA (Ad-Sal-shRNA) or a scramble shRNA. Salusin-β levels in plasma, myocardium and mesenteric artery were increased in SHR. Silencing salusin-β had no significant effect on blood pressure in WKY, but reduced blood pressure in SHR. It reduced the ratio of left ventricle weight to body weight, cross-sectional areas of cardiocytes and perivascular fibrosis, and decreased the media thickness and the media/lumen ratio of arteries in SHR. Silencing salusin-β almost normalized plasma norepinephrine and angiotensin II levels in SHR. It prevented the upregulation of angiotensin II and AT1 receptors, and reduced the NAD(P)H oxidase activity and superoxide anion levels in myocardium and mesenteric artery of SHR. Knockdown of salusin-β attenuated cell proliferation and fibrosis in vascular smooth muscle cells from SHR. These results indicate that silencing salusin-β attenuates hypertension and cardiovascular remodeling in SHR. PMID:28230187

  7. Soy protein hydrolysate ameliorates cardiovascular remodeling in rats with L-NAME-induced hypertension.

    PubMed

    Yang, Hsin-Yi; Yang, Suh-Ching; Chen, Shu-Tzu; Chen, Jiun-Rong

    2008-12-01

    Pepsin-digested soy protein hydrolysate has been reported to be responsible for many of the physiological benefits associated with soy protein consumption. In the present study, we investigated the effects of soy protein hydrolysate with angiotensin-converting enzyme (ACE) inhibitory potential on the blood pressure and cardiovascular remodeling in rats with N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertension. Rats were fed a diet containing L-NAME (50 mg/kg body weight) with or without soy protein hydrolysate (1%, 3% or 5%) for 6 weeks. We found that ingestion of soy protein hydrolysate retarded the development of hypertension during the 6-week experimental period without affecting the amount of food intake. Although there was no difference in plasma ACE activity or tissue nitric oxide levels, ACE activity in the heart of rats consuming soy protein hydrolysate was significantly lower than that of the control group. Moreover, cardiac malonaldehyde and tumor necrosis factor-alpha concentrations were also lower in the soy protein hydrolysate group. No difference in plasminogen activator inhibitor-1 level was found in plasma or cardiovascular tissue. In the histopathological analysis, we also found that soy protein hydrolysate ameliorated inflammation and left ventricle hypertrophy in the heart. These findings suggest that soy protein hydrolysate might not only improve the balance between circulating nitric oxide and renin-angiotensin system but also show beneficial effects on cardiovascular tissue through its ACE inhibitory activity.

  8. Elastin-insufficient mice show normal cardiovascular remodeling in 2K1C hypertension despite higher baseline pressure and unique cardiovascular architecture.

    PubMed

    Wagenseil, Jessica E; Knutsen, Russell H; Li, Dean Y; Mecham, Robert P

    2007-07-01

    Mice heterozygous for the elastin gene (ELN(+/-)) show unique cardiovascular properties, including increased blood pressure and smaller, thinner arteries with an increased number of lamellar units. Some of these properties are also observed in humans with supravalvular aortic stenosis, a disease caused by functional heterozygosity of the elastin gene. The arterial geometry in ELN(+/-) mice is contrary to the increased thickness that would be expected in an animal demonstrating hypertensive remodeling. To determine whether this is due to a decreased capability for cardiovascular remodeling or to a novel adaptation of the ELN(+/-) cardiovascular system, we increased blood pressure in adult ELN(+/+) and ELN(+/-) mice using the two-kidney, one-clip Goldblatt model of hypertension. Successfully clipped mice have a systolic pressure increase of at least 15 mmHg over sham-operated animals. ELN(+/+) and ELN(+/-)-clipped mice show significant increases over sham-operated mice in cardiac weight, arterial thickness, and arterial cross-sectional area with no changes in lamellar number. There are no significant differences in most mechanical properties with clipping in either genotype. These results indicate that ELN(+/+) and ELN(+/-) hearts and arteries remodel similarly in response to adult induced hypertension. Therefore, the cardiovascular properties of ELN(+/-) mice are likely due to developmental remodeling in response to altered hemodynamics and reduced elastin levels.

  9. Role of MicroRNAs in Renin-Angiotensin-Aldosterone System-Mediated Cardiovascular Inflammation and Remodeling

    PubMed Central

    Tchounwou, Paul B.

    2015-01-01

    MicroRNAs are endogenous regulators of gene expression either by inhibiting translation or protein degradation. Recent studies indicate that microRNAs play a role in cardiovascular disease and renin-angiotensin-aldosterone system- (RAAS-) mediated cardiovascular inflammation, either as mediators or being targeted by RAAS pharmacological inhibitors. The exact role(s) of microRNAs in RAAS-mediated cardiovascular inflammation and remodeling is/are still in early stage of investigation. However, few microRNAs have been shown to play a role in RAAS signaling, particularly miR-155, miR-146a/b, miR-132/122, and miR-483-3p. Identification of specific microRNAs and their targets and elucidating microRNA-regulated mechanisms associated RAS-mediated cardiovascular inflammation and remodeling might lead to the development of novel pharmacological strategies to target RAAS-mediated vascular pathologies. This paper reviews microRNAs role in inflammatory factors mediating cardiovascular inflammation and RAAS genes and the effect of RAAS pharmacological inhibition on microRNAs and the resolution of RAAS-mediated cardiovascular inflammation and remodeling. Also, this paper discusses the advances on microRNAs-based therapeutic approaches that may be important in targeting RAAS signaling. PMID:26064773

  10. Low-grade inflammation and tryptophan-kynurenine pathway activation are associated with adverse cardiac remodeling in primary hyperparathyroidism: the EPATH trial.

    PubMed

    Verheyen, Nicolas; Meinitzer, Andreas; Grübler, Martin Robert; Ablasser, Klemens; Kolesnik, Ewald; Fahrleitner-Pammer, Astrid; Belyavskiy, Evgeny; Trummer, Christian; Schwetz, Verena; Pieske-Kraigher, Elisabeth; Voelkl, Jakob; Alesutan, Ioana; Catena, Cristiana; Sechi, Leonardo Alberto; Brussee, Helmut; Lewinski, Dirk von; März, Winfried; Pieske, Burkert; Pilz, Stefan; Tomaschitz, Andreas

    2017-06-27

    Primary hyperparathyroidism (pHPT) is associated with low-grade inflammation, left ventricular hypertrophy and increased cardiovascular mortality, but the association between inflammatory markers and parameters of adverse cardiac remodeling is unknown. We investigated the relationship between C-reactive protein (CRP), the essential amino acid tryptophan and its pro-inflammatory derivatives kynurenine and quinolinic acid (QUIN) with echocardiographic parameters. Cross-sectional baseline data from the "Eplerenone in Primary Hyperparathyroidism" trial were analyzed. Patients with any acute illness were excluded. We assessed associations between CRP, serum levels of tryptophan, kynurenine and QUIN and left ventricular mass index (LVMI), left atrial volume index (LAVI) and E/e'. Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%. Multivariate linear regression analyses with LVMI, LAVI and E/e' as respective dependent variables, and C-reactive protein and tryptophan, kynurenine and QUIN as respective independent variables were performed. Analyses were adjusted for age, sex, blood pressure, parathyroid hormone, calcium and other cardiovascular risk factors. LVMI was independently associated with CRP (adjusted β-coefficient=0.193, p=0.030) and QUIN (β=0.270, p=0.007), but not kynurenine. LAVI was related with CRP (β=0.315, p<0.001), kynurenine (β=0.256, p=0.005) and QUIN (β=0.213, p=0.044). E/e' was related with kynurenine (β=0.221, p=0.022) and QUIN (β=0.292, p=0.006). Tryptophan was not associated with any of the remodeling parameters. [Correction added after online publication (22 April 2017: The sentence "Among 136 subjects with pHPT (79% females), 100 (73%) had left ventricular hypertrophy." was corrected to "Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%."] Conclusions: Cardiac

  11. Safe Oral Triiodo-L-Thyronine Therapy Protects from Post-Infarct Cardiac Dysfunction and Arrhythmias without Cardiovascular Adverse Effects

    PubMed Central

    Rajagopalan, Viswanathan; Zhang, Youhua; Ojamaa, Kaie; Chen, Yue-feng; Pingitore, Alessandro; Pol, Christine J.; Saunders, Debra; Balasubramanian, Krithika; Towner, Rheal A.; Gerdes, A. Martin

    2016-01-01

    Background A large body of evidence suggests that thyroid hormones (THs) are beneficial for the treatment of cardiovascular disorders. We have shown that 3 days of triiodo-L-thyronine (T3) treatment in myocardial infarction (MI) rats increased left ventricular (LV) contractility and decreased myocyte apoptosis. However, no clinically translatable protocol is established for T3 treatment of ischemic heart disease. We hypothesized that low-dose oral T3 will offer safe therapeutic benefits in MI. Methods and Results Adult female rats underwent left coronary artery ligation or sham surgeries. T3 (~6 μg/kg/day) was available in drinking water ad libitum immediately following MI and continuing for 2 month(s) (mo). Compared to vehicle-treated MI, the oral T3-treated MI group at 2 mo had markedly improved anesthetized Magnetic Resonance Imaging-based LV ejection fraction and volumes without significant negative changes in heart rate, serum TH levels or heart weight, indicating safe therapy. Remarkably, T3 decreased the incidence of inducible atrial tachyarrhythmias by 88% and improved remodeling. These were accompanied by restoration of gene expression involving several key pathways including thyroid, ion channels, fibrosis, sympathetic, mitochondria and autophagy. Conclusions Low-dose oral T3 dramatically improved post-MI cardiac performance, decreased atrial arrhythmias and cardiac remodeling, and reversed many adverse changes in gene expression with no observable negative effects. This study also provides a safe and effective treatment/monitoring protocol that should readily translate to humans. PMID:26981865

  12. Cardiovascular function, compliance, and connective tissue remodeling in the turtle, Trachemys scripta, following thermal acclimation

    PubMed Central

    Keen, Adam N.; Crossley, Dane A.

    2016-01-01

    Low temperature directly alters cardiovascular physiology in freshwater turtles, causing bradycardia, arterial hypotension, and a reduction in systemic blood pressure. At the same time, blood viscosity and systemic resistance increase, as does sensitivity to cardiac preload (e.g., via the Frank-Starling response). However, the long-term effects of these seasonal responses on the cardiovascular system are unclear. We acclimated red-eared slider turtles to a control temperature (25°C) or to chronic cold (5°C). To differentiate the direct effects of temperature from a cold-induced remodeling response, all measurements were conducted at the control temperature (25°C). In anesthetized turtles, cold acclimation reduced systemic resistance by 1.8-fold and increased systemic blood flow by 1.4-fold, resulting in a 2.3-fold higher right to left (R-L; net systemic) cardiac shunt flow and a 1.8-fold greater shunt fraction. Following a volume load by bolus injection of saline (calculated to increase stroke volume by 5-fold, ∼2.2% of total blood volume), systemic resistance was reduced while pulmonary blood flow and systemic pressure increased. An increased systemic blood flow meant the R-L cardiac shunt was further pronounced. In the isolated ventricle, passive stiffness was increased following cold acclimation with 4.2-fold greater collagen deposition in the myocardium. Histological sections of the major outflow arteries revealed a 1.4-fold higher elastin content in cold-acclimated animals. These results suggest that cold acclimation alters cardiac shunting patterns with an increased R-L shunt flow, achieved through reducing systemic resistance and increasing systemic blood flow. Furthermore, our data suggests that cold-induced cardiac remodeling may reduce the stress of high cardiac preload by increasing compliance of the vasculature and decreasing compliance of the ventricle. Together, these responses could compensate for reduced systolic function at low temperatures in

  13. Circulating Endothelial Cells and Endothelial Function predict Major Adverse Cardiac Events and Early Adverse Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction

    PubMed Central

    Magdy, Abdel Hamid; Bakhoum, Sameh; Sharaf, Yasser; Sabry, Dina; El-Gengehe, Ahmed T; Abdel-Latif, Ahmed

    2016-01-01

    Endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) are mobilized from the bone marrow and increase in the early phase after ST-elevation myocardial infarction (STEMI). The aim of this study was to assess the prognostic significance of CECs and indices of endothelial dysfunction in patients with STEMI. In 78 patients with acute STEMI, characterization of CD34+/VEGFR2+ CECs, and indices of endothelial damage/dysfunction such as brachial artery flow mediated dilatation (FMD) were determined. Blood samples for CECs assessment and quantification were obtained within 24 hours of admission and FMD was assessed during the index hospitalization. At 30 days follow up, the primary composite end point of major cardiac adverse events (MACE) consisting of all-cause mortality, recurrent non-fatal MI, or heart failure and the secondary endpoint of early adverse left ventricular (LV) remodeling were analyzed. The 17 patients (22%) who developed MACE had significantly higher CEC level (P = 0.004), vWF level (P =0.028), and significantly lower FMD (P = 0.006) compared to the remaining patients. Logistic regression analysis showed that CECs level and LV ejection fraction were independent predictors of MACE. The areas under the receiver operating characteristic curves (ROC) for CEC level, FMD, and the logistic model with both markers were 0.73, 0.75, and 0.82 respectively for prediction of the MACE. The 16 patients who developed the secondary endpoint had significantly higher CEC level compared to remaining patients (p =0.038). In conclusion, increased circulating endothelial cells and endothelial dysfunction predicted the occurrence of major adverse cardiac events and adverse cardiac remodeling in patients with STEMI. PMID:26864952

  14. Pattern of Adverse Drug Reactions Reported with Cardiovascular Drugs in a Tertiary Care Teaching Hospital

    PubMed Central

    Palaniappan, Muthiah; George, Melvin; Subramaniyan, Ganesan; Dkhar, Steven Aibor; Pillai, Ajith Ananthakrishna; Jayaraman, Balachander; Chandrasekaran, Adithan

    2015-01-01

    Background Cardiovascular diseases (CVD) are one of the leading causes of non-communicable disease related deaths globally. Patients with cardiovascular diseases are often prescribed multiple drugs and have higher risk for developing more adverse drug reactions due to polypharmacy. Aim To evaluate the pattern of adverse drug reactions reported with cardiovascular drugs in an adverse drug reaction monitoring centre (AMC) of a tertiary care hospital. Settings and Design Adverse drug reactions related to cardiovascular drugs reported to an AMC of a tertiary care hospital were included in this prospective observational study. Materials and Methods All cardiovascular drugs related adverse drug reactions (ADRs) received in AMC through spontaneous reporting system and active surveillance method from January 2011 to March 2013 were analysed for demographic profile, ADR pattern, severity and causality assessment. Statistical Analysis used The study used descriptive statistics and the values were expressed in numbers and percentages. Results During the study period, a total of 463 ADRs were reported from 397 patients which included 319 males (80.4%) and 78 females (19.6%). The cardiovascular drug related reports constituted 18.1% of the total 2188 ADR reports. In this study, the most common ADRs observed were cough (17.3%), gastritis (7.5%) and fatigue (6.5%). Assessment of ADRs using WHO-causality scale revealed that 62% of ADRs were possible, 28.2% certain and 6.8% probable. As per Naranjo’s scale most of the reports were possible (68.8%) followed by probable (29.7%). According to Hartwig severity scale majority of the reports were mild (95%) followed by moderate (4.5%). A system wise classification of ADRs showed that gastrointestinal system (20.7%) related reactions were the most frequently observed adverse reactions followed by respiratory system (18.4%) related adverse effects. From the reported ADRs, the drugs most commonly associated with ADRs were found to be

  15. Effect of Intensive Blood Pressure Control on Cardiovascular Remodeling in Hypertensive Patients with Nephrosclerosis

    PubMed Central

    Kwagyan, John; Pogue, Velvie; Xu, Shichen; Greene, Tom; Wang, Xuelei; Agodoa, Lawrence

    2013-01-01

    Pulse pressure (PP), a marker of arterial system properties, has been linked to cardiovascular (CV) complications. We examined (a) association between unit changes of PP and (i) composite CV outcomes and (ii) development of left-ventricular hypertrophy (LVH) and (b) effect of mean arterial pressure (MAP) control on rate of change in PP. We studied 1094 nondiabetics with nephrosclerosis in the African American Study of Kidney Disease and Hypertension. Subjects were randomly assigned to usual MAP goal (102–107 mmHg) or a lower MAP goal (≤92 mmHg) and randomized to beta-blocker, angiotensin converting enzyme inhibitor, or calcium channel blocker. After covariate adjustment, a higher PP was associated with increased risk of CV outcome (RR = 1.28, CI = 1.11–1.47, P < 0.01) and new LVH (RR = 1.26, CI = 1.04–1.54, P = 0.02). PP increased at a greater rate in the usual than in lower MAP groups (slope ± SE: 1.08 ± 0.15 versus 0.42 ± 0.15 mmHg/year, P = 0.002), but not by the antihypertensive treatment assignment. Observations indicate that control to a lower MAP slows the progression of PP, a correlate of cardiovascular remodeling and complications, and may be beneficial to CV health. PMID:24102027

  16. An update on predictive biomarkers for major adverse cardiovascular events in patients undergoing vascular surgery.

    PubMed

    Patelis, Nikolaos; Kouvelos, George N; Koutsoumpelis, Andreas; Moris, Demetrios; Matsagkas, Miltiadis I; Arnaoutoglou, Eleni

    2016-09-01

    Cardiovascular complications signify a major cause of morbidity and mortality in patients undergoing vascular surgery adversely affecting both short- and long-term prognosis. During the last decade, unmet needs for a distinct cardiovascular risk assessment have led to an intensive research for establishment of biomarkers with sufficient predictive value. This literature review aims in examining the value of several biomarkers in predicting the incidence of major adverse cardiac events in vascular surgery patients. We reviewed the English language literature and analyzed the biomarkers as independent predictors or in correlation with other factors. We found several biomarkers showing a significant predictive value for a major adverse cardiovascular event in patients undergoing vascular surgery. These biomarkers can be used in clinical practice as outcome predictors, although sensitivity and specificity varies. Detection of subclinical cardiovascular damage may improve total risk estimation and facilitate clinical assessment of patients at risk for future cardiovascular events. The wide variety of sensitivity and specificity in predicting a MACE of these biomarkers exert the need for future trials in which these markers will be tested as adjunctive tools of cardiovascular risk estimation scoring systems.

  17. Beneficial and adverse effects of testosterone on the cardiovascular system in men.

    PubMed

    Ruige, Johannes B; Ouwens, D Margriet; Kaufman, Jean-Marc

    2013-11-01

    The widespread use of T therapy, particularly in aging males, necessitates knowledge of the relationship between T and the cardiovascular system. The review is based on a 1970 to 2013 PubMed search with terms related to androgens in combination with cardiovascular disease, including T, dihydrotestosterone, trial, mortality, cardiovascular disease, myocardial infarction, blood pressure, endothelial function, dyslipidemia, thrombosis, ventricular function, and arrhythmia. Original articles, systematic reviews and meta-analyses, and relevant citations were screened. Low T has been linked to increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, endothelial dysfunction, as well as to impaired left ventricular function. On the one hand, a modest association is suggested between low endogenous T and incident cardiovascular disease or cardiovascular mortality, implying unrecognized beneficial T effects, residual confounding, or a relationship with health status. On the other hand, treatments with T to restore "normal concentrations" have so far not been proven to be beneficial with respect to cardiovascular disease; neither have they definitely shown specific adverse cardiovascular effects. The cardiovascular risk-benefit profile of T therapy remains largely evasive in view of a lack of well-designed and adequately powered randomized clinical trials. The important knowledge gap as to the exact relationship between T and cardiovascular disease would support a cautious, restrained approach to T therapy in aging men, pending clarification of benefits and risks by adequately powered clinical trials of sufficient duration.

  18. Oral administration of veratric acid, a constituent of vegetables and fruits, prevents cardiovascular remodelling in hypertensive rats: a functional evaluation.

    PubMed

    Saravanakumar, Murugesan; Raja, Boobalan; Manivannan, Jeganathan; Silambarasan, Thangarasu; Prahalathan, Pichavaram; Kumar, Subramanian; Mishra, Santosh Kumar

    2015-11-14

    In our previous studies, veratric acid (VA) shows beneficial effect on hypertension and its associated dyslipidaemia. In continuation, this study was designed to investigate the effect of VA, one of the major benzoic acid derivatives from vegetables and fruits, on cardiovascular remodelling in hypertensive rats, primarily assessed by functional studies using Langendorff isolated heart system and organ bath system. Hypertension was induced in male albino Wistar rats by oral administration of N ω -nitro-l-arginine methyl ester hydrochloride (l-NAME) (40 mg/kg body weight (b.w.)) in drinking water for 4 weeks. VA was orally administered at a dose of 40 mg/kg b.w. l-NAME-treated rats showed impaired cardiac ventricular and vascular function, evaluated by Langendorff isolated heart system and organ bath studies, respectively; a significant increase in the lipid peroxidation products such as thiobarbituric acid-reactive substances and lipid hydroperoxides in aorta; and a significant decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase and levels of GSH, vitamin C and vitamin E in aorta. Fibrotic remodelling of the aorta and heart were assessed by Masson's Trichrome staining and Van Gieson's staining, respectively. In addition, l-NAME rats showed increased heart fibronectin expression assessed by immunohistochemical analysis. VA supplementation throughout the experimental period significantly normalised cardiovascular function, oxidative stress, antioxidant status and fibrotic remodelling of tissues. These results of the present study conclude that VA acts as a protective agent against hypertension-associated cardiovascular remodelling.

  19. Sinapic Acid Prevents Hypertension and Cardiovascular Remodeling in Pharmacological Model of Nitric Oxide Inhibited Rats

    PubMed Central

    Silambarasan, Thangarasu; Manivannan, Jeganathan; Krishna Priya, Mani; Suganya, Natarajan; Chatterjee, Suvro; Raja, Boobalan

    2014-01-01

    Objectives Hypertensive heart disease is a constellation of abnormalities that includes cardiac fibrosis in response to elevated blood pressure, systolic and diastolic dysfunction. The present study was undertaken to examine the effect of sinapic acid on high blood pressure and cardiovascular remodeling. Methods An experimental hypertensive animal model was induced by L-NAME intake on rats. Sinapic acid (SA) was orally administered at a dose of 10, 20 and 40 mg/kg body weight (b.w.). Blood pressure was measured by tail cuff plethysmography system. Cardiac and vascular function was evaluated by Langendorff isolated heart system and organ bath studies, respectively. Fibrotic remodeling of heart and aorta was assessed by histopathologic analyses. Oxidative stress was measured by biochemical assays. mRNA and protein expressions were assessed by RT-qPCR and western blot, respectively. In order to confirm the protective role of SA on endothelial cells through its antioxidant property, we have utilized the in vitro model of H2O2-induced oxidative stress in EA.hy926 endothelial cells. Results Rats with hypertension showed elevated blood pressure, declined myocardial performance associated with myocardial hypertrophy and fibrosis, diminished vascular response, nitric oxide (NO) metabolites level, elevated markers of oxidative stress (TBARS, LOOH), ACE activity, depleted antioxidant system (SOD, CAT, GPx, reduced GSH), aberrant expression of TGF-β, β-MHC, eNOS mRNAs and eNOS protein. Remarkably, SA attenuated high blood pressure, myocardial, vascular dysfunction, cardiac fibrosis, oxidative stress and ACE activity. Level of NO metabolites, antioxidant system, and altered gene expression were also repaired by SA treatment. Results of in vitro study showed that, SA protects endothelial cells from oxidative stress and enhance the production of NO in a concentration dependent manner. Conclusions Taken together, these results suggest that SA may have beneficial role in the

  20. The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling.

    PubMed

    Janicki, Joseph S; Brower, Gregory L; Gardner, Jason D; Chancey, Amanda L; Stewart, James A

    2004-01-01

    The process of cardiac remodeling in response to cardiac injury and/or persistent elevations in wall stress generally relates to the progressive changes that occur in ventricular chamber dimensions and the various components of the myocardium, in particular the cardiomyocytes and the extracellular matrix. Volume overload, pressure overload or myocardial injury produces a sustained abnormal elevation in myocardial wall stress which initiates cardiac remodeling that frequently results in ventricular decompensation and heart failure. Regardless of the inciting cause, there appear to be three distinct phases to this process. In the initial phase, fibrillar collagen is partially degraded secondary to increased matrix metalloproteinase (MMP) activity. Following this, there is a chronic compensatory phase during which MMP activity and collagen concentration return to normal while cardiomyocyte size continues to progressively increase. The final phase is attained once the compensatory hypertrophic mechanisms are exhausted and is characterized by elevated MMP activity, marked ventricular dilatation and prominent fibrosis. Details of this progressive, dynamic remodeling process and its effect on ventricular function during chronic volume overload, chronic pressure overload and following myocardial infarction will be the focus of this article.

  1. Cardiovascular recovery from psychological and physiological challenge and risk for adverse cardiovascular outcomes and all-cause mortality

    PubMed Central

    Panaite, Vanessa; Salomon, Kristen; Jin, Alvin; Rottenberg, Jonathan

    2015-01-01

    Objective Exaggerated cardiovascular (CV) reactivity to laboratory challenge has been shown to predict future CV morbidity and mortality. CV recovery, has been less studied, and has yielded inconsistent findings, possibly due to presence of moderators. Reviews on the relationship between CV recovery and CV outcomes have been limited to cross-sectional studies and have not considered methodological factors. We performed a comprehensive meta-analytic review of the prospective literature investigating CV recovery to physical and psychological challenge and adverse cardiovascular outcomes. Methods We searched PsycINFO and PubMed for prospective studies investigating the relationship between CV recovery and adverse CV outcomes. Studies were coded for variables of interest and for effect sizes (ES). We conducted a random effects weighted meta-analysis. Moderators were examined with ANOVA-analog and meta-regression analyses. Results Thirty seven studies met inclusion criteria (N=125386). Impaired recovery from challenge predicted adverse cardiovascular outcomes (summary effect, r = .17, p < .001). Physical challenge was associated with larger predictive effects than psychological challenge. Moderator analyses revealed that recovery measured at 1 minute post-exercise, passive recovery, use of mortality as an outcome measure, and older sample age were associated with larger effects. Conclusions Poor recovery from laboratory challenges predicts adverse CV outcomes, with recovery from exercise serving as a particularly strong predictor of CV outcomes. The overall ES for recovery and CV outcomes is similar to that observed for CV reactivity and suggests that the study of recovery may have incremental value for understanding adverse CV outcomes. PMID:25829236

  2. Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1

    PubMed Central

    Bai, Bo; Man, Andy W.C.; Yang, Kangmin; Guo, Yumeng; Xu, Cheng; Tse, Hung-Fat; Han, Weiping; Bloksgaard, Maria; De Mey, Jo G.R.; Vanhoutte, Paul M.; Xu, Aimin; Wang, Yu

    2016-01-01

    Aims-SIRT1 exerts potent activity against cellular senescence and vascular ageing. By decreasing LKB1 protein levels, it promotes the survival and regeneration of endothelial cells. The present study aims to investigate the molecular mechanisms underlying SIRT1-mediated LKB1 degradation for the prevention of vascular ageing. Methods and Results-Co-immunoprecipitation assay demonstrated that SIRT1, via its amino-terminus, binds to the DOC domain of HERC2 [HECT and RLD domain containing E3 ubiquitin protein ligase 2], which then ubiquitinates LKB1 in the nuclear compartment of endothelial cells. Site-directed mutagenesis revealed that acetylation at lysine (K) 64 of LKB1 triggers the formation of SIRT1/HERC2/LKB1 protein complex and subsequent proteasomal degradation. In vitro cellular studies suggested that accumulation of acetylated LKB1 in the nucleus leads to endothelial activation, in turn stimulating the proliferation of vascular smooth muscle cells and the production of extracellular matrix proteins. Chromatin immunoprecipitation quantitative PCR confirmed that acetylated LKB1 interacts with and activates TGFβ1 promoter, which is inhibited by SIRT1. Knocking down either SIRT1 or HERC2 results in an increased association of LKB1 with the positive regulatory elements of TGFβ1 promoter. In mice without endothelial nitric oxide synthase, selective overexpression of human SIRT1 in endothelium prevents hypertension and age-related adverse arterial remodeling. Lentiviral-mediated knockdown of HERC2 abolishes the beneficial effects of endothelial SIRT1 on both arterial remodeling and arterial blood pressure control. Conclusion-By downregulating acetylated LKB1 protein via HERC2, SIRT1 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis. PMID:27259994

  3. Tumor Necrosis Factor Receptor Associated Factor 2 Signaling Provokes Adverse Cardiac Remodeling in the Adult Mammalian Heart

    PubMed Central

    Divakaran, Vijay G.; Evans, Sarah; Topkara, Veli K.; Diwan, Abhinav; Burchfield, Jana; Gao, Feng; Dong, Jianwen; Tzeng, Huei-Ping; Sivasubramanian, Natarajan; Barger, Philip M.; Mann, Douglas L.

    2013-01-01

    Background Tumor necrosis factor (TNF) superfamily ligands that provoke a dilated cardiac phenotype signal through a common scaffolding protein termed TNF receptor associated factor 2 (TRAF2); however, virtually nothing is known with regard to TRAF2 signaling in the adult mammalian heart. Methods and Results We generated multiple founder lines of mice with cardiac restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (MHC-TRAF2HC). MHC-TRAF2HC transgenic mice developed a time-dependent increase in cardiac hypertrophy, LV dilation and adverse LV remodeling, and a significant decrease in LV +dP/dt and −dP/dt when compared to littermate (LM) controls (p < 0.05 compared to LM). During the early phases of LV remodeling there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2HC mice aged, there was a significant decrease in total MMP activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in NF-κB activation at 4 – 12 weeks and JNK activation at 4 weeks in the MHCs TRAF2HC mice. Transciptional profiling revealed that > 95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2HC hearts contained κB elements in their promoters. Conclusions These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart. PMID:23493088

  4. Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1.

    PubMed

    Bai, Bo; Man, Andy W C; Yang, Kangmin; Guo, Yumeng; Xu, Cheng; Tse, Hung-Fat; Han, Weiping; Bloksgaard, Maria; De Mey, Jo G R; Vanhoutte, Paul M; Xu, Aimin; Wang, Yu

    2016-06-28

    Aims-SIRT1 exerts potent activity against cellular senescence and vascular ageing. By decreasing LKB1 protein levels, it promotes the survival and regeneration of endothelial cells. The present study aims to investigate the molecular mechanisms underlying SIRT1-mediated LKB1 degradation for the prevention of vascular ageing.Methods and Results-Co-immunoprecipitation assay demonstrated that SIRT1, via its amino-terminus, binds to the DOC domain of HERC2 [HECT and RLD domain containing E3 ubiquitin protein ligase 2], which then ubiquitinates LKB1 in the nuclear compartment of endothelial cells. Site-directed mutagenesis revealed that acetylation at lysine (K) 64 of LKB1 triggers the formation of SIRT1/HERC2/LKB1 protein complex and subsequent proteasomal degradation. In vitro cellular studies suggested that accumulation of acetylated LKB1 in the nucleus leads to endothelial activation, in turn stimulating the proliferation of vascular smooth muscle cells and the production of extracellular matrix proteins. Chromatin immunoprecipitation quantitative PCR confirmed that acetylated LKB1 interacts with and activates TGFβ1 promoter, which is inhibited by SIRT1. Knocking down either SIRT1 or HERC2 results in an increased association of LKB1 with the positive regulatory elements of TGFβ1 promoter. In mice without endothelial nitric oxide synthase, selective overexpression of human SIRT1 in endothelium prevents hypertension and age-related adverse arterial remodeling. Lentiviral-mediated knockdown of HERC2 abolishes the beneficial effects of endothelial SIRT1 on both arterial remodeling and arterial blood pressure control.Conclusion-By downregulating acetylated LKB1 protein via HERC2, SIRT1 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis.

  5. Adverse Pregnancy Conditions, Infertility, and Future Cardiovascular Risk: Implications for Mother and Child

    PubMed Central

    Park, Ki; Wei, Janet; Minissian, Margo; Merz, C. Noel Bairey

    2016-01-01

    Adverse pregnancy conditions in women are common and have been associated with adverse cardiovascular and metabolic outcomes such as myocardial infarction and stroke. As risk stratification in women is often suboptimal, recognition of non-traditional risk factors such as hypertensive disorders of pregnancy and premature delivery has become increasingly important. Additionally, such conditions may also increase the risk of cardiovascular disease in the children of afflicted women. In this review, we aim to highlight these conditions, along with infertility, and the association between such conditions and various cardiovascular outcomes and related maternal risk along with potential translation of risk to offspring. We will also discuss proposed mechanisms driving these associations as well as potential opportunities for screening and risk modification. PMID:26037616

  6. Adverse Remodeling of the Electrophysiological Response to Ischemia-Reperfusion in Human Heart Failure Is Associated with Remodeling of Metabolic Gene Expression

    PubMed Central

    Ng, Fu Siong; Holzem, Katherine M.; Koppel, Aaron C.; Janks, Deborah; Gordon, Fabiana; Wit, Andrew L.; Peters, Nicholas S.; Efimov, Igor R.

    2014-01-01

    Background Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion (I-R), although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute I-R in heart failure, and its potential causes, including the remodeling of metabolic gene expression. Methods and Results We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to I-R, with greater action potential duration (APD) shortening (p<0.001 at 8 minutes ischemia; p=0.001 at 12 minutes ischemia) and greater conduction slowing during ischemia, delayed recovery of electrical excitability following reperfusion (F 4.8±1.8 vs. D 1.0±0 mins, p<0.05), and incomplete restoration of APD and conduction velocity early after reperfusion. Expression of 46 metabolic genes were probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. Conclusions We demonstrate, for the first time in human hearts, that the electrophysiological response to I-R in heart failure is accelerated during ischemia with slower recovery following reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes. PMID:25114062

  7. Wine polyphenols improve cardiovascular remodeling and vascular function in NO-deficient hypertension.

    PubMed

    Bernátová, Iveta; Pechánová, Olga; Babál, Pavel; Kyselá, Sona; Stvrtina, Svetoslav; Andriantsitohaina, Ramaroson

    2002-03-01

    The effects of the red wine polyphenolic compounds (Provinol) on hypertension, left ventricular hypertrophy, myocardial fibrosis, and vascular remodeling were investigated after chronic inhibition of nitric oxide (NO) synthase by administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats. Rats were divided into four groups: a control group, a group treated for 4 wk with L-NAME (40 mg x kg(-1) x day(-1)), and two groups treated with L-NAME followed by 3 wk of either spontaneous recovery or recovery with Provinol treatment (40 mg x kg(-1) x day(-1)). Administration of Provinol produced a greater readiness of the decrease in blood pressure than that in the spontaneous recovery group. Provinol significantly depressed myocardial fibrosis and expedited the decrease in aortic cross-sectional area, the increase in endothelium-dependent relaxation, and the decrease in contraction of the aorta. These effects of Provinol were associated with a greater increase of NO synthase activity in the left ventricle and the aorta. The present study provides evidence that Provinol accelerates the regression of blood pressure and improves structural and functional cardiovascular changes produced by chronic inhibition of NO synthesis.

  8. Acute effect of static exercise in patients with aortic regurgitation assessed by cardiovascular magnetic resonance: role of left ventricular remodelling.

    PubMed

    Alegret, Josep M; Martinez-Micaelo, Neus; La Gerche, Andre; Franco-Bonafonte, Luis; Rubio-Pérez, Francisco; Calvo, Nahum; Montero, Manuel

    2017-04-01

    In patients with aortic regurgitation (AR), the effect of static exercise (SE) on global ventricular function and AR severity has not been previously studied. Resting and SE cardiovascular magnetic resonance (CMR) were prospectively performed in 23 asymptomatic patients with AR. During SE, we observed a decrease in regurgitant volume in both end-diastolic (EDV) and end-systolic (ESV) volume in both ventricles, as well as a slight decrease in LV ejection fraction (EF). Interestingly, responses varied depending on the degree of LV remodelling. Among patients with a greater degree of LV remodelling, we observed a decrease in LVEF (56 ± 4 % at rest vs 48 ± 7 % during SE, p = 0.001) as a result of a lower decrease in LVESV (with respect to LVEDV. Among patients with a lower degree of LV remodelling, LVEF remained unchanged. RVEF remained unchanged in both groups. In patients with AR, SE provoked a reduction in preload, LV stroke volume, and regurgitant volume. In those patients with higher LV remodelling, we observed a decrease in LVEF, suggesting a lower LV contractile reserve. • In patients with aortic regurgitation, static exercise reduced preload volume. • In patients with aortic regurgitation, static exercise reduced stroke volume. • In patients with aortic regurgitation, static exercise reduced regurgitant volume. • In patients with greater remodelling, static exercise unmasked a lower contractile reserve. • Effect of static exercise on aortic regurgitation was assessed by cardiac MR.

  9. No evidence of adverse cardiac remodeling in former elite endurance athletes.

    PubMed

    Sanchis-Gomar, Fabian; López-Ramón, Marta; Alis, Rafael; Garatachea, Nuria; Pareja-Galeano, Helios; Santos-Lozano, Alejandro; Catalán, Pilar; Sansoni, Veronica; Perego, Silvia; Lombardi, Giovanni; Löllgen, Herbert; Bueno, Hector; Serrano-Ostáriz, Enrique; Lucia, Alejandro

    2016-11-01

    The impact of high exercise loads on a previously healthy heart remains controversial. We examined the consequences of decades of strenuous endurance exercise at the highest competition level on heart dimensions and volumes as well as on serum biomarkers of cardiac fibrosis/remodeling. We compared echocardiographic measurements and serum biomarkers of cardiac fibrosis/remodeling [troponin I, galectin-3, matrix metallopeptidase-2 and -9, N-terminal pro-brain natriuretic peptide, carboxy-terminal propeptide of type I procollagen, and soluble suppressor of tumorigenicity-2 (sST-2)/interleukin(IL)-1R4] in 53 male athletes [11 former professional ('elite') and 42 amateur-level ('sub-elite') cyclists or runners, aged 40-70years] and 18 aged-matched controls. A subset of 15 subjects (5 controls, 3 sub-elite and 7 elite athletes) also underwent cardiac magnetic resonance imaging (cMRI). Elite and sub-elite athletes had greater echocardiography-determined left ventricular myocardial mass indexed to body surface area than controls (113±22, 115.2±23.1 and 94.8±21g/m(2), respectively, p=0.008 for group effect), with similar results for left (50.5±4.4, 48.2±4.3 and 46.4±5.2mm, p=0.008) and right (38.6±3.8, 41.1±5.5 and 34.7±4.3mm, p<0.001) ventricular end-diastolic diameter, and cMRI-determined left atrial volume indexed to body surface area (62.7±8.1, 56.4±16.0 and 39.0±14.1ml/m(2), p=0.026). Two athletes showed a non-coronary pattern of small, fibrotic left ventricular patches detected by late gadolinium enhancement. No group effect was noted for biomarkers. Regardless of their competition level at a younger age, veteran endurance athletes showed an overall healthy, non-pathological pattern of cardiac remodeling. Nonetheless, the physiopathology of the ventricular fibrotic patches detected warrants further investigation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction

    PubMed Central

    Beaumont, Eric; Southerland, Elizabeth M.; Hardwick, Jean C.; Wright, Gary L.; Ryan, Shannon; Li, Ying; KenKnight, Bruce H.; Armour, J. Andrew

    2015-01-01

    This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P < 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P < 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P < 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P < 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P < 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions. PMID:26276818

  11. Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction.

    PubMed

    Beaumont, Eric; Southerland, Elizabeth M; Hardwick, Jean C; Wright, Gary L; Ryan, Shannon; Li, Ying; KenKnight, Bruce H; Armour, J Andrew; Ardell, Jeffrey L

    2015-10-01

    This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P < 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P < 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P < 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P < 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P < 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions.

  12. Targeted inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis and Preserves Heart Function in Adverse Cardiac Remodeling

    PubMed Central

    Zhang, Jie; Fan, Guangpu; Zhao, Hui; Wang, Zhiwei; Li, Fei; Zhang, Peide; Zhang, Jing; Wang, Xu; Wang, Wei

    2017-01-01

    Cardiac fibrosis in post-myocardial infarction (MI), seen in both infarcted and non-infarcted myocardium, is beneficial to the recovery of heart function. But progressively pathological fibrosis impairs ventricular function and leads to poor prognosis. FAK has recently received attention as a potential mediator of fibrosis, our previous study reported that pharmacological inhibition of FAK can attenuate cardiac fibrosis in post MI models. However, the long-term effects on cardiac function and adverse cardiac remodelling were not clearly investigated. In this study, we tried to determine the preliminary mechanisms in regulating CF transformation to myofibroblasts and ECM synthesis relevant to the development of adverse cardiac remolding in vivo and in vitro. Our study provides even more evidence that FAK is directly related to the activation of CF in hypoxia condition in a dose-dependent and time-dependent manner. Pharmacological inhibition of FAK significantly reduces myofibroblast differentiation; our in vivo data demonstrated that a FAK inhibitor significantly decreases fibrotic score, and preserves partial left ventricular function. Both PI3K/AKT signalling and ERK1/2 are necessary for hypoxia-induced CF differentiation and ECM synthesis; this process also involves lysyl oxidase (LOX). These findings suggest that pharmacological inhibition of FAK may become an effective therapeutic strategy against adverse fibrosis. PMID:28225063

  13. The effects of fish oil consumption on cardiovascular remodeling in ApoE deficient mice.

    PubMed

    Cleverley, Kelby; Du, Xiaozhou; Premecz, Sheena; Le, Khuong; Zeglinski, Matthew; Nicholson, Tiffany; Goh, Chun Y; Lu, Yan; Anderson, Hope D; Moghadasian, Mohammed H; Jassal, Davinder S

    2013-11-01

    Owing to their spontaneous development of atherosclerosis, apolipoprotein E knockout mice (ApoE(KO)) are one of the best studied animal models for this disease. Little is known about the utility of various omega-3 fatty acid regimens, in particular fish oils, in preventing cardiac disease in ApoE(KO) mice. The purpose of this study was to determine the cardiovascular effects of omega-3 fatty acid supplementation with either safflower oil (control), fish oil, flaxseed oil, or designed oil in ApoE(KO) mice fed a high-fat diet for a total of 16 weeks. In-vivo cardiac function was assessed weekly using murine echocardiography. Blood pressure, plasma lipid levels, and brain natriuretic peptide (BNP) were serially measured. The results show that ApoE(KO) mice fed fish oil demonstrated an increase in left ventricular wall thickness as a result of increased afterload. Despite chronic treatment with fish oil over 16 weeks, blood pressure increased in ApoE(KO) mice by 20% compared with the baseline. Both echocardiographic evidence of left ventricular hypertrophy and biochemical increase in BNP levels confirmed diastolic dysfunction in ApoE(KO) mice fed fish oil. This suggests that high-fat diet supplemented with fish oil may lead to adverse cardiovascular effects in ApoE deficient mice.

  14. Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling.

    PubMed

    Erikson, John M; Valente, Anthony J; Mummidi, Srinivas; Kandikattu, Hemanth Kumar; DeMarco, Vincent G; Bender, Shawn B; Fay, William P; Siebenlist, Ulrich; Chandrasekar, Bysani

    2017-02-10

    Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both IκB kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-κB and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore, Traf3ip2 gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destruction-mediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-κB and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.

  15. Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats.

    PubMed

    Loch, David; Levick, Scott; Hoey, Andrew; Brown, Lindsay

    2006-03-01

    The pleiotropic effects of statins represent potential mechanisms for the treatment of end-organ damage in hypertension. This study has investigated the effects of rosuvastatin in a model of cardiovascular remodeling, the DOCA-salt hypertensive rat. Male Wistar rats weighing 300 to 330 g were uninephrectomized (UNX) or UNX and treated with DOCA (25 mg subcutaneously every fourth day) and 1% NaCl in the drinking water. Compared with UNX controls, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, inflammation with perivascular and interstitial cardiac fibrosis, endothelial dysfunction, and prolongation of ventricular action potential duration at 28 days. Rosuvastatin-treated rats received 20 mg/kg/d of the drug in 10% Tween 20 by oral gavage for 32 days commencing 4 days before uninephrectomy. UNX and DOCA-salt controls received vehicle only. Rosuvastatin therapy attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation, but did not modify hypertension or vascular dysfunction. We conclude that the pleiotropic effects of rosuvastatin include attenuation of aspects of cardiovascular remodeling in the DOCA-salt model of hypertension in rats without altering systolic blood pressure.

  16. Systemic glucocorticoid therapy: a review of its metabolic and cardiovascular adverse events.

    PubMed

    Fardet, Laurence; Fève, Bruno

    2014-10-01

    The prevalence of use of long-term systemic glucocorticoid therapy in the general adult population is 1 %. This figure increases to up to 3 % in elderly women. Metabolic (i.e. diabetes mellitus, dyslipidemia, weight gain, lipodystrophy) and cardiovascular (i.e. hypertension, cardiovascular events) adverse events are commonly observed in these patients and can be life threatening. Paradoxically, there is very few data on some of these adverse events and many of the available studies remain inconclusive. Incidence of and risk factors for dyslipidemia, weight gain and lipodystrophy are poorly defined. The optimal treatment plan for patients diagnosed with glucocorticoid-induced diabetes or hypertension is undetermined. Finally, there is no medical consensus on the best strategies for the prevention and detection of these complications. However, certain of these questions can be answered by looking at available data on patients with endogenous hypercortisolism (i.e. Cushing's syndrome). This article reviews the pathophysiology, incidence, risk factors, screening, and treatment of glucocorticoid-induced weight gain, lipodystrophy, diabetes, dyslipidemia, hypertension, and cardiovascular events. It also focuses on the possible prevention of these adverse events by targeting the glucocorticoid receptor using selective glucocorticoid receptor modulators.

  17. Residual Risk Factors to Predict Major Adverse Cardiovascular Events in Atherosclerotic Cardiovascular Disease Patients with and without Diabetes Mellitus.

    PubMed

    Lin, Fang-Ju; Tseng, Wei-Kung; Yin, Wei-Hsian; Yeh, Hung-I; Chen, Jaw-Wen; Wu, Chau-Chung

    2017-08-23

    A prospective observational study was conducted to investigate the residual risk factors to predict recurrence of major adverse cardiovascular events (MACE) in atherosclerotic cardiovascular disease (ASCVD) patients with a high prevalence under lipid-lowering therapy, particularly in the subpopulations of diabetic and nondiabetic individuals. A total of 5,483 adults (with a mean age of 66.4 and 73.3% male) with established coronary heart disease, cerebrovascular disease, or peripheral artery disease were identified from the T-SPARCLE multi-center registry. Of them, 38.6% had diabetes. The residual risk factors for MACE are divergent in these atherosclerotic patients with and without diabetes. In diabetic subpopulation, the risk of MACE was significantly increased with heart failure (HF), chronic kidney disease (CKD) stage 4-5 (vs. stage 1-2), without beta blocker use, and higher non-HDL-C, after controlling for covariates including statin use and the intensity of therapy. Increased LDL-C and TG levels were also associated with increased risk, but to a much less extent. Among nondiabetic individuals, HF, CKD stage 4-5, and history of myocardial infarction were the significant independent predictors of MACE. It is suggested that ASCVD patients with concomitant diabetes need stricter control of lipid, particularly non-HDL-C levels, to reduce cardiovascular risk when on statin therapy.

  18. Increased systolic load causes adverse remodeling of fetal aortic and mitral valves

    PubMed Central

    Louey, Samantha; Espinoza, Herbert; Chattergoon, Natasha; You, Fanglei; Thornburg, Kent L.; Giraud, George

    2015-01-01

    While abnormal hemodynamic forces alter fetal myocardial growth, little is known about whether such insults affect fetal cardiac valve development. We hypothesized that chronically elevated systolic load would detrimentally alter fetal valve growth. Chronically instrumented fetal sheep received either a continuous infusion of adult sheep plasma to increase fetal blood pressure, or a lactated Ringer's infusion as a volume control beginning on day 126 ± 4 of gestation. After 8 days, mean arterial pressure was higher in the plasma infusion group (63.0 mmHg vs. 41.8 mmHg, P < 0.05). Mitral annular septal-lateral diameter (11.9 mm vs. 9.1 mm, P < 0.05), anterior leaflet length (7.7 mm vs. 6.4 mm, P < 0.05), and posterior leaflet length (P2; 4.0 mm vs. 3.0 mm, P < 0.05) were greater in the elevated load group. mRNA levels of Notch-1, TGF-β2, Wnt-2b, BMP-1, and versican were suppressed in aortic and mitral valve leaflets; elastin and α1 type I collagen mRNA levels were suppressed in the aortic valves only. We conclude that sustained elevated arterial pressure load on the fetal heart valve leads to anatomic remodeling and, surprisingly, suppression of signaling and extracellular matrix genes that are important to valve development. These novel findings have important implications on the developmental origins of valve disease and may have long-term consequences on valve function and durability. PMID:26354842

  19. Fibroblast Growth Factor-9 Enhances M2 Macrophage Differentiation and Attenuates Adverse Cardiac Remodeling in the Infarcted Diabetic Heart

    PubMed Central

    Singla, Dinender K.; Singla, Reetu D.; Abdelli, Latifa S.; Glass, Carley

    2015-01-01

    Inflammation has been implicated as a perpetrator of diabetes and its associated complications. Monocytes, key mediators of inflammation, differentiate into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages upon infiltration of damaged tissue. However, the inflammatory cell types, which propagate diabetes progression and consequential adverse disorders, remain unclear. The current study was undertaken to assess monocyte infiltration and the role of fibroblast growth factor-9 (FGF-9) on monocyte to macrophage differentiation and cardioprotection in the diabetic infarcted heart. Db/db diabetic mice were assigned to sham, myocardial infarction (MI), and MI+FGF-9 groups. MI was induced by permanent coronary artery ligation and animals were subjected to 2D transthoracic echocardiography two weeks post-surgery. Immunohistochemical and immunoassay results from heart samples collected suggest significantly increased infiltration of monocytes (Mean ± SEM; MI: 2.02% ± 0.23% vs. Sham 0.75% ± 0.07%; p<0.05) and associated pro-inflammatory cytokines (TNF-α, MCP-1, and IL-6), adverse cardiac remodeling (Mean ± SEM; MI: 33% ± 3.04% vs. Sham 2.2% ± 0.33%; p<0.05), and left ventricular dysfunction (Mean ± SEM; MI: 35.4% ± 1.25% vs. Sham 49.19% ± 1.07%; p<0.05) in the MI group. Importantly, treatment of diabetic infarcted myocardium with FGF-9 resulted in significantly decreased monocyte infiltration (Mean ± SEM; MI+FGF-9: 1.39% ± 0.1% vs. MI: 2.02% ± 0.23%; p<0.05), increased M2 macrophage differentiation (Mean ± SEM; MI+FGF-9: 4.82% ± 0.86% vs. MI: 0.85% ± 0.3%; p<0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs. MI: 33% ± 3.04%; p<0.05), and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs. MI: 35.4% ± 1.25%; p<0.05). In conclusion, our data suggest FGF-9 possesses novel therapeutic potential in its ability to

  20. Plasma Osteopontin Levels and Adverse Cardiovascular Outcomes in the PEACE Trial.

    PubMed

    Abdalrhim, Ahmed D; Marroush, Tariq S; Austin, Erin E; Gersh, Bernard J; Solak, Nusret; Rizvi, Syed A; Bailey, Kent R; Kullo, Iftikhar J

    2016-01-01

    Osteopontin (OPN) is a secreted glycophosphoprotein that has a role in inflammation, immune response and calcification. We hypothesized that plasma OPN levels are associated with adverse cardiovascular outcomes in patients with stable coronary artery disease (CAD) and preserved ejection fraction (EF) enrolled in the PEACE trial. We measured plasma OPN levels at baseline in 3567 CAD patients (mean age 64.5 ± 8.1 years, 81% men) by a sandwich chemiluminescent assay (coefficient of variation = 4.1%). OPN levels were natural log (Ln) transformed prior to analyses. We assessed whether Ln OPN levels were associated with the composite primary endpoint of cardiovascular death, non-fatal myocardial infarction and hospitalization for heart failure using multiple event multivariable Cox proportional hazards regression. Adjustment was performed for: (a) age and sex; (b) additional potential confounders; and (c) a parsimonious set of statistically significant 10 variates. During a median follow-up of 4.8 years, 416 adverse cardiovascular outcomes occurred in 366 patients. Ln OPN was significantly associated with the primary endpoint; HR (95% CI) = 1.56 (1.27, 1.92); P <0.001, and remained significant after adjustment for age and sex [1.31 (1.06, 1.61); P = 0.01] and after adjustment for relevant covariates [1.24 (1.01, 1.52); P = 0.04]. In a secondary analysis of the individual event types, Ln OPN was significantly associated with incident hospitalization for heart failure: HR (95% CI) = 2.04 (1.44, 2.89); P <0.001, even after adjustment for age, sex and additional relevant covariates. In conclusion, in patients with stable CAD and preserved EF on optimal medical therapy, plasma OPN levels were independently associated with the composite incident endpoint of adverse cardiovascular outcomes as well as incident hospitalization for heart failure.

  1. Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling

    PubMed Central

    Vandenwijngaert, Sara; Pokreisz, Peter; Hermans, Hadewich; Gillijns, Hilde; Pellens, Marijke; Bax, Noortje A. M.; Coppiello, Giulia; Oosterlinck, Wouter; Balogh, Agnes; Papp, Zoltan; Bouten, Carlijn V. C.; Bartunek, Jozef; D'hooge, Jan; Luttun, Aernout; Verbeken, Erik; Herregods, Marie Christine; Herijgers, Paul; Bloch, Kenneth D.; Janssens, Stefan

    2013-01-01

    Background The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC). Methodology/Principal Findings In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro. Conclusions/Significance Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target. PMID:23527037

  2. Biomass fuel smoke exposure was associated with adverse cardiac remodeling and left ventricular dysfunction in Peru.

    PubMed

    Burroughs Peña, M S; Velazquez, E J; Rivera, J D; Alenezi, F; Wong, C; Grigsby, M; Davila-Roman, V G; Gilman, R H; Miranda, J J; Checkley, W

    2016-12-19

    While household air pollution from biomass fuel combustion has been linked to cardiovascular disease, the effects on cardiac structure and function have not been well described. We sought to determine the association between biomass fuel smoke exposure and cardiac structure and function by transthoracic echocardiography. We identified a random sample of urban and rural residents living in the high-altitude region of Puno, Peru. Daily biomass fuel use was self-reported. Participants underwent transthoracic echocardiography. Multivariable linear regression was used to examine the relationship of biomass fuel use with echocardiographic measures of cardiac structure and function, adjusting for age, sex, height, body mass index, diabetes, physical activity, and tobacco use. One hundred and eighty-seven participants (80 biomass fuel users and 107 non-users) were included in this analysis (mean age 59 years, 58% women). After adjustment, daily exposure to biomass fuel smoke was associated with increased left ventricular internal diastolic diameter (P=.004), left atrial diameter (P=.03), left atrial area (four-chamber) (P=.004) and (two-chamber) (P=.03), septal E' (P=.006), and lateral E' (P=.04). Exposure to biomass fuel smoke was also associated with worse global longitudinal strain in the two-chamber view (P=.01). Daily biomass fuel use was associated with increased left ventricular size and decreased left ventricular systolic function by global longitudinal strain.

  3. Injected nanoparticles: the combination of experimental systems to assess cardiovascular adverse effects.

    PubMed

    Vlasova, Maria A; Tarasova, Olga S; Riikonen, Joakim; Raula, Janne; Lobach, Anatoly S; Borzykh, Anna A; Smirin, Boris V; Kauppinen, Esko I; Eletskii, Alexander V; Herzig, Karl-Heinz; Salonen, Jarno; Tavi, Pasi; Lehto, Vesa-Pekka; Järvinen, Kristiina

    2014-05-01

    When nanocarriers are used for drug delivery they can often achieve superior therapeutic outcomes over standard drug formulations. However, concerns about their adverse effects are growing due to the association between exposure to certain nanosized particles and cardiovascular events. Here we examine the impact of intravenously injected drug-free nanocarriers on the cardiovasculature at both the systemic and organ levels. We combine in vivo and in vitro methods to enable monitoring of hemodynamic parameters in conscious rats, assessments of the function of the vessels after sub-chronic systemic exposure to nanocarriers and evaluation of the direct effect of nanocarriers on vascular tone. We demonstrate that nanocarriers can decrease blood pressure and increase heart rate in vivo via various mechanisms. Depending on the type, nanocarriers induce the dilation of the resistance arteries and/or change the responses induced by vasoconstrictor or vasodilator drugs. No direct correlation between physicochemical properties and cardiovascular effects of nanoparticles was observed. The proposed combination of methods empowers the studies of cardiovascular adverse effects of the nanocarriers.

  4. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know.

    PubMed

    Thomas, Grace; Kloner, Robert A; Rezkalla, Shereif

    2014-01-01

    Marijuana is the most widely used illicit drug, with approximately 200 million users worldwide. Once illegal throughout the United States, cannabis is now legal for medicinal purposes in several states and for recreational use in 3 states. The current wave of decriminalization may lead to more widespread use, and it is important that cardiologists be made aware of the potential for marijuana-associated adverse cardiovascular effects that may begin to occur in the population at a greater frequency. In this report, the investigators focus on the known cardiovascular, cerebrovascular, and peripheral effects of marijuana inhalation. Temporal associations between marijuana use and serious adverse events, including myocardial infarction, sudden cardiac death, cardiomyopathy, stroke, transient ischemic attack, and cannabis arteritis have been described. In conclusion, the potential for increased use of marijuana in the changing legal landscape suggests the need for the community to intensify research regarding the safety of marijuana use and for cardiologists to maintain an awareness of the potential for adverse effects. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. The association between B vitamins supplementation and adverse cardiovascular events: a meta-analysis

    PubMed Central

    Li, Wen-Feng; Zhang, Dan-Dan; Xia, Ji-Tian; Wen, Shan-Fan; Guo, Jun; Li, Zi-Cheng

    2014-01-01

    This study is to explore the association of adverse cardiovascular events with B vitamins supplementation. Rev.Man 5.1 and Stata 11.0 software were applied for the meta-analysis. The number of cardiovascular events was collected and calculated using indicates of odds ratio and 95% confidence intervals in a fixed-effects or a random-effects model when appropriate. The study includes 15 studies which consists of 37,358 study objects (experimental group: 19,601; control group: 17,757). This study showed that the pooled ORs was 1.01 (95% CI = 0.96~1.06, P > 0.05) for objects with Experimental group (B vitamins supplementation) vs. Control group (placebo or regular treatment), which suggests no significant differences were found in the overall effect of the number of cardiovascular events between the two groups. Further stratification of subgroup analysis indicates no significant differences were found between the two groups as well. There were also no publication bias existing by the Egger’s linear regression test (P > 0.05). Our result indicates that the number of cardiovascular events in experimental group using B vitamins supplementation during the treatment is equal to placebo or regular treatment group thus further studies is necessary. PMID:25232372

  6. Aspirin Resistance Predicts Adverse Cardiovascular Events in Patients with Symptomatic Peripheral Artery Disease.

    PubMed

    Pasala, Tilak; Hoo, Jennifer Soo; Lockhart, Mary Kate; Waheed, Rehan; Sengodan, Prasanna; Alexander, Jeffrey; Gandhi, Sanjay

    2016-12-01

    Antiplatelet therapy reduces the risk of myocardial infarction, stroke, and vascular death in patients who have symptomatic peripheral artery disease. However, a subset of patients who take aspirin continues to have recurrent cardiovascular events. There are few data on cardiovascular outcomes in patients with peripheral artery disease who manifest aspirin resistance. Patients with peripheral artery disease on long-term aspirin therapy (≥4 wk) were tested for aspirin responsiveness by means of the VerifyNow Aspirin Assay. The mean follow-up duration was 22.6 ± 8.3 months. The primary endpoint was a composite of death, myocardial infarction, or ischemic stroke. Secondary endpoints were the incidence of vascular interventions (surgical or percutaneous), or of amputation or gangrene caused by vascular disease. Of the 120 patients enrolled in the study, 31 (25.8%) were aspirin-resistant and 89 (74.2%) were aspirin-responsive. The primary endpoint occurred in 10 (32.3%) patients in the aspirin-resistant group and in 13 (14.6%) patients in the aspirin-responsive group (hazard ratio=2.48; 95% confidence interval, 1.08-5.66; P=0.03). There was no significant difference in the secondary outcome of revascularization or tissue loss. By multivariate analysis, aspirin resistance and history of chronic kidney disease were the only independent predictors of long-term adverse cardiovascular events. Aspirin resistance is highly prevalent in patients with symptomatic peripheral artery disease and is an independent predictor of adverse cardiovascular risk. Whether intervening in these patients with additional antiplatelet therapies would improve outcomes needs to be explored.

  7. Aspirin Resistance Predicts Adverse Cardiovascular Events in Patients with Symptomatic Peripheral Artery Disease

    PubMed Central

    Pasala, Tilak; Hoo, Jennifer Soo; Lockhart, Mary Kate; Waheed, Rehan; Sengodan, Prasanna; Alexander, Jeffrey

    2016-01-01

    Antiplatelet therapy reduces the risk of myocardial infarction, stroke, and vascular death in patients who have symptomatic peripheral artery disease. However, a subset of patients who take aspirin continues to have recurrent cardiovascular events. There are few data on cardiovascular outcomes in patients with peripheral artery disease who manifest aspirin resistance. Patients with peripheral artery disease on long-term aspirin therapy (≥4 wk) were tested for aspirin responsiveness by means of the VerifyNow Aspirin Assay. The mean follow-up duration was 22.6 ± 8.3 months. The primary endpoint was a composite of death, myocardial infarction, or ischemic stroke. Secondary endpoints were the incidence of vascular interventions (surgical or percutaneous), or of amputation or gangrene caused by vascular disease. Of the 120 patients enrolled in the study, 31 (25.8%) were aspirin-resistant and 89 (74.2%) were aspirin-responsive. The primary endpoint occurred in 10 (32.3%) patients in the aspirin-resistant group and in 13 (14.6%) patients in the aspirin-responsive group (hazard ratio=2.48; 95% confidence interval, 1.08–5.66; P=0.03). There was no significant difference in the secondary outcome of revascularization or tissue loss. By multivariate analysis, aspirin resistance and history of chronic kidney disease were the only independent predictors of long-term adverse cardiovascular events. Aspirin resistance is highly prevalent in patients with symptomatic peripheral artery disease and is an independent predictor of adverse cardiovascular risk. Whether intervening in these patients with additional antiplatelet therapies would improve outcomes needs to be explored. PMID:28100965

  8. Association of Multiorgan Computed Tomographic Phenomap With Adverse Cardiovascular Health Outcomes: The Framingham Heart Study.

    PubMed

    Shah, Ravi V; Yeri, Ashish S; Murthy, Venkatesh L; Massaro, Joe M; D'Agostino, Ralph; Freedman, Jane E; Long, Michelle T; Fox, Caroline S; Das, Saumya; Benjamin, Emelia J; Vasan, Ramachandran S; O'Donnell, Christopher J; Hoffmann, Udo

    2017-09-20

    Increased ability to quantify anatomical phenotypes across multiple organs provides the opportunity to assess their cumulative ability to identify individuals at greatest susceptibility for adverse outcomes. To apply unsupervised machine learning to define the distribution and prognostic importance of computed tomography-based multiorgan phenotypes associated with adverse health outcomes. This asymptomatic community-based cohort study included 2924 Framingham Heart Study participants between July 2002 and April 2005 undergoing computed tomographic imaging of the chest and abdomen. Participants are from the offspring and third-generation cohorts. Eleven computed tomography-based measures of valvular/vascular calcification, adiposity, and muscle attenuation. All-cause mortality and cardiovascular disease (myocardial infarction, stroke, or cardiovascular death). The median age of the participants was 50 years (interquartile range, 43-60 years), and 1422 (48.6%) were men. Principal component analysis identified 3 major anatomic axes: (1) global calcification (defined by aortic, thoracic, coronary, and valvular calcification); (2) adiposity (defined by pericardial, visceral, hepatic, and intrathoracic fat); and (3) muscle attenuation that explained 65.7% of the population variation. Principal components showed different evolution with age (continuous increase in global calcification, decrease in muscle attenuation, and U-shaped association with adiposity) but similar patterns in men and women. Using unsupervised clustering approaches in the offspring cohort (n = 1150), we identified a cohort (n = 232; 20.2%) with an unfavorable multiorgan phenotype across all 3 anatomic axes as compared with a favorable multiorgan phenotype. Membership in the unfavorable phenotypic cluster was associated with a greater prevalence of cardiovascular disease risk factors and with increased all-cause mortality (hazard ratio, 2.61; 95% CI, 1.74-3.92; P < .001), independent of

  9. Involvement of Inflammation and Adverse Vascular Remodelling in the Blood Pressure Raising Effect of Repeatedly Heated Palm Oil in Rats

    PubMed Central

    Ng, Chun-Yi; Kamisah, Yusof; Faizah, Othman; Jubri, Zakiah; Qodriyah, Hj Mohd Saad; Jaarin, Kamsiah

    2012-01-01

    Oil thermoxidation during deep frying generates harmful oxidative free radicals that induce inflammation and increase the risk of hypertension. This study aimed to investigate the effect of repeatedly heated palm oil on blood pressure, aortic morphometry, and vascular cell adhesion molecule-1 (VCAM-1) expression in rats. Male Sprague-Dawley rats were divided into five groups: control, fresh palm oil (FPO), one-time-heated palm oil (1HPO), five-time-heated palm oil (5HPO), or ten-time-heated palm oil (10HPO). Feeding duration was six months. Blood pressure was measured at baseline and monthly using tail-cuff method. After six months, the rats were sacrificed and the aortic arches were dissected for morphometric and immunohistochemical analyses. FPO group showed significantly lower blood pressure than all other groups. Blood pressure was increased significantly in 5HPO and 10HPO groups. The aortae of 5HPO and 10HPO groups showed significantly increased thickness and area of intima-media, circumferential wall tension, and VCAM-1 than other groups. Elastic lamellae were disorganised and fragmented in 5HPO- and 10HPO-treated rats. VCAM-1 expression showed a significant positive correlation with blood pressure. In conclusion, prolonged consumption of repeatedly heated palm oil causes blood pressure elevation, adverse remodelling, and increased VCAM-1, which suggests a possible involvement of inflammation. PMID:22778962

  10. Onset of hypertension during pregnancy is associated with long-term worse blood pressure control and adverse cardiac remodeling.

    PubMed

    Mesquita, Roberto F; Reis, Muriel; Beppler, Ana Paula; Bellinazzi, Vera Regina; Mattos, Sandra S; Lima-Filho, José L; Cipolli, José A; Coelho-Filho, Otavio R; Pio-Magalhães, José A; Sposito, Andrei C; Matos-Souza, José R; Nadruz, Wilson

    2014-11-01

    Up to 20% of women with hypertensive pregnancy disorders might persist with chronic hypertension. This study compared clinical and echocardiographic features between women whose hypertension began as hypertensive pregnancy disorders (PH group) and women whose diagnosis of hypertension did not occur during pregnancy (NPH group). Fifty PH and 100 NPH women were cross-sectionally evaluated by clinical, laboratory, and echocardiography analysis, and the groups were matched by duration of hypertension. PH exhibited lower age (46.6 ± 1.4 vs. 65.3 ± 1.1 years; P < .001), but higher systolic (159.8 ± 3.9 vs. 148.0 ± 2.5 mm Hg; P = .009) and diastolic (97.1 ± 2.4 vs. 80.9 ± 1.3 mm Hg; P < .001) blood pressure than NPH, although used more antihypertensive classes (3.4 ± 0.2 vs. 2.6 ± 0.1; P < .001). Furthermore, PH showed higher left ventricular wall thickness and increased prevalence of concentric hypertrophy than NPH after adjusting for age and blood pressure. In conclusion, this study showed that PH may exhibit worse blood pressure control and adverse left ventricular remodeling compared with NPH.

  11. Cardiovascular thromboembolic events associated with febuxostat: investigation of cases from the FDA adverse event reporting system database.

    PubMed

    Gandhi, Pranav K; Gentry, William M; Bottorff, Michael B

    2013-06-01

    Uloric (Febuxostat) has been linked with cardiovascular thromboembolic events in gout patients. However, no post-marketing data analysis has investigated these drug-associated adverse event reports. The study objective was to identify febuxostat-associated cardiovascular thromboembolic event reports in the US using the Food and Drug Administration adverse event reporting system (AERS) database. Reports listing uloric and febuxostat as the suspect drug and cardiovascular thromboembolic events (combined in a single term based on adverse event reports of myocardial infarction, stroke, among others) as the adverse event were extracted from the drug's approval date through the fourth quarter of 2011. Bayesian statistics within the neural network architecture was implemented to identify potential signals of febuxostat-associated cardiovascular thromboembolic events. A potential signal for the drug-adverse event combination reports is generated when the lower limit of the 95% two-sided confidence interval of the information component (IC), denoted by IC025 is greater than zero. Twenty-one combination reports of febuxostat-associated cardiovascular thromboembolic events were identified in gout patients in the US. The mean age of combination cases was 64 years. Potential signals (IC025 = 4.09) was generated for combination reports of febuxostat-associated cardiovascular thromboembolic events. AERS indicated potential signals of febuxostat-associated cardiovascular thromboembolic events. AERS is not capable of establishing the causal link and detecting the true frequency of an adverse event associated with a drug. The positive IC value found in this study merits continued surveillance and assessment of cardiovascular thromboembolic events associated with Febuxostat. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review.

    PubMed

    Atkinson, Hartley C; Potts, Amanda L; Anderson, Brian J

    2015-08-01

    Increased bioavailability of phenylephrine is reported when combined with paracetamol in over-the-counter formulations for the symptomatic treatment of the common cold and influenza. Such formulations could increase phenylephrine-related cardiovascular adverse events particularly in susceptible individuals. Quantification of the effect of phenylephrine concentration on blood pressure allows simulation of potential adverse combination therapy effects. MEDLINE and EMBASE databases were searched for papers discussing or describing any adverse effect, hypersensitivity or safety concerns related to phenylephrine alone or in combination with other drugs. The pharmacodynamic relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using published observations of blood pressure changes after ophthalmic eye drops. The resulting pharmacokinetic and pharmacodynamic parameters were then used to predict mean arterial blood pressure (MAP) changes in that population if given an oral combination of phenylephrine and paracetamol. There were 1172 papers identified for examination. Forty-seven reports fulfilled the inclusion criteria. Increases in blood pressure and decreases in heart rate have been reported with doses over 15 mg. It has been estimated that a 20-mmHg increase in systolic blood pressure would occur with an oral dose of 45 mg phenylephrine in normotensive healthy people. Those taking monoamine oxidase inhibitors report increased systolic blood pressure of greater than 60 mmHg. Blood pressure and heart rate changes are potentiated in patients with underlying hypertension. Simulation showed a modest increase in MAP when phenylephrine 10 mg was co-administered with paracetamol 1 g (4.2 vs 12.3 mmHg). Combination paracetamol phenylephrine oral therapy has potential to increase blood pressure more than phenylephrine alone in those with cardiovascular compromise.

  13. Cardiovascular magnetic resonance in pregnancy: Insights from the cardiac hemodynamic imaging and remodeling in pregnancy (CHIRP) study

    PubMed Central

    2014-01-01

    Background Cardiovascular disease in pregnancy is the leading cause of maternal mortality in North America. Although transthoracic echocardiography (TTE) is the most widely used imaging modality for the assessment of cardiovascular function during pregnancy, little is known on the role of cardiovascular magnetic resonance (CMR). The objective of the Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) study was to compare TTE and CMR in the non-invasive assessment of maternal cardiac remodeling during the peripartum period. Methods Between 2010–2012, healthy pregnant women aged 18 to 35 years were prospectively enrolled. All women underwent TTE and CMR during the third trimester and at least 3 months postpartum (surrogate for non-pregnant state). Results The study population included a total of 34 women (mean age 29 ± 3 years). During the third trimester, TTE and CMR demonstrated an increase in left ventricular end-diastolic volume from 95 ± 11 mL to 115 ± 14 mL and 98 ± 6 mL to 125 ± 5 mL, respectively (p < 0.05). By TTE and CMR, there was also an increase in left ventricular (LV) mass during pregnancy from 111 ± 10 g to 163 ± 11 g and 121 ± 5 g to 179 ± 5 g, respectively (p < 0.05). Although there was good correlation between both imaging modalities for LV mass, stroke volume, and cardiac output, the values were consistently underestimated by TTE. Conclusion This CMR study provides reference values for cardiac indices during normal pregnancy and the postpartum state. PMID:24387349

  14. Relation of Adiponectin to All-Cause Mortality, Cardiovascular Mortality, and Major Adverse Cardiovascular Events (from the Dallas Heart Study).

    PubMed

    Witberg, Guy; Ayers, Colby R; Turer, Aslan T; Lev, Eli; Kornowski, Ran; de Lemos, James; Neeland, Ian J

    2016-02-15

    Adiponectin is a key component in multiple metabolic pathways. Studies evaluating associations of adiponectin with clinical outcomes in older adults have reported conflicting results. We investigated the association of adiponectin with mortality and cardiovascular disease (CVD) morbidity in a young, multiethnic adult population. We analyzed data from participants in the Dallas Heart Study without baseline CVD who underwent assessment of total adiponectin from 2000 to 2002. The primary outcome of all-cause mortality was assessed over median 10.4 years of follow-up using multivariable-adjusted Cox proportional hazards models. Secondary outcomes included CVD mortality, major adverse cardiovascular and cerebrovascular events (MACCE), and heart failure (HF). The study cohort included 3,263 participants, mean age 43.4 years, 44% women, and 50% black. There were 184 deaths (63 CVD), 207 MACCE, and 46 HF events. In multivariable models adjusted for age, gender, race, hypertension, diabetes, smoking, high-density lipoprotein cholesterol-C, hyperlipidemia, high-sensitivity C-reactive protein level, estimated glomerular filtration rate, and body mass index, increasing adiponectin quartiles were positively associated with all-cause mortality Q4 versus Q1 (hazard ratio [HR] = 2.27; 95% confidence interval [CI] 1.47, 3.50); CVD mortality Q4 versus Q1 (HR = 2.43; 95% CI 1.15, 5.15); MACCE Q4 versus Q1 (HR = 1.71; 95% CI 1.13, 2.60); and HF Q4 versus Q1 (HR = 2.95; 95% CI 1.14, 7.67). Findings were similar with adiponectin as a continuous variable and consistent across subgroups defined by age, gender, race, obesity, diabetes, metabolic syndrome, or elevated high-sensitivity C-reactive protein. In conclusion, higher adiponectin was associated with increased mortality and CVD morbidity in a young, multiethnic population. These findings may have implications for strategies aimed at lowering adiponectin to prevent adverse outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Beneficial cardiovascular remodeling following arterio-venous fistula ligation post-renal transplantation: a longitudinal magnetic resonance imaging study.

    PubMed

    Dundon, Benjamin K; Torpey, David K; Nelson, Adam J; Wong, Dennis T L; Duncan, Rae F; Meredith, Ian T; Faull, Randall J; Worthley, Stephen G; Worthley, Matthew I

    2014-08-01

    Despite improvements in survival following renal transplantation, high rates of cardiovascular morbidity and mortality remain. Persistence of arterio-venous fistulae (AVF) may contribute to maladaptive cardiovascular remodeling and poor health outcomes in this cohort. Utilizing recent advances in cardiovascular magnetic resonance imaging (CMR), we prospectively evaluated alterations in cardiac and vascular structure and function six months after elective ligation of AVF, following stable, successful renal transplantation. Eighteen subjects underwent CMR evaluation of cardiac structure and function, aortic distensibility and endothelial function prior to AVF ligation and at six months. At follow-up, while left ventricular ejection fraction was unchanged, mean cardiac output decreased by 15.6% (9.6 ± 2.9 L/min vs. 8.1 ± 2.3 L/min, p = 0.004) and left ventricular mass had regressed by 10% (166 ± 56 g vs. 149 ± 51 g, p = 0.0001). Significant improvements were also noted in right ventricular and biatrial structure and function. Aortic distensibility was unchanged at follow-up, but endothelial dependent vasodilatation had improved (2.5 ± 6.5% vs. 8.0 ± 5.9%, p = 0.04). Elective AVF ligation following successful renal transplantation is associated with improvements in left ventricular mass, right ventricular, and biatrial structure and function. Further randomized studies are warranted to determine the potential clinical improvement following AVF ligation in this cohort. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Assessment of CardiOvascular Remodelling following Endovascular aortic repair through imaging and computation: the CORE prospective observational cohort study protocol

    PubMed Central

    Nauta, Foeke J H; Kamman, Arnoud V; Ibrahim, El-Sayed H; Agarwal, Prachi P; Yang, Bo; Kim, Karen; Williams, David M; van Herwaarden, Joost A; Moll, Frans L; Eagle, Kim A; Trimarchi, Santi; Patel, Himanshu J; Figueroa, C Alberto

    2016-01-01

    Introduction Thoracic aortic stent grafts are orders of magnitude stiffer than the native aorta. These devices have been associated with acute hypertension, elevated pulse pressure, cardiac remodelling and reduced coronary perfusion. However, a systematic assessment of such cardiovascular effects of thoracic endovascular aortic repair (TEVAR) is missing. The CardiOvascular Remodelling following Endovascular aortic repair (CORE) study aims to (1) quantify cardiovascular remodelling following TEVAR and compare echocardiography against MRI, the reference method; (2) validate computational modelling of cardiovascular haemodynamics following TEVAR using clinical measurements, and virtually assess the impact of more compliant stent grafts on cardiovascular haemodynamics; and (3) investigate diagnostic accuracy of ECG and serum biomarkers for cardiac remodelling compared to MRI. Methods and analysis This is a prospective, nonrandomised, observational cohort study. We will use MRI, CT, echocardiography, intraluminal pressures, ECG, computational modelling and serum biomarkers to assess cardiovascular remodelling in two groups of patients with degenerative thoracic aneurysms or penetrating aortic ulcers: (1) patients managed with TEVAR and (2) control patients managed with medical therapy alone. Power analysis revealed a minimum total sample size of 20 patients (α=0.05, power=0.97) to observe significant left ventricular mass increase following TEVAR after 1 year. Consequently, we will include 12 patients in both groups. Advanced MRI sequences will be used to assess myocardial and aortic strain and distensibility, myocardial perfusion and aortic flow. ECG, echocardiography and serum biomarkers will be collected and compared against the imaging data. Computational models will be constructed from each patient imaging data, analysed and validated. All measurements will be collected at baseline (prior to TEVAR) and 1-year follow-up. The expected study period is 3

  17. Giant splenic artery aneurysm: managed in the cardiovascular catheterization laboratory using the modified neck remodeling technique.

    PubMed

    Pappy, Reji; Sech, Candice; Hennebry, Thomas A

    2010-10-01

    We report the first case of coil embolization using the "modified neck remodeling technique" in the management of a splenic artery aneurysm. This technique was feasible due to the unique and complex anatomy of the aneurysm. This condition has been largely treated by vascular surgeons and interventional radiologists; however, this patient was referred to the interventional cardiologists for endovascular coiling. © 2010 Wiley-Liss, Inc.

  18. Charge is an important determinant of hemodynamic and adverse cardiovascular effects of cationic drugs.

    PubMed

    Pugsley, Michael K; Authier, Simon; Curtis, Michael J

    2015-12-01

    Cationic compounds are diverse and atypical therapeutic substances. In the present study we examined whether a prototypical class effect of cationic drugs in the cardiovascular system exists and whether this might be predictable on the basis of chemistry. The dose-dependent effects of cationic compounds of varying molecular weights and charge were examined on the blood pressure (BP), heart rate (HR) and the ECG in anesthetized rats. The compounds examined were protamine, hexadimethrine, tetraethylammonium (TEA), low molecular weight poly-L-lysine (LMW-PLL) and high molecular weight PLL (HMW-PLL). All of the compounds examined except TEA produced a dose-dependent reduction in BP. No changes occurred in HR even when high doses were administered. The ECG effects of these cationic compounds included a dose-dependent prolongation of the QT interval, especially at higher doses. All compounds transiently decreased the size of the P-wave after i.v. bolus administration whereas only protamine and hexadimethrine prolonged the PR and QRS intervals and only at the highest dose (32 mg/kg) administered. All cationic compounds, except TEA and saline, evoked ventricular premature beats (VPB), and protamine and HMW-PLL also evoked brief episodes of ventricular tachycardia (VT). The incidence and frequency of arrhythmias was not dose-dependent and no animals experienced protracted episodes of arrhythmia incidence. These dose dependent effects of the polycationic compounds tested suggest a collective mechanism of action that relates the effect of charge of the compound to the onset and persistence of observed cardiovascular toxicity, and adverse cardiovascular effect risk appears to be predictable on this basis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Milan PM1 Induces Adverse Effects on Mice Lungs and Cardiovascular System

    PubMed Central

    Farina, Francesca; Sancini, Giulio; Longhin, Eleonora; Mantecca, Paride; Camatini, Marina; Palestini, Paola

    2013-01-01

    Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with cardiorespiratory diseases. Since the response to PM1 has not yet been deeply investigated, its impact on mice lungs and cardiovascular system is here examined. A repeated exposure to Milan PM1 was performed on BALB/c mice. The bronchoalveolar lavage fluid (BALf) and the lung parenchyma were screened for markers of inflammation (cell counts, tumor necrosis factor-α (TNF-α); macrophage inflammatory protein-2 (MIP-2); heme oxygenase-1 (HO-1); nuclear factor kappa-light-chain-enhancer of activated B cells p50 subunit (NFκB-p50); inducible nitric oxide synthetase (iNOS); endothelial-selectin (E-selectin)), cytotoxicity (lactate dehydrogenase (LDH); alkaline phosphatase (ALP); heat shock protein 70 (Hsp70); caspase-8-p18), and a putative pro-carcinogenic marker (cytochrome 1B1 (Cyp1B1)). Heart tissue was tested for HO-1, caspase-8-p18, NFκB-p50, iNOS, E-selectin, and myeloperoxidase (MPO); plasma was screened for markers of platelet activation and clot formation (soluble platelet-selectin (sP-selectin); fibrinogen; plasminogen activator inhibitor 1 (PAI-1)). PM1 triggers inflammation and cytotoxicity in lungs. A similar cytotoxic effect was observed on heart tissues, while plasma analyses suggest blood-endothelium interface activation. These data highlight the importance of lung inflammation in mediating adverse cardiovascular events following increase in ambient PM1 levels, providing evidences of a positive correlation between PM1 exposure and cardiovascular morbidity. PMID:23509745

  20. Adverse childhood experiences and the cardiovascular health of children: a cross-sectional study.

    PubMed

    Pretty, Chelsea; O'Leary, Deborah D; Cairney, John; Wade, Terrance J

    2013-12-17

    Adverse childhood experiences (ACEs), such as abuse, household dysfunction, and neglect, have been shown to increase adults' risk of developing chronic conditions and risk factors for chronic conditions, including cardiovascular disease (CVD). Much less work has investigated the effect of ACEs on children's physical health status that may lead to adult chronic health conditions. Therefore, the present study examined the relationship between ACEs and early childhood risk factors for adult cardiovascular disease. 1 234 grade six to eight students participated in school-based data collection, which included resting measures of blood pressure (BP), heart rate (HR), body mass index (BMI) and waist circumference (WC). Parents of these children completed an inventory of ACEs taken from the Childhood Trust Events Survey. Linear regression models were used to assess the relationship between experiencing more than 4 ACEs experienced, systolic BP, HR, BMI and WC. In additional analysis, ACEs were assessed ordinally in their relationship with systolic BP, HR, and BMI as well as clinical obesity and hypertension status. After adjustment for family education, income, age, sex, physical activity, and parental history of hypertension, and WC for HR models, four or more ACEs had a significant effect on HR (b = 1.8 bpm, 95% CI (0.1-3.6)) BMI (b =1.1 kg/m2, 95% CI (0.5-1.8)), and WC (b = 3.6 cm, 95% CI (1.8-5.3)). A dose-response relationship between ACE accumulation and both BMI and WC was also found to be significant. Furthermore, accumulation of 4 or more ACEs was significantly associated with clinical obesity (95th percentile), after controlling for the aforementioned covariates. In a community sample of grade six to eight children, accumulation of 4 or more ACEs significantly increased BMI, WC and resting HR. Therefore, risk factors related to reported associations between ACEs and cardiovascular outcomes among adults are identifiable in childhood suggesting earlier

  1. Cardiac CaM Kinase II Genes δ and γ Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy

    PubMed Central

    Kreusser, Michael M.; Lehmann, Lorenz H.; Keranov, Stanislav; Hoting, Marc-Oscar; Oehl, Ulrike; Kohlhaas, Michael; Reil, Jan-Christian; Neumann, Kay; Schneider, Michael D.; Hill, Joseph A.; Dobrev, Dobromir; Maack, Christoph; Maier, Lars S.; Gröne, Hermann-Josef; Katus, Hugo A.; Olson, Eric N.; Backs, Johannes

    2014-01-01

    Background Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions We established a mouse model in which CaMKII’s activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure. PMID:25124496

  2. Fish oil and olive oil supplements attenuate the adverse cardiovascular effects of concentrated ambient air pollution particles exposure in healthy middle-aged adult human volunteers

    EPA Science Inventory

    Exposure to ambient levels of air pollution increases cardiovascular morbidity and mortality. Advanced age is among the factors associated with susceptibility to the adverse effects of air pollution. Dietary fatty acid supplementation has been shown to decrease cardiovascular ris...

  3. Fish oil and olive oil supplements attenuate the adverse cardiovascular effects of concentrated ambient air pollution particles exposure in healthy middle-aged adult human volunteers

    EPA Science Inventory

    Exposure to ambient levels of air pollution increases cardiovascular morbidity and mortality. Advanced age is among the factors associated with susceptibility to the adverse effects of air pollution. Dietary fatty acid supplementation has been shown to decrease cardiovascular ris...

  4. Evidence behind FDA alerts for drugs with adverse cardiovascular effects: implications for clinical practice.

    PubMed

    Rackham, Daniel M; C Herink, Megan; Stevens, Ian G; Cardoza, Natalie M; Singh, Harleen

    2014-01-01

    The U.S. Food and Drug Administration (FDA) periodically publishes Drug Safety Communications and Drug Alerts notifying health care practitioners and the general public of important information regarding drug therapies following FDA approval. These alerts can result in both positive and negative effects on patient care. Most clinical trials are not designed to detect long-term safety end points, and postmarketing surveillance along with patient reported events are often instrumental in signaling the potential harmful effect of a drug. Recently, many cardiovascular (CV) safety announcements have been released for FDA-approved drugs. Because a premature warning could discourage a much needed treatment or prompt a sudden discontinuation, it is essential to evaluate the evidence supporting these FDA alerts to provide effective patient care and to avoid unwarranted changes in therapy. Conversely, paying attention to these warnings in cases involving high-risk patients can prevent adverse effects and litigation. This article reviews the evidence behind recent FDA alerts for drugs with adverse CV effects and discusses the clinical practice implications.

  5. Preventing Heart Attacks and Strokes: Increasing Awareness of the Adverse Cardiovascular Health Impacts of Air Pollution

    EPA Science Inventory

    Summary: Chronic cardiovascular disease imposes a significant health and economic burden on individuals and communities. Despite decades of improvement in cardiovascular mortality, cardiovascular disease and stroke remain the leading cause of death in the U.S. and disparities i...

  6. Acute and Prolonged Adverse Effects of Temperature on Mortality from Cardiovascular Diseases

    PubMed Central

    Lin, Yu-Kai; Chang, Chin-Kuo; Wang, Yu-Chun; Ho, Tsung-Jung

    2013-01-01

    Background Cardiovascular diseases are the leading causes of death worldwide, especially for developed countries. Elevated mortality from cardiovascular diseases has been shown related to extreme temperature. We thus assessed the risk of mortality from cerebrovascular diseases, heart diseases, and ischemic heart disease (IHD) in relation to temperature profiles in four subtropical metropolitans (Taipei, Taichung, Tainan, and Kaohsiung) from 1994 to 2007 in Taiwan. Methods Distributed lag non-linear models were applied to estimate the cumulative relative risks (RRs) with confidence intervals of cause-specific mortality associated with daily temperature from lag 0 to 20 days, and specific effect of extreme temperature episodes with PM10, NOx, and O3, and other potential confounders controlled. Estimates for cause-specific mortalities were then pooled by random-effect meta-analysis. Results Comparing to centered temperature at 27°C, the cumulative 4-day (lag 0 to 3) risk of mortality was significantly elevated at 31°C for cerebrovascular diseases (RR = 1.14; 95% CI: 1.00, 1.31) and heart diseases (RR =  1.22; 95% CI: 1.02, 1.46) , but not for IHD (RR =  1.09; 95% CI: 0.99, 1.21). To the other extreme, at 15°C, the cumulative 21-day (lag 0 to 20) risk of mortality were also remarkably increased for cerebrovascular diseases, heart diseases, and IHD (RRs  =  1.48 with 95% CI: 1.04, 2.12, 2.04 with 95% CI: 1.61, 2.58, and 1.62 with 95% CI: 1.30, 2.01, respectively). Mortality risks for cardiovascular diseases were generally highest on the present day (lag 0) of extreme heat. No particular finding was detected on prolonged extreme temperature event by pooling estimations for cause-specific mortality. Conclusions Low temperature was associated with greater risk of mortality from cardiovascular diseases in comparison with that of high temperature. Adverse effects of extreme temperatures are acute at the beginning of exposure. PMID:24349335

  7. Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

    PubMed Central

    Wang, Xiang; Bosonea, Ana-Maria; Odenbach, Jeffrey; Fernandez-Patron, Carlos

    2014-01-01

    Hypertension, the condition characterized by sustained elevated blood pressure, affects over 25% of adults in developed countries and is accompanied by pathological cardiac remodeling (i.e., hypertrophy and fibrosis), thus being a major risk factor for cardiac failure. Life style, the environment, genetic factors, diabetes or obesity can all promote development and progression of hypertension associated cardiovascular disease in part because these conditions induce an excess production of pro-hypertensive, pro-hypertrophic and pro-fibrotic agonists. Here we review signaling pathways shared by major agonists including angiotensin II, catecholamines and endothelins. At the cellular level, these agonists initiate disease signaling by activating cognate G protein-coupled receptors (GPCRs). Early events in agonist-signaling include Ca2+ release from intracellular stores, Ca2+ uptake from extracellular millieu into cells and reactive oxygen species (ROS) generation by NADPH oxidase. ROS production in turn contributes to activation of matrix metalloproteinases (MMPs) and ‘a disintegrin and metalloproteinases’ (ADAMs). Activated MMPs and ADAMs cleave growth factors, cytokines as well as cell surface receptors, including GPCRs. Excessive activation of MMPs and ADAMs links agonist receptors with transcription and translation of disease-associated genes, including those of MMPs and ADAMs. Recent research indicates a complex and dynamic regulation of MMPs and ADAMs activity and expression by agonists, which poses a significant challenge to strategies aiming at targeting specific MMPs or ADAMs in cardiovascular disease. PMID:24976815

  8. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

    PubMed Central

    Zeng, Lingyao; Willenborg, Christina; Tragante, Vinicius; Kessler, Thorsten; Willer, Cristen J.; Laakso, Markku; Wallentin, Lars; Franks, Paul W.; Salomaa, Veikko; Dehghan, Abbas; Meitinger, Thomas; Samani, Nilesh J.; Asselbergs, Folkert W.; Erdmann, Jeanette; Schunkert, Heribert

    2017-01-01

    Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10−12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10−10 and 2.21 × 10−6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples. PMID:28829817

  9. Ozone exposure and systemic biomarkers: Evaluation of evidence for adverse cardiovascular health impacts.

    PubMed

    Goodman, Julie E; Prueitt, Robyn L; Sax, Sonja N; Pizzurro, Daniella M; Lynch, Heather N; Zu, Ke; Venditti, Ferdinand J

    2015-05-01

    The US Environmental Protection Agency (EPA) recently concluded that there is likely to be a causal relationship between short-term (< 30 days) ozone exposure and cardiovascular (CV) effects; however, biological mechanisms to link transient effects with chronic cardiovascular disease (CVD) have not been established. Some studies assessed changes in circulating levels of biomarkers associated with inflammation, oxidative stress, coagulation, vasoreactivity, lipidology, and glucose metabolism after ozone exposure to elucidate a biological mechanism. We conducted a weight-of-evidence (WoE) analysis to determine if there is evidence supporting an association between changes in these biomarkers and short-term ozone exposure that would indicate a biological mechanism for CVD below the ozone National Ambient Air Quality Standard (NAAQS) of 75 parts per billion (ppb). Epidemiology findings were mixed for all biomarker categories, with only a few studies reporting statistically significant changes and with no consistency in the direction of the reported effects. Controlled human exposure studies of 2 to 5 hours conducted at ozone concentrations above 75 ppb reported small elevations in biomarkers for inflammation and oxidative stress that were of uncertain clinical relevance. Experimental animal studies reported more consistent results among certain biomarkers, although these were also conducted at ozone exposures well above 75 ppb and provided limited information on ozone exposure-response relationships. Overall, the current WoE does not provide a convincing case for a causal relationship between short-term ozone exposure below the NAAQS and adverse changes in levels of biomarkers within and across categories, but, because of study limitations, they cannot not provide definitive evidence of a lack of causation.

  10. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk.

    PubMed

    Brænne, Ingrid; Zeng, Lingyao; Willenborg, Christina; Tragante, Vinicius; Kessler, Thorsten; Willer, Cristen J; Laakso, Markku; Wallentin, Lars; Franks, Paul W; Salomaa, Veikko; Dehghan, Abbas; Meitinger, Thomas; Samani, Nilesh J; Asselbergs, Folkert W; Erdmann, Jeanette; Schunkert, Heribert

    2017-01-01

    Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.

  11. Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure.

    PubMed

    Wang, Han-Jun; Wang, Wei; Cornish, Kurtis G; Rozanski, George J; Zucker, Irving H

    2014-10-01

    The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor-expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 μg/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-β receptor I in CHF rats. Pressure-volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF. © 2014 American Heart Association, Inc.

  12. Clean Indoor Air Acts reduce the burden of adverse cardiovascular outcomes.

    PubMed

    Lippert, W C; Gustat, J

    2012-04-01

    Second-hand smoke is associated with an increased risk of adverse health outcomes, such as acute myocardial infarction (AMI) and coronary heart disease (CHD). At present, 38 US states/territories have enacted Clean Indoor Air Acts (CIAAs). The purpose of the current study was to compare the prevalence of self-reported health outcomes on a state/territory-wide level 1 year prior to CIAA implementation and at least 1 year after CIAA implementation for each respective state/territory. Pre-test, post-test study. Seventeen states/territories with pre- and post-CIAA data were included in the current study. All data (AMI, CHD/angina, former and current smoker rates) were collected from the Behavioral Risk Factor Surveillance System (BRFSS) in the year prior to each state/territory's respective CIAA implementation (baseline) and 2009 (most recent year with BRFSS data). Between baseline and 2009, 10 states/territories (58.8%) had a significant decrease in the prevalence of CHD/angina or AMI, 11 states/territories (64.7%) had a significant decrease in the prevalence of current smokers, and three states/territories (17.7%) had a significant decrease in the prevalence of both current and former smokers. Six states/territories (35.3%) had a significant increase in the prevalence of former smokers. State/territory-wide CIAAs are beneficial in reducing adverse cardiovascular health outcomes in the short term. The prevalence of AMI, CHD/angina, and former and current smokers decreased significantly following CIAA implementation. The current study adds further support for the passage and implementation of CIAAs on a state/territory-wide level. However, further studies need to be conducted to assess the long-term outcomes of CIAAs. Copyright © 2012 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  13. Kinetics of Betamethasone and Fetal Cardiovascular Adverse Effects in Pregnant Sheep After Different Doses

    PubMed Central

    Schwab, Matthias; Coksaygan, Turhan; Samtani, Mahesh N.; Jusko, William J.; Nathanielsz, Peter W.

    2014-01-01

    OBJECTIVE To study the pharmacokinetics of different betamethasone doses and preparations used to enhance fetal lung maturation in the maternal and fetal circulation of sheep and the adverse effects on fetal blood pressure. METHODS Doses of 170 (n = 6) and 110 µg/kg (n = 6) betamethasone phosphate equivalent to 12 or 8mg, respectively, administered to a 70kg pregnant woman or 170 µg/kg (n = 6) of a depot formulation (50% betamethasone phosphate and 50% betamethasone acetate) were injected intramuscularly to chronically instrumented pregnant sheep. RESULTS Both betamethasone preparations produced highest maternal concentrations after 15 min followed by an exponential decline with a t1/2 of about 3 hours. The drug fell below the limit of detection at 8 to 12 hours. Betamethasone was first detectable in the fetal circulation at 1 hour, peaked at 3 hours, and decreased below the limit of detection at 8 hours independently of the dose or preparation. Maternal and fetal betamethasone concentrations achieved with the phosphate and acetate formulation were one half of those obtained with betamethasone phosphate, suggesting that very little betamethasone is released from the acetate within the first 8 hours when the effect on lung maturation is needed. Betamethasone led to a maximal increase of mean fetal blood pressure from 42 ± 1 to 51 ± 1 mm Hg (P<.05) and did not differ between the doses and preparations, although plasma concentrations showed a clear dose–concentration relationship. CONCLUSION The doses of betamethasone used in obstetrics are supramaximal in terms of cardiovascular effects in sheep. Risk-benefit studies are needed to find the effective steroid dose with the least adverse effects. PMID:16946223

  14. Angiotensin-Converting Enzyme Inhibitor Captopril Reverses the Adverse Cardiovascular Effects of Polymerized Hemoglobin

    PubMed Central

    Zhou, Ronghua; Yao, Yusheng; Yang, Qian; Zhou, Cheng; Wu, Wei; Li, Qian; You, Zhen; Zhao, Xiaolin; Yang, Linhui; Li, Chen; Zhu, Da; Qiu, Yanhua; Luo, Ming; Tan, Zhaoxia; Li, Huan; Chen, Yanfang; Gong, Gu; Feng, Yuan; Dian, Ke

    2014-01-01

    Abstract Aim: Cell-free hemoglobin-based oxygen carriers (HBOCs) may increase the risk of myocardial infarction and death. We studied the effect of an angiotensin-converting enzyme (ACE) inhibitor on HBOC-induced adverse cardiovascular outcomes and elucidated the underlying mechanisms. Results: With a dog cardiopulmonary bypass model, we demonstrated that a high-dose HBOC (3%, w/v) did not reduce—but aggravated—cardiac ischemia/reperfusion injury. Animals administered a high-dose HBOC experienced coronary artery constriction and depression of cardiac function. Exposure of isolated coronary arteries or human umbilical vein endothelial cells to high-dose HBOC caused impaired endothelium-dependent relaxation, increased endothelial cell necrosis/apoptosis, and elevated NAD(P)H oxidase expression (gp91phox, p47phox, p67phox, and Nox1) and reactive oxygen species (ROS) production. All observed adverse outcomes could be suppressed by the ACE inhibitor captopril (100 μM). Co-incubation with free radical scavenger tempol or NAD(P)H oxidase inhibitor apocynin had no effect on captopril action, suggesting that the positive effects of captopril are ROS- and NAD(P)H oxidase dependent. ACE inhibition by captopril also contributed to these effects. In addition, bioavailable nitrite oxide (NO) reduced by high-dose HBOC was preserved by captopril. Furthermore, HBOC, at concentrations greater than 0.5%, inhibited large conductance Ca2+-activated K+ channel currents in vascular smooth muscle cells in a dose-dependent manner, although captopril failed to improve current activity, providing additional evidence that captopril's effects are mediated by the endothelium, but not by the smooth muscle. Innovation and Conclusion: Captopril alleviates high-dose HBOC-induced endothelial dysfunction and myocardial toxicity, which is mediated by synergistic depression of NAD(P)H oxidase subunit overproduction and increases in vascular NO bioavailability. Antioxid. Redox Signal. 21, 2095

  15. Angiotensin-converting enzyme inhibitor captopril reverses the adverse cardiovascular effects of polymerized hemoglobin.

    PubMed

    Li, Tao; Zhou, Ronghua; Yao, Yusheng; Yang, Qian; Zhou, Cheng; Wu, Wei; Li, Qian; You, Zhen; Zhao, Xiaolin; Yang, Linhui; Li, Chen; Zhu, Da; Qiu, Yanhua; Luo, Ming; Tan, Zhaoxia; Li, Huan; Chen, Yanfang; Gong, Gu; Feng, Yuan; Dian, Ke; Liu, Jin

    2014-11-20

    Cell-free hemoglobin-based oxygen carriers (HBOCs) may increase the risk of myocardial infarction and death. We studied the effect of an angiotensin-converting enzyme (ACE) inhibitor on HBOC-induced adverse cardiovascular outcomes and elucidated the underlying mechanisms. With a dog cardiopulmonary bypass model, we demonstrated that a high-dose HBOC (3%, w/v) did not reduce-but aggravated-cardiac ischemia/reperfusion injury. Animals administered a high-dose HBOC experienced coronary artery constriction and depression of cardiac function. Exposure of isolated coronary arteries or human umbilical vein endothelial cells to high-dose HBOC caused impaired endothelium-dependent relaxation, increased endothelial cell necrosis/apoptosis, and elevated NAD(P)H oxidase expression (gp91(phox), p47(phox), p67(phox), and Nox1) and reactive oxygen species (ROS) production. All observed adverse outcomes could be suppressed by the ACE inhibitor captopril (100 μM). Co-incubation with free radical scavenger tempol or NAD(P)H oxidase inhibitor apocynin had no effect on captopril action, suggesting that the positive effects of captopril are ROS- and NAD(P)H oxidase dependent. ACE inhibition by captopril also contributed to these effects. In addition, bioavailable nitrite oxide (NO) reduced by high-dose HBOC was preserved by captopril. Furthermore, HBOC, at concentrations greater than 0.5%, inhibited large conductance Ca(2+)-activated K(+) channel currents in vascular smooth muscle cells in a dose-dependent manner, although captopril failed to improve current activity, providing additional evidence that captopril's effects are mediated by the endothelium, but not by the smooth muscle. Captopril alleviates high-dose HBOC-induced endothelial dysfunction and myocardial toxicity, which is mediated by synergistic depression of NAD(P)H oxidase subunit overproduction and increases in vascular NO bioavailability.

  16. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study).

    PubMed

    Abbate, Antonio; Kontos, Michael C; Grizzard, John D; Biondi-Zoccai, Giuseppe G L; Van Tassell, Benjamin W; Robati, Roshanak; Roach, Lenore M; Arena, Ross A; Roberts, Charlotte S; Varma, Amit; Gelwix, Christopher C; Salloum, Fadi N; Hastillo, Andrea; Dinarello, Charles A; Vetrovec, George W

    2010-05-15

    Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m(2) median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/m(2) median decrease (interquartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m(2). On echocardiography, the median difference in the LVESVi change was 13.4 ml/m(2) (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m(2), p = 0.033) and echocardiography (9.4 ml/m(2), p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R = +0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI. Copyright 2010 Elsevier Inc. All rights reserved.

  17. Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot Study)

    PubMed Central

    Abbate, Antonio; Kontos, Michael C.; Grizzard, John D.; Biondi-Zoccai, Giuseppe G. L.; Van Tassell, Benjamin W.; Robati, Roshanak; Roach, Lenore M.; Arena, Ross A.; Roberts, Charlotte S.; Varma, Amit; Gelwix, Christopher C.; Salloum, Fadi N.; Hastillo, Andrea; Dinarello, Charles A.; Vetrovec, George W.

    2013-01-01

    Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m2 median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a –3.2 ml/m2 median decrease (interquartile range –4.5, –1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m2. On echocardiography, the median difference in the LVESVi change was 13.4 ml/m2 (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m2, p = 0.033) and echocardiography (9.4 ml/m2, p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R =+0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI. PMID:23453459

  18. SWI/SNF Chromatin-Remodeling Complexes in Cardiovascular Development and Disease

    PubMed Central

    Bevilacqua, Ariana; Willis, Monte S.; Bultman, Scott J.

    2013-01-01

    Our understanding of congenital heart defects has been recently advanced by whole exome sequencing projects, which have identified de novo mutations in many genes encoding epigenetic regulators. Notably, multiple subunits of SWI/SNF chromatin-remodeling complexes have been identified as strong candidates underlying these defects because they physically and functionally interact with cardiogenic transcription factors critical to cardiac development, such as TBX5, GATA-4, and NKX2-5. While these studies indicate a critical role of SWI/SNF complexes in cardiac development and congenital heart disease, many exciting new discoveries have identified their critical role in the adult heart in both physiological and pathological conditions involving multiple cell types in the heart, including cardiomyocytes, vascular endothelial cells, pericytes, and neural crest cells. This review summarizes the role of SWI/SNF chromatinremodeling complexes in cardiac development, congenital heart disease, cardiac hypertrophy, and vascular endothelial cell survival. Although the clinical relevance of SWI/SNF mutations has traditionally been focused primarily on their role in tumor suppression, these recent studies illustrate their critical role in the heart whereby they regulate cell proliferation, differentiation, and apoptosis of cardiac derived cell lines. PMID:24183004

  19. High Triglycerides Predicts Arteriogenic Erectile Dysfunction and Major Adverse Cardiovascular Events in Subjects With Sexual Dysfunction.

    PubMed

    Corona, Giovanni; Cipriani, Sarah; Rastrelli, Giulia; Sforza, Alessandra; Mannucci, Edoardo; Maggi, Mario

    2016-09-01

    The atherogenic role of triglycerides (TG) remains controversial. The aim of the present study is to analyze the contribution of TG in the pathogenesis of erectile dysfunction (ED) and to verify the value of elevated TG in predicting major adverse cardiovascular events (MACE). An unselected series of 3,990 men attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (n = 1,687) was enrolled in a longitudinal study. Several clinical, biochemical, and instrumental (penile color Doppler ultrasound; PCDU) factors were evaluated. Among the patients studied, after adjustment for confounders, higher TG levels were associated with arteriogenic ED and a higher risk of clinical and biochemical hypogonadism. Conversely, no association between TG and other sexual dysfunctions was observed. When pathological PCDU parameters-including flaccid acceleration (<1.17 m/sec(2)) or dynamic peak systolic velocity (PSV <35 cm/sec)-were considered, the negative association between impaired penile flow and higher TG levels was confirmed, even when subjects taking lipid-lowering drugs or those with diabetes were excluded from the analysis (OR = 6.343 [1.243;32.362], P = .026 and 3.576 [1.104;11.578]; P = .34 for impaired acceleration and PSV, respectively). Similarly, when the same adjusted models were applied, TG levels were associated with a higher risk of hypogonadism, independently of the definition criteria (OR = 2.892 [1.643;5.410], P < .0001 and 4.853 [1.965;11.990]; P = .001 for total T <12 and 8 nM, respectively). In the longitudinal study, after adjusting for confounders, elevated TG levels (upper quartile: 162-1686 mg/dL) were independently associated with a higher incidence of MACE (HR = 2.469 [1.019;5.981]; P = .045), when compared to the rest of the sample. Our data suggest an association between elevated TG and arteriogenic ED and its cardiovascular (CV) risk stratification. Whether the use of TG lowering drugs

  20. Low-dose dobutamine adds incremental value to late gadolinium enhancement cardiac magnetic resonance in the prediction of adverse remodelling following acute myocardial infarction.

    PubMed

    Scott, Anne E; Semple, Scott I K; Redpath, Thomas W; Hillis, Graham S

    2013-09-01

    To examine the relative and combined value of late gadolinium enhancement (LGE) and low-dose dobutamine (LDD) cardiac magnetic resonance (CMR) to predict 'adverse remodelling' (AR) following acute myocardial infarction (AMI). Forty-five patients with AMI were recruited. CMR was performed 2-4 days after presentation and at 6 months. Ventricular wall motion and volume were recorded at rest and following dobutamine infusion. Measures of first pass perfusion, persistent microvascular obstruction (PMO), and LGE were obtained following contrast administration. Quantitation was performed using the MEDIS 6.2 software. Regression analysis was employed to determine the univariables and multivariate models most predictive of AR at 6 months. The incremental and relative value of LDD over LGE was investigated. The most predictive univariable was 'volume of PMO' (r = 0.51, r2 = 0.26, P < 0.001). The optimal 'combined' multivariate model, utilizing data from all components, was highly predictive of AR (r = 0.82, r2 = 0.67, P < 0.001). The optimal model using parameters only from the LGE component also predicted remodelling (r = 0.65, r2 = 42.0, P = 0.001) but with less accuracy. In contrast, the optimal model using variables from the LDD component alone predicted remodelling with a similar accuracy to the optimal combined model (r = 0.82, r2 = 0.67, P < 0.001). A comprehensive CMR examination accurately predicts AR following AMI. LDD is superior to LGE CMR in this respect. These data suggest that LDD not only adds incremental value to LGE in the prediction of remodelling post-AMI but also may be utilized alone with the same predictive power.

  1. Garcinia mangostana pericarp extract protects against oxidative stress and cardiovascular remodeling via suppression of p47(phox) and iNOS in nitric oxide deficient rats.

    PubMed

    Boonprom, Pattanapong; Boonla, Orachorn; Chayaburakul, Kanokporn; Welbat, Jariya Umka; Pannangpetch, Patchareewan; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Pakdeechote, Poungrat; Prachaney, Parichat

    2017-07-01

    N(ω)-Nitro-l-arginine methyl ester (l-NAME)-induced hypertension and cardiovascular remodeling are associated with oxidative stress and inflammation. Garcinia mangostana Linn., has been reported to have antioxidant and anti-inflammatory properties. This study investigated whether G. mangostana pericarp extract (GME) could prevent l-NAME-induced hemodynamic alterations, cardiovascular remodeling, oxidative stress and inflammation in rats. Male Sprague-Dawley rats were given 40mg/kg/day of l-NAME in drinking water to induce hypertension, and were simultaneously treated with GME at a dose of 200mg/kg/day. Rats that received l-NAME for five weeks had high blood pressure, left ventricular hypertrophy and thickening of aortic wall. Vascular superoxide production, plasma malondialdehyde (MDA), and plasma tumor necrosis factor alpha (TNF-α) were significantly increased in l-NAME-hypertensive rats (p<0.05). This was consistent with up-regulation of the p47(phox) NADPH oxidase subunit and iNOS protein expression in aortic tissues (p<0.05). Low levels of plasma nitric oxide metabolites were observed in l-NAME hypertension. GME prevented the development of hypertension and cardiovascular remodeling induced by l-NAME with reduced oxidative stress and inflammation. These data suggest that GME had a protective effect against l-NAME-induced hypertension and cardiovascular remodeling via suppressing p47(phox) NADPH oxidase subunit and iNOS protein expression resulting in enhancing NO bioavailability. Copyright © 2017 Elsevier GmbH. All rights reserved.

  2. Clinical Risk Factors for In-Hospital Adverse Cardiovascular Events After Acute Drug Overdose

    PubMed Central

    Manini, Alex F.; Hoffman, Robert S.; Stimmel, Barry; Vlahov, David

    2015-01-01

    Objectives It was recently demonstrated that adverse cardiovascular events (ACVE) complicate a high proportion of hospitalizations for patients with acute drug overdoses. The aim of this study was to derive independent clinical risk factors for ACVE in patients with acute drug overdoses. Methods This prospective cohort study was conducted over 3 years at two urban university hospitals. Patients were adults with acute drug overdoses enrolled from the ED. In-hospital ACVE was defined as any of myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest. Results There were 1,562 patients meeting inclusion/exclusion criteria (mean age, 41.8 years; female, 46%; suicidal, 38%). ACVE occurred in 82 (5.7%) patients (myocardial injury, 61; shock, 37; dysrhythmia, 23; cardiac arrests, 22) and there were 18 (1.2%) deaths. On univariate analysis, ACVE risk increased with age, lower serum bicarbonate, prolonged QTc interval, prior cardiac disease, and altered mental status. In a multivariable model adjusting for these factors as well as patient sex and hospital site, independent predictors were: QTc > 500 msec (3.8% prevalence, odds ratio [OR] 27.6), bicarbonate < 20 mEql/L (5.4% prevalence, OR 4.4), and prior cardiac disease (7.1% prevalence, OR 9.5). The derived prediction rule had 51.6% sensitivity, 93.7% specificity, and 97.1% negative predictive value; while presence of two or more risk factors had 90.9% positive predictive value. Conclusions The authors derived independent clinical risk factors for ACVE in patients with acute drug overdose, which should be validated in future studies as a prediction rule in distinct patient populations and clinical settings. PMID:25903997

  3. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice

    PubMed Central

    Usher, Michael G.; Duan, Sheng Zhong; Ivaschenko, Christine Y.; Frieler, Ryan A.; Berger, Stefan; Schütz, Günther; Lumeng, Carey N.; Mortensen, Richard M.

    2010-01-01

    Inappropriate excess of the steroid hormone aldosterone, which is a mineralocorticoid receptor (MR) agonist, is associated with increased inflammation and risk of cardiovascular disease. MR antagonists are cardioprotective and antiinflammatory in vivo, and evidence suggests that they mediate these effects in part by aldosterone-independent mechanisms. Here we have shown that MR on myeloid cells is necessary for efficient classical macrophage activation by proinflammatory cytokines. Macrophages from mice lacking MR in myeloid cells (referred to herein as MyMRKO mice) exhibited a transcription profile of alternative activation. In vitro, MR deficiency synergized with inducers of alternatively activated macrophages (for example, IL-4 and agonists of PPARγ and the glucocorticoid receptor) to enhance alternative activation. In vivo, MR deficiency in macrophages mimicked the effects of MR antagonists and protected against cardiac hypertrophy, fibrosis, and vascular damage caused by L-NAME/Ang II. Increased blood pressure and heart rates and decreased circadian variation were observed during treatment of MyMRKO mice with L-NAME/Ang II. We conclude that myeloid MR is an important control point in macrophage polarization and that the function of MR on myeloid cells likely represents a conserved ancestral MR function that is integrated in a transcriptional network with PPARγ and glucocorticoid receptor. Furthermore, myeloid MR is critical for blood pressure control and for hypertrophic and fibrotic responses in the mouse heart and aorta. PMID:20697155

  4. Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats

    PubMed Central

    Kang, Kyu-Tae; Coggins, Matthew; Xiao, Chunyang; Rosenzweig, Anthony

    2013-01-01

    Cell-based therapies to restore heart function after infarction have been tested in pre-clinical models and clinical trials with mixed results, and will likely require both contractile cells and a vascular network to support them. We and others have shown that human endothelial colony forming cells (ECFC) combined with mesenchymal progenitor cells (MPC) can be used to “bio-engineer” functional human blood vessels. Here we investigated whether ECFC + MPC form functional vessels in ischemic myocardium and whether this affects cardiac function or remodeling. Myocardial ischemia/reperfusion injury (IRI) was induced in 12-week-old immunodeficient rats by ligation of the left anterior descending coronary artery. After 40 min, myocardium was reperfused and ECFC + MPC (2 × 106 cells, 2:3 ratio) or PBS was injected. Luciferase assays after injection of luciferase-labeled ECFC + MPC showed that 1,500 ECFC were present at day 14. Human ECFC-lined perfused vessels were directly visualized by femoral vein injection of a fluorescently-tagged human-specific lectin in hearts injected with ECFC + MPC but not PBS alone. While infarct size at day 1 was no different, LV dimensions and heart weight to tibia length ratios were lower in cell-treated hearts compared with PBS at 4 months, suggesting post-infarction remodeling was ameliorated by local cell injection. Fractional shortening, LV wall motion score, and fibrotic area were not different between groups at 4 months. However, pressure–volume loops demonstrated improved cardiac function and reduced volumes in cell-treated animals. These data suggest that myocardial delivery of ECFC + MPC at reperfusion may provide a therapeutic strategy to mitigate LV remodeling and cardiac dysfunction after IRI. PMID:23666122

  5. Anti-CCP antibody in patients with established rheumatoid arthritis: Does it predict adverse cardiovascular profile?

    PubMed Central

    Arnab, Banerjee; Biswadip, Ghosh; Arindam, Pande; Shyamash, Mandal; Anirban, Ghosh; Rajan, Palui

    2013-01-01

    Background Rheumatoid arthritis (RA) is an independent risk factor for adverse cardiovascular (CV) events that accounts for a significant proportion of mortality among these patients. Anti-CCP antibodies are associated with higher frequency of extra-articular manifestations and poorer outcomes in RA. Aims To determine the role of anti-cyclic citrullinated peptide (CCP) antibody as an independent risk factor for developing CV complications as documented by carotid intima medial thickness and abnormal echocardiography in established RA patients. Materials and methods Eighty patients of RA having disease duration of at least 3 years participated in this hospital-based, cross-sectional, and observational study. Forty patients were anti-CCP antibody positive. Patients of established RA having known CV risk factors, known heart disease, or family history of premature ischemic heart disease were excluded. Results Anti-CCP positive group had early morning stiffness, tender and swollen joint count, and c-reactive protein (CRP) level significantly higher than those in anti-CCP negative group. Average intima-medial thicknesses of common carotid arteries were also significantly higher among anti-CCP positive group (P = 0.029) and were positively correlated with patients' age and disease duration. Lower left ventricular ejection fraction and left ventricular diastolic dysfunction were more commonly dispersed among the anti-CCP positive patients with P values of 0.01 and 0.034, respectively. Mild pericardial thickening was documented among 12.5% patients of anti-CCP positive group, while none of the anti-CCP negative patients had similar findings in echocardiography. Conclusion This study stressed on the important role of anti-CCP antibody in myocardial dysfunction due to inflammation in RA patients. Both atherosclerotic vascular involvement and cardiac abnormalities including pericardial, myocardial, and endocardial involvements were higher among anti-CCP positive RA patients

  6. Time-varying maximal proteinuria correlates with adverse cardiovascular events and graft failure in kidney transplant recipients.

    PubMed

    Jeon, Hee Jung; Kim, Clara Tammy; An, Jung Nam; Lee, Hajeong; Kim, Hyosang; Park, Su-Kil; Joo, Kwon Wook; Lim, Chun Soo; Jung, In Mok; Ahn, Curie; Kim, Yon Su; Kim, Young Hoon; Lee, Jung Pyo

    2015-12-01

    In the general population, proteinuria is associated with progression to kidney failure, cardiovascular disease, and mortality. Here, we analyzed the effects of proteinuria on outcomes in kidney transplant recipients. We performed a retrospective, multi-centre cohort study involving 2047 recipients to evaluate the effects of post-transplant proteinuria on adverse cardiovascular events, graft failure, and mortality. Patients were classified into two groups according to their levels of proteinuria: patients without proteinuria (<150 mg/day, n = 1113) and proteinuric patients (≥ 150 mg/day, n = 934). Multivariate Cox hazard model was conducted with using the maximal proteinuria as time-varying covariate. During a median 55.3-month (range, 0.6-167.1) follow-up, there were 50 cases of major adverse cardiac events (cardiac death, nonfatal myocardial infarction, or coronary revascularization), 115 cases of graft failure, and 52 patient deaths. In multivariate Cox regression with time-varying covariate, proteinuric recipients were significantly associated with major adverse cardiac events (hazard ratio [HR] 8.689, 95% confidence interval [CI] 2.929-25.774, P < 0.001) compared to those without proteinuria. Recipients with proteinuria showed significantly higher incidences of acute rejection (23.1% vs. 9.4%, P < 0.001) and graft failure rate (HR 6.910, 95% CI 3.270-14.601, P < 0.001). In addition, mortality rate was also significantly higher in patients with proteinuria (HR 6.815, 95% CI 2.164-21.467, P = 0.001). Post-transplant proteinuria correlates with adverse cardiovascular events, graft failure, and mortality. Therefore, proteinuria should be evaluated and managed to improve the outcomes of renal recipients. © 2015 Asian Pacific Society of Nephrology.

  7. IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

    PubMed Central

    Tejada, Thor; Tan, Lin; Torres, Rebecca A.; Calvert, John W.; Lambert, Jonathan P.; Zaidi, Madiha; Husain, Murtaza; Berce, Maria D.; Naib, Hussain; Pejler, Gunnar; Abrink, Magnus; Graham, Robert M.; Lefer, David J.; Naqvi, Nawazish; Husain, Ahsan

    2016-01-01

    Heart disease is a leading cause of death in adults. Here, we show that a few days after coronary artery ligation and reperfusion, the ischemia-injured heart elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1), which activates IGF-1 receptor prosurvival signaling and improves cardiac left ventricular systolic function. However, this signaling is antagonized by the chymase, mouse mast cell protease 4 (MMCP-4), which degrades IGF-1. We found that deletion of the gene encoding MMCP-4 (Mcpt4), markedly reduced late, but not early, infarct size by suppressing IGF-1 degradation and, consequently, diminished cardiac dysfunction and adverse structural remodeling. Our findings represent the first demonstration to our knowledge of tissue IGF-1 regulation through proteolytic degradation and suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease. PMID:27274047

  8. [Adverse effects of ultrafine particles on the cardiovascular system and its mechanisms].

    PubMed

    Yi, Tie-ci; Li, Jian-ping

    2014-12-18

    Cardiovascular disease is one of the major threats to human. Air pollution, which , as it become a problem too serious to be ignored in China, is known to be an important risk factor for cardiovascular disease. Among all pollutants, ultrafine particles ( UFPs) , defined as particles with their diameter less than 0. 1 f.Lm, are a specific composition. They are very small in size, large in quantity and surface area, and most important, capable of passing through the air-blood barrier. These unique features of UFPs make them special in their impact on cardiovascular system. Nowadays, the influence of UFPs on the cardiovascular system has become a hot topic. On the one side, studies have shown that UFPs can cause inflammation and oxidative stress in the lung, and then induce systemic inflammation by releasing cytokine and reactive oxygen species into the circulation. On the other side, UFPs themselves can "spillout"into the circulation and interact with their targets. By this way, UFPs directly affect endothelial cells, myocardial cells and the autonomic nervous system, which ultimately result in increased cardiovascular events. We intend to make an overview about the recent progress about the influence of UFPs on human cardiovascular disease and the related mechanisms, and argue for more attention to this issue.

  9. Left Atrial Reverse Remodeling: Mechanisms, Evaluation, and Clinical Significance.

    PubMed

    Thomas, Liza; Abhayaratna, Walter P

    2017-01-01

    The left atrium is considered a biomarker for adverse cardiovascular outcomes, particularly in patients with left ventricular diastolic dysfunction and atrial fibrillation in whom left atrial (LA) enlargement is of prognostic importance. LA enlargement with a consequent decrease in LA function represents maladaptive structural and functional "remodeling" that in turn promotes electrical remodeling and a milieu conducive for incident atrial fibrillation. Medical and nonmedical interventions may arrest this pathophysiologic process to the extent that subsequent reverse remodeling results in a reduction in LA size and improvement in LA function. This review examines cellular and basic mechanisms involved in LA remodeling, evaluates the noninvasive techniques that can assess these changes, and examines potential mechanisms that may initiate reverse remodeling.

  10. Better Adherence to the Mediterranean Diet Could Mitigate the Adverse Consequences of Obesity on Cardiovascular Disease: The SUN Prospective Cohort.

    PubMed

    Eguaras, Sonia; Toledo, Estefanía; Hernández-Hernández, Aitor; Cervantes, Sebastián; Martínez-González, Miguel A

    2015-11-05

    Strong observational evidence supports the association between obesity and cardiovascular events. In elderly high-risk subjects, the Mediterranean diet (MedDiet) was reported to counteract the adverse cardiovascular effects of adiposity. Whether this same attenuation is also present in younger subjects is not known. We prospectively examined the association between obesity and cardiovascular clinical events (myocardial infarction, stroke or cardiovascular death) after 10.9 years follow-up in 19,065 middle-aged men and women (average age 38 year) according to their adherence to the MedDiet (<6 points or ≥6 points in the Trichopoulou's Mediterranean Diet Score). We observed 152 incident cases of cardiovascular disease (CVD). An increased risk of CVD across categories of body mass index (BMI) was apparent if adherence to the MedDiet was low, with multivariable-adjusted hazard ratios (HRs): 1.44 (95% confidence interval: 0.93-2.25) for ≥25 - <30 kg/m² of BMI and 2.00 (1.04-3.83) for ≥30 kg/m² of BMI, compared to a BMI < 25 kg/m². In contrast, these estimates were 0.77 (0.35-1.67) and 1.15 (0.39-3.43) with good adherence to MedDiet. Better adherence to the MedDiet was associated with reduced CVD events (p for trend = 0.029). Our results suggest that the MedDiet could mitigate the harmful cardiovascular effect of overweight/obesity.

  11. Better Adherence to the Mediterranean Diet Could Mitigate the Adverse Consequences of Obesity on Cardiovascular Disease: The SUN Prospective Cohort

    PubMed Central

    Eguaras, Sonia; Toledo, Estefanía; Hernández-Hernández, Aitor; Cervantes, Sebastián; Martínez-González, Miguel A.

    2015-01-01

    Strong observational evidence supports the association between obesity and cardiovascular events. In elderly high-risk subjects, the Mediterranean diet (MedDiet) was reported to counteract the adverse cardiovascular effects of adiposity. Whether this same attenuation is also present in younger subjects is not known. We prospectively examined the association between obesity and cardiovascular clinical events (myocardial infarction, stroke or cardiovascular death) after 10.9 years follow-up in 19,065 middle-aged men and women (average age 38 year) according to their adherence to the MedDiet (<6 points or ≥6 points in the Trichopoulou’s Mediterranean Diet Score). We observed 152 incident cases of cardiovascular disease (CVD). An increased risk of CVD across categories of body mass index (BMI) was apparent if adherence to the MedDiet was low, with multivariable-adjusted hazard ratios (HRs): 1.44 (95% confidence interval: 0.93–2.25) for ≥25 – <30 kg/m2 of BMI and 2.00 (1.04–3.83) for ≥30 kg/m2 of BMI, compared to a BMI < 25 kg/m2. In contrast, these estimates were 0.77 (0.35–1.67) and 1.15 (0.39–3.43) with good adherence to MedDiet. Better adherence to the MedDiet was associated with reduced CVD events (p for trend = 0.029). Our results suggest that the MedDiet could mitigate the harmful cardiovascular effect of overweight/obesity. PMID:26556370

  12. Prognostic value of depression, anxiety, and anger in hospitalized cardiovascular disease patients for predicting adverse cardiac outcomes.

    PubMed

    Nakamura, Shunichi; Kato, Koji; Yoshida, Asuka; Fukuma, Nagaharu; Okumura, Yasuyuki; Ito, Hiroto; Mizuno, Kyoichi

    2013-05-15

    Although attention has recently been focused on the role of psychosocial factors in patients with cardiovascular disease (CVD), the factors that have the greatest influence on prognosis have not yet been elucidated. The aim of this study was to evaluate the effects of depression, anxiety, and anger on the prognosis of patients with CVD. Four hundred fourteen consecutive patients hospitalized with CVD were prospectively enrolled. Depression was evaluated using the Patient Health Questionnaire, anxiety using the Generalized Anxiety Disorder Questionnaire, and anger using the Spielberger Trait Anger Scale. Cox proportional-hazards regression was used to examine the individual effects of depression, anxiety, and anger on a combined primary end point of cardiac death or cardiac hospitalization and on a combined secondary end point of all-cause death or hospitalization during follow-up (median 14.2 months). Multivariate analysis showed that depression was a significant risk factor for cardiovascular hospitalization or death after adjusting for cardiac risk factors and other psychosocial factors (hazard ratio 2.62, p = 0.02), whereas anxiety was not significantly associated with cardiovascular hospitalization or death after adjustment (hazard ratio 2.35, p = 0.10). Anger was associated with a low rate of cardiovascular hospitalization or death (hazard ratio 0.34, p <0.01). In conclusion, depression in hospitalized patients with CVD is a stronger independent risk factor for adverse cardiac events than either anxiety or anger. Anger may help prevent adverse outcomes. Routine screening for depression should therefore be performed in patients with CVD, and the potential effects of anger in clinical practice should be reconsidered.

  13. Cardioprotective effect of a combination of Rho-kinase inhibitor and p38 MAPK inhibitor on cardiovascular remodeling and oxidative stress in Dahl rats.

    PubMed

    Takeshima, Hiroshi; Kobayashi, Naohiko; Koguchi, Wataru; Ishikawa, Mayuko; Sugiyama, Fumihiro; Ishimitsu, Toshihiko

    2012-01-01

    Rho-kinase plays a critical role in various cellular functions. p38 mitogen-activated protein kinase (p38 MAPK) plays a central role in the inflammatory cytokine response to immune challenge. We evaluated the effects of a combination of fasudil, a Rho-kinase inhibitor, and FR167653, a p38 MAPK inhibitor, on cardiovascular remodeling, inflammation, and oxidative stress in Dahl salt-sensitive hypertensive (DS) rats. DS and Dahl salt-resistant (DR) rats were fed a high-salt diet at 6 weeks of age. Vehicle, fasudil (100 mg/kg per day), FR167653 (2 mg/kg per day), and a combination of fasudil and FR167653 were administered to 6-week-old DS rats for 5 weeks. At the age of 11 weeks, in the left ventricle, DS rats were characterized by increased myocardial fibrosis, phosphorylation of p38 MAPK, and myosin phosphatase targeting subunit (MYPT-1), and NAD(P)H oxidase p22(phox), p47(phox), gp91(phox), tumor necrosis factor-α and interleukin-1β expression compared with DR rats. Fasudil improved cardiovascular remodeling, inflammation, NAD(P)H oxidase subunits, and phosphorylation of p38 MAPK and MYPT-1. FR167653 also similarly ameliorated these indices but not MYPT-1 phosphorylation. Compared with either agent alone, a combination of fasudil and FR167653 was more effective for the improvement of myocardial damage, inflammation and oxidative stress. These findings suggest that the Rho-kinase and p38 MAPK pathways may play a pivotal role in ventricular hypertrophy; thus, we obtained the first evidence that a combination of Rho-kinase inhibitor and p38 MAPK inhibitor may provide a potential therapeutic target in hypertension with cardiovascular remodeling.

  14. Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K Limits Oxidative Stress, Injury, and Adverse Remodeling in the Ischemic Heart

    PubMed Central

    Vagnozzi, Ronald J.; Gatto, Gregory J.; Kallander, Lara S.; Hoffman, Nicholas E.; Mallilankaraman, Karthik; Ballard, Victoria L. T.; Lawhorn, Brian G.; Stoy, Patrick; Philp, Joanne; Graves, Alan P.; Naito, Yoshiro; Lepore, John J.; Gao, Erhe; Madesh, Muniswamy; Force, Thomas

    2015-01-01

    Percutaneous coronary intervention is first-line therapy for acute coronary syndromes (ACS) but can promote cardiomyocyte death and cardiac dysfunction via reperfusion injury, a phenomenon driven in large part by oxidative stress. Therapies to limit this progression have proven elusive, with no major classes of new agents since the development of anti-platelets/anti-thrombotics. We report that cardiac troponin I–interacting kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes ischemia/reperfusion injury, oxidative stress, and myocyte death. TNNI3K-mediated injury occurs through increased mitochondrial superoxide production and impaired mitochondrial function and is largely dependent on p38 mitogen-activated protein kinase (MAPK) activation. We developed a series of small-molecule TNNI3K inhibitors that reduce mitochondrial-derived superoxide generation, p38 activation, and infarct size when delivered at reperfusion to mimic clinical intervention. TNNI3K inhibition also preserves cardiac function and limits chronic adverse remodeling. Our findings demonstrate that TNNI3K modulates reperfusion injury in the ischemic heart and is a tractable therapeutic target for ACS. Pharmacologic TNNI3K inhibition would be cardiac-selective, preventing potential adverse effects of systemic kinase inhibition. PMID:24132636

  15. c-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II-Induced Hypertension.

    PubMed

    Callera, Glaucia E; Antunes, Tayze T; He, Ying; Montezano, Augusto C; Yogi, Alvaro; Savoia, Carmine; Touyz, Rhian M

    2016-11-01

    c-Src plays an important role in angiotensin II (Ang II) signaling. Whether this member of the Src family kinases is involved in the development of Ang II-induced hypertension and associated cardiovascular damage in vivo remains unknown. Here, we studied Ang II-infused (400 ng/kg/min) mice in which c-Src was partially deleted (c-Src(+/-)) and in wild-type (WT, c-Src(+/+)) mice treated with a c-Src inhibitor (CGP077675; 25 mg/kg/d). Ang II increased blood pressure and induced endothelial dysfunction in WT mice, responses that were ameliorated in c-Src(+/-) and CGP077675-treated mice. Vascular wall thickness and cross-sectional area were similarly increased by Ang II in WT and c-Src(+/-) mice. CGP077675 further increased cross-sectional area in hypertensive mice. Cardiac dysfunction (ejection fraction and fractional shortening) in Ang II-infused WT mice was normalized in c-Src(+/-) mice. Increased oxidative stress (plasma thiobarbituric acid-reactive substances, hydrogen peroxide, and vascular superoxide generation) in Ang II-infused WT mice was attenuated in c-Src-deficient and CGP077675-treated mice. Hyperactivation of vascular c-Src, ERK1/2 (extracellular signal-regulated kinase 1/2), and JNK (c-Jun N-terminal kinase) in hypertensive mice was normalized in CGP077675-treated and c-Src(+/-) mice. Vascular fibronectin was increased by Ang II in all groups and further augmented by CGP077675. Cardiac fibrosis and inflammation induced by Ang II were amplified in c-Src(+/-) and CGP-treated mice. Our data indicate that although c-Src downregulation attenuates development of hypertension, improves endothelial and cardiac function, reduces oxidative stress, and normalizes vascular signaling, it has little beneficial effect on fibrosis. These findings suggest a divergent role for c-Src in Ang II-dependent hypertension, where c-Src may be more important in regulating redox-sensitive cardiac and vascular function than fibrosis and remodeling. © 2016 American Heart Association

  16. The Role of Adverse Childhood Experiences in Cardiovascular Disease Risk: a Review with Emphasis on Plausible Mechanisms

    PubMed Central

    Su, Shaoyong; Jimenez, Marcia P.; Roberts, Cole T. F.; Loucks, Eric B.

    2016-01-01

    Childhood adversity, characterized by abuse, neglect, and household dysfunction, is a problem that exerts a significant impact on individuals, families, and society. Growing evidence suggests that adverse childhood experiences (ACEs) are associated with health decline in adulthood, including cardiovascular disease (CVD). In the current review, we first provide an overview of the association between ACEs and CVD risk, with updates on the latest epidemiological evidence. Second, we briefly review plausible pathways by which ACEs could influence CVD risk, including traditional risk factors and novel mechanisms. Finally, we highlight the potential implications of ACEs in clinical and public health. Information gleaned from this review should help physicians and researchers in better understanding potential long-term consequences of ACEs and considering adapting current strategies in treatment or intervention for patients with ACEs. PMID:26289252

  17. The role of adverse childhood experiences in cardiovascular disease risk: a review with emphasis on plausible mechanisms.

    PubMed

    Su, Shaoyong; Jimenez, Marcia P; Roberts, Cole T F; Loucks, Eric B

    2015-10-01

    Childhood adversity, characterized by abuse, neglect, and household dysfunction, is a problem that exerts a significant impact on individuals, families, and society. Growing evidence suggests that adverse childhood experiences (ACEs) are associated with health decline in adulthood, including cardiovascular disease (CVD). In the current review, we first provide an overview of the association between ACEs and CVD risk, with updates on the latest epidemiological evidence. Second, we briefly review plausible pathways by which ACEs could influence CVD risk, including traditional risk factors and novel mechanisms. Finally, we highlight the potential implications of ACEs in clinical and public health. Information gleaned from this review should help physicians and researchers in better understanding potential long-term consequences of ACEs and considering adapting current strategies in treatment or intervention for patients with ACEs.

  18. The influence of a triclosan toothpaste on adverse events in patients with cardiovascular disease over 5-years.

    PubMed

    Cullinan, Mary P; Palmer, Janet E; Carle, Anne D; West, Malcolm J; Westerman, Bill; Seymour, Gregory J

    2015-03-01

    Adverse effects of long-term usage of triclosan-containing toothpaste in humans are currently unknown. We assessed the effect of long-term use of 0.3% triclosan-toothpaste on serious adverse events (SAEs) in patients with cardiovascular disease (CVD). 438 patients with a history of stable CVD were entered into the 5-year longitudinal Cardiovascular and Periodontal Study at Prince Charles Hospital, Brisbane, Australia and randomised into test (triclosan) or placebo groups. There were no significant differences in demographics or clinical features between the groups. Patients were examined at baseline, and annually for 5-years. SAEs were classified according to the System Organ Classes defined by MedDRA (Medical Dictionary for Regulatory Activities). Results were analysed using chi square and Kaplan Meier analysis. Overall, 232 patients (123 in the triclosan group; 109 in the placebo group) experienced 569 SAEs (288 in the triclosan group and 281 in the placebo group). There was no significant difference between the groups in numbers of patients experiencing SAEs (p=0.35) or specific cardiovascular SAEs (p=0.82), nor in time to the first SAE or first cardiovascular SAE, irrespective of gender, age or BMI after adjusting for multiple comparisons (p>0.05). The adjusted odds of experiencing an SAE were estimated to increase by 2.7% for each year of age (p=0.02) and the adjusted odds of experiencing a cardiovascular SAE were estimated to increase by 5.1% for each unit increase in BMI (p=0.02). Most cardiovascular events were related to unstable angina or myocardial infarcts, 21 were associated with arrhythmia and 41 were vascular events such as aortic aneurysm and cerebrovascular accident. Within the limitations of the present study the data suggest that the use of triclosan-toothpaste may not be associated with any increase in SAEs in this CVD population. The long-term impact of triclosan on hormone-related disease, such as cancer, in humans remains to be determined.

  19. Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial.

    PubMed

    Nissen, Steven E; Wolski, Kathy E; Prcela, Lisa; Wadden, Thomas; Buse, John B; Bakris, George; Perez, Alfonso; Smith, Steven R

    2016-03-08

    Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents. To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients. Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed. An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n=4456). Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval. Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion-treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the

  20. Elevated depressive affect is associated with adverse cardiovascular outcomes among African Americans with chronic kidney disease.

    PubMed

    Fischer, Michael J; Kimmel, Paul L; Greene, Tom; Gassman, Jennifer J; Wang, Xuelei; Brooks, Deborah H; Charleston, Jeanne; Dowie, Donna; Thornley-Brown, Denyse; Cooper, Lisa A; Bruce, Marino A; Kusek, John W; Norris, Keith C; Lash, James P

    2011-09-01

    This study was designed to examine the impact of elevated depressive affect on health outcomes among participants with hypertensive chronic kidney disease in the African-American Study of Kidney Disease and Hypertension (AASK) Cohort Study. Elevated depressive affect was defined by Beck Depression Inventory II (BDI-II) thresholds of 11 or more, above 14, and by 5-Unit increments in the score. Cox regression analyses were used to relate cardiovascular death/hospitalization, doubling of serum creatinine/end-stage renal disease, overall hospitalization, and all-cause death to depressive affect evaluated at baseline, the most recent annual visit (time-varying), or average from baseline to the most recent visit (cumulative). Among 628 participants at baseline, 42% had BDI-II scores of 11 or more and 26% had a score above 14. During a 5-year follow-up, the cumulative incidence of cardiovascular death/hospitalization was significantly greater for participants with baseline BDI-II scores of 11 or more compared with those with scores <11. The baseline, time-varying, and cumulative elevated depressive affect were each associated with a significant higher risk of cardiovascular death/hospitalization, especially with a time-varying BDI-II score over 14 (adjusted HR 1.63) but not with the other outcomes. Thus, elevated depressive affect is associated with unfavorable cardiovascular outcomes in African Americans with hypertensive chronic kidney disease.

  1. Elevated depressive affect is associated with adverse cardiovascular outcomes among African Americans with chronic kidney disease

    PubMed Central

    Fischer, Michael J.; Kimmel, Paul L.; Greene, Tom; Gassman, Jennifer J.; Wang, Xuelei; Brooks, Deborah H.; Charleston, Jeanne; Dowie, Donna; Thornley-Brown, Denyse; Cooper, Lisa A.; Bruce, Marino A.; Kusek, John W.; Norris, Keith C.; Lash, James P.

    2011-01-01

    This study was designed to examine the impact of elevated depressive affect on health outcomes among participants with hypertensive chronic kidney disease in the African-American Study of Kidney Disease and Hypertension (AASK) Cohort Study. Elevated depressive affect was defined by Beck Depression Inventory II (BDI-II) thresholds of 11 or more, above 14, and by 5-Unit increments in the score. Cox regression analyses were used to relate cardiovascular death/hospitalization, doubling of serum creatinine/end-stage renal disease, overall hospitalization, and all-cause death to depressive affect evaluated at baseline, the most recent annual visit (time-varying), or average from baseline to the most recent visit (cumulative). Among 628 participants at baseline, 42% had BDI-II scores of 11 or more and 26% had a score above 14. During a 5-year follow-up, the cumulative incidence of cardiovascular death/hospitalization was significantly greater for participants with baseline BDI-II scores of 11 or more compared with those with scores <11. The baseline, time-varying, and cumulative elevated depressive affect were each associated with a significant higher risk of cardiovascular death/hospitalization, especially with a time-varying BDI-II score over 14 (adjusted HR 1.63) but not with the other outcomes. Thus, elevated depressive affect is associated with unfavorable cardiovascular outcomes in African Americans with hypertensive chronic kidney disease. PMID:21633409

  2. Soluble TWEAK and Major Adverse Cardiovascular Events in Patients with CKD

    PubMed Central

    Fernández-Laso, Valvanera; Sastre, Cristina; Valdivielso, Jose M.; Betriu, Angels; Fernández, Elvira; Egido, Jesús; Martín-Ventura, Jose L.

    2016-01-01

    Background and objectives Soluble TNF–like weak inducer of apoptosis (sTWEAK) is a proinflammatory cytokine belonging to the TNF superfamily. sTWEAK concentrations have been associated with the presence of CKD and cardiovascular disease (CVD). We hypothesized that sTWEAK levels may relate to a higher prevalence of atherosclerotic plaques, vascular calcification, and cardiovascular outcomes observed in patients with CKD. Design, setting, participants, & measurements A 4-year prospective, multicenter, longitudinal study was conducted in 1058 patients with CKD stages 3–5D (mean age =58±13 years old; 665 men) but without any history of CVD from the NEFRONA Study (a study design on the prevalence of surrogate markers of CVD). Ankle-brachial index and B-mode ultrasound were performed to detect the presence of carotid and/or femoral atherosclerotic plaques together with biochemical measurements and sTWEAK assessment. Patients were followed for cardiovascular outcomes (follow-up of 3.13±1.15 years). Results Patients with more advanced CKD had lower sTWEAK levels. sTWEAK concentrations were independently and negatively associated with carotid intima-media thickness. sTWEAK levels were lower in patients with carotid atherosclerotic plaques but not in those with femoral plaques. After adjustment by confounders, the odds ratio (OR) for presenting carotid atherosclerotic plaques in patients in the lowest versus highest tertile of sTWEAK was 4.18 (95% confidence interval [95% CI], 2.89 to 6.08; P<0.001). Furthermore, sTWEAK levels were lower in patients with calcified carotid atherosclerotic plaques. The OR for presenting calcified carotid plaques was 1.77 (95% CI, 1.06 to 2.93; P=0.02) after multivariable adjustment. After the follow-up, 41 fatal and 68 nonfatal cardiovascular events occurred. In a Cox model, after controlling for potential confounding factors, patients in the lowest tertile of sTWEAK concentrations had a higher risk of fatal and nonfatal cardiovascular

  3. Sustained myocardial production of stromal cell-derived factor-1α was associated with left ventricular adverse remodeling in patients with myocardial infarction.

    PubMed

    Uematsu, Manabu; Yoshizaki, Toru; Shimizu, Takuya; Obata, Jun-ei; Nakamura, Takamitsu; Fujioka, Daisuke; Watanabe, Kazuhiro; Watanabe, Yosuke; Kugiyama, Kiyotaka

    2015-11-15

    The role of stromal cell-derived factor-1α (SDF-1α) expressed in infarcted myocardium is unknown in humans. We examined whether SDF-1α produced in an infarcted myocardial lesion may play a role in left ventricle (LV) remodeling and dysfunction in patients with acute myocardial infarction (AMI). We measured SDF-1α levels in plasma obtained from aortic root (AO) and anterior interventricular vein (AIV) in the early phase (2 wk after MI) and the chronic phase (6 mo after MI) in 80 patients with anterior MI. An increment in SDF-1α level from AO to AIV, reflecting SDF-1α release from infarcted myocardium, was more frequent in patients with MI in the early phase of MI [n = 52 (65%), P = 0.03] but not in the chronic phase of MI [n = 46 (58%), P = 0.11] compared with that in control patients [n = 6/17 (35%)]. On linear regression analysis, the transmyocardial gradient in SDF-1α level in the chronic phase of MI was correlated with percentage changes in LV end-diastolic volume index (r = 0.39, P < 0.001), LV end-systolic volume index (r = 0.38, P < 0.001), and LV ejection fraction (r = -0.26, P = 0.01) 6 mo after AMI. By contrast, the transmyocardial gradient of SDF-1α in the early phase of MI had no significant correlations. In conclusion, the production of SDF-1α in infarcted myocardium in the chronic phase of MI was associated with LV adverse remodeling and progressive dysfunction in AMI survivors.

  4. Adverse events in cardiovascular-related training programs in people with spinal cord injury: a systematic review.

    PubMed

    Warms, Catherine A; Backus, Deborah; Rajan, Suparna; Bombardier, Charles H; Schomer, Katherine G; Burns, Stephen P

    2014-11-01

    There are anecdotal reports of adverse events (AEs) associated with exercise in people with spinal cord injury (SCI) and consequent concern by people with SCI and their providers about potential risks of exercise. Enumeration of specific events has never been performed and the extent of risk of exercise to people with SCI is not understood. To systematically review published evidence to identify and enumerate reports of adverse events or AEs associated with training in persons with SCI. Review was limited to peer-reviewed studies published in English from 1970 to 2011: (1) in adults with SCI, (2) evaluating training protocols consisting of repeated sessions over at least 4 weeks to maintain or improve cardiovascular health, (3) including volitional exercise modalities and functional electrical stimulation (FES)-enhanced exercise modalities, and (4) including a specific statement about AEs. Trained reviewers initially identified a total of 145 studies. After further screening, 38 studies were included in the review. Quality of evidence was evaluated using established procedures. There were no serious AEs reported. There were no common AEs reported across most types of interventions, except for musculoskeletal AEs related to FES walking. There were few AEs in volitional exercise studies. There is no evidence to suggest that cardiovascular exercise done according to guidelines and established safety precautions is harmful. To improve the strength of these conclusions, future publications should include definition of AEs, information about pre-intervention screening, and statements of the nature and extent of AEs.

  5. Adverse events in cardiovascular-related training programs in people with spinal cord injury: A systematic review

    PubMed Central

    Warms, Catherine A.; Backus, Deborah; Rajan, Suparna; Bombardier, Charles H.; Schomer, Katherine G.; Burns, Stephen P.

    2014-01-01

    Context There are anecdotal reports of adverse events (AEs) associated with exercise in people with spinal cord injury (SCI) and consequent concern by people with SCI and their providers about potential risks of exercise. Enumeration of specific events has never been performed and the extent of risk of exercise to people with SCI is not understood. Objective To systematically review published evidence to identify and enumerate reports of adverse events or AEs associated with training in persons with SCI. Methods Review was limited to peer-reviewed studies published in English from 1970 to 2011: (1) in adults with SCI, (2) evaluating training protocols consisting of repeated sessions over at least 4 weeks to maintain or improve cardiovascular health, (3) including volitional exercise modalities and functional electrical stimulation (FES)-enhanced exercise modalities, and (4) including a specific statement about AEs. Trained reviewers initially identified a total of 145 studies. After further screening, 38 studies were included in the review. Quality of evidence was evaluated using established procedures. Results There were no serious AEs reported. There were no common AEs reported across most types of interventions, except for musculoskeletal AEs related to FES walking. There were few AEs in volitional exercise studies. Conclusion There is no evidence to suggest that cardiovascular exercise done according to guidelines and established safety precautions is harmful. To improve the strength of these conclusions, future publications should include definition of AEs, information about pre-intervention screening, and statements of the nature and extent of AEs. PMID:24090603

  6. Minimizing Cardiovascular Adverse Effects of Atypical Antipsychotic Drugs in Patients with Schizophrenia

    PubMed Central

    Khasawneh, Fadi T.; Shankar, Gollapudi S.

    2014-01-01

    The use of atypical antipsychotic agents has rapidly increased in the United States and worldwide in the last decade. Nonetheless, many health care practitioners do not appreciate the significance of the cardiovascular side effects that may be associated with their use and the means to minimize them. Thus, atypical antipsychotic medications can cause cardiovascular side effects such as arrhythmias and deviations in blood pressure. In rare cases, they may also cause congestive heart failure, myocarditis, and sudden death. Patients with schizophrenia have a higher risk of cardiovascular mortality than healthy individuals, possibly because of excessive smoking, the underlying disorder itself, or a combination of both factors. Increased awareness of these potential complications can allow pharmacists and physicians to better manage and monitor high risk patients. Accurate assessments are very important to avoid medications from being given to patients inappropriately. Additionally, monitoring patients regularly via blood draws and checking blood pressure, heart rate, and electrocardiogram can help catch any clinical problems and prevent further complications. Finally, patient and family-member education, which pharmacists in particular can play key roles in, is central for the management and prevention of side effects, which is known to reflect positively on morbidity and mortality in these patients. PMID:24649390

  7. The predictive value of arterial stiffness on major adverse cardiovascular events in individuals with mildly impaired renal function

    PubMed Central

    Han, Jie; Wang, Xiaona; Ye, Ping; Cao, Ruihua; Yang, Xu; Xiao, Wenkai; Zhang, Yun; Bai, Yongyi; Wu, Hongmei

    2016-01-01

    Objectives Despite growing evidence that arterial stiffness has important predictive value for cardiovascular disease in patients with advanced stages of chronic kidney disease, the predictive significance of arterial stiffness in individuals with mildly impaired renal function has not been established. The aim of this study was to evaluate the predictive value of arterial stiffness on cardiovascular disease in this specific population. Materials and methods We analyzed measurements of arterial stiffness (carotid–femoral pulse-wave velocity [cf-PWV]) and the incidence of major adverse cardiovascular events (MACEs) in 1,499 subjects from a 4.8-year longitudinal study. Results A multivariate Cox proportional-hazard regression analysis showed that in individuals with normal renal function (estimated glomerular filtration rate [eGFR] ≥90 mL/min/1.73 m2), the baseline cf-PWV was not associated with occurrence of MACEs (hazard ratio 1.398, 95% confidence interval 0.748–2.613; P=0.293). In individuals with mildly impaired renal function (eGFR <90 mL/min/1.73 m2), a higher baseline cf-PWV level was associated with a higher risk of MACEs (hazard ratio 2.334, 95% confidence interval 1.082–5.036; P=0.031). Conclusion Arterial stiffness is a moderate and independent predictive factor for MACEs in individuals with mildly impaired renal function (eGFR <90 mL/min/1.73 m2). PMID:27621605

  8. Tenascin-X, collagen, and Ehlers-Danlos syndrome: tenascin-X gene defects can protect against adverse cardiovascular events.

    PubMed

    Petersen, John W; Douglas, J Yellowlees

    2013-09-01

    Long thought to be two separate syndromes, Ehlers-Danlos syndrome hypermobility type (EDS-HT) and benign joint hypermobility syndrome (BJHS) appear on close examination to represent the same syndrome, with virtually identical clinical manifestations. While both EDS-HT and BJHS were long thought to lack the genetic loci of other connective tissue disorders, including all other types of EDS, researchers have discovered a genetic locus that accounts for manifestations of both EDS-HT and BJHS in a small population of patients. However, given the modest sample size of these studies and the strong correlation between serum levels of tenascin-X with clinical symptoms of both EDS-HT and BJHS, strong evidence exists for the origins of both types of hypermobility originating in haploinsufficiency or deficiency of the gene TNXB, responsible for tenascin-X. Tenascin-X regulates both the structure and stability of elastic fibers and organizes collagen fibrils in the extra-cellular matrix (ECM), impacting the rigidity or elasticity of virtually every cell in the body. While the impacts of tenascin-X insufficiency or deficiency on the skin and joints have received some attention, its potential cardiovascular impacts remain relatively unexplored. Here we set forth two novel hypotheses. First, TNXB haploinsufficiency or deficiency causes the range of clinical manifestations long identified with both EDS-HT and BJHS. And, second, that haploinsufficiency or deficiency of TNXB may provide some benefits against adverse cardiovascular events, including heart attack and stroke, by lowering levels of arterial stiffness associated with aging, as well as by enhancing accommodation of accrued atherosclerotic plaques. This two-fold hypothesis provides insights into the mechanisms underlying the syndromes previous identified with joint hypermobility, at the same time the hypothesis also sheds light on the role of the composition of the extracellular matrix and its impacts on endothelial sheer

  9. Pathways between childhood/adolescent adversity, adolescent socioeconomic status, and long-term cardiovascular disease risk in young adulthood.

    PubMed

    Doom, Jenalee R; Mason, Susan M; Suglia, Shakira F; Clark, Cari Jo

    2017-09-01

    The current study investigated mediators between childhood/adolescent adversities (e.g., dating violence, maltreatment, homelessness, and parental death), low socioeconomic status (SES) during adolescence, and cardiovascular disease (CVD) risk in young adulthood. The purpose of these analyses was to understand whether SES during adolescence and childhood/adolescent adversities affect CVD risk through similar pathways, including maternal relationship quality, health behaviors, financial stress, medical/dental care, educational attainment, sleep problems, and depressive symptoms. Using the National Longitudinal Study of Adolescent to Adult Health (N = 14,493), which has followed US adolescents (Wave 1; M = 15.9 years) through early adulthood (Wave 4; M = 28.9 years), associations were examined between childhood/adolescent adversity and SES to 30-year CVD risk in young adulthood. The outcome was a Framingham-based prediction model of CVD risk that included age, sex, body mass index, smoking, systolic blood pressure, diabetes, and antihypertensive medication use at Wave 4. Path analysis was used to examine paths through the adolescent maternal relationship to young adult mediators of CVD risk. Childhood/adolescent adversity significantly predicted greater adult CVD risk through the following pathways: maternal relationship, health behaviors, financial stress, lack of medical/dental care, and educational attainment; but not through depressive symptoms or sleep problems. Lower SES during adolescence significantly predicted greater adult CVD risk through the following pathways: health behaviors, financial stress, lack of medical/dental care, and educational attainment, but not maternal relationship, depressive symptoms, or sleep problems. Childhood/adolescent adversities and SES affected CVD risk in young adulthood through both similar and unique pathways that may inform interventions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction.

    PubMed

    Jugdutt, Bodh I; Idikio, Halliday; Uwiera, Richard R E

    2007-09-01

    To determine whether therapy with the angiotensin II type 1 receptor blocker (ARB) candesartan and the comparator angiotensin-converting-enzyme inhibitor (ACEI) enalapril during healing after reperfused ST-elevation myocardial infarction (RSTEMI) limit adverse remodeling of infarct zone (IZ) collagens and left ventricular (LV) diastolic dysfunction, we randomized 24 dogs surviving anterior RSTEMI (90-min coronary occlusion) to placebo, candesartan, and enalapril therapy between day 2 and 42. Six other dogs were sham. We measured regional IZ and non-infarct zone (NIZ) collagens (hydroxyproline; types I/III; cross-linking), transforming growth factor-beta (TGF-beta) and topography at 6 weeks, and hemodynamics, LV diastolic and systolic function, and remodeling over 6 weeks. Compared to sham, placebo-RSTEMI differentially altered regional collagens, with more pronounced increase in TGF-beta, hydroxyproline, and type I, insoluble, and cross-linked collagens in the IZ than NIZ, and increased IZ soluble and type III collagens at 6 weeks, and induced persistent LV filling pressure elevation, diastolic and systolic dysfunction, and LV remodeling over 6 weeks. Compared to placebo-RSTEMI, candesartan and enalapril limited adverse regional collagen remodeling, with normalization of type III, soluble and insoluble collagens and decrease in pyridinoline cross-linking in the IZ at 6 weeks, and attenuation of LV filling pressure, diastolic dysfunction, and remodeling over 6 weeks. The results suggest that candesartan and enalapril during healing after RSTEMI prevent rather than worsen adverse remodeling of IZ collagens and LV diastolic dysfunction, supporting the clinical use of ARBs and ACEIs during subacute RSTEMI.

  11. [Impact of adherence to statins on cardiovascular adverse events in patients with coronary artery disease: a meta-analysis].

    PubMed

    Li, S T; Xu, J Y; Huang, R C

    2016-08-24

    To evaluate the impact of different adherence mode to statins on cardiovascular adverse events in patients with coronary artery disease (CAD). Electronic searches, including PubMed, Scopus, Ovid MEDLINE, Ovid EMBASE, Ovid EBM Reviews CENTRAL, CINAHL, The Cochrane Library, Ovid PsycInfo, Wanfang data, CNKI and Science & Technology Magazine Online, were performed and all related literatures of all languages were retrieval till to March 1, 2015. The full text was obtained through manual retrieval, inter-library loan and document delivery service, or by contacting the author directly. According to inclusion and exclusion criteria, data was extracted dependently by two raters. The high adherence to statin was use defined by the ratio of statins cover time and the total time (proportion of days covered, PDC≥80%). Data were analyzed quantitatively using RevMan 5.1. Then implement subgroup analysis was made according to different statin adherence and classification of clinical outcomes. The impact of adherence to statin on cardiovascular events (all-cause mortality, non-fatal myocardial infarction, hospitalization due to unstable angina pectoris, heart insufficiency attack) in CAD patients was evaluated. Present analysis enrolled eight relevant retrospective and observational studies. Because there were only few literatures describing the impact of statin adherence on clinical outcomes, we also included literatures with low adherence group (4 studies in PDC<80%, 2 studies in PDC<40% and 2 studies in PDC<20%). High adherence group includes 189 556 cases; low adherence group includes 11 384 cases. Compare with low adherence group, cardiovascular events rate reduced by 32% in high adherence group (OR=0.68, 95%CI 0.58-0.80, P<0.001). Subgroup analysis with 4 literatures with PDC≥80% or<80% showed that the cardiovascular events prominently decreased in high adherence group compared to low adherence group (OR=0.63, 95%CI 0.53-0.76, P<0.001). According to 5 literatures with

  12. [Weightlessness or weightlessness simulation and vascular remodeling].

    PubMed

    Yue, Yong; Yao, Yong-jie; Sun, Xi-qing; Wu, Xing-yu

    2003-04-01

    Weightlessness is inavoidable during spaceflight. It brings profound physiological effects on human body. Vascular remodeling is one of the important changes of cardiovascular system caused by weightlessness or simulated weightlessness. The paper summarized the studies on the effects of weightlessness or weightlessness simulation on vascular remodeling in recent years. The emergence and development of the concept of vascular remodeling were briefly reviewed. The advances of study on vascular remodeling in recent years was briefly discussed with the points focused on the effects of weightlessness or weightlessness simulation on cardiovascular remodeling and its mechanism. It is proposed that cardiovascular remodeling might be important in studying the causes of orthostatic intolerance after spaceflight.

  13. Adverse outcome analyses of observational data: assessing cardiovascular risk in HIV disease.

    PubMed

    Triant, V A; Josephson, F; Rochester, C G; Althoff, K N; Marcus, K; Munk, R; Cooper, C; D'Agostino, R B; Costagliola, D; Sabin, C A; Williams, P L; Hughes, S; Post, W S; Chandra-Strobos, N; Guaraldi, G; Young, S S; Obenchain, R; Bedimo, R; Miller, V; Strobos, J

    2012-02-01

    Clinical decisions are ideally based on randomized trials but must often rely on observational data analyses, which are less straightforward and more influenced by methodology. The authors, from a series of expert roundtables convened by the Forum for Collaborative HIV Research on the use of observational studies to assess cardiovascular disease risk in human immunodeficiency virus infection, recommend that clinicians who review or interpret epidemiological publications consider 7 key statistical issues: (1) clear explanation of confounding and adjustment; (2) handling and impact of missing data; (3) consistency and clinical relevance of outcome measurements and covariate risk factors; (4) multivariate modeling techniques including time-dependent variables; (5) how multiple testing is addressed; (6) distinction between statistical and clinical significance; and (7) need for confirmation from independent databases. Recommendations to permit better understanding of potential methodological limitations include both responsible public access to de-identified source data, where permitted, and exploration of novel statistical methods.

  14. Adverse Outcome Analyses of Observational Data: Assessing Cardiovascular Risk in HIV Disease

    PubMed Central

    Triant, V. A.; Josephson, F.; Rochester, C. G.; Althoff, K. N.; Marcus, K.; Munk, R.; Cooper, C.; D’Agostino, R. B.; Costagliola, D.; Sabin, C. A.; Williams, P. L.; Hughes, S.; Post, W. S.; Chandra-Strobos, N.; Guaraldi, G.; Young, S. S.; Obenchain, R.; Bedimo, R.; Miller, V.

    2012-01-01

    Clinical decisions are ideally based on randomized trials but must often rely on observational data analyses, which are less straightforward and more influenced by methodology. The authors, from a series of expert roundtables convened by the Forum for Collaborative HIV Research on the use of observational studies to assess cardiovascular disease risk in human immunodeficiency virus infection, recommend that clinicians who review or interpret epidemiological publications consider 7 key statistical issues: (1) clear explanation of confounding and adjustment; (2) handling and impact of missing data; (3) consistency and clinical relevance of outcome measurements and covariate risk factors; (4) multivariate modeling techniques including time-dependent variables; (5) how multiple testing is addressed; (6) distinction between statistical and clinical significance; and (7) need for confirmation from independent databases. Recommendations to permit better understanding of potential methodological limitations include both responsible public access to de-identified source data, where permitted, and exploration of novel statistical methods. PMID:22095570

  15. Rapid Surface Cooling by ThermoSuit System Dramatically Reduces Scar Size, Prevents Post-Infarction Adverse Left Ventricular Remodeling, and Improves Cardiac Function in Rats

    PubMed Central

    Dai, Wangde; Herring, Michael J; Hale, Sharon L; Kloner, Robert A

    2015-01-01

    Background The long-term effects of transient hypothermia by the non-invasive ThermoSuit apparatus on myocardial infarct (MI) scar size, left ventricular (LV) remodeling, and LV function were assessed in rat MI model. Methods and Results Rats were randomized to normothermic or hypothermic groups (n=14 in each group) and subjected to 30 minutes coronary artery occlusion and 6 weeks of reperfusion. For hypothermia therapy, rats were placed into the ThermoSuit apparatus at 2 minutes after the onset of coronary artery occlusion, were taken out of the apparatus when the core body temperature reached 32°C (in ≈8 minutes), and were then allowed to rewarm. After 6 weeks of recovery, rats treated with hypothermia demonstrated markedly reduced scar size (expressed as % of left ventricular area: hypothermia, 6.5±1.1%; normothermia, 19.4±1.7%; P=1.3×10−6); and thicker anterior LV wall (hypothermia, 1.57±0.09 mm; normothermia, 1.07±0.05 mm; P=3.4×10−5); decreased postmortem left ventricular volume (hypothermia, 0.45±0.04 mL; normothermia, 0.6±0.03 mL; P=0.028); and better LV fractional shortening by echocardiography (hypothermia, 37.2±2.8%; normothermia, 18.9±2.3%; P=0.0002) and LV ejection fraction by LV contrast ventriculography (hypothermia, 66.8±2.3%; normothermia, 56.0±2.0%; P=0.0014). Conclusions Rapid, transient non-invasive surface cooling with the ThermoSuit apparatus in the acute phase of MI decreased scar size by 66.5%, attenuated adverse post-infarct left ventricular dilation and remodeling, and improved cardiac function in the chronic phase of experimental MI. PMID:26116692

  16. Hormonal regulation of energy-protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes.

    PubMed

    Suneja, Manish; Murry, Daryl J; Stokes, John B; Lim, Victoria S

    2011-01-01

    To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with

  17. Hormonal regulation of energy-protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes

    PubMed Central

    Suneja, Manish; Murry, Daryl J.; Stokes, John B.

    2011-01-01

    To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with

  18. Monocyte to HDL Cholesterol Ratio Predicts Coronary Artery Disease Severity and Future Major Cardiovascular Adverse Events in Acute Coronary Syndrome.

    PubMed

    Cetin, Mehmet Serkan; Ozcan Cetin, Elif Hande; Kalender, Erol; Aydin, Selahattin; Topaloglu, Serkan; Kisacik, Halil Lutfi; Temizhan, Ahmet

    2016-11-01

    We aimed to investigate the usefulness of monocyte to HDL cholesterol ratio (MHR) in predicting coronary artery disease severity and future major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS). 2661 patient with ACS were enrolled and followed up during median 31.6 months. MHR were significantly positively correlated with neutrophil to lymphocyte ratio (r=0.438), CRP (r=0.394), Gensini (r=0.407), and SYNTAX score (r=0.333). During in-hospital and long-term follow-up, MACE, stent thrombosis, non-fatal MI, and mortality occurred more frequently in the third tertile group. Kaplan-Meier analysis revealed the higher occurrence of MACE in the third tertile group compared with other tertiles. Adjusting for other factors, a MHR value in the third tertile group was determined as an independent predictor of in-hospital and long-term MACE. MHR as a novel inflammation-based marker seemed to be an independent predictor of severity of coronary artery disease and future cardiovascular events in patients with ACS. MHR may utilise the identification of patients who are at higher risk for MACE and individualisation of targeted therapy. 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.

  19. High estimated pulmonary artery systolic pressure predicts adverse cardiovascular outcomes in stage 2-4 chronic kidney disease.

    PubMed

    Bolignano, Davide; Lennartz, Simone; Leonardis, Daniela; D'Arrigo, Graziella; Tripepi, Rocco; Emrich, Insa E; Mallamaci, Francesca; Fliser, Danilo; Heine, Gunnar; Zoccali, Carmine

    2015-07-01

    High estimated pulmonary artery systolic pressure (ePASP) is an established risk factor for mortality and cardiovascular (CV) events in the general population. High ePASP predicts mortality in dialysis patients but such a relationship has not been tested in patients with early CKD. Here we estimated the prevalence and the risk factors of high ePASP in 468 patients with CKD stage 2-4 and determined its prognostic power for a combined end point including cardiovascular death, acute heart failure, coronary artery disease, and cerebrovascular and peripheral artery events. High ePASP (35 mm Hg and above) was present in 108 CKD patients. In a multivariate logistic regression model adjusted for age, diabetes, hemoglobin, left atrial volume (LAV/BSA), left ventricular mass (LVM/BSA), and history of CV disease, age (OR, 1.06; 95% CI, 12 1.04-1.09) and LAV/BSA (OR, 1.05; 95% CI, 1.03-1.07) were the sole significant independent predictors of high ePASP. Elevated ePASP predicted a significantly high risk for the combined cardiovascular end point both in unadjusted analyses (HR, 2.70; 95% CI, 1.68-4.32) and in analyses adjusting for age, eGFR, hemoglobin, LAV/BSA, LVM/BSA, and the presence of diabetes and CV disease (HR, 1.75; 95% CI, 1.05-2.91). High ePASP is relatively common in patients with stage 2-4 CKD and predicts adverse CV outcomes independent of established classical and CKD-specific risk factors. Whether high ePASP is a modifiable risk factor in patients with CKD remains to be determined in randomized clinical trials.

  20. Left atrial volume index is an independent predictor of major adverse cardiovascular events in acute coronary syndrome.

    PubMed

    Gunasekaran, Ramsamy; Maskon, Oteh; Hassan, Hamat H Che; Safian, Nazarudin; Sakthiswary, Rajalingham

    2012-01-01

    Left atrial volume index (LAVI) is well proven to be a reliable method of determining left atrial size, which has prognostic implications in cardiovascular diseases. Studies demonstrate that increased LAVI is a predictor of mortality in myocardial infarction, but its association with other major adverse cardiovascular events (MACEs) among patients post acute coronary syndrome (ACS) has not been adequately evaluated. We calculated the baseline LAVI for all patients who were admitted with ACS between December 2010 and August 2011. The patients were stratified into 2 arms: normal LAVI and increased LAVI, with a cutoff value of 28 mL/m(2). All patients were prospectively followed up during 6 months for development of MACEs. Of the 75 patients who completed the study, 32 had increased LAVI, and 43 had normal LAVI. More than half (55%) of the patients were diagnosed with unstable angina. During the follow-up period of 6 months, 30 patients (93.8%) in the increased-LAVI arm and 23 patients (53.5%) in the normal-LAVI arm developed at least a single MACE. Patients with increased LAVI had significantly more MACEs (P = 0.021). The occurrence of MACE remained significantly higher in the increased-LAVI group even when atrial fibrillation was excluded (P = 0.016). After adjusting for confounding variables by multivariate analysis, LAVI was found to have a significant association with MACEs (P = 0.030, odds ratio = 1.229 (95% confidence interval, 1.020-1.481). LAVI is a useful tool for prognostication and an independent predictor of MACEs post ACS. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  1. Diagnostic and prognostic value of miR-1 and miR-29b on adverse ventricular remodeling after acute myocardial infarction - The SITAGRAMI-miR analysis.

    PubMed

    Grabmaier, U; Clauss, S; Gross, L; Klier, I; Franz, W M; Steinbeck, G; Wakili, R; Theiss, H D; Brenner, C

    2017-10-01

    MicroRNAs (miRs) have shown to exert fibrotic and anti-fibrotic effects in preclinical models of acute myocardial infarction (AMI). The aim of this study was to evaluate miR-1, miR-21, miR-29b and miR-92a as circulating biomarkers for adverse ventricular remodeling (AVR) in post-AMI patients. Plasma levels of miR-1, miR-21, miR-29b and miR-92a were measured in 44 patients of the SITAGRAMI trial population at day 4, day 9 and 6month after AMI and in 18 matched controls (CTL). MiR expression patterns were correlated with magnetic resonance imaging (MRI) parameters for AVR (absolute change (Δ) in infarct volume (IV), left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) between day 4 and 6months after AMI) and a combined cardiovascular endpoint. Expression of miR-1, miR-21 and miR-29b but not miR-92a was increased in AMI vs. CTL cohort showing highest miR levels at d9. However, only miR-1 and miR-29b levels significantly correlated with ΔIV and showed a trend for correlation with ΔLVEF. Only miR-29b levels at day 9 correlated with ΔLVEDV at 6-month follow-up. There was no correlation of miR levels with an adverse outcome. Mir-1 and miR-29b plasma levels post-AMI correlate with IV changes. In addition, miR-29b levels are associated with changes of LVEDV over time. These results provide insights into the role of miRs as diagnostic AVR surrogate markers. Further large scale clinical trials will be needed to evaluate the real prognostic relevance of these miRs with respect to a clinical implication in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. The lysyl oxidase inhibitor (β-aminopropionitrile) reduces leptin profibrotic effects and ameliorates cardiovascular remodeling in diet-induced obesity in rats.

    PubMed

    Martínez-Martínez, Ernesto; Rodríguez, Cristina; Galán, María; Miana, María; Jurado-López, Raquel; Bartolomé, María Visitación; Luaces, María; Islas, Fabián; Martínez-González, José; López-Andrés, Natalia; Cachofeiro, Victoria

    2016-03-01

    Lysyl oxidase (LOX) is an extracellular matrix (ECM)-modifying enzyme that has been involved in cardiovascular remodeling. We explore the impact of LOX inhibition in ECM alterations induced by obesity in the cardiovascular system. LOX is overexpressed in the heart and aorta from rats fed a high-fat diet (HFD). β-Aminopropionitrile (BAPN), an inhibitor of LOX activity, significantly attenuated the increase in body weight and cardiac hypertrophy observed in HFD rats. No significant differences were found in cardiac function or blood pressure among any group. However, HFD rats showed cardiac and vascular fibrosis and enhanced levels of superoxide anion (O2(-)), collagen I and transforming growth factor β (TGF-β) in heart and aorta and connective tissue growth factor (CTGF) in aorta, effects that were attenuated by LOX inhibition. Interestingly, BAPN also prevented the increase in circulating leptin levels detected in HFD fed animals. Leptin increased protein levels of collagen I, TGF-β and CTGF, Akt phosphorylation and O2(-) production in both cardiac myofibroblasts and vascular smooth muscle cells in culture, while LOX inhibition ameliorated these alterations. LOX knockdown also attenuated leptin-induced collagen I production in cardiovascular cells. Our findings indicate that LOX inhibition attenuates the fibrosis and the oxidative stress induced by a HFD on the cardiovascular system. The reduction of leptin levels by BAPN in vivo and the ability of this compound to inhibit leptin-induced profibrotic mediators and ROS production in cardiac and vascular cells suggest that interactions between leptin and LOX regulate downstream events responsible for myocardial and vascular fibrosis in obesity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in hypertension and associated with left ventricular remodeling.

    PubMed

    Wang, Shuli; Hu, Hongjie; Lu, Minjie; Sirajuddin, Arlene; Li, Jinghui; An, Jing; Chen, Xiuyu; Yin, Gang; Lan, Tian; Dai, Linlin; Zhang, Yan; Yin, Xiaorong; Song, Lei; Dang, Aimin; Kellman, Peter; Arai, Andrew E; Zhao, Shihua

    2017-04-24

    To determine whether extracellular volume fraction (ECV) quantification by cardiac magnetic resonance (CMR) can demonstrate left ventricle (LV) abnormalities and relationship between ECV and LV remodeling in hypertension (HTN) patients METHODS: ECV quantification was prospectively performed in 134 consecutive HTN patients and 97 healthy subjects. Individual and regional ECV were compared to the regions on late gadolinium enhancement (LGE) images. Statistical analysis of the relationship between LV global functional parameters and ECV was carried out using Pearson's correlation, Student's t test and multiple regressions. In the HTN group, 70.1% (94/134) were LGE negative and 29.9% (40/134) LGE positive. The mean ECV after adjusting for age, sex, BMI, diabetes, smoking and dyslipidaemia in healthy controls and LGE-negative patients were 26.9 ± 2.67% and 28.5 ± 2.9% (p < 0.001), respectively. The differences in ECV reached statistical significance among the regions of LGE, LGE-Peri, LGE remote and the normal area between the control and LGE-positive subgroup (all p < 0.05). Global ECV significantly correlated with LVEF (r = -0.466, p < 0 .001) and LV hypertrophy (r = 0.667, p < 0.001). ECV can identify LV abnormalities at an early stage in HTN patients without LGE. These abnormalities may reflect an increase in diffuse myocardial fibrosis and are associated with LV remodeling. • Diffuse myocardial fibrosis may develop in hypertensive cardiomyopathy before conventional MRI detectable LGE. • ECV can identify myocardial fibrosis at an early stage in hypertensive patients. • Elevated ECV is associated with decreased LV global function and LV remodeling in hypertension.

  4. Association of a 4-tiered classification of left ventricular hypertrophy with adverse cardiovascular outcomes in the general population

    PubMed Central

    Garg, Sonia; de Lemos, James A.; Ayers, Colby; Khouri, Michel G.; Pandey, Ambarish; Berry, Jarett D.; Peshock, Ronald M.; Drazner, Mark H.

    2015-01-01

    Objectives This study was performed to determine whether a 4-tiered classification of left ventricular hypertrophy (LVH) defines subgroups in the general population which are at variable risk of adverse cardiovascular outcomes. Background We recently proposed a 4-tiered classification of LVH where eccentric LVH is subdivided into “indeterminate hypertrophy” and “dilated hypertrophy” and concentric LVH into “thick hypertrophy” and “both thick and dilated hypertrophy,” based on the presence of increased left ventricular end-diastolic volume. Methods Participants from the Dallas Heart study who underwent cardiac magnetic resonance imaging and did not have LV dysfunction or history of heart failure (HF) (n = 2,458) were followed for a median of 9 years for the primary outcome of HF or cardiovascular (CV) death. Multivariable Cox proportional hazard models were used to adjust for age, sex, African-American race, hypertension, diabetes, and history of cardiovascular disease (CVD). Results In the cohort, 70% had no LVH, 404 (16%) had indeterminate hypertrophy, 30 (1%) had dilated hypertrophy, 289 (12%) had thick hypertrophy, and 7 (0.2%) had both thick and dilated hypertrophy. The cumulative incidence of HF or CV death was 2% with no LVH, 1.7% with indeterminate, 16.7% with dilated, 11.1% with thick, and 42.9% with both thick and dilated hypertrophy (log rank p< 0.0001). Compared with participants without LVH, those with dilated (HR 7.3, 95% CI 2.8–18.8), thick (HR 2.4, 95% CI 1.4–4.0), and both thick and dilated (HR 5.8, 95% CI 1.7–19.5) hypertrophy remained at increased risk for HF or CV death after multivariable adjustment, whereas the group with indeterminate hypertrophy was not (HR 0.9, 95% CI 0.4–2.2). Conclusion In the general population, the 4-tiered classification system for LVH stratified LVH into subgroups with differential risk of adverse CV outcomes. Unstructured Abstract: Participants from the Dallas Heart Study were stratified using

  5. Assessment of valve haemodynamics, reverse ventricular remodelling and myocardial fibrosis following transcatheter aortic valve implantation compared to surgical aortic valve replacement: a cardiovascular magnetic resonance study

    PubMed Central

    Fairbairn, Timothy A; Steadman, Christopher D; Mather, Adam N; Motwani, Manish; Blackman, Daniel J; Plein, Sven; McCann, Gerry P; Greenwood, John P

    2013-01-01

    Objective To compare the effects of transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) on aortic valve haemodynamics, ventricular reverse remodelling and myocardial fibrosis (MF) by cardiovascular magnetic resonance (CMR) imaging. Design A 1.5 T CMR scan was performed preoperatively and 6 months postoperatively. Setting University hospitals of Leeds and Leicester, UK. Patients 50 (25 TAVI, 25 SAVR; age 77±8 years) high-risk severe symptomatic aortic stenosis (AS) patients. Main outcome measures Valve haemodynamics, ventricular volumes, ejection fraction (EF), mass and MF. Results Patients were matched for gender and AS severity but not for age (80±6 vs 73±7 years, p=0.001) or EuroSCORE (22±14 vs 7±3, p<0.001). Aortic valve mean pressure gradient decreased to a greater degree post-TAVI compared to SAVR (21±8 mm Hg vs 35±13 mm Hg, p=0.017). Aortic regurgitation reduced by 8% in both groups, only reaching statistical significance for TAVI (p=0.003). TAVI and SAVR improved (p<0.05) left ventricular (LV) end-systolic volumes (46±18 ml/m2 vs 41±17 ml/m2; 44±22 ml/m2 vs32±6 ml/m2) and mass (83±20 g/m2 vs 65±15 g/m2; 74±11 g/m2 vs 59±8 g/m2). SAVR reduced end-diastolic volumes (92±19 ml/m2 vs 74±12 ml/m2, p<0.001) and TAVI increased EF (52±12% vs 56±10%, p=0.01). MF reduced post-TAVI (10.9±6% vs 8.5±5%, p=0.03) but not post-SAVR (4.2±2% vs 4.1±2%, p=0.98). Myocardial scar (p≤0.01) and baseline ventricular volumes (p<0.001) were the major predictors of reverse remodelling. Conclusions TAVI was comparable to SAVR at LV reverse remodelling and superior at reducing the valvular pressure gradient and MF. Future work should assess the prognostic importance of reverse remodelling and fibrosis post-TAVI to aid patient selection. PMID:23749779

  6. High intake of dietary tyramine does not deteriorate glucose handling and does not cause adverse cardiovascular effects in mice.

    PubMed

    Carpéné, Christian; Schaak, Stéphane; Guilbeau-Frugier, Céline; Mercader, Josep; Mialet-Perez, Jeanne

    2016-09-01

    Tyramine is naturally occurring in food and induces pressor responses. Low-tyramine diets are recommended for patients treated with MAO inhibitors to avoid the fatal hypertensive crisis sadly known as "cheese effect". Hence, tyramine intake is suspected to have toxicological consequences in humans, while its administration to type 1 diabetic rodents has been reported to improve glucose tolerance. We investigated in mice whether prolonged tyramine ingestion could alter glucose homeostasis, insulin sensitivity, adipose tissue physiology or cardiovascular functions. Tyramine was added at 0.04 or 0.14 % in the drinking water since this was estimated to increase by 10- to 40-fold the spontaneous tyramine intake of control mice fed a standard diet. Ten to 12 weeks of such tyramine supplementation did not influence body weight gain, adiposity or food consumption. Both doses (reaching approx. 300 and 1100 μmol tyramine/kg bw/day) decreased nonfasting blood glucose but did not modify glucose tolerance or fasting levels of glucose, insulin or circulating lipids. Blood pressure was not increased in tyramine-drinking mice, while only the higher tested dose moderately increased heart rate without change in its variability. Markers of cardiac tissue injury or oxidative stress remained unaltered, except an increased hydrogen peroxide production in heart preparations. In isolated adipocytes, tyramine inhibited lipolysis similarly in treated and control groups, as did insulin. The lack of serious adverse cardiovascular effects of prolonged tyramine supplementation in normoglycemic mice together with the somewhat insulin-like effects found on adipose cells should lead to reconsider favourably the risk/benefit ratio of the intake of this dietary amine.

  7. Associations between obesity, adverse behavioral patterns and cardiovascular risk factors among adolescent inhabitants of a Greek island.

    PubMed

    Garoufi, Anastasia; Grammatikos, Evangelos E; Kollias, Anastasios; Grammatikos, Emmanuel; Stergiou, George S; Soldatou, Alexandra

    2017-04-01

    Excess weight, unhealthy lifestyle habits and their sequelae have become a well-recognized public health problem in most countries. The objective of the study was to examine the relationship of adolescent overweight/obesity with behavioral habits and their association with blood pressure (BP) and lipid profile. Anthropometric parameters, lifestyle, BP and lipid profile of 736 adolescents were evaluated cross-sectionally. The classifications of normal weight, overweight and obese were based on BMI z-scores. About 42.1% of adolescents were overweight/obese, 11.3% were smokers, 33.2% consumed alcohol and 34% reported low activity. Males began smoking earlier, consumed alcohol more often, exercised less and spent more screen time than females. Alcohol consumption was more prevalent among smokers and was associated with higher BP and dyslipidemia. Smokers exercised less intensely and had lower high density lipoprotein-cholesterol (HDL-C) than non-smokers. Obesity was a risk factor for higher BP and dyslipidemia. Longer screen time was associated with higher triglycerides, while intense physical activity with lower systolic BP. Obesity is related to an adverse lipid and BP profile during adolescence. Clustering of hazardous habits was observed, which is known to aggravate the cardiovascular risk.

  8. Same-day discharge or overnight stay after percutaneous coronary intervention: comparison of net adverse cardiovascular events.

    PubMed

    Nascimento, Francisco O; Pineda, Andres M; Benjo, Alexandre; Mas, Ildefonso; Podesta, Carlos; Heimowitz, Todd B; Kirtane, Ajay; Beohar, Nirat

    2014-05-01

    Same-day discharge after percutaneous coronary intervention (PCI), if achieved with acceptable safety, could result in greater patient satisfaction and potential cost savings. Comparative analyses reporting the safety outcomes of same-day discharge vs overnight stay after elective PCI are lacking. Data of same-day discharge and overnight-stay patients undergoing elective PCI in a high-volume center were compared. We specifically evaluated the incidence of net adverse cardiovascular events (NACE; i.e., death, myocardial infarction, stroke, target vessel revascularization, vascular complication, and major bleeding) within 48 hours post index procedure among both groups and at 30 days. A total of 188 cases were evaluated, with 93 discharged the same day and 95 after overnight stay following elective PCI. Baseline characteristics were similar, except for older age (73.0 ± 7 years vs. 64.0 ± 12 years; P<.001), more prior PCI (49.5% vs. 34.7%; P<.001), and prior coronary artery bypass graft surgery (16.1% vs. 11.6%; P=.01) in the same-day discharge group. Procedural characteristics were similar in both groups. No significant difference in the NACE rate was found between the groups at 48 hours (0 [0%] vs. 2 [2.1%]; P=.25) or at 30 days (3 [3.2%] vs. 6 [6.3%]; P=.26). In the population studied, same-day discharge after PCI is safe and feasible. Adequately powered randomized prospective studies are necessary to confirm these results.

  9. The presence of remodeled and mixed atherosclerotic plaques at coronary ct angiography predicts major cardiac adverse events - The CAFÉ-PIE Study.

    PubMed

    Guaricci, Andrea Igoren; Pontone, Gianluca; Brunetti, Natale Daniele; De Rosa, Fiorella; Montrone, Deodata; Guglielmo, Marco; Mushtaq, Saima; Fusini, Laura; Maffei, Erica; Cademartiri, Filippo; Macarini, Luca; Andreini, Daniele; Di Biase, Matteo; Bartorelli, Antonio L; Pepi, Mauro

    2016-07-15

    It is still unclear how to exploit information made available by coronary computed tomography angiography (CCTA) on coronary artery disease (CAD) features in order to better predicting major adverse cardiac events (MACEs). Aim of this study was to validate the prognostic role of a comprehensive and simplified CT-derived score in patients evaluated for suspected CAD. A prospective registry included 477 consecutive symptomatic patients without known CAD who underwent clinically-indicated CCTA. All patients were followed-up for MACE occurrence for a period of 49±15-month. The mean CT Score was 10.5±10.8, with a MACE rate of 11.3%. There was a stepwise relationship between MACE rate during follow-up and CT Score values. MACEs were 1.9% in patients with CT Score<10 (reference group), 16.6% in those with CT Score 10-20 (OR 9.9, 95% C.I. 3.5-27.8 vs. reference group, p<0.001), 24.5% in those with CT Score 21-30 (OR 16.6, 95% C.I. 6.1-45.0 vs. reference group, p<0.001), and 47.4% in those with CT Score>30 (OR 46.1, 95% C.I. 13.0-162.9 vs. reference group, p<0.001) (p for trend <0.001). At ROC curve analysis, CT Score was the best predictor of MACE (AUC: 0.81, CI 95%: 0.78-0.84) as compared to Diamond and Forrester score (p<0.001), segment stenosis score (p<0.05) and segment involved score (p<.0.01). The use of an integrated score obtained with CCTA and based on the presence of remodeled and mixed atherosclerotic coronary plaques may improve MACE prediction in symptomatic patients at intermediate risk outweighing that provided by standard clinical and CCTA scores. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Prospective associations of psychosocial adversity in childhood with risk factors for cardiovascular disease in adulthood: the MRC National Survey of Health and Development.

    PubMed

    Anderson, Emma L; Caleyachetty, Rishi; Stafford, Mai; Kuh, Diana; Hardy, Rebecca; Lawlor, Debbie A; Fraser, Abigail; Howe, Laura D

    2017-09-07

    Studies assessing associations of childhood psychosocial adversity (e.g. sexual abuse, physical neglect, parental death), as opposed to socioeconomic adversity, with cardiovascular disease (CVD) risk factors in adulthood are scarce. We aimed to assess associations of various forms of psychosocial adversity and cumulative adversity in childhood, with multiple CVD risk factors in mid-life. Participants were from the MRC National Survey of Health and Development. Childhood psychosocial risk factors were reported prospectively by parents from 1950-1957, and retrospectively by participants at mean age 43 years in 1989. CVD risk factors were assessed at mean age 60-64 years in 2006-2011. Associations of a summary score of total psychosocial adversity and CVD risk in adulthood were assessed. There was no consistent evidence that cumulative psychosocial adversity, nor any specific form of psychosocial adversity in childhood, was associated with CVD risk factors in late adulthood. There was some evidence that parental death in the first 15 years was associated with higher SBP (Beta: 0.23, 95% confidence interval: 0.06 to 0.40, P=0.01) and DBP (Beta: 0.15, 95% confidence interval: -0.01 to 0.32, P=0.07). We found no evidence that exposure to greater psychosocial adversity, or specific forms of psychosocial adversity during childhood is associated with adult CVD risk factors. Further large population studies are needed to clarify whether parental death is associated with higher systolic and diastolic blood pressure.

  11. Cardiovascular

    NASA Image and Video Library

    Overview of Cardiovascular research which addresses risks of space flight, including adaptive changes to the cephalad fluid shift (such as reduced circulating blood volume), potential for heart rhy...

  12. Relationship between Left Ventricular Structural and Metabolic Remodelling in Type 2 Diabetes Mellitus

    PubMed Central

    Levelt, Eylem; Mahmod, Masliza; Piechnik, Stefan K.; Ariga, Rina; Francis, Jane M.; Rodgers, Christopher T.; Clarke, William T.; Sabharwal, Nikant; Schneider, Jurgen E.; Karamitsos, Theodoros D.; Clarke, Kieran; Rider, Oliver J.; Neubauer, Stefan

    2016-01-01

    Concentric left ventricular (LV) remodelling is associated with adverse cardiovascular events and is frequently observed in patients with type 2 diabetes mellitus (T2DM). Despite this, the cause of concentric remodelling in diabetes, per se, is unclear, but may be related to cardiac steatosis and impaired myocardial energetics. Thus, we investigated the relationship amongst myocardial metabolic changes and LV remodelling in T2DM. Forty-six non-hypertensive T2DM patients and twenty matched controls underwent cardiovascular magnetic resonance to assess LV remodelling (LV mass to LV end diastolic volume ratio-LVMVR), function, pre- and post-contrast tissue characterisation using T1 mapping, 1H-, 31P-magnetic resonance spectroscopy for myocardial triglyceride content (MTG) and phosphocreatine to ATP ratio (PCr/ATP) respectively. When compared to body mass index and blood pressure matched controls, diabetes was associated with: concentric LV remodelling, higher MTG, impaired myocardial energetics and impaired systolic strain indicating a subtle contractile dysfunction. Importantly, cardiac steatosis independently predicted concentric remodelling and systolic strain. Extracellular volume fraction was unchanged, indicating absence of fibrosis. In conclusion, cardiac steatosis may contribute to LV concentric remodelling and contractile dysfunction in diabetes. As cardiac steatosis is modifiable, strategies aimed at reducing myocardial triglyceride may be beneficial in reversing concentric remodelling and improving contractile function in the diabetic heart. PMID:26438611

  13. Hypertension and cardiovascular remodelling in rats exposed to continuous light: protection by ACE-inhibition and melatonin.

    PubMed

    Simko, Fedor; Pechanova, Olga; Repova Bednarova, Kristina; Krajcirovicova, Kristina; Celec, Peter; Kamodyova, Natalia; Zorad, Stefan; Kucharska, Jarmila; Gvozdjakova, Anna; Adamcova, Michaela; Paulis, Ludovit

    2014-01-01

    Exposure of rats to continuous light attenuates melatonin production and results in hypertension development. This study investigated whether hypertension induced by continuous light (24 hours/day) exposure induces heart and aorta remodelling and if these alterations are prevented by melatonin or angiotensin converting enzyme inhibitor captopril. Four groups of 3-month-old male Wistar rats (10 per group) were treated as follows for six weeks: untreated controls, exposed to continuous light, light-exposed, and treated with either captopril (100 mg/kg/day) or melatonin (10 mg/kg/day). Exposure to continuous light led to hypertension, left ventricular (LV) hypertrophy and fibrosis, and enhancement of the oxidative load in the LV and aorta. Increase in systolic blood pressure by continuous light exposure was prevented completely by captopril and partially by melatonin. Both captopril and melatonin reduced the wall thickness and cross-sectional area of the aorta and reduced the level of oxidative stress. However, only captopril reduced LV hypertrophy development and only melatonin reduced LV hydroxyproline concentration in insoluble and total collagen in rats exposed to continuous light. In conclusion, captopril prevented LV hypertrophy development in the continuous light-induced hypertension model, while only melatonin significantly reduced fibrosis. This antifibrotic action of melatonin may be protective in hypertensive heart disease.

  14. Relationship of testis size and LH levels with incidence of major adverse cardiovascular events in older men with sexual dysfunction.

    PubMed

    Rastrelli, Giulia; Corona, Giovanni; Lotti, Francesco; Boddi, Valentina; Mannucci, Edoardo; Maggi, Mario

    2013-11-01

    Measurement of testis volume (TV) is a reliable clinical procedure that predicts reproductive fitness. However, the role of TV in overall and cardiovascular (CV) fitness has never been studied. The study aims to analyze the clinical correlates of TV in patients with sexual dysfunction (SD) and to verify the value of this parameter and its determinants (i.e., luteinizing hormone [LH] levels) in predicting major adverse CV events (MACE). A consecutive series of 2,809 subjects without testiculopathy (age 51.2 ± 13.1) consulting for SD was retrospectively studied. A subset of this sample (n=1,395) was enrolled in a longitudinal study. Several clinical and biochemical parameters were investigated. After adjusting for confounders, TV was negatively associated with both LH (Adj. r=-0.234; P<0.0001) and follicle-stimulating hormone (Adj. r=-0.326; P<0.0001). In addition, overweight/obesity, smoking, and alcohol abuse increased as a function of TV (hazard ratio [HR]=1.041 [1.021-1.061], P<0.0001; 1.024 [1.005-1.044], P=0.012; 1.063 [1.015-1.112], P=0.009, respectively). Furthermore, mean blood pressure was positively related to increased TV (Adj. r=0.157; P<0.0001). The effect of these lifestyle factors on TV were only partially related to changes in gonadotropin levels. In the longitudinal analysis, after adjusting for confounders, TV was associated with a higher incidence of MACE (HR=1.066 [1.013-1.122]; P=0.014), and the stepwise introduction in the Cox model of lifestyle factors, mean blood pressure and body mass index progressively smoothed out the association, which was no longer statistically significant in the fully adjusted model. Conversely, the association of higher LH levels with increased incidence of MACE was not attenuated by the progressive introduction of the aforementioned confounders in the model. Our data show that in SD subjects, TV and LH are associated with an adverse CV risk profile that mediate the higher TV-associated incidence of MACE. High

  15. Financial barriers and adverse clinical outcomes among patients with cardiovascular-related chronic diseases: a cohort study.

    PubMed

    Campbell, David J T; Manns, Braden J; Weaver, Robert G; Hemmelgarn, Brenda R; King-Shier, Kathryn M; Sanmartin, Claudia

    2017-02-15

    Some patients with cardiovascular-related chronic diseases such as diabetes and heart disease report financial barriers to achieving optimal health. Previous surveys report that the perception of having a financial barrier is associated with self-reported adverse clinical outcomes. We sought to confirm these findings using linked survey and administrative data to determine, among patients with cardiovascular-related chronic diseases, if there is an association between perceived financial barriers and the outcomes of: (1) disease-related hospitalizations, (2) all-cause mortality and (3) inpatient healthcare costs. We used ten cycles of the nationally representative Canadian Community Health Survey (administered between 2000 and 2011) to identify a cohort of adults aged 45 and older with hypertension, diabetes, heart disease or stroke. Perceived financial barriers to various aspects of chronic disease care and self-management were identified (including medications, healthful food and home care) from the survey questions, using similar questions to those used in previous studies. The cohort was linked to administrative data sources for outcome ascertainment (Discharge Abstract Database, Canadian Mortality Database, Patient Cost Estimator). We utilized Poisson regression techniques, adjusting for potential confounding variables (age, sex, education, multimorbidity, smoking status), to assess for associations between perceived financial barriers and disease-related hospitalization and all-cause mortality. We used gross costing methodology and a variety of modelling approaches to assess the impact of financial barriers on hospital costs. We identified a cohort of 120,752 individuals over the age of 45 years with one or more of the following: hypertension, diabetes, heart disease or stroke. One in ten experienced financial barriers to at least one aspect of their care, with the two most common being financial barriers to accessing medications and healthful food. Even

  16. t-10, c-12 CLA Dietary Supplementation Inhibits Atherosclerotic Lesion Development Despite Adverse Cardiovascular and Hepatic Metabolic Marker Profiles

    PubMed Central

    Mitchell, Patricia L.; Karakach, Tobias K.; Currie, Deborah L.; McLeod, Roger S.

    2012-01-01

    Animal and human studies have indicated that fatty acids such as the conjugated linoleic acids (CLA) found in milk could potentially alter the risk of developing metabolic disorders including diabetes and cardiovascular disease (CVD). Using susceptible rodent models (apoE−/− and LDLr−/− mice) we investigated the interrelationship between mouse strain, dietary conjugated linoleic acids and metabolic markers of CVD. Despite an adverse metabolic risk profile, atherosclerosis (measured directly by lesion area), was significantly reduced with t-10, c-12 CLA and mixed isomer CLA (Mix) supplementation in both apoE−/− (p<0.05, n = 11) and LDLr−/− mice (p<0.01, n = 10). Principal component analysis was utilized to delineate the influence of multiple plasma and tissue metabolites on the development of atherosclerosis. Group clustering by dietary supplementation was evident, with the t-10, c-12 CLA supplemented animals having distinct patterns, suggestive of hepatic insulin resistance, regardless of mouse strain. The effect of CLA supplementation on hepatic lipid and fatty acid composition was explored in the LDLr−/− strain. Dietary supplementation with t-10, c-12 CLA significantly increased liver weight (p<0.05, n = 10), triglyceride (p<0.01, n = 10) and cholesterol ester content (p<0.01, n = 10). Furthermore, t-10, c-12 CLA also increased the ratio of 18∶1 to 18∶0 fatty acid in the liver suggesting an increase in the activity of stearoyl-CoA desaturase. Changes in plasma adiponectin and liver weight with t-10, c-12 CLA supplementation were evident within 3 weeks of initiation of the diet. These observations provide evidence that the individual CLA isomers have divergent mechanisms of action and that t-10, c-12 CLA rapidly changes plasma and liver markers of metabolic syndrome, despite evidence of reduction in atherosclerosis. PMID:23285120

  17. t-10, c-12 CLA dietary supplementation inhibits atherosclerotic lesion development despite adverse cardiovascular and hepatic metabolic marker profiles.

    PubMed

    Mitchell, Patricia L; Karakach, Tobias K; Currie, Deborah L; McLeod, Roger S

    2012-01-01

    Animal and human studies have indicated that fatty acids such as the conjugated linoleic acids (CLA) found in milk could potentially alter the risk of developing metabolic disorders including diabetes and cardiovascular disease (CVD). Using susceptible rodent models (apoE(-/-) and LDLr(-/-) mice) we investigated the interrelationship between mouse strain, dietary conjugated linoleic acids and metabolic markers of CVD. Despite an adverse metabolic risk profile, atherosclerosis (measured directly by lesion area), was significantly reduced with t-10, c-12 CLA and mixed isomer CLA (Mix) supplementation in both apoE(-/-) (p<0.05, n = 11) and LDLr(-/-) mice (p<0.01, n = 10). Principal component analysis was utilized to delineate the influence of multiple plasma and tissue metabolites on the development of atherosclerosis. Group clustering by dietary supplementation was evident, with the t-10, c-12 CLA supplemented animals having distinct patterns, suggestive of hepatic insulin resistance, regardless of mouse strain. The effect of CLA supplementation on hepatic lipid and fatty acid composition was explored in the LDLr(-/-) strain. Dietary supplementation with t-10, c-12 CLA significantly increased liver weight (p<0.05, n = 10), triglyceride (p<0.01, n = 10) and cholesterol ester content (p<0.01, n = 10). Furthermore, t-10, c-12 CLA also increased the ratio of 18∶1 to 18∶0 fatty acid in the liver suggesting an increase in the activity of stearoyl-CoA desaturase. Changes in plasma adiponectin and liver weight with t-10, c-12 CLA supplementation were evident within 3 weeks of initiation of the diet. These observations provide evidence that the individual CLA isomers have divergent mechanisms of action and that t-10, c-12 CLA rapidly changes plasma and liver markers of metabolic syndrome, despite evidence of reduction in atherosclerosis.

  18. Intravascular Ultrasound Predictors of Major Adverse Cardiovascular Events After Implantation of Everolimus-eluting Stents for Long Coronary Lesions.

    PubMed

    Lee, Seung-Yul; Shin, Dong-Ho; Kim, Jung-Sun; Kim, Byeong-Keuk; Ko, Young-Guk; Choi, Donghoon; Jang, Yangsoo; Hong, Myeong-Ki

    2017-02-01

    There are limited data on the usefulness of intravascular ultrasound (IVUS) for long coronary lesions treated with second-generation drug-eluting stents. We evaluated IVUS predictors of major adverse cardiovascular events (MACE) 12 months after implantation of everolimus-eluting stents for long coronary lesions. A total of 804 patients who underwent both postintervention IVUS examination and long everolimus-eluting stent (≥ 28mm in length) implantation were included from 2 randomized trials. MACE was defined as a composite of cardiac death, myocardial infarction, and target-lesion revascularization. MACE occurred in 24 patients (3.0%) over 12 months. On multivariable Cox regression analysis, independent IVUS predictors of MACE included the postintervention minimum lumen area (MLA) at the target lesion (HR = 0.623; 95%CI, 0.433-0.895; P=.010) and the ratio of MLA/distal reference segment lumen area (HR = 0.744; 95%CI, 0.572-0.969; P=.028). The MLA and MLA-to-distal reference segment lumen area ratio that best predicted patients with MACE from those without these events were 5.0 mm(2) and 1.0, respectively. Patients with MLA<5.0 mm(2) or a distal reference segment lumen area had a higher risk of MACE (HR = 6.231; 95%CI, 1.859-20.891; P=.003) than those without MACE. Patients with a postintervention IVUS-measured MLA of<5.0 mm(2) or a distal reference segment lumen area were at risk for MACE after long everolimus-eluting stent implantation. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  19. Cardiac remodeling following reperfused acute myocardial infarction is linked to the concomitant evolution of vascular function as assessed by cardiovascular magnetic resonance.

    PubMed

    Huttin, Olivier; Mandry, Damien; Eschalier, Romain; Zhang, Lin; Micard, Emilien; Odille, Freddy; Beaumont, Marine; Fay, Renaud; Felblinger, Jacques; Camenzind, Edoardo; Zannad, Faïez; Girerd, Nicolas; Marie, Pierre Y

    2017-01-04

    Left ventricular (LV) remodeling following acute myocardial infarction (MI) is difficult to predict at an individual level although a possible interfering role of vascular function has yet to be considered to date. This study aimed to determine the extent to which this LV remodeling is influenced by the concomitant evolution of vascular function and LV loading conditions, as assessed by phase-contrast Cardiovascular Magnetic Resonance (CMR) of the ascending aorta. CMR was performed in 121 patients, 2-4 days after reperfusion of a first ST-segment elevation myocardial infarction and 6 months thereafter. LV remodeling was: (i) assessed by the 6-month increase in end-diastolic volume (EDV) and/or ejection fraction (EF) and (ii) correlated with the indexed aortic stroke volume (mL.m(-2)), determined by a CMR phase-contrast sequence, along with derived functional vascular parameters (total peripheral vascular resistance (TPVR), total arterial compliance index, effective arterial elastance). At 6 months, most patients were under angiotensin enzyme converting inhibitors (86%) and beta-blockers (84%) and, on average, all functional vascular parameters were improved whereas blood pressure levels were not. An increase in EDV only (EDV+/EF-) was documented in 17% of patients at 6 months, in EF only (EDV-/EF+) in 31%, in both EDV and EF (EDV+/EF+) in 12% and neither EDV nor EF (EDV-/EF-) in 40%. The increase in EF was mainly and independently linked to a concomitant decline in TPVR (6-month change in mmHg.min.m(2).L(-1), EDV-/EF-: +1 ± 8, EDV+/EF-: +3 ± 9, EDV-/EF+: -7 ± 6, EDV+/EF+: -15 ± 20, p < 0.001) while the absence of any EF improvement was associated with high persisting rates of abnormally high TPVR at 6 months (EDV-/EF-: 31%, EDV+/EF-: 38%, EDV-/EF+: 5%, EDV+/EF+: 13%, p = 0.007). By contrast, the 6-month increase in EDV was mainly dependent on cardiac as opposed to vascular parameters and particularly on the presence of microvascular

  20. Automatic signal extraction, prioritizing and filtering approaches in detecting post-marketing cardiovascular events associated with targeted cancer drugs from the FDA Adverse Event Reporting System (FAERS).

    PubMed

    Xu, Rong; Wang, Quanqiu

    2014-02-01

    Targeted drugs dramatically improve the treatment outcomes in cancer patients; however, these innovative drugs are often associated with unexpectedly high cardiovascular toxicity. Currently, cardiovascular safety represents both a challenging issue for drug developers, regulators, researchers, and clinicians and a concern for patients. While FDA drug labels have captured many of these events, spontaneous reporting systems are a main source for post-marketing drug safety surveillance in 'real-world' (outside of clinical trials) cancer patients. In this study, we present approaches to extracting, prioritizing, filtering, and confirming cardiovascular events associated with targeted cancer drugs from the FDA Adverse Event Reporting System (FAERS). The dataset includes records of 4,285,097 patients from FAERS. We first extracted drug-cardiovascular event (drug-CV) pairs from FAERS through named entity recognition and mapping processes. We then compared six ranking algorithms in prioritizing true positive signals among extracted pairs using known drug-CV pairs derived from FDA drug labels. We also developed three filtering algorithms to further improve precision. Finally, we manually validated extracted drug-CV pairs using 21 million published MEDLINE records. We extracted a total of 11,173 drug-CV pairs from FAERS. We showed that ranking by frequency is significantly more effective than by the five standard signal detection methods (246% improvement in precision for top-ranked pairs). The filtering algorithm we developed further improved overall precision by 91.3%. By manual curation using literature evidence, we show that about 51.9% of the 617 drug-CV pairs that appeared in both FAERS and MEDLINE sentences are true positives. In addition, 80.6% of these positive pairs have not been captured by FDA drug labeling. The unique drug-CV association dataset that we created based on FAERS could facilitate our understanding and prediction of cardiotoxic events associated with

  1. Presence of Late Gadolinium Enhancement by Cardiac Magnetic Resonance Among Patients With Suspected Cardiac Sarcoidosis Is Associated With Adverse Cardiovascular Prognosis: A Systematic Review and Meta-Analysis.

    PubMed

    Hulten, Edward; Agarwal, Vikram; Cahill, Michael; Cole, Geoff; Vita, Tomas; Parrish, Scott; Bittencourt, Marcio Sommer; Murthy, Venkatesh L; Kwong, Raymond; Di Carli, Marcelo F; Blankstein, Ron

    2016-09-01

    Individuals with cardiac sarcoidosis have an increased risk of ventricular arrhythmia and death. Several small cohort studies have evaluated the ability of late gadolinium enhancement (LGE) by cardiac magnetic resonance imaging (MRI) to predict adverse cardiovascular events. However, studies have yielded inconsistent results, and some analyses were underpowered. Therefore, we sought to systematically review and perform meta-analysis of the prognostic value of cardiac MRI for patients with known or suspected cardiac sarcoidosis. We systematically searched for cohort studies of patients with known sarcoidosis with suspected cardiac involvement who underwent cardiac MRI with LGE with at least 12 months of either prospective or retrospective follow-up data regarding post-MRI adverse cardiovascular outcomes. We identified 7 studies of 694 subjects (mean age 53; 42% men).One hundred and ninety-nine patients (29%) were LGE positive. All-cause mortality occurred in 19 LGE-positive versus 17 LGE-negative subjects (annualized incidence, 3.1% versus 0.6%). The pooled relative risk was 3.38 (95% confidence interval, 1.07-10.7; P=0.04). Cardiovascular mortality occurred in 10 LGE-positive versus 2 LGE-negative subjects (annualized incidence, 1.9% versus 0.3%; relative risk 10.7 [95% confidence interval, 1.34-86.3]; P=0.03). Ventricular arrhythmia occurred in 41 LGE-positive versus 0 LGE-negative subjects (annualized incidence, 5.9% versus 0%; relative risk 19.5 [95% confidence interval, 2.68-143]; P=0.003). A combined end point of death or ventricular arrhythmia occurred in 64 LGE-positive versus 18 LGE-negative subjects (annualized incidence, 8.8% versus 0.6%; relative risk 6.20 [95% confidence interval, 2.47-15.6]; P<0.001). There was no significant heterogeneity for any outcomes. LGE is associated with future cardiovascular death and ventricular arrhythmia among patients referred to MRI for known or suspected cardiac sarcoidosis. © 2016 American Heart Association, Inc.

  2. The blocking of angiotensin II type 1 receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling.

    PubMed

    Ravarotto, Verdiana; Pagnin, Elisa; Maiolino, Giuseppe; Fragasso, Antonio; Carraro, Gianni; Rossi, Barbara; Calò, Lorenzo A

    2015-12-01

    The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22(phox) reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity. The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment. Olmesartan normalized systolic and diastolic BP (p < 0.001), reduced p63RhoGEF level: 1.3±0.25 d.u. (baseline) vs 1.0±0.29 (three months), p < 0.0001 vs 1.0±0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 ±0.14 (baseline) vs 0.9±0.19 (three months), p = 0.008, vs 0.8±0.16 (six months), p = 0.001. These data added to our previous results further provide a mechanistic rationale for olmesartan's antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials. © The Author(s) 2015.

  3. Relationship Between Left Ventricular Structural and Metabolic Remodeling in Type 2 Diabetes.

    PubMed

    Levelt, Eylem; Mahmod, Masliza; Piechnik, Stefan K; Ariga, Rina; Francis, Jane M; Rodgers, Christopher T; Clarke, William T; Sabharwal, Nikant; Schneider, Jurgen E; Karamitsos, Theodoros D; Clarke, Kieran; Rider, Oliver J; Neubauer, Stefan

    2016-01-01

    Concentric left ventricular (LV) remodeling is associated with adverse cardiovascular events and is frequently observed in patients with type 2 diabetes mellitus (T2DM). Despite this, the cause of concentric remodeling in diabetes per se is unclear, but it may be related to cardiac steatosis and impaired myocardial energetics. Thus, we investigated the relationship between myocardial metabolic changes and LV remodeling in T2DM. Forty-six nonhypertensive patients with T2DM and 20 matched control subjects underwent cardiovascular magnetic resonance to assess LV remodeling (LV mass-to-LV end diastolic volume ratio), function, tissue characterization before and after contrast using T1 mapping, and (1)H and (31)P magnetic resonance spectroscopy for myocardial triglyceride content (MTG) and phosphocreatine-to-ATP ratio, respectively. When compared with BMI- and blood pressure-matched control subjects, subjects with diabetes were associated with concentric LV remodeling, higher MTG, impaired myocardial energetics, and impaired systolic strain indicating a subtle contractile dysfunction. Importantly, cardiac steatosis independently predicted concentric remodeling and systolic strain. Extracellular volume fraction was unchanged, indicating the absence of fibrosis. In conclusion, cardiac steatosis may contribute to concentric remodeling and contractile dysfunction of the LV in diabetes. Because cardiac steatosis is modifiable, strategies aimed at reducing MTG may be beneficial in reversing concentric remodeling and improving contractile function in the hearts of patients with diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  4. Association of CYP2C19*2 polymorphism with clopidogrel response and 1-year major adverse cardiovascular events in a multiethnic population with drug-eluting stents.

    PubMed

    Tan, Shirley Siang Ning; Fong, Alan Yean Yip; Mejin, Melissa; Gerunsin, Jerry; Kong, Khai Liy; Chin, Felicia Yien Yin; Tiong, Lee Len; Lim, Melissa Siaw Han; Asri, Said; Khiew, Ning Zan; Voon, Chi Yen; Mohd Amin, Nor Hanim; Cham, Yee Ling; Koh, Keng Tat; Oon, Yen Yee; Ong, Tiong Kiam

    2017-08-01

    Patients undergoing elective percutaneous coronary intervention (PCI) with drug-eluting stents (DES) who have impaired clopidogrel response, have a higher risk of subsequent major adverse cardiovascular events (MACE). To establish the relationship between CYP2C19 genotype, clopidogrel responsiveness and 1-year MACE. Aspirin/clopidogrel responses were assessed with Multiplate Analyzer and CYP2C19*2 allele by SpartanRx. A total of 42.0% carried ≥1 CYP2C19*2 allele. Prevalences of aspirin and clopidogrel high on-treatment platelet reactivity (HPR; local cutoffs: 300 AU*min for aspirin and 600 AU*min for clopidogrel) were 11.5% and 19.8% respectively. In multivariate ana-lysis, clopidogrel HPR was found to be an independent predictor for 1-year MACE (adj HR: 3.48, p = 0.022 ). Having clopidogrel HPR could be a potentially modifiable risk factor guided by phenotyping.

  5. Low levels of high-density lipoprotein cholesterol: an independent risk factor for late adverse cardiovascular events in renal transplant recipients.

    PubMed

    Barn, Kulpreet; Laftavi, Mark; Pierce, Drew; Ying, Chin; Boden, William E; Pankewycz, Oleh

    2010-06-01

    Long-term kidney transplant graft and patient survival is often limited by cardiovascular (CV) disease. Risk factors for CV disease such as diabetes, hypertension and elevated low-density lipoprotein levels are well documented; however, the impact of low levels of high-density lipoprotein (HDL) has not been defined. We performed a retrospective chart review of 324 consecutive renal transplant recipients from 2001 to 2007 to correlate baseline HDL levels with major adverse cardiovascular events (MACEs) defined as a composite of new onset CV illness, cerebral vascular events and peripheral vascular disease. A total of 92 MACEs occurred over a total of 1913 patient years of follow-up. Low HDL cholesterol levels were noted in 58.3% of patients. Compared with those with normal HDL levels, a greater percentage of patients with low HDL levels had post-transplant MACEs (20% vs. 60% respectively) and experienced an increased rate of all cause mortality. Sixty-two percent of all MACEs occurred in patients with low HDL levels. In the low HDL group, the odds ratio for experiencing a MACE was 1.92. Therefore, HDL cholesterol may provide an important new therapeutic target to prevent vascular morbidity and mortality following renal transplantation.

  6. Resveratrol improves cardiovascular function in DOCA-salt hypertensive rats.

    PubMed

    Chan, Vincent; Fenning, Andrew; Iyer, Abishek; Hoey, Andrew; Brown, Lindsay

    2011-03-01

    The phytoalexin resveratrol (3,4',5-trihydroxy-trans-stilbene) may attenuate cardiovascular disease in man. This study has determined whether treatment with resveratrol (1 mg/kg/day orally) prevented cardiac fibrosis and the decreased cardiovascular function in the DOCA-salt hypertensive rat as a model of human hypertension. Uninephrectomised rats (UNX) administered DOCA (25mg every 4th day sc) and 1% NaCl in drinking water for 28 days developed cardiac and vascular remodelling. In these DOCA-salt rats, resveratrol decreased inflammatory cell infiltration, decreased cardiac fibrosis (left ventricular interstitial and perivascular collagen content) and improved cardiac and vascular function. Resveratrol attenuated other features of cardiovascular remodelling such as increases in systolic blood pressure, left ventricular wet weight, left ventricular wall thickness, diastolic stiffness constant, as well as decreased cardiac contractility and prolonged action potential duration characteristic of DOCA-salt rats. In summary, resveratrol, at a nutritionally relevant dose, prevents or attenuates the adverse changes in the cardiovascular system. We propose that the anti-inflammatory and anti-fibrotic effects of resveratrol are responsible, at least in part, for its amelioration in cardiovascular remodelling in DOCA-salt rats. These actions of resveratrol could play an important role in the protective effects on the human cardiovascular system reported for this constituent of red wine.

  7. Whole-body cardiovascular MRI for the comparison of atherosclerotic burden and cardiac remodelling in healthy South Asian and European adults

    PubMed Central

    Cassidy, Deirdre B; Belch, Jill J F; Gandy, Stephen J; Lambert, Matthew A; Littleford, Roberta C; Rowland, Janice; Struthers, Allan D; Khan, Faisel

    2016-01-01

    Objective: To determine the feasibility of using whole-body cardiovascular MRI (WB-CVMR) to compare South Asians (SAs)—a population known to have a higher risk of cardiovascular disease (CVD) but paradoxically lower prevalence of peripheral arterial disease—and Western Europeans (WEs). Methods: 19 SAs and 38 age-, gender- and body mass index-matched WEs were recruited. All were aged 40 years and over, free from CVD and with a 10-year risk of CVD <20% as assessed by the adult treatment panel (ATP) III risk score. WB-CVMR was performed, comprising a whole-body angiogram (WBA) and cardiac MR (CMR), on a 3-T MRI scanner (Magnetom® Trio; Siemens, Erlangen, Germany) following dual-phase injection of gadolinium-based contrast agent. A standardized atheroma score (SAS) was calculated from the WBA while indexed left ventricular mass and volumes were calculated from the CMR. Results: SAs exhibited a significantly lower iliofemoral atheroma burden (regional SAS 0.0 ± 0.0 vs 1.9 ± 6.9, p = 0.048) and a trend towards lower overall atheroma burden (whole-body SAS 0.7 ± 0.8 vs 1.8 ± 2.3, p = 0.1). They had significantly lower indexed left ventricular mass (46.9 ± 11.8 vs 56.9 ± 13.4 ml m−2, p = 0.008), end diastolic volume (63.9 ± 10.4 vs 75.2 ± 11.4 ml m−2, p=0.001), end systolic volume (20.5 ± 6.1 vs 24.6 ± 6.8 ml m−2, p = 0.03) and stroke volume (43.4 ± 6.6 vs 50.6 ± 7.9 ml m−2, p = 0.001), but with no significant difference in ejection fraction, mass-volume ratio or global functioning index. These differences persisted after accounting for CVD risk factors. Conclusion: WB-CVMR can quantify cardiac and atheroma burden and can detect differences in these metrics between ethnic groups that, if validated, may suggest that the paradoxical high risk of CVD compared with PVD risk may be due to an adverse cardiac haemodynamic status incurred by the smaller heart rather than

  8. Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta-Analysis of More Than 20 000 Patients.

    PubMed

    Totzeck, Matthias; Mincu, Raluca Ileana; Rassaf, Tienush

    2017-08-10

    The monoclonal antibody bevacizumab effectively inhibits angiogenesis in several types of cancers by blocking vascular endothelial growth factor. However, life-threatening cardiovascular adverse effects could limit its use and may warrant specific follow-up strategies. We systematically searched MEDLINE, Cochrane, EMBASE, and Web of Science for randomized controlled trials published until November 2016 that assessed patients with cancer treated with or without bevacizumab in addition to standard chemotherapy. A total of 20 050 patients with a broad range of cancer types from 22 studies were included in this analysis (10 394 in the bevacizumab group and 9656 in the control group). The risks of arterial and venous adverse events were higher in the bevacizumab groups (relative risk [RR], 1.37; 95% CI, 1.10-1.70 [P=0.004] and RR, 1.29; 95% CI, 1.12-1.47 [P<0.001], respectively), and more arterial adverse events occurred in patients taking high-dose bevacizumab regimens. Bevacizumab treatment was associated with the highest risk of cardiac and cerebral ischemia in the high-dose bevacizumab groups (RR, 4.4; 95% CI, 1.59-12.70 [P=0.004] and RR, 6.67; 95% CI, 2.17-20.66 [P=0.001], respectively). In addition, the risk of bleeding and arterial hypertension were higher in the bevacizumab groups (RR, 2.74; 95% CI, 2.38-3.15 [P<0.001] and RR, 4.73; 95% CI, 4.15-5.39 [P<0.00001], respectively), with higher values for patiens taking high-dose regimens. Treatment with bevacizumab increases the risk of arterial adverse events, particularly cardiac and cerebral ischemia, venous adverse events, bleeding, and arterial hypertension. This risk is additionally increased with high doses of bevacizumab. Further studies should determine the appropriate options for cardio-oncology management. URL: https://www.crd.york.ac.uk. Unique identifier: PROSPERO(CRD42016054305). © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  9. The Personality and Psychological Stress Predict Major Adverse Cardiovascular Events in Patients With Coronary Heart Disease After Percutaneous Coronary Intervention for Five Years.

    PubMed

    Du, Jinling; Zhang, Danyang; Yin, Yue; Zhang, Xiaofei; Li, Jifu; Liu, Dexiang; Pan, Fang; Chen, Wenqiang

    2016-04-01

    To investigate the effects of personality type and psychological stress on the occurrence of major adverse cardiovascular events (MACEs) at 5 years in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Two hundred twenty patients with stable angina (SA) or non-ST segment elevation acute coronary syndrome (NSTE-ACS) treated with PCI completed type A behavioral questionnaire, type D personality questionnaire, Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), Trait Coping Style Questionnaire (TCSQ), and Symptom Checklist 90 (SCL-90) at 3 days after PCI operation. Meanwhile, biomedical markers (cTnI, CK-MB, LDH, LDH1) were assayed. MACEs were monitored over a 5-year follow-up. NSTE-ACS group had higher ratio of type A behavior, type A/D behavior, and higher single factor scores of type A personality and type D personality than control group and SAP group. NSTE-ACS patients had more anxiety, depression, lower level of mental health (P < 0.05; P < 0.01), more negative coping styles and less positive coping styles. The plasma levels of biomedical predictors had positive relation with anxiety, depression, and lower level of mental health. Type D patients were at a cumulative increased risk of adverse outcome compared with non-type D patients (P < 0.05). Patients treated with PCI were more likely to have type A and type D personality and this tendency was associated with myocardial injury. They also had obvious anxiety, depression emotion, and lower level of mental health, which were related to personality and coping style. Type D personality was an independent predictor of adverse events.

  10. The Personality and Psychological Stress Predict Major Adverse Cardiovascular Events in Patients With Coronary Heart Disease After Percutaneous Coronary Intervention for Five Years

    PubMed Central

    Du, Jinling; Zhang, Danyang; Yin, Yue; Zhang, Xiaofei; Li, Jifu; Liu, Dexiang; Pan, Fang; Chen, Wenqiang

    2016-01-01

    Abstract To investigate the effects of personality type and psychological stress on the occurrence of major adverse cardiovascular events (MACEs) at 5 years in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Two hundred twenty patients with stable angina (SA) or non-ST segment elevation acute coronary syndrome (NSTE-ACS) treated with PCI completed type A behavioral questionnaire, type D personality questionnaire, Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), Trait Coping Style Questionnaire (TCSQ), and Symptom Checklist 90 (SCL-90) at 3 days after PCI operation. Meanwhile, biomedical markers (cTnI, CK-MB, LDH, LDH1) were assayed. MACEs were monitored over a 5-year follow-up. NSTE-ACS group had higher ratio of type A behavior, type A/D behavior, and higher single factor scores of type A personality and type D personality than control group and SAP group. NSTE-ACS patients had more anxiety, depression, lower level of mental health (P < 0.05; P < 0.01), more negative coping styles and less positive coping styles. The plasma levels of biomedical predictors had positive relation with anxiety, depression, and lower level of mental health. Type D patients were at a cumulative increased risk of adverse outcome compared with non-type D patients (P < 0.05). Patients treated with PCI were more likely to have type A and type D personality and this tendency was associated with myocardial injury. They also had obvious anxiety, depression emotion, and lower level of mental health, which were related to personality and coping style. Type D personality was an independent predictor of adverse events. PMID:27082597

  11. Cardiac Remodeling in Obesity

    PubMed Central

    ABEL, E. DALE; LITWIN, SHELDON E.; SWEENEY, GARY

    2010-01-01

    The dramatic increase in the prevalence of obesity and its strong association with cardiovascular disease have resulted in unprecedented interest in understanding the effects of obesity on the cardiovascular system. A consistent, but puzzling clinical observation is that obesity confers an increased susceptibility to the development of cardiac disease, while at the same time affording protection against subsequent mortality (termed the obesity paradox). In this review we focus on evidence available from human and animal model studies and summarize the ways in which obesity can influence structure and function of the heart. We also review current hypotheses regarding mechanisms linking obesity and various aspects of cardiac remodeling. There is currently great interest in the role of adipokines, factors secreted from adipose tissue, and their role in the numerous cardiovascular complications of obesity. Here we focus on the role of leptin and the emerging promise of adiponectin as a cardioprotective agent. The challenge of understanding the association between obesity and heart failure is complicated by the multifaceted interplay between various hemodynamic, metabolic, and other physiological factors that ultimately impact the myocardium. Furthermore, the end result of obesity-associated changes in the myocardial structure and function may vary at distinct stages in the progression of remodeling, may depend on the individual pathophysiology of heart failure, and may even remain undetected for decades before clinical manifestation. Here we summarize our current knowledge of this complex yet intriguing topic. PMID:18391168

  12. Association Between Paradoxical HDL Cholesterol Decrease and Risk of Major Adverse Cardiovascular Events in Patients Initiated on Statin Treatment in a Primary Care Setting.

    PubMed

    Hasvold, Pål; Thuresson, Marcus; Sundström, Johan; Hammar, Niklas; Kjeldsen, Sverre E; Johansson, Gunnar; Holme, Ingar; Bodegård, Johan

    2016-03-01

    Statin-induced changes in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are unrelated. Many patients initiated on statins experience a paradoxical decrease in HDL-C. The aim of this study was to evaluate the association between a decrease in HDL-C and risk of major adverse cardiovascular events (MACE). Data from 15,357 primary care patients initiated on statins during 2004-2009 were linked with data from mandatory national hospital, drug-dispensing, and cause-of-death registers, and were grouped according to HDL-C change: decreased ≥0.1 mmol/L, unchanged ±0.1 or ≥0.1 mmol/L increased. To evaluate the association between decrease in HDL-C and risk of MACE, a sample of propensity score-matched patients from the decreased and unchanged groups was created, using the latter group as reference. MACE was defined as myocardial infarction, unstable angina pectoris, ischaemic stroke, or cardiovascular mortality. Cox proportional hazards models were used to estimate relative risks. HDL-C decreased in 20%, was unchanged in 58%, and increased in 22% of patients initiated on statin treatment (96% treated with simvastatin). The propensity score-matched sample comprised 5950 patients with mean baseline HDL-C and LDL-C of 1.69 and 4.53 mmol/L, respectively. HDL-C decrease was associated with 56% higher MACE risk (hazard ratio 1.56; 95% confidence interval 1.12-2.16; p < 0.01) compared with the unchanged HDL-C group. Paradoxical statin-induced reduction in HDL-C was relatively common and was associated with increased risk of MACE.

  13. Dietary patterns and the risk of major adverse cardiovascular events in a global study of high-risk patients with stable coronary heart disease

    PubMed Central

    Stewart, Ralph A. H.; Wallentin, Lars; Benatar, Jocelyne; Danchin, Nicolas; Hagström, Emil; Held, Claes; Husted, Steen; Lonn, Eva; Stebbins, Amanda; Chiswell, Karen; Vedin, Ola; Watson, David; White, Harvey D.

    2016-01-01

    Objectives To determine whether dietary pattern assessed by a simple self-administered food frequency questionnaire is associated with major adverse cardiovascular events (MACE) in high-risk patients with stable coronary artery disease. Background A Mediterranean dietary pattern has been associated with lower cardiovascular (CV) mortality. It is less certain whether foods common in western diets are associated with CV risk. Methods At baseline, 15 482 (97.8%) patients (mean age 67 ± 9 years) with stable coronary heart disease from 39 countries who participated in the Stabilisation of atherosclerotic plaque by initiation of darapladib therapy (STABILITY) trial completed a life style questionnaire which included questions on common foods. A Mediterranean diet score (MDS) was calculated for increasing consumption of whole grains, fruits, vegetables, legumes, fish, and alcohol, and for less meat, and a ‘Western diet score’ (WDS) for increasing consumption of refined grains, sweets and deserts, sugared drinks, and deep fried foods. A multi-variable Cox proportional hazards models assessed associations between MDS or WDS and MACE, defined as CV death, non-fatal myocardial infarction, or non-fatal stroke. Results After a median follow-up of 3.7 years MACE occurred in 7.3% of 2885 subjects with an MDS ≥15, 10.5% of 4018 subjects with an MDS of 13–14, and 10.8% of 8579 subjects with an MDS ≤12. A one unit increase in MDS >12 was associated with lower MACE after adjusting for all covariates (+1 category HR 0.95, 95% CI 0.91, 0.98, P = 0.002). There was no association between WDS (adjusted model +1 category HR 0.99, 95% CI 0.97, 1.01) and MACE. Conclusion Greater consumption of healthy foods may be more important for secondary prevention of coronary artery disease than avoidance of less healthy foods typical of Western diets. PMID:27109584

  14. Association Between Vascular Access Dysfunction and Subsequent Major Adverse Cardiovascular Events in Patients on Hemodialysis: A Population-Based Nested Case-Control Study.

    PubMed

    Kuo, Te-Hui; Tseng, Chien-Tzu; Lin, Wei-Hung; Chao, Jo-Yen; Wang, Wei-Ming; Li, Chung-Yi; Wang, Ming-Cheng

    2015-07-01

    The association between dialysis vascular access dysfunction and the risk of developing major adverse cardiovascular events (MACE) in hemodialysis patients is unclear and has not yet been investigated. We analyzed data from the National Health Insurance Research Database of Taiwan to quantify this association. Adopting a case-control design nested within a cohort of patients who received hemodialysis from 2001 to 2010, we identified 9711 incident cases of MACE during the stage of stable maintenance dialysis and 19,422 randomly selected controls matched to cases on age, gender, and duration of dialysis. Events of vascular access dysfunction in the 6-month period before the date of MACE onset (ie, index date) for cases and before index dates for controls were evaluated retrospectively. The presence of vascular access dysfunction was associated with a 1.385-fold higher odds of developing MACE as estimated from the logistic regression analysis. This represents a significantly increased adjusted odds ratio (OR) at 1.268 (95% confidence interval [CI] = 1.186-1.355) after adjustment for comorbidities and calendar years of initiating dialysis. We also noted a significant exposure-response trend (P < 0.001) between the frequency of vascular access dysfunction and MACE, with the greatest risk (adjusted OR = 1.840, 95% CI = 1.549-2.186) noted in patients with ≥3 vascular access events. We concluded that dialysis vascular access dysfunction was significantly associated with an increased risk of MACE. Hence, vascular access failure can be an early sign for MACE in patients receiving maintenance hemodialysis. Active monitoring and treatment of cardiovascular risk factors and related diseases, not merely managing vascular access dysfunction, would be required to reduce the risk of MACE.

  15. Association between hyperglycaemic crisis and long-term major adverse cardiovascular events: a nationwide population-based, propensity score-matched, cohort study

    PubMed Central

    Chang, Li-Hsin; Lin, Liang-Yu; Tsai, Ming-Tsun; How, Chorng-Kuang; Chiang, Jen-Huai; Hsieh, Vivian Chia-Rong; Hu, Sung-Yuan; Hsieh, Ming-Shun

    2016-01-01

    Objective Hyperglycaemic crisis was associated with significant intrahospital morbidity and mortality. However, the association between hyperglycaemic crisis and long-term cardiovascular outcomes remained unknown. This study aimed to investigate the association between hyperglycaemic crisis and subsequent long-term major adverse cardiovascular events (MACEs). Participants and methods This population-based cohort study was conducted using data from Taiwan's National Health Insurance Research Database for the period of 1996–2012. A total of 2171 diabetic patients with hyperglycaemic crisis fit the inclusion criteria. Propensity score matching was used to match the baseline characteristics of the study cohort to construct a comparison cohort which comprised 8684 diabetic patients without hyperglycaemic crisis. The risk of long-term MACEs was compared between the two cohorts. Results Six hundred and seventy-six MACEs occurred in the study cohort and the event rate was higher than that in the comparison cohort (31.1% vs 24.1%, p<0.001). Patients with hyperglycaemic crisis were associated with a higher risk of long-term MACEs even after adjusting for all baseline characteristics and medications (adjusted HR=1.76, 95% CI 1.62 to 1.92, p<0.001). Acute myocardial infarction had the highest adjusted HR (adjusted HR=2.19, 95% CI 1.75 to 2.75, p<0.001) in the four types of MACEs, followed by congestive heart failure (adjusted HR=1.97, 95% CI 1.70 to 2.28, p<0.001). Younger patients with hyperglycaemic crisis had a higher risk of MACEs than older patients (adjusted HR=2.69 for patients aged 20–39 years vs adjusted HR=1.58 for patients aged >65 years). Conclusions Hyperglycaemic crisis was significantly associated with long-term MACEs, especially in the young population. Further prospective longitudinal study should be conducted for validation. PMID:27554106

  16. Role of thyroid hormones in ventricular remodeling.

    PubMed

    Rajagopalan, Viswanathan; Gerdes, A Martin

    2015-04-01

    Cardiac remodeling includes alterations in molecular, cellular, and interstitial systems contributing to changes in size, shape, and function of the heart. This may be the result of injury, alterations in hemodynamic load, neurohormonal effects, electrical abnormalities, metabolic changes, etc. Thyroid hormones (THs) serve as master regulators for diverse remodeling processes of the cardiovascular system-from the prenatal period to death. THs promote a beneficial cardiomyocyte shape and improve contractility, relaxation, and survival via reversal of molecular remodeling. THs reduce fibrosis by decreasing interstitial collagen and reduce the incidence and duration of arrhythmias via remodeling ion channel expression and function. THs restore metabolic function and also improve blood flow both by direct effects on the vessel architecture and decreasing atherosclerosis. Optimal levels of THs both in the circulation and in cardiac tissues are critical for normal homeostasis. This review highlights TH-based remodeling and clinically translatable strategies for diverse cardiovascular disorders.

  17. Long-term Tolerability of Ticagrelor for the Secondary Prevention of Major Adverse Cardiovascular Events: A Secondary Analysis of the PEGASUS-TIMI 54 Trial.

    PubMed

    Bonaca, Marc P; Bhatt, Deepak L; Oude Ophuis, Ton; Steg, P Gabriel; Storey, Robert; Cohen, Marc; Kuder, Julia; Im, Kyungah; Magnani, Giulia; Budaj, Andrzej; Theroux, Pierre; Hamm, Christian; Špinar, Jindrich; Kiss, Robert G; Dalby, Anthony J; Medina, Felix A; Kontny, Frederic; Aylward, Philip E; Jensen, Eva C; Held, Peter; Braunwald, Eugene; Sabatine, Marc S

    2016-07-01

    In the PEGASUS-TIMI 54 trial, treatment with ticagrelor reduced the incidence of cardiovascular death, myocardial infarction, or stroke by 15% to 16% among stable patients compared with placebo. However, more patients prematurely discontinued treatment with ticagrelor than with placebo. To investigate the reasons and timing of discontinuation of treatment with ticagrelor among stable patients prior myocardial infarction. In the PEGASUS-TIMI 54 trial, 21 162 stable outpatients with prior myocardial infarction were randomly assigned to 90 mg of ticagrelor twice daily, 60 mg of ticagrelor twice daily, or placebo, with all of the patients receiving a low dose of aspirin. These participants were followed up for a median of 33 months (study start date: October 2010; completion date: December 2014). Discontinuation of treatment was evaluated by treatment arm, cause, and timing. This analysis was initiated in May 2015. Discontinuation of treatment. Over 33 months, 32%, 29%, and 21% of patients receiving 90 mg of ticagrelor, 60 mg of ticagrelor, and placebo, respectively, discontinued treatment (P < .001). Discontinuation of treatment due to an adverse event occurred in 19%, 16%, and 9% of patients, respectively (P < .001). The most frequent adverse events leading to discontinuation of treatment were bleeding (with Kaplan-Meier event rates of 7.8%, 6.2%, and 1.5% of patients, respectively; P < .001) and dyspnea (6.5%, 4.6%, and 0.8% of patients, respectively; P < .001). Eighty-six percent of bleeding events that led to the discontinuation of treatment with ticagrelor were nonmajor, and 86% of adverse events due to dyspnea that led to discontinuation of treatment with ticagrelor were mild or moderate in severity. The discontinuation rates are annualized for patients who received 90 mg of ticagrelor twice daily (hazard ratio [HR], 2.00 [95% CI, 1.84-2.16] for the first year; HR, 1.12 [95% CI, 1.00-1.26] for the second and third years) and patients who

  18. Retinal remodeling.

    PubMed

    Jones, B W; Kondo, M; Terasaki, H; Lin, Y; McCall, M; Marc, R E

    2012-07-01

    Retinal photoreceptor degeneration takes many forms. Mutations in rhodopsin genes or disorders of the retinal pigment epithelium, defects in the adenosine triphosphate binding cassette transporter, ABCR gene defects, receptor tyrosine kinase defects, ciliopathies and transport defects, defects in both transducin and arrestin, defects in rod cyclic guanosine 3',5'-monophosphate phosphodiesterase, peripherin defects, defects in metabotropic glutamate receptors, synthetic enzymatic defects, defects in genes associated with signaling, and many more can all result in retinal degenerative disease like retinitis pigmentosa (RP) or RP-like disorders. Age-related macular degeneration (AMD) and AMD-like disorders are possibly due to a constellation of potential gene targets and gene/gene interactions, while other defects result in diabetic retinopathy or glaucoma. However, all of these insults as well as traumatic insults to the retina result in retinal remodeling. Retinal remodeling is a universal finding subsequent to retinal degenerative disease that results in deafferentation of the neural retina from photoreceptor input as downstream neuronal elements respond to loss of input with negative plasticity. This negative plasticity is not passive in the face of photoreceptor degeneration, with a phased revision of retinal structure and function found at the molecular, synaptic, cell, and tissue levels involving all cell classes in the retina, including neurons and glia. Retinal remodeling has direct implications for the rescue of vision loss through bionic or biological approaches, as circuit revision in the retina corrupts any potential surrogate photoreceptor input to a remnant neural retina. However, there are a number of potential opportunities for intervention that are revealed through the study of retinal remodeling, including therapies that are designed to slow down photoreceptor loss, interventions that are designed to limit or arrest remodeling events, and

  19. Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation.

    PubMed

    Bernardo, Bianca C; Sapra, Geeta; Patterson, Natalie L; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A; McMullen, Julie R

    2015-01-01

    Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions.

  20. Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation

    PubMed Central

    Bernardo, Bianca C.; Sapra, Geeta; Patterson, Natalie L.; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A.; McMullen, Julie R.

    2015-01-01

    Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions. PMID:26660322

  1. Role of reactive oxygen species in myocardial remodeling.

    PubMed

    Zhang, Min; Shah, Ajay M

    2007-03-01

    Adverse cardiac remodeling is a fundamental process in the progression to chronic heart failure. Although the mechanisms underlying cardiac remodeling are multi-factorial, a significant body of evidence points to the crucial roles of increased reactive oxygen species. This article reviews recent advances in delineating the different sources of production for reactive oxygen species (namely mitochondria, xanthine oxidase, uncoupled nitric oxide synthases, and NADPH oxidases) that may be involved in cardiac remodeling and the aspects of the remodeling process that they affect. These data could suggest new ways of targeting redox pathways for the prevention and treatment of adverse cardiac remodeling.

  2. Association between hyperglycaemic crisis and long-term major adverse cardiovascular events: a nationwide population-based, propensity score-matched, cohort study.

    PubMed

    Chang, Li-Hsin; Lin, Liang-Yu; Tsai, Ming-Tsun; How, Chorng-Kuang; Chiang, Jen-Huai; Hsieh, Vivian Chia-Rong; Hu, Sung-Yuan; Hsieh, Ming-Shun

    2016-08-23

    Hyperglycaemic crisis was associated with significant intrahospital morbidity and mortality. However, the association between hyperglycaemic crisis and long-term cardiovascular outcomes remained unknown. This study aimed to investigate the association between hyperglycaemic crisis and subsequent long-term major adverse cardiovascular events (MACEs). This population-based cohort study was conducted using data from Taiwan's National Health Insurance Research Database for the period of 1996-2012. A total of 2171 diabetic patients with hyperglycaemic crisis fit the inclusion criteria. Propensity score matching was used to match the baseline characteristics of the study cohort to construct a comparison cohort which comprised 8684 diabetic patients without hyperglycaemic crisis. The risk of long-term MACEs was compared between the two cohorts. Six hundred and seventy-six MACEs occurred in the study cohort and the event rate was higher than that in the comparison cohort (31.1% vs 24.1%, p<0.001). Patients with hyperglycaemic crisis were associated with a higher risk of long-term MACEs even after adjusting for all baseline characteristics and medications (adjusted HR=1.76, 95% CI 1.62 to 1.92, p<0.001). Acute myocardial infarction had the highest adjusted HR (adjusted HR=2.19, 95% CI 1.75 to 2.75, p<0.001) in the four types of MACEs, followed by congestive heart failure (adjusted HR=1.97, 95% CI 1.70 to 2.28, p<0.001). Younger patients with hyperglycaemic crisis had a higher risk of MACEs than older patients (adjusted HR=2.69 for patients aged 20-39 years vs adjusted HR=1.58 for patients aged >65 years). Hyperglycaemic crisis was significantly associated with long-term MACEs, especially in the young population. Further prospective longitudinal study should be conducted for validation. 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/

  3. Serial measurement of NT-proBNP predicts adverse cardiovascular outcome in children with primary myocardial dysfunction and acute decompensated heart failure (ADHF)

    PubMed Central

    Medar, Shivanand; Hsu, Daphne T.; Ushay, H. Michael; Lamour, Jacqueline M.; Cohen, Hillel W; Killinger, James S.

    2015-01-01

    Introduction In children, elevated amino terminal pro B-type naturetic peptide (NT-proBNP) levels are associated with impaired heart function. The predictive value of serial monitoring of NT-proBNP levels in acute decompensated heart failure (ADHF) is unclear. Methods This prospective observational study enrolled patients ≤ 21 years with primary myocardial dysfunction and ADHF. NT-proBNP levels were obtained on enrollment (D0), day 2 (D2) and day 7 (D7). Clinical, laboratory and imaging data were collected on enrollment. CV outcome was defined as Heart Transplant (HTx), Ventricular Assist Device (VAD) placement, Extracorporeal Membrane Oxygenation or death at 1 year after admission. NT-proBNP levels and the percent change from D0 to D2 and D0 to D7 were calculated and compared between those with and without adverse cardiovascular (ACV) outcome. Results Sixteen consecutive patients were enrolled. ACV outcome occurred in 6 (37.5%, 4 HTx and 2 VAD). In patients with an ACV outcome, median NT-ProBNP levels at D7 were significantly higher (7,365 Vs. 1,196 pg/ml; p= 0.02) and the percent decline in NT-proBNP was significantly smaller (28% vs. 73%, p=0.02) compared to those without an ACV outcome. ROC curve analysis revealed that a less than 55% decline in NT-proBNP levels at D7 had a sensitivity and specificity of 83% and 90% respectively in predicting an ACV [AUC 0.86, CI (0.68,1.0), p=0.02]. Conclusions In conclusion, children with primary myocardial dysfunction and ADHF, a persistently elevated NT-proBNP and/or a lesser degree of decline in NT-proBNP during the first week of presentation were strongly associated with ACV outcome. Serial NT-proBNP monitoring may allow the early identification of children at risk for worse outcome. PMID:25856472

  4. Resting heart rate associates with one-year risk of major adverse cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention.

    PubMed

    Wang, Shao-Li; Wang, Cheng-Long; Wang, Pei-Li; Xu, Hao; Du, Jian-Peng; Zhang, Da-Wu; Gao, Zhu-Ye; Zhang, Lei; Fu, Chang-Geng; Chen, Ke-Ji; Shi, Da-Zhuo

    2016-03-01

    The study was to access the association between resting heart rate (RHR) and one-year risk of major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI). Patients with ACS after PCI (n = 808) were prospectively followed-up for MACE. RHR was obtained from electrocardiogram. MACE was defined as a composite of cardiac death, nonfatal recurrent myocardial infarction, ischemic-driven revascularization, and ischemic stroke. The association between RHR and one-year risk of MACE was assessed using Cox proportional hazards regression model. Compared with patients with RHR >76 bpm, the adjusted hazard ratio (AHR) was 0.51 (95% confidence intervals [CI]: 0.23-1.14; P = 0.100) for patients with RHR < 61 bpm, and 0.44 (95%CI: 0.23-0.85; P = 0.014) for those with RHR 61-76 bpm. For patients with RHR ≥ 61 bpm, an increase of 10 bpm in RHR was associated with an increase by 38.0% in the risk of MACE (AHR: 1.38; 95% CI: 1.04-1.83; P = 0.026). ACS patients after PCI with RHR >76 bpm were at higher risk of MACE during one-year follow-up compared with patients with RHR 61-76 bpm. An elevated RHR ≥ 61 bpm was associated with increased risk of one-year MACE in ACS patients.

  5. Troponin T in Prediction of Culprit Lesion Coronary Artery Disease and 1-Year Major Adverse Cerebral and Cardiovascular Events in Patients with Acute Stroke.

    PubMed

    Zeus, Tobias; Ketterer, Ulrike; Leuf, Daniela; Dannenberg, Lisa; Wagstaff, Rabea; Bönner, Florian; Gliem, Michael; Jander, Sebastian; Kelm, Malte; Polzin, Amin

    2016-06-01

    Troponin T (TnT) elevation above the 99th percentile upper reference limit (URL) is considered diagnostic of acute myocardial infarction (MI). Non-specific increases of TnT are frequent in acute stroke patients. However, in these patients, correct diagnosis of MI is crucial because the antithrombotic medications used to treat acute MI might be harmful and produce intracranial bleeding. In this study, we aimed to associate enhanced TnT levels defined by different cutoff values with occurrence of culprit lesion coronary artery disease (CAD) as well as 1-year major adverse cerebral and cardiovascular events (MACCEs). In this cohort study, we investigated 84 consecutive patients with acute ischemic stroke and concomitant MI. TnT levels were measured using a fourth-generation TnT assay. The incidence of culprit lesion CAD was determined by coronary angiography. MACCEs were recorded during 1-year follow-up. Culprit lesion CAD occurred in 55 % of patients, and 1-year MACCE in 37 %. TnT levels above the manufacturers' provided 99th URL (TnT > 0.01) were not associated with culprit lesion CAD (relative risk [RR], 1.3; 95 % confidence interval [CI] 0.96-1.8; P = 0.09). Slightly increased cutoff level (TnT > 0.03) increased specificity and was associated with culprit lesion CAD without decreasing sensitivity (RR, 1.5; 95 % CI 1.1-2.2; P = 0.021) and 1-year MACCE (RR, 1.7; 95 % CI 1.3-2.3; P < 0.001). Slightly increasement of the TnT cutoff level predicted MACCEs and is superior in prediction of culprit lesion CAD in stroke patients without being less sensitive. This finding has to be confirmed in large-scale clinical trials.

  6. Resting heart rate associates with one-year risk of major adverse cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention

    PubMed Central

    Wang, Shao-Li; Wang, Cheng-Long; Wang, Pei-Li; Xu, Hao; Du, Jian-Peng; Zhang, Da-Wu; Gao, Zhu-Ye; Zhang, Lei; Fu, Chang-Geng; Chen, Ke-Ji

    2015-01-01

    The study was to access the association between resting heart rate (RHR) and one-year risk of major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI). Patients with ACS after PCI (n = 808) were prospectively followed-up for MACE. RHR was obtained from electrocardiogram. MACE was defined as a composite of cardiac death, nonfatal recurrent myocardial infarction, ischemic-driven revascularization, and ischemic stroke. The association between RHR and one-year risk of MACE was assessed using Cox proportional hazards regression model. Compared with patients with RHR >76 bpm, the adjusted hazard ratio (AHR) was 0.51 (95% confidence intervals [CI]: 0.23–1.14; P = 0.100) for patients with RHR < 61 bpm, and 0.44 (95%CI: 0.23–0.85; P = 0.014) for those with RHR 61–76 bpm. For patients with RHR ≥ 61 bpm, an increase of 10 bpm in RHR was associated with an increase by 38.0% in the risk of MACE (AHR: 1.38; 95% CI: 1.04–1.83; P = 0.026). ACS patients after PCI with RHR >76 bpm were at higher risk of MACE during one-year follow-up compared with patients with RHR 61–76 bpm. An elevated RHR ≥ 61 bpm was associated with increased risk of one-year MACE in ACS patients. PMID:26585407

  7. Six-month adherence to Statin use and subsequent risk of major adverse cardiovascular events (MACE) in patients discharged with acute coronary syndromes.

    PubMed

    Xie, Gaoqiang; Sun, Yihong; Myint, Phyo Kyaw; Patel, Anushka; Yang, Xingzi; Li, Min; Li, Xian; Wu, Tao; Li, Shenshen; Gao, Runlin; Wu, Yangfeng

    2017-08-15

    The evidence of adherence to statin decreasing risk of major adverse cardiovascular events (MACEs) is still lack among patients discharged with acute coronary syndrome (ACS). Our objective is to determine the relationship between six-month adherence to statins and subsequent risk of MACEs in patients discharged with ACS. Using two prospective registry cohorts (CPACS-1 and -2), we analyzed data from 12,516 consecutive patients with ACS who were prescribed statin at hospital discharge and survived beyond 6 months without recurrent myocardial infarction (MI) or stroke. Adherence to statin was defined as good (using statin at discharge and 6 months without declined dosage) and poor adherence groups (using statin at discharge but declining dosage or stopping at 6 months). We compared the hazard ratios of all-cause mortality and MACE in subsequent 6 months between groups, using Cox-regression models, adjusting for multiple potential confounders. Seventy two percent of patients adhered to statin therapy at 6 months. The incident MACE in the poor adherence group was significantly higher than in good adherence group (2.7% vs. 1.8%, p = 0.002). Compared with poor adherence group, the good adherence group showed a 27% lower relative risk of MACE during the 6 month follow up (fully-adjusted hazard ratio (HR) = 0.73; 95%CI: 0.56-0.97). The protective effects of good adherence were similar in groups with different statin dose as well as groups by other baseline clinical characteristics and treatments (p > 0.05 for interaction). Our study highlights the importance of adherence to statin therapy in prevention of MACE and clinicians should aim to achieve higher dosage if tolerable. CPACS2 was registered on URL: http://www.anzctr.org.au/default.aspx and unique identifier is ACTRN12609000491268 . CPACS1 was not a clinical trial and thus not registered.

  8. Mechanosensitive channels in striated muscle and the cardiovascular system: not quite a stretch anymore.

    PubMed

    Stiber, Jonathan A; Seth, Malini; Rosenberg, Paul B

    2009-08-01

    Stretch-activated or mechanosensitive channels transduce mechanical forces into ion fluxes across the cell membrane. These channels have been implicated in several aspects of cardiovascular physiology including regulation of blood pressure, vasoreactivity, and cardiac arrhythmias, as well as the adverse remodeling associated with cardiac hypertrophy and heart failure. This review discusses mechanosensitive channels in skeletal muscle and the cardiovascular system and their role in disease pathogenesis. We describe the regulation of gating of mechanosensitive channels including direct mechanisms and indirect activation by signaling pathways, as well as the influence on activation of these channels by the underlying cytoskeleton and scaffolding proteins. We then focus on the role of transient receptor potential channels, several of which have been implicated as mechanosensitive channels, in the pathogenesis of adverse cardiac remodeling and as potential therapeutic targets in the treatment of heart failure.

  9. The effects of non-calcium-based phosphate binders versus calcium-based phosphate binders on cardiovascular calcification and bone remodeling among dialysis patients: a meta-analysis of randomized trials.

    PubMed

    Liu, Ling; Wang, Yongjun; Chen, Hongyu; Zhu, Xiaoling; Zhou, Liusha; Yang, Yazhen

    2014-09-01

    Vascular calcification significantly increases the rates of cardiovascular mortality in hemodialysis (HD) patients. Abnormalities in mineral metabolism may play a role in the pathogenesis of arterial calcification. Whether patients treated with non-calcium-based phosphate binders had reduced aortic vascular calcification compared to those treated with calcium-based phosphate binders is still unclear. We searched multiple databases for studies published through August 2013 that evaluated the effects of non-calcium-based phosphate binders (NCBP) versus calcium-based phosphate binders (CBP) on cardiovascular calcification and bone remodeling among dialysis patients. We summarized test performance characteristics with the use of forest plots, fixed and random effects models, and Egger regression test. Eighteen eligible randomized controlled trials totaling 3676 patients were included. Meta-analysis results showed NCBP could significantly attenuate the progression of coronary artery calcification than CBP (WMD: -144.62, 95% CI: -285.62 to -3.63). The serum calcium levels significant lower in NCPB group than in CPB groups (WMD: -0.26, 95% CI: -0.37 to -0.14), but the serum iPTH levels were significantly higher in NCPB groups (WMD: 57.1, 95% CI: 13.42 to 100.78). The osteoid volume and osteoblast numbers were significant higher in NCPB group than in CPB group (WMD: 1.75, 95% CI: 0.78 to 2.73 for osteoid volume; WMD: 4.49, 95% CI: 1.83 to 7.15 for osteoblast numbers). The Egger regression test also showed no potential publication bias (p = 0.725). Based on available data, NCBPs have equally effective with CBPs for serum phosphate control. But there was significantly lower incidence of coronary artery calcification and a significant higher bone formatting rate in NCBP groups than in CBP groups. So we recommend NCBPs as phosphate binders for HD patients.

  10. Sex-Specific Associations Between Coronary Artery Plaque Extent and Risk of Major Adverse Cardiovascular Events: from the CONFIRM Long-Term Registry

    PubMed Central

    Gransar, Heidi; Lin, Fay; Valenti, Valentina; Cho, Iksung; Berman, Daniel; Callister, Tracy; DeLago, Augustin; Hadamitzky, Martin; Hausleiter, Joerg; Al-Mallah, Mouaz; Budoff, Matthew; Kaufmann, Philipp; Achenbach, Stephan; Raff, Gilbert; Chinnaiyan, Kavitha; Cademartiri, Filippo; Maffei, Erica; Villines, Todd; Kim, Yong-Jin; Leipsic, Jonathon; Feuchtner, Gudrun; Rubinshtein, Ronen; Pontone, Gianluca; Andreini, Daniele; Marques, Hugo; Shaw, Leslee; Min, James K.

    2016-01-01

    Objective To examine sex-specific associations, if any, between per-vessel CAD extent and the risk of major adverse cardiovascular events (MACE) over a five-year study duration. Background The presence and extent of coronary artery disease (CAD) diagnosed by coronary computed tomography angiography (CCTA) is associated with increased short-term mortality and MACE. Nevertheless, some uncertainty remains regarding the influence of gender on these findings. Methods 5,632 patients (mean age 60.2 + 11.8 years, 36.5% female) from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry were followed over the course of 5 years. Obstructive CAD was defined as ≥50% luminal stenosis in a coronary vessel. Using Cox proportional-hazards models, we calculated the hazard ratio (HR) for incident MACE among women and men, defined as death or myocardial infarction (MI). Results Obstructive CAD was more prevalent in men (42% vs. 26%, p<0.001) whereas women were more likely to have normal coronary arteries (43% vs. 27%, p<0.001). There were a total of 798 incident MACE events. After adjustment, there was a strong association between increased MACE risk and non-obstructive CAD (HR 2.16 for women, 2.56 for men, p<0.001 for both), obstructive one-vessel CAD (HR 3.69 and 2.66, p<0.001), two-vessel CAD (HR 3.92 and 3.55, p<0.001) and three-vessel/left-main CAD (HR 5.94 and 4.44, p<0.001). Further exploratory analyses of atherosclerotic burden did not identify gender-specific patterns predictive of MACE. Conclusion In a large prospective CCTA cohort followed long-term, we did not observe an interaction of gender for the association between MACE risk and increased per-vessel extent of obstructive CAD. These findings highlight the persistent prognostic significance of anatomic CAD subsets as detected by CCTA for the risk of MACE in both women and men. PMID:27056154

  11. Two unconventional risk factors for major adverse cardiovascular events in subjects with sexual dysfunction: low education and reported partner's hypoactive sexual desire in comparison with conventional risk factors.

    PubMed

    Rastrelli, Giulia; Corona, Giovanni; Fisher, Alessandra D; Silverii, Antonio; Mannucci, Edoardo; Maggi, Mario

    2012-12-01

    The classification of subjects as low or high cardiovascular (CV) risk is usually performed by risk engines, based upon multivariate prediction algorithms. However, their accuracy in predicting major adverse CV events (MACEs) is lower in high-risk populations as they take into account only conventional risk factors. To evaluate the accuracy of Progetto Cuore risk engine in predicting MACE in subjects with erectile dysfunction (ED) and to test the role of unconventional CV risk factors, specifically identified for ED. A consecutive series of 1,233 men (mean age 53.33 ± 9.08 years) attending our outpatient clinic for sexual dysfunction was longitudinally studied for a mean period of 4.4 ± 2.6 years. Several clinical, biochemical, and instrumental parameters were evaluated. Subjects were classified as high or low risk, according to previously reported ED-specific risk factors. In the overall population, Progetto Cuore-predicted population survival was not significantly different from the observed one (P = 0.545). Accordingly, receiver operating characteristic (ROC) analysis shows that Progetto Cuore has an accuracy of 0.697 ± 0.037 (P < 0.001) in predicting MACE. Considering subjects at high risk according to ED-specific risk factors, the observed incidence of MACE was significantly higher than the expected for both low educated and patients reporting partner's hypoactive sexual desire (HSD, both <0.05), but not for other described factors. The area under ROC curves of Progetto Cuore for MACE in subjects with low education and reported partner's HSD were 0.659 ± 0.053 (P = 0.008) and 0.550 ± 0.076 (P = 0.570), respectively. Overall, Progetto Cuore is a proper instrument for evaluating CV risk in ED subjects. However, in ED, other factors such as low education and partner's HSD concur to risk profile. At variance with low education, Progetto Cuore is not accurate enough to predict MACE in subjects with partner's HSD, suggesting that the latter effect is not

  12. Prognostic Value of the CHADS2 Score for Adverse Cardiovascular Events in Coronary Artery Disease Patients Without Atrial Fibrillation-A Multi-Center Observational Cohort Study.

    PubMed

    Tabata, Noriaki; Yamamoto, Eiichiro; Hokimoto, Seiji; Yamashita, Takayoshi; Sueta, Daisuke; Takashio, Seiji; Arima, Yuichiro; Izumiya, Yasuhiro; Kojima, Sunao; Kaikita, Koichi; Matsui, Kunihiko; Fujimoto, Kazuteru; Sakamoto, Kenji; Shimomura, Hideki; Tsunoda, Ryusuke; Hirose, Toyoki; Nakamura, Natsuki; Sakaino, Naritsugu; Nakamura, Shinichi; Yamamoto, Nobuyasu; Matsumura, Toshiyuki; Kajiwara, Ichiro; Koide, Shunichi; Sakamoto, Tomohiro; Nakao, Koichi; Oshima, Shuichi; Tsujita, Kenichi

    2017-08-16

    The CHADS2 score has mainly been used to predict the likelihood of cerebrovascular accidents in patients with atrial fibrillation. However, increasing attention is being paid to this scoring system for risk stratification of patients with coronary artery disease. We investigated the value of the CHADS2 score in predicting cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. This was a multicenter, observational cohort study. The subjects had been admitted to one of the participating institutions with coronary artery disease requiring percutaneous coronary intervention. We calculated the CHADS2 scores for 7082 patients (mean age, 69.7 years; males, 71.9%) without clinical evidence of atrial fibrillation. Subjects were subdivided into low- (0-1), intermediate- (2-3), and high-score (4-6) groups and followed for 1 year. The end point was a composite of cardiovascular/cerebrovascular death, nonfatal myocardial infarction, and ischemic stroke at 1-year follow-up. Rates of triple-vessel/left main trunk disease correlated positively with CHADS2 score categories. CHADS2 scores among single, double, and triple-vessel/left main trunk groups were 2 (1-2), 2 (1-3), and 2 (2-3), respectively (P<0.001). A total of 194 patients (2.8%) had a cardiovascular/cerebrovascular event, and Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular/cerebrovascular events in proportion to a higher CHADS2 score (log-rank test, P<0.001). Multivariate Cox hazard analysis identified CHADS2 score (per 1 point) as an independent predictor of cardiovascular/cerebrovascular events (hazard ratio, 1.31; 95% CI, 1.17-1.47; P<0.001). This large cohort study indicated that the CHADS2 score is useful for the prediction of cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  13. Depression as a mediator between spousal bereavement and mortality from cardiovascular disease: appreciating and managing the adverse health consequences of depression in an elderly surviving spouse.

    PubMed

    Williams, Jonathan Richard

    2005-01-01

    Bereavement in the elderly is becoming a more frequent phenomenon as a result of the aging of the population. The death of an elderly spouse increases psychologic morbidity, particularly depressive symptoms, as well as mortality. Depression increases the risk of death independent of age or bereavement, and can thus exacerbate the health effects of losing a spouse. This magnifier effect is especially pernicious because bereavement and depression both tend to increase cardiovascular mortality rates. Primary care physicians should be alert for signs of mood disorders in elderly persons who have recently lost a spouse. Potential therapies for depression in an elderly bereaved individual include pharmacologic agents, psychotherapy, and psychosocial support. Data also support the value of encouraging religious patients to continue with spiritual observances. Although these approaches decrease mood disorders, it is not yet clear whether they also reduce the risk of death or cardiovascular disease.

  14. Mediterranean diet reduces the adverse effect of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence: a randomized controlled trial in a high-cardiovascular-risk population

    USDA-ARS?s Scientific Manuscript database

    Transcription factor 7-like 2 (TCF7L2) polymorphisms are strongly associated with type 2 diabetes, but controversially with plasma lipids and cardiovascular disease. Interactions of the Mediterranean diet (MedDiet) on these associations are unknown. We investigated whether the TCF7L2-rs7903146 (C>T)...

  15. Teaching resources. Chromatin remodeling.

    PubMed

    Lue, Neal F

    2005-07-26

    This Teaching Resource provides lecture notes and slides for a class covering chromatin remodeling mechanisms and is part of the course "Cell Signaling Systems: a Course for Graduate Students." The lecture begins with a discussion of chromatin organization and then proceeds to describe the process of chromatin remodeling through a review of chromatin remodeling complexes and methods used to study their function.

  16. Immune modulation of resistance artery remodelling.

    PubMed

    Schiffrin, Ernesto L

    2012-01-01

    Low-grade inflammation plays a role in cardiovascular disease. The innate and the adaptive immune responses participate in mechanisms that contribute to inflammatory responses. It has been increasingly appreciated that different subsets of lymphocytes and the cytokines they produce modulate the vascular remodelling that occurs in cardiovascular disease. Effector T cells such as T-helper (Th) 1 (interferon-γ-producing) and Th2 lymphocytes (that produce interleukin-4), as well as Th17 (that produce interleukin-17), and T suppressor lymphocytes including regulatory T cells (Treg), which express the transcription factor forkhead box P3 (Foxp3), are involved in the remodelling of small arteries that occurs under the action of angiotensin II, deoxycorticosterone-salt and aldosterone-salt, as well as in models of hypertension such as the Dahl-salt-sensitive rat. The mechanism whereby the immune system is activated is unclear, but it has been suggested that neo-antigens may be generated by the elevation of blood pressure or other stimuli, leading to the activation of the immune response. Activated Th1 may contribute to vascular remodelling directly on blood vessels via effects of the cytokines produced or indirectly by actions on the kidney. The protective effect of Treg may be mediated similarly directly or via renal effects. These data offer promise for the discovery of new therapeutic targets to ameliorate vascular remodelling, which could lead to improved outcome in cardiovascular disease in humans.

  17. Does coronary artery calcium scoring add to the predictive value of coronary computed tomography angiography for adverse cardiovascular events in low-risk chest pain patients?

    PubMed

    Chang, Anna Marie; Le, Jeffrey; Matsuura, Asako C; Litt, Harold I; Hollander, Judd E

    2011-10-01

    Coronary angiography calcium score (CACS) is included for patients who receive coronary computed tomography angiography (CTA) as part of diagnostic testing for low-risk chest pain. Both tests add radiation exposure, and it is unclear whether the combination provides more information than either test alone. The objective was to asses if CACS = 0 determines freedom from coronary artery disease (CAD) and whether the addition of CACS to coronary CT angiography provides additional risk stratification information or helps predict 30-day cardiovascular outcomes. This was a secondary analysis of a prospective cohort study at an urban university hospital emergency department (ED), of patients with symptoms suggestive of potential acute coronary syndrome (ACS) and low Thrombolysis in Myocardial Infarction (TIMI) risk scores who received coronary CTA. Data collected included demographics and medical history. The main outcome was CAD, defined as the presence of a maximal stenosis >50% on coronary CTA, stratified by CACS results. The secondary outcome was cardiovascular events including death, myocardial infarction, or revascularization at 30 days. Data were analyzed with standard descriptive techniques and relative risks (RR) with 95% confidence intervals (CIs). A total of 1,049 patients were enrolled (median age = 48.1 years; interquartile range [IQR] = 42.4 to 53.3 years); 55% were female, and 63% were black or African American. Of these, 17 of 795 (2.1%) with CACS of 0 had CAD, 16 of 169 patients (9.5%) with CACS of 0.1 to 99 had CAD, 53.3% (32 of 60) with CACS between 100 and 399 had CAD, and 10 of 23 (43.5%) with CACS ≥ 400 had CAD. There was a higher likelihood of significant CAD with increased CACS. Patients who had a calcium score of 0 but still had CAD were more likely to be young (50 years old or less; RR = 1.73, 95% CI = 1.01 to 2.96). For the secondary outcome, there were 15 cardiovascular events within 30 days: one patient with CACS = 0 and no CAD (1 of 733; 0

  18. Mediterranean Diet Reduces the Adverse Effect of the TCF7L2-rs7903146 Polymorphism on Cardiovascular Risk Factors and Stroke Incidence

    PubMed Central

    Corella, Dolores; Carrasco, Paula; Sorlí, Jose V.; Estruch, Ramón; Rico-Sanz, Jesús; Martínez-González, Miguel Ángel; Salas-Salvadó, Jordi; Covas, M. Isabel; Coltell, Oscar; Arós, Fernando; Lapetra, José; Serra-Majem, Lluís; Ruiz-Gutiérrez, Valentina; Warnberg, Julia; Fiol, Miquel; Pintó, Xavier; Ortega-Azorín, Carolina; Muñoz, Miguel Ángel; Martínez, J. Alfredo; Gómez-Gracia, Enrique; González, José I.; Ros, Emilio; Ordovás, José M.

    2013-01-01

    OBJECTIVE Transcription factor 7-like 2 (TCF7L2) polymorphisms are strongly associated with type 2 diabetes, but controversially with plasma lipids and cardiovascular disease. Interactions of the Mediterranean diet (MedDiet) on these associations are unknown. We investigated whether the TCF7L2-rs7903146 (C>T) polymorphism associations with type 2 diabetes, glucose, lipids, and cardiovascular disease incidence were modulated by MedDiet. RESEARCH DESIGN AND METHODS A randomized trial (two MedDiet intervention groups and a control group) with 7,018 participants in the PREvención con DIetaMEDiterránea study was undertaken and major cardiovascular events assessed. Data were analyzed at baseline and after a median follow-up of 4.8 years. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for cardiovascular events. RESULTS The TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes (odds ratio 1.87 [95% CI 1.62–2.17] for TT compared with CC). MedDiet interacted significantly with rs7903146 on fasting glucose at baseline (P interaction = 0.004). When adherence to the MedDiet was low, TT had higher fasting glucose concentrations (132.3 ± 3.5 mg/dL) than CC+CT (127.3 ± 3.2 mg/dL) individuals (P = 0.001). Nevertheless, when adherence was high, this increase was not observed (P = 0.605). This modulation was also detected for total cholesterol, LDL cholesterol, and triglycerides (P interaction < 0.05 for all). Likewise, in the randomized trial, TT subjects had a higher stroke incidence in the control group (adjusted HR 2.91 [95% CI 1.36–6.19]; P = 0.006 compared with CC), whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes (adjusted HR 0.96 [95% CI 0.49–1.87]; P = 0.892 for TT compared with CC). CONCLUSIONS Our novel results suggest that MedDiet may not only reduce increased fasting glucose and lipids in TT individuals, but also stroke incidence. PMID:23942586

  19. Roles of High Mobility Group Box 1 in Cardiovascular Calcification.

    PubMed

    Chen, Qiang; Wang, Ze-Yang; Chen, Li-Yuan; Hu, Hou-Yuan

    2017-01-01

    Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development. © 2017 The Author(s). Published by S. Karger AG, Basel.

  20. Radiation-induced cardiovascular effects

    NASA Astrophysics Data System (ADS)

    Tapio, Soile

    Recent epidemiological studies indicate that exposure to ionising radiation enhances the risk of cardiovascular mortality and morbidity in a moderate but significant manner. Our goal is to identify molecular mechanisms involved in the pathogenesis of radiation-induced cardiovascular disease using cellular and mouse models. Two radiation targets are studied in detail: the vascular endothelium that plays a pivotal role in the regulation of cardiac function, and the myocardium, in particular damage to the cardiac mitochondria. Ionising radiation causes immediate and persistent alterations in several biological pathways in the endothelium in a dose- and dose-rate dependent manner. High acute and cumulative doses result in rapid, non-transient remodelling of the endothelial cytoskeleton, as well as increased lipid peroxidation and protein oxidation of the heart tissue, independent of whether exposure is local or total body. Proteomic and functional changes are observed in lipid metabolism, glycolysis, mitochondrial function (respiration, ROS production etc.), oxidative stress, cellular adhesion, and cellular structure. The transcriptional regulators Akt and PPAR alpha seem to play a central role in the radiation-response of the endothelium and myocardium, respectively. We have recently started co-operation with GSI in Darmstadt to study the effect of heavy ions on the endothelium. Our research will facilitate the identification of biomarkers associated with adverse cardiac effects of ionising radiation and may lead to the development of countermeasures against radiation-induced cardiac damage.

  1. Prenatal programming: adverse cardiac programming by gestational testosterone excess

    PubMed Central

    Vyas, Arpita K.; Hoang, Vanessa; Padmanabhan, Vasantha; Gilbreath, Ebony; Mietelka, Kristy A.

    2016-01-01

    Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30–90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells –c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess. PMID:27328820

  2. Cardiovascular pharmacogenetics.

    PubMed

    Myburgh, Renier; Hochfeld, Warren E; Dodgen, Tyren M; Ker, James; Pepper, Michael S

    2012-03-01

    Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (e.g. drug metabolizing enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimizing drug toxicity and optimizing drug efficacy in cardiovascular medicine.

  3. Sleep-disordered breathing does not affect nocturnal dipping, as assessed by pulse transit time, in preschool children: evidence for early intervention to prevent adverse cardiovascular effects?

    PubMed

    Nisbet, Lauren C; Nixon, Gillian M; Yiallourou, Stephanie R; Biggs, Sarah N; Davey, Margot J; Trinder, John; Walter, Lisa M; Horne, Rosemary S C

    2014-04-01

    Sleep-disordered breathing (SDB) is associated with reduced nocturnal dipping of blood pressure (BP) and sleep disruption in adults, and these features confer an increased risk of cardiovascular events. As SDB prevalence in children peaks during the preschool years, we investigated nocturnal dipping and sleep fragmentation in preschool children with SDB. Children (3-5 years; n=163) grouped by obstructive apnoea hypopnoea index (OAHI): control, no snoring history and OAHI ≤1 event/h; primary snoring, OAHI ≤1 event/h; mild SDB, >1-≤5 events/h; moderate-severe SDB, >5 events/h. Pulse transit time (PTT), an inverse continuous indicator of BP changes, and heart rate (HR) during total sleep time and the first period of rapid eye movement (REM), non-REM (NREM)1/2 and NREM3/4 sleep were expressed as percentage change from wake before sleep onset. The sleep fragmentation index (SFI) was calculated as the number of sleep stage transitions or awakenings per hour of sleep. There were no group differences in the change in PTT or HR from wake to total sleep time or to individual sleep stages or in the proportion of children in the quartile with the smallest change in PTT during total sleep. Children with moderate-severe SDB had higher SFI than primary snoring (PS) or mild SDB groups (p<0.05 for both) and controls (p=0.07). In contrast to adults, nocturnal dipping is preserved in young children with SDB, despite increased sleep fragmentation. As there is evidence that nocturnal dipping is similarly preserved at the school age, childhood may pose a window of opportunity for resolution of SDB when the cardiovascular effects are less marked. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Depression increases sympathetic activity and exacerbates myocardial remodeling after myocardial infarction: evidence from an animal experiment.

    PubMed

    Shi, Shaobo; Liang, Jinjun; Liu, Tao; Yuan, Xiaoran; Ruan, Bing; Sun, Lifang; Tang, Yanhong; Yang, Bo; Hu, Dan; Huang, Congxin

    2014-01-01

    Depression is an independent risk factor for cardiovascular events and mortality in patients with myocardial infarction (MI). Excessive sympathetic activation and serious myocardial remodeling may contribute to this association. The aim of this study was to discuss the effect of depression on sympathetic activity and myocardial remodeling after MI. Wild-type (WT) rats were divided into a sham group (Sham), a myocardial infarction group (MI), a depression group (D), and a myocardial infarction plus depression group (MI+D). Compared with controls, the MI+D animals displayed depression-like behaviors and attenuated body weight gain. The evaluation of sympathetic activity showed an increased level in plasma concentrations of epinephrine and norepinephrine and higher expression of myocardial tyrosine hydroxylase in the MI+D group than the control groups (p<0.05 for all). Cardiac function and morphologic analyses revealed a decreased fractional shortening accompanied by increased left ventricular dimensions, thinning myocardium wall, and reduced collagen repair in the MI+D group compared with the MI group (p<0.05 for all). Frequent premature ventricular contractions, prolonged QT duration and ventricular repolarization duration, shorted effective refractory period, and increased susceptibility to ventricular arrhythmia were displayed in MI+D rats. These results indicate that sympathetic hyperactivation and exacerbated myocardial remodeling may be a plausible mechanism linking depression to an adverse prognosis after MI.

  5. ADMA, cardiovascular disease and diabetes.

    PubMed

    Krzyzanowska, Katarzyna; Mittermayer, Friedrich; Wolzt, Michael; Schernthaner, Guntram

    2008-12-15

    The endogenous competitive nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an emerging risk marker for future cardiovascular events. Elevated ADMA concentrations have been described in patients with an adverse cardiovascular risk profile. Recently, various studies investigated the independent role of ADMA as a cardiovascular risk predictor in several patient cohorts. In addition, ADMA might not only be a risk marker but also a causative factor for cardiovascular disease. This review summarizes the literature on the relationship between ADMA, cardiovascular disease and diabetes.

  6. Fructose Containing Sugars at Normal Levels of Consumption Do Not Effect Adversely Components of the Metabolic Syndrome and Risk Factors for Cardiovascular Disease

    PubMed Central

    Angelopoulos, Theodore J.; Lowndes, Joshua; Sinnett, Stephanie; Rippe, James M.

    2016-01-01

    The objective of the current study was to explore our hypothesis that average consumption of fructose and fructose containing sugars would not increase risk factors for cardiovascular disease (CVD) and the metabolic syndrome (MetS). A randomized, double blind, parallel group study was conducted where 267 individuals with BMI between 23 and 35 kg/m2 consumed low fat sugar sweetened milk, daily for ten weeks as part of usual weight-maintenance diet. One group consumed 18% of calories from high fructose corn syrup (HFCS), another group consumed 18% of calories from sucrose, a third group consumed 9% of calories from fructose, and the fourth group consumed 9% of calories from glucose. There was a small change in waist circumference (80.9 ± 9.5 vs. 81.5 ± 9.5 cm) in the entire cohort, as well as in total cholesterol (4.6 ± 1.0 vs. 4.7 ± 1.0 mmol/L, p < 0.01), triglycerides (TGs) (11.5 ± 6.4 vs. 12.6 ± 8.9 mmol/L, p < 0.01), and systolic (109.2 ± 10.2 vs. 106.1 ± 10.4 mmHg, p < 0.01) and diastolic blood pressure (69.8 ± 8.7 vs. 68.1 ± 9.7 mmHg, p < 0.01). The effects of commonly consumed sugars on components of the MetS and CVD risk factors are minimal, mixed and not clinically significant. PMID:27023594

  7. Fructose Containing Sugars at Normal Levels of Consumption Do Not Effect Adversely Components of the Metabolic Syndrome and Risk Factors for Cardiovascular Disease.

    PubMed

    Angelopoulos, Theodore J; Lowndes, Joshua; Sinnett, Stephanie; Rippe, James M

    2016-03-23

    The objective of the current study was to explore our hypothesis that average consumption of fructose and fructose containing sugars would not increase risk factors for cardiovascular disease (CVD) and the metabolic syndrome (MetS). A randomized, double blind, parallel group study was conducted where 267 individuals with BMI between 23 and 35 kg/m² consumed low fat sugar sweetened milk, daily for ten weeks as part of usual weight-maintenance diet. One group consumed 18% of calories from high fructose corn syrup (HFCS), another group consumed 18% of calories from sucrose, a third group consumed 9% of calories from fructose, and the fourth group consumed 9% of calories from glucose. There was a small change in waist circumference (80.9 ± 9.5 vs. 81.5 ± 9.5 cm) in the entire cohort, as well as in total cholesterol (4.6 ± 1.0 vs. 4.7 ± 1.0 mmol/L, p < 0.01), triglycerides (TGs) (11.5 ± 6.4 vs. 12.6 ± 8.9 mmol/L, p < 0.01), and systolic (109.2 ± 10.2 vs. 106.1 ± 10.4 mmHg, p < 0.01) and diastolic blood pressure (69.8 ± 8.7 vs. 68.1 ± 9.7 mmHg, p < 0.01). The effects of commonly consumed sugars on components of the MetS and CVD risk factors are minimal, mixed and not clinically significant.

  8. Risk of cardiovascular adverse events from trastuzumab (Herceptin(®)) in elderly persons with breast cancer: a population-based study.

    PubMed

    Tsai, H-T; Isaacs, C; Fu, A Z; Warren, J L; Freedman, A N; Barac, A; Huang, C-Y; Potosky, A L

    2014-02-01

    Randomized controlled trials have reported a 4-5 times increased risk of heart failure (HF) in breast cancer patients receiving trastuzumab (Herceptin (®) ) compared to patients who do not receive trastuzumab. However, data regarding the cardiac effects of trastuzumab on elderly patients treated in general practice remain very limited. Using the US surveillance, epidemiology, and end results (SEER)-Medicare database, we conducted a retrospective cohort study on the cardiac effects of trastuzumab use in all incident breast cancer patients diagnosed from 1998 to 2007 who were 66 years and older, had no prior recent claims for cardiomyopathy (CM) or HF, and were followed through 2009. We defined our outcome as the first CM/HF event after diagnosis. We performed Cox-proportional hazard models with propensity score adjustment to estimate CM/HF risk associated with trastuzumab use. A total of 6,829 out of 68,536 breast cancer patients (median age: 75) had an incident CM/HF event. Patients who received trastuzumab tended to be younger, non-white, diagnosed more recently, and had a stage IV diagnosis. Trastuzumab use was associated with an increased risk of CM/HF (HR = 2.08, 95 % CI 1.77-2.44, p < 0.001). The trastuzumab-associated CM/HF risk was stronger in patients who were younger (HR = 2.52 for 66-75 years and HR = 1.44 for 76 years and older, p < 0.001) and diagnosed in recent years (HR = 2.58 for 2006-2007 vs. 1.86 for 1998-2005, p = 0.01). The twofold risk of CM/HF associated with trastuzumab remained regardless of patients' diagnosis stage, presence of hypertension, cardiovascular comorbidities, or receipt of anthracyclines, taxanes, or radiation. Trastuzumab may double CM/HF risk among elderly breast cancer patients. Our findings reinforce the need to prevent and manage cardiac risk among elderly breast cancer patients receiving trastuzumab.

  9. Value of early cardiovascular magnetic resonance for the prediction of adverse arrhythmic cardiac events after a first noncomplicated ST-segment-elevation myocardial infarction.

    PubMed

    Izquierdo, Maite; Ruiz-Granell, Ricardo; Bonanad, Clara; Chaustre, Fabian; Gomez, Cristina; Ferrero, Angel; Lopez-Lereu, Pilar; Monmeneu, Jose V; Nuñez, Julio; Chorro, F Javier; Bodi, Vicent

    2013-09-01

    Infarct size (IS) determined by cardiac magnetic resonance (CMR) has proven an additional value, on top of left ventricular ejection fraction (LVEF), in prediction of adverse arrhythmic cardiac events (AACEs) in chronic ischemic heart disease. Its value soon after an acute ST-segment-elevation myocardial infarction remains unknown. Our aim was to determine whether early CMR can improve AACE risk prediction after acute ST-segment-elevation myocardial infarction. Patients admitted for a first noncomplicated ST-segment-elevation myocardial infarction were prospectively followed up. A total of 440 patients were included. All of them underwent CMR 1 week after admission. CMR-derived LVEF and IS (grams per meter squared) were quantified. AACEs included postdischarge sudden death, sustained ventricular tachycardia, and ventricular fibrillation either documented on ECG or recorded via an implantable cardioverter-defibrillator. Within a median follow-up of 2 years, 11 AACEs (2.5%) were detected: 5 sudden deaths (1.1%) and 6 spontaneous ventricular tachycardia/ventricular fibrillation. In the whole group, AACEs associated with more depressed LVEF (adjusted hazard ratio [95% confidence interval], 0.90 [0.83-0.97]; P<0.01) and larger IS (adjusted hazard ratio [95% confidence interval], 1.06 [1.01-1.12]; P=0.01). According to the corresponding area under the receiver operating characteristic curve, LVEF ≤36% and IS ≥23.5 g/m(2) best predicted AACEs. The vast majority of AACEs (10/11) occurred in patients with simultaneous depressed LVEF ≤36% and IS ≥23.5 g/m(2) (n=39). In the era of reperfusion therapies, occurrence of AACEs in patients with an in-hospital noncomplicated first ST-segment-elevation myocardial infarction is low. In this setting, assessment of an early CMR-derived IS could be useful for further optimization of AACE risk prediction.

  10. Adverse cardiac events in children with Williams syndrome undergoing cardiovascular surgery: An analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database.

    PubMed

    Hornik, Christoph P; Collins, Ronnie Thomas; Jaquiss, Robert D B; Jacobs, Jeffrey P; Jacobs, Marshall L; Pasquali, Sara K; Wallace, Amelia S; Hill, Kevin D

    2015-06-01

    Patients with Williams syndrome (WS) undergoing cardiac surgery are at risk for major adverse cardiac events (MACE). Prevalence and risk factors for such events have not been well described. We sought to define frequency and risk of MACE in patients with WS using a multicenter clinical registry. We identified cardiac operations performed in patients with WS using the Society of Thoracic Surgeons Congenital Heart Surgery Database (2000-2012). Operations were divided into 4 groups: isolated supravalvular aortic stenosis, complex left ventricular outflow tract (LVOT), isolated right ventricular outflow tract (RVOT), and combined LVOT/RVOT procedures. The proportion of patients with MACE (in-hospital mortality, cardiac arrest, or postoperative mechanical circulatory support) was described and the association with preoperative factors was examined. Of 447 index operations (87 centers), median (interquartile range) age and weight at surgery were 2.4 years (0.6-7.4 years) and 10.6 kg (6.5-21.5 kg), respectively. Mortality occurred in 20 patients (5%). MACE occurred in 41 patients (9%), most commonly after combined LVOT/RVOT (18 out of 87; 21%) and complex LVOT (12 out of 131; 9%) procedures, but not after isolated RVOT procedures. Odds of MACE decreased with age (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.98-0.99), weight (OR, 0.97; 95% CI, 0.93-0.99), but increased in the presence of any preoperative risk factor (OR, 2.08; 95% CI, 1.06-4.00), and in procedures involving coronary artery repair (OR, 5.37; 95% CI, 2.05-14.06). In this multicenter analysis, MACE occurred in 9% of patients with WS undergoing cardiac surgery. Demographic and operative characteristics were associated with risk. Further study is needed to elucidate mechanisms of MACE in this high-risk population. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  11. Paroxetine markedly increases plasma concentrations of ophthalmic timolol; CYP2D6 inhibitors may increase the risk of cardiovascular adverse effects of 0.5% timolol eye drops.

    PubMed

    Mäenpää, Jukka; Volotinen-Maja, Marjo; Kautiainen, Hannu; Neuvonen, Mikko; Niemi, Mikko; Neuvonen, Pertti J; Backman, Janne T

    2014-12-01

    Although ophthalmic timolol is generally well tolerated, a significant fraction of topically administered timolol can be systemically absorbed. We investigated the effect of the strong CYP2D6 inhibitor paroxetine on the pharmacokinetics of timolol after ophthalmic administration. In a four-phase crossover study, 12 healthy volunteers ingested either paroxetine (20 mg) or placebo daily for 3 days. In phases 1-2, timolol 0.1% gel, and in phases 3-4, timolol 0.5% drops were administered to both eyes. Paroxetine increased the plasma concentrations of timolol with both timolol formulations to a similar degree. The geometric mean ratio (95% confidence interval) of timolol peak concentration was 1.53-fold (1.23-1.91) with 0.1% timolol and 1.49-fold (0.94-2.36) with 0.5% timolol, and that of timolol area under the plasma concentration-time curve (AUC) from time 0 to 12 hours was 1.61-fold (1.26- to 2.06-fold) and 1.78-fold (1.21-2.62), respectively. During paroxetine administration, six subjects on 0.5% timolol drops, but none on 0.1% timolol gel, had plasma timolol concentrations exceeding 0.7 ng/ml, which can cause systemic adverse effects in patients at risk. There was a positive correlation between the AUC from time 0 to 13 hours of paroxetine and the placebo phase AUC from time 0 to infinity of timolol after timolol 0.5% drops (P < 0.05), and a nonsignificant trend after timolol 0.1% gel, consistent with the role of CYP2D6 in the metabolism of both agents. In the orthostatic test, heart rate immediately after upright standing was significantly lower (P < 0.05) during the paroxetine phase than during the placebo phase at 1 and 3 hours after 0.5% timolol dosing. In conclusion, paroxetine and other CYP2D6 inhibitors can have a clinically important interaction with ophthalmic timolol, particularly when patients are using 0.5% timolol formulations.

  12. Exercise-induced cardiac remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2012-01-01

    Early investigations in the late 1890s and early 1900s documented cardiac enlargement in athletes with above-normal exercise capacity and no evidence of cardiovascular disease. Such findings have been reported for more than a century and continue to intrigue scientists and clinicians. It is well recognized that repetitive participation in vigorous physical exercise results in significant changes in myocardial structure and function. This process, termed exercise-induced cardiac remodeling (EICR), is characterized by structural cardiac changes including left ventricular hypertrophy with sport-specific geometry (eccentric vs concentric). Associated alterations in both systolic and diastolic functions are emerging as recognized components of EICR. The increasing popularity of recreational exercise and competitive athletics has led to a growing number of individuals exhibiting these findings in routine clinical practice. This review will provide an overview of EICR in athletes.

  13. Small artery remodelling in diabetes.

    PubMed

    Rosei, Enrico Agabiti; Rizzoni, Damiano

    2010-05-01

    The aim of this article is to briefly review available data regarding changes in the structure of microvessels observed in patients with diabetes mellitus, and possible correction by effective treatment. The development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, small arteries of smooth muscle cells are restructured around a smaller lumen and there is no net growth of the vascular wall, although in some secondary forms of hypertension, a hypertrophic remodelling may be detected. Moreover, in non-insulin-dependent diabetes mellitus a hypertrophic remodelling of subcutaneous small arteries is present. Indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive and diabetic patients, over and above all other known cardiovascular risk factors. Therefore, regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effect on vascular structure. In diabetic hypertensive patients, a significant regression of structural alterations of small resistance arteries with drugs blocking the renin-angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) was demonstrated. Alterations in the microcirculation represent a common pathological finding, and microangiopathy is one of the most important mechanisms involved in the development of organ damage as well as of clinical events in patients with diabetes mellitus. Renin-angiotensin system blockade seems to be effective in preventing/regressing alterations in microvascular structure.

  14. Small artery remodelling in diabetes

    PubMed Central

    Rosei, Enrico Agabiti; Rizzoni, Damiano

    2010-01-01

    Abstract The aim of this article is to briefly review available data regarding changes in the structure of microvessels observed in patients with diabetes mellitus, and possible correction by effective treatment. The development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, small arteries of smooth muscle cells are restructured around a smaller lumen and there is no net growth of the vascular wall, although in some secondary forms of hypertension, a hypertrophic remodelling may be detected. Moreover, in non-insulin-dependent diabetes mellitus a hypertrophic remodelling of subcutaneous small arteries is present. Indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive and diabetic patients, over and above all other known cardiovascular risk factors. Therefore, regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effect on vascular structure. In diabetic hypertensive patients, a significant regression of structural alterations of small resistance arteries with drugs blocking the renin–angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) was demonstrated. Alterations in the microcirculation represent a common pathological finding, and microangiopathy is one of the most important mechanisms involved in the development of organ damage as well as of clinical events in patients with diabetes mellitus. Renin–angiotensin system blockade seems to be effective in preventing/regressing alterations in microvascular structure. PMID:20646125

  15. Cardiovascular risk

    PubMed Central

    Payne, Rupert A

    2012-01-01

    Cardiovascular disease is a major, growing, worldwide problem. It is important that individuals at risk of developing cardiovascular disease can be effectively identified and appropriately stratified according to risk. This review examines what we understand by the term risk, traditional and novel risk factors, clinical scoring systems, and the use of risk for informing prescribing decisions. Many different cardiovascular risk factors have been identified. Established, traditional factors such as ageing are powerful predictors of adverse outcome, and in the case of hypertension and dyslipidaemia are the major targets for therapeutic intervention. Numerous novel biomarkers have also been described, such as inflammatory and genetic markers. These have yet to be shown to be of value in improving risk prediction, but may represent potential therapeutic targets and facilitate more targeted use of existing therapies. Risk factors have been incorporated into several cardiovascular disease prediction algorithms, such as the Framingham equation, SCORE and QRISK. These have relatively poor predictive power, and uncertainties remain with regards to aspects such as choice of equation, different risk thresholds and the roles of relative risk, lifetime risk and reversible factors in identifying and treating at-risk individuals. Nonetheless, such scores provide objective and transparent means of quantifying risk and their integration into therapeutic guidelines enables equitable and cost-effective distribution of health service resources and improves the consistency and quality of clinical decision making. PMID:22348281

  16. Fetal cardiac remodeling in twin pregnancies conceived by assisted reproductive technologies.

    PubMed

    Valenzuela-Alcaraz, Brenda; Cruz-Lemini, Mónica; Rodríguez-López, Mérida; Goncé, Ana; García-Otero, Laura; Ayuso, Helena; Sitges, Marta; Bijnens, Bart; Balasch, Juan; Gratacós, Eduard; Crispi, Fátima

    2017-05-15

    Recent data suggest that singleton fetuses conceived by assisted reproductive technologies (ART) present cardiovascular remodeling that may persist postnatally. Twin pregnancies are more frequent in the ART population, and are associated with increased adverse perinatal outcomes like hypertensive disorders, gestational diabetes and preterm birth. However, it is unknown whether cardiac remodeling is also present in twin pregnancies conceived by ART. Our aim was to assess the presence of fetal cardiac remodeling and dysfunction in twin pregnancies conceived by ART, as compared to spontaneously conceived (SC) ones. A prospective cohort study including 50 dichorionic twin fetuses conceived by ART and 50 SC twins. The study protocol included structural and functional fetal echocardiography at 28-30 weeks of gestation. ART twin fetuses showed significant cardiac changes, predominantly affecting the right heart, such as dilated atria (right atrial/heart area: controls mean 15.7 (SD 3.1) vs ART 18.4 (3.2), p < 0.001), more globular ventricles (right ventricular sphericity index: SC 1.57 (0.25) vs ART 1.41 (0.23), p = 0.001) and thicker myocardial walls (septal wall thickness: SC 2.57 mm (0.45) vs ART 2.84 mm (0.41), p = 0.034) together with reduced longitudinal motion (tricuspid annular plane systolic excursion: SC 6.36 mm ( 0.89) vs ART 5.18 mm (0.93), p < 0.001) as compared to SC twins. ART twin fetuses present signs of fetal cardiac remodeling and dysfunction. These changes are similar to those observed in ART singletons and reinforce the concept of fetal cardiac programming in ART. These results open opportunities for early detection and intervention in infants conceived by ART. This article is protected by copyright. All rights reserved.

  17. Myocardial remodeling in low-renin hypertension: molecular pathways to cellular injury in relative aldosteronism.

    PubMed

    Bhattacharya, Syamal K; Gandhi, Malay S; Kamalov, German; Ahokas, Robert A; Sun, Yao; Gerling, Ivan C; Weber, Karl T

    2009-12-01

    The pathologic hypertrophy of hypertensive heart disease is related to the quality, not the quantity, of myocardium; the presence of fibrosis is inevitably linked to structural and functional insufficiencies with increased cardiovascular risk. Elevations in plasma aldosterone that are inappropriate relative to dietary sodium, or relative aldosteronism, are accompanied by suppressed plasma renin activity, elevation in arterial pressure, and dyshomeostasis of divalent cations. The accompanying hypocalcemia, hypomagnesemia, and hypozincemia of aldosteronism contribute to the appearance of secondary hyperparathyroidism. Parathyroid hormone-mediated intracellular calcium overloading of cardiac myocytes and mitochondria leads to the induction of oxidative stress and molecular pathways associated with cardiomyocyte necrosis and scarring of myocardium, whereas the dyshomeostasis of zinc compromises antioxidant defenses. This dys-homeostasis of calcium and zinc, intrinsically coupling prooxidant calcium and antioxidant zinc, raises the prospect for therapeutic strategies designed to mitigate intracellular calcium overloading while enhancing zinc-mediated antioxidant defenses, thus preventing adverse myocardial remodeling with fibrosis, associated diastolic dysfunction, and cardiac arrhythmias.

  18. Pharmacovigilance and the cardiovascular system: two sides to every story.

    PubMed

    Keller, Guillermo Alberto; Di Girolamo, Guillermo; Alvarez, Paulino Antonio

    2011-09-01

    The objective of the present study was to quantify the reported cardiovascular adverse reactions and adverse reactions to cardiovascular drugs to help to design and implement monitoring and prevention strategies. The pharmacovigilance unit (PU) is a peripheral effector of National Pharmacovigilance Center and receives adverse drug reactions notifications from 10 teaching hospitals. Data on adverse reactions beginning in 2004 and notified to the PU were extracted from the database. Cardiovascular adverse drug reactions and adverse reactions to cardiovascular drugs were identified using Medical Dictionary for Regulatory Activities (MedDRA), and the Anatomical Therapeutic Chemical (ATC) Classification System respectively. The reports of adverse reactions were classified according to their seriousness. From 2004 to 2010, 2516 notifications were received (2383 adverse reactions, 106 lack of efficacy, 26 quality failures). These notifications included 151 cardiovascular adverse reactions and 594 adverse reactions caused by cardiovascular drugs. In the first group, of the 151 cardiovascular adverse reactions through MedDRA SOC classification caused by all ATC group classes, 118 (78.2%) were caused by non cardiovascular drugs. Among them antimicrobials (27,2%) and neurologic drugs (21,2%) were the most frequent. 22 (14.6%) adverse reactions were serious. Long QT syndrome, peripheral edema, hypotension, tachycardia, and bradycardia, were the most frequent. In the second group, of the 594 reports identifying adverse reactions involving all MedDRA SOCs but caused only by cardiovascular drugs, 559 reports (94.1%) were non cardiovascular adverse reactions. Enalapril and furosemide accounted for 65.2% there were 33 (5.6%) serious adverse reactions. The most frequent adverse reactions were hyponatremia, impaired renal function, hypokalemia, metabolic alkalosis, asymptomatic elevation of liver enzymes, hyperkalemia, hyperglycemia, edema, and cough. Non-cardiovascular adverse

  19. Remodeling A School Shop?

    ERIC Educational Resources Information Center

    Baker, G. E.

    1970-01-01

    Presents guidelines for remodeling a school shop combining major considerations of funds, program changes, class management, and flexibility, with the needs of wiring, painting, and placement of equipment. (Author)

  20. Disorders of Bone Remodeling

    PubMed Central

    Feng, Xu; McDonald, Jay M.

    2013-01-01

    The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms. PMID:20936937

  1. Aldosterone and the cardiovascular system: a dangerous association.

    PubMed

    Cachofeiro, Victoria; López-Andrés, Natalia; Miana, Maria; Martín-Fernández, Beatriz; de Las Heras, Natalia; Martínez, Ernesto; Lahera, Vicente; Fortuño, María Antonia

    2010-12-01

    Initial studies have focussed on the actions of aldosterone in renal electrolyte handling and, as a consequence, blood pressure control. More recently, attention has primarily been focussed on its actions on the heart and vascular system, where it is locally produced. Aldosterone by binding mineralocorticoid receptors causes oxidative stress, fibrosis and triggers an inflammatory response in the cardiovascular system. All these effects could be underlying the role of aldo-sterone on cardiac and vascular remodelling associated with different pathological situations. At the vascular level, aldo-sterone affects endothelial function because administration of aldosterone to rats impaired endothelium-dependent relaxations. In addition, the administration of mineralocorticoid receptor antagonists ameliorates endothelium-dependent relaxation in models of both hypertension and atherosclerosis, and in patients with heart failure. Several mechanisms can participate in this effect, including production of vasoconstrictor factors and a reduction in nitric oxide levels. This reduction can involve both a decrease in its production as well as an increase in its degradation by reactive oxygen species. Aldosterone can produce oxidative stress by the activation of transcription factors such as the NF-κB system, which can also trigger an inflammatory process through the production of different cytokines. At cardiac level, high levels of aldosterone can also adversely impact heart function by producing cardiac hypertrophy, diastolic dysfunction and electrical remodelling through changes in ionic channels. All these effects can explain the beneficial effect of mineralocorticoid blockade in the cardiovascular system.

  2. The CHADS2 and CHA2DS2-VASc scores predict adverse vascular function, ischemic stroke and cardiovascular death in high-risk patients without atrial fibrillation: role of incorporating PR prolongation.

    PubMed

    Chan, Yap-Hang; Yiu, Kai-Hang; Lau, Kui-Kai; Yiu, Yuen-Fung; Li, Sheung-Wai; Lam, Tai-Hing; Lau, Chu-Pak; Siu, Chung-Wah; Tse, Hung-Fat

    2014-12-01

    To investigate whether the CHADS2 and CHA2DS2-VASc scores have clinical utility for prediction of adverse vascular function and vascular dysfunction-mediated incident cardiovascular (CV) events among high-risk patients without atrial fibrillation (AF), and the additional value of incorporating PR prolongation to the scores. We analyzed 579 high-risk CV outpatients without clinical AF in a prospective cohort for new-onset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and CV death. Brachial flow-mediated dilation (FMD) and nitroglycerin-mediated dilatation (NMD), carotid intima-media thickness (IMT) and pulse wave velocity (PWV) were determined. Baseline CHADS2 score was associated with lower FMD (Pearson r = -0.16, P < 0.001) and NMD (r = -0.17, P < 0.001), higher carotid IMT (r = 0.30, P < 0.001) and PWV (r = 0.35, P < 0.001; similar for CHA2DS2-VASc score: All P < 0.05). After follow-up of 63 ± 11 months, 82 patients (14.2%) developed combined CV endpoint. ROC curve analysis showed that both CHADS2 and CHA2DS2-VASc scores were predictors for ischemic stroke (C-Statistic: CHADS2 0.70, P = 0.004; CHA2DS2-VASc 0.68, P = 0.010), MI (CHADS2 0.63, P = 0.030; CHA2DS2-VASc 0.70, P = 0.001), and CV death (CHADS2 0.63, P = 0.022; CHA2DS2-VASc 0.65, P = 0.011). Higher CHADS2 score was associated with reduced event-free survival from combined CV endpoints (log-rank = 16.7, P < 0.001) with differences potentiated if stratified by CHA2DS2-VASc score (log-rank = 29.2, P < 0.001). Incorporating PR prolongation, the CHA2DS2-VASc-PR score achieved the highest C-Statistic for CV death prediction (0.70, P < 0.001) superior to the CHADS2 score (chi-square: 12.1, P = 0.0005). The CHADS2 and CHA2DS2-VASc predict vascular dysfunction and cardiovascular events in high-risk CV patients without clinical AF, with further improved performance incorporating PR prolongation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. [Cardiovascular involvement in rheumatic diseases].

    PubMed

    Driazhenko, I V

    2005-01-01

    Cardiovascular system involvement with early development of atherosclerosis is characteristic for rheumatic diseases. Among causes of death in various rheumatic diseases cardiovascular pathology also prevails. This paper contains a review of most important studies of impairment of the heart, arterial and venous parts of cardiovascular system in patients with diffuse diseases of connective tissue, rheumatoid arthritis and systemic vasculitides. The role of immune mechanisms, endothelial dysfunction, dyslipidemia in pathogenesis of cardiovascular disturbances with development of myocardial and vascular remodeling in rheumatic diseases is also discussed. Major risk factors of cardiovascular pathology in rheumatic patients are presented. Treatment of a cardiovascular pathology in these patients presumes the use of angiotensin converting enzyme inhibitors, aldosterone antagonists and statins.

  4. Prognostic Value of Combined CT Angiography and Myocardial Perfusion Imaging versus Invasive Coronary Angiography and Nuclear Stress Perfusion Imaging in the Prediction of Major Adverse Cardiovascular Events: The CORE320 Multicenter Study.

    PubMed

    Chen, Marcus Y; Rochitte, Carlos E; Arbab-Zadeh, Armin; Dewey, Marc; George, Richard T; Miller, Julie M; Niinuma, Hiroyuki; Yoshioka, Kunihiro; Kitagawa, Kakuya; Sakuma, Hajime; Laham, Roger; Vavere, Andrea L; Cerci, Rodrigo J; Mehra, Vishal C; Nomura, Cesar; Kofoed, Klaus F; Jinzaki, Masahiro; Kuribayashi, Sachio; Scholte, Arthur J; Laule, Michael; Tan, Swee Yaw; Hoe, John; Paul, Narinder; Rybicki, Frank J; Brinker, Jeffrey A; Arai, Andrew E; Matheson, Matthew B; Cox, Christopher; Clouse, Melvin E; Di Carli, Marcelo F; Lima, João A C

    2017-07-01

    Purpose To compare the prognostic importance (time to major adverse cardiovascular event [MACE]) of combined computed tomography (CT) angiography and CT myocardial stress perfusion imaging with that of combined invasive coronary angiography (ICA) and stress single photon emission CT myocardial perfusion imaging. Materials and Methods This study was approved by all institutional review boards, and written informed consent was obtained. Between November 2009 and July 2011, 381 participants clinically referred for ICA and aged 45-85 years were enrolled in the Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-Detector Row Computed Tomography (CORE320) prospective multicenter diagnostic study. All images were analyzed in blinded independent core laboratories, and a panel of physicians adjudicated all adverse events. MACE was defined as revascularization (>30 days after index ICA), myocardial infarction, or cardiac death; hospitalization for chest pain or congestive heart failure; or arrhythmia. Late MACE was defined similarly, except for patients who underwent revascularization within the first 182 days after ICA, who were excluded. Comparisons of 2-year survival (time to MACE) used standard Kaplan-Meier curves and restricted mean survival times bootstrapped with 2000 replicates. Results An MACE (49 revascularizations, five myocardial infarctions, one cardiac death, nine hospitalizations for chest pain or congestive heart failure, and one arrhythmia) occurred in 51 of 379 patients (13.5%). The 2-year MACE-free rates for combined CT angiography and CT perfusion findings were 94% negative for coronary artery disease (CAD) versus 82% positive for CAD and were similar to combined ICA and single photon emission CT findings (93% negative for CAD vs 77% positive for CAD, P < .001 for both). Event-free rates for CT angiography and CT perfusion versus ICA and single photon emission CT for either positive or negative results were not

  5. Large lipid-rich coronary plaques detected by near-infrared spectroscopy at non-stented sites in the target artery identify patients likely to experience future major adverse cardiovascular events.

    PubMed

    Madder, Ryan D; Husaini, Mustafa; Davis, Alan T; VanOosterhout, Stacie; Khan, Mohsin; Wohns, David; McNamara, Richard F; Wolschleger, Kevin; Gribar, John; Collins, J Stewart; Jacoby, Mark; Decker, Jeffrey M; Hendricks, Michael; Sum, Stephen T; Madden, Sean; Ware, James H; Muller, James E

    2016-04-01

    A recent study demonstrated that intracoronary near-infrared spectroscopy (NIRS) findings in non-target vessels are associated with major adverse cardiovascular and cerebrovascular events (MACCE). It is unknown whether NIRS findings at non-stented sites in target vessels are similarly associated with future MACCE. This study evaluated the association between large lipid-rich plaques (LRP) detected by NIRS at non-stented sites in a target artery and subsequent MACCE. This study evaluated 121 consecutive registry patients undergoing NIRS imaging in a target artery. After excluding stented segments, target arteries were evaluated for a large LRP, defined as a maximum lipid core burden index in 4 mm (maxLCBI4 mm) ≥400. Excluding events in stented segments, Cox regression analysis was performed to evaluate for an association between a maxLCBI4 mm ≥400 and future MACCE, defined as all-cause mortality, non-fatal acute coronary syndrome, and cerebrovascular events. NIRS detected a maxLCBI4 mm ≥400 in a non-stented segment of the target artery in 17.4% of patients. The only baseline clinical variable marginally associated with MACCE was ejection fraction (HR 0.96, 95% CI 0.93-1.00, P = 0.054). A maxLCBI4 mm ≥400 in a non-stented segment at baseline was significantly associated with MACCE during follow-up (HR 10.2, 95% CI 3.4-30.6, P < 0.001). Detection of large LRP by NIRS at non-stented sites in a target artery was associated with an increased risk of future MACCE. These findings support ongoing prospective studies to further evaluate the ability of NIRS to identify vulnerable patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

  6. Melatonin alleviates postinfarction cardiac remodeling and dysfunction by inhibiting Mst1.

    PubMed

    Hu, Jianqiang; Zhang, Lei; Yang, Yang; Guo, Yanjie; Fan, Yanhong; Zhang, Mingming; Man, Wanrong; Gao, Erhe; Hu, Wei; Reiter, Russel J; Wang, Haichang; Sun, Dongdong

    2017-01-01

    Melatonin reportedly protects against several cardiovascular diseases including ischemia/reperfusion (I/R), atherosclerosis, and hypertension. The present study investigated the effects and mechanisms of melatonin on cardiomyocyte autophagy, apoptosis, and mitochondrial injury in the context of myocardial infarction (MI). We demonstrated that melatonin significantly alleviated cardiac dysfunction after MI. Four weeks after MI, echocardiography and Masson staining indicated that melatonin notably mitigated adverse left ventricle remodeling. The mechanism may be associated with increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin significantly inhibited Mst1 phosphorylation while promoting Sirt1 expression after MI, which indicates that Mst1/Sirt1 signaling may serve as the downstream target of melatonin. We thus constructed a MI model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1(-/-) ) mice. The absence of Mst1 abolished the favorable effects of melatonin on cardiac injury after MI. Consistently, melatonin administration did not further increase autophagy, decrease apoptosis, or alleviate mitochondrial integrity and biogenesis in Mst1 knockout mice subjected to MI injury. These results suggest that melatonin alleviates postinfarction cardiac remodeling and dysfunction by upregulating autophagy, decreasing apoptosis, and modulating mitochondrial integrity and biogenesis. The attributed mechanism involved, at least in part, Mst1/Sirt1 signaling. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Rosiglitazone promotes cardiac hypertrophy and alters chromatin remodeling in isolated cardiomyocytes.

    PubMed

    Pharaon, Lama Fawaz; El-Orabi, Naglaa Fathi; Kunhi, Muhammad; Al Yacoub, Nadya; Awad, Salma Mahmoud; Poizat, Coralie

    2017-10-05

    Rosiglitazone is an anti-diabetic agent that raised a major controversy over its cardiovascular adverse effects. There is in vivo evidence that Rosiglitazone promotes cardiac hypertrophy by PPAR-γ-independent mechanisms. However, whether Rosiglitazone directly alters hypertrophic growth in cardiac cells is unknown. Chromatin remodeling by histone post-translational modifications has emerged as critical for many cardiomyopathies. Based on these observations, this study was initiated to investigate the cardiac hypertrophic effect of Rosiglitazone in a cellular model of primary neonatal rat cardiomyocytes (NRCM). We assessed whether the drug alters cardiac hypertrophy and its relationship with histone H3 phosphorylation. Our study showed that Rosiglitazone is a mild pro-hypertrophic agent. Rosiglitazone caused a significant increase in the release of brain natriuretic peptide (BNP) into the cell media and also increased cardiomyocytes surface area and atrial natriuretic peptide (ANP) protein expression significantly. These changes correlated with increased cardiac phosphorylation of p38 MAPK and enhanced phosphorylation of H3 at serine 10 globally and at one cardiac hypertrophic gene locus. These results demonstrate that Rosiglitazone causes direct cardiac hypertrophy in NRCM and alters H3 phosphorylation status. They suggest a new mechanism of Rosiglitazone cardiotoxicity implicating chromatin remodeling secondary to H3 phosphorylation, which activate the fetal cardiac gene program. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. The Role of Hippo/YAP Signaling in Vascular Remodeling and Related Diseases.

    PubMed

    He, Jinlong; Bao, Qiankun; Yan, Meng; Liang, Jing; Zhu, Yi; Wang, Chunjiong; Ai, Ding

    2017-04-03

    Vascular remodeling is a vital process of a wide range of cardiovascular diseases and represents the altered structure and arrangement of blood vessels. The Hippo pathway controls organ size by regulating cell survival, proliferation and apoptosis. Yes-associated protein (YAP), a transcription coactivator, is a downstream effector of the Hippo pathway. Emerging evidence supports that the Hippo/YAP pathway plays an important role in vascular-remodeling and related cardiovascular diseases. The Hippo/YAP pathway has been shown to alter extracellular matrix production or degradation and the growth, death and migration of vascular smooth muscle cells and endothelial cells, which contributes to vascular remodeling in cardiovascular diseases such as pulmonary hypertension, atherosclerosis, restenosis, aortic aneurysms and angiogenesis. In this review, we summarize and discuss recent findings about the roles and mechanisms of Hippo/YAP signaling in vascular-remodeling and related diseases.

  9. Remodeling the Media Center.

    ERIC Educational Resources Information Center

    Baule, Steven M.

    1998-01-01

    Discusses items that need to be considered when remodeling a school media center. Highlights include space and location for various functions, including projections of print versus electronic media; electrical and data wiring needs; lighting; security and supervision; and reuse of existing furniture and equipment. (LRW)

  10. Inhalation of hydrogen gas attenuates left ventricular remodeling induced by intermittent hypoxia in mice.

    PubMed

    Hayashi, Tetsuya; Yoshioka, Toshitaka; Hasegawa, Kenichi; Miyamura, Masatoshi; Mori, Tatsuhiko; Ukimura, Akira; Matsumura, Yasuo; Ishizaka, Nobukazu

    2011-09-01

    Sleep apnea syndrome increases the risk of cardiovascular morbidity and mortality. We previously reported that intermittent hypoxia increases superoxide production in a manner dependent on nicotinamide adenine dinucleotide phosphate and accelerates adverse left ventricular (LV) remodeling. Recent studies have suggested that hydrogen (H(2)) may have an antioxidant effect by reducing hydroxyl radicals. In this study, we investigated the effects of H(2) gas inhalation on lipid metabolism and LV remodeling induced by intermittent hypoxia in mice. Male C57BL/6J mice (n = 62) were exposed to intermittent hypoxia (repetitive cycle of 1-min periods of 5 and 21% oxygen for 8 h during daytime) for 7 days. H(2) gas (1.3 vol/100 vol) was given either at the time of reoxygenation, during hypoxic conditions, or throughout the experimental period. Mice kept under normoxic conditions served as controls (n = 13). Intermittent hypoxia significantly increased plasma levels of low- and very low-density cholesterol and the amount of 4-hydroxy-2-nonenal-modified protein adducts in the LV myocardium. It also upregulated mRNA expression of tissue necrosis factor-α, interleukin-6, and brain natriuretic peptide, increased production of superoxide, and induced cardiomyocyte hypertrophy, nuclear deformity, mitochondrial degeneration, and interstitial fibrosis. H(2) gas inhalation significantly suppressed these changes induced by intermittent hypoxia. In particular, H(2) gas inhaled at the timing of reoxygenation or throughout the experiment was effective in preventing dyslipidemia and suppressing superoxide production in the LV myocardium. These results suggest that inhalation of H(2) gas was effective for reducing oxidative stress and preventing LV remodeling induced by intermittent hypoxia relevant to sleep apnea.

  11. Effects of CYP2C19 allelic variants on inhibition of platelet aggregation and major adverse cardiovascular events in Japanese patients with acute coronary syndrome: The PRASFIT-ACS study.

    PubMed

    Ogawa, Hisao; Isshiki, Takaaki; Kimura, Takeshi; Yokoi, Hiroyoshi; Nanto, Shinsuke; Takayama, Morimasa; Kitagawa, Kazuo; Nishikawa, Masakatsu; Miyazaki, Shunichi; Ikeda, Yasuo; Nakamura, Masato; Tanaka, Yuko; Saito, Shigeru

    2016-07-01

    We examined the effects of cytochrome P450 2C19 (CYP2C19) polymorphisms on the efficacy and safety of prasugrel and clopidogrel in a post hoc analysis of the PRASugrel compared with clopidogrel For Japanese patIenTs with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) (PRASFIT-ACS) study. Japanese ACS patients undergoing PCI were randomized (double-blind) to receive prasugrel (loading/maintenance dose: 20/3.75mg) or clopidogrel (300/75mg) plus aspirin for 24-48 weeks. Pharmacogenomic analyses were conducted in 773/1363 patients. P2Y12 reaction units (PRU) were determined using the VerifyNow(®) P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotypes were classified as extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). Overall, 39.2% and 60.8% of patients in the prasugrel group and 35.2% and 64.8% of patients in the clopidogrel group were classified as EM and IM+PM, respectively. Among EM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group at 2-4 and 5-12h after the loading dose, but was similar in both groups from week 4 onwards. Among IM+PM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group throughout the study. Among EM patients, the incidence of major adverse cardiovascular events (MACE) at 24 weeks was 11.8% in the prasugrel group and 11.9% in the clopidogrel group [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.50-1.96]. Among IM+PM patients, the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78, 95% CI: 0.45-1.35). The incidences of major, minor, and clinically relevant bleeding were similar between the two groups for each genotype. Prasugrel showed more consistent antiplatelet effects than clopidogrel in Japanese ACS patients irrespective of the CYP2C19 phenotype. Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All

  12. Nucleosome Remodeling and Epigenetics

    PubMed Central

    Becker, Peter B.; Workman, Jerry L.

    2013-01-01

    Eukaryotic chromatin is kept flexible and dynamic to respond to environmental, metabolic, and developmental cues through the action of a family of so-called “nucleosome remodeling” ATPases. Consistent with their helicase ancestry, these enzymes experience conformation changes as they bind and hydrolyze ATP. At the same time they interact with DNA and histones, which alters histone–DNA interactions in target nucleosomes. Their action may lead to complete or partial disassembly of nucleosomes, the exchange of histones for variants, the assembly of nucleosomes, or the movement of histone octamers on DNA. “Remodeling” may render DNA sequences accessible to interacting proteins or, conversely, promote packing into tightly folded structures. Remodeling processes participate in every aspect of genome function. Remodeling activities are commonly integrated with other mechanisms such as histone modifications or RNA metabolism to assemble stable, epigenetic states. PMID:24003213

  13. Is a pre-operative brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement an independent predictor of adverse cardiovascular outcomes within 30 days of noncardiac surgery? A systematic review and meta-analysis of observational studies.

    PubMed

    Karthikeyan, Ganesan; Moncur, Ross A; Levine, Oren; Heels-Ansdell, Diane; Chan, Matthew T V; Alonso-Coello, Pablo; Yusuf, Salim; Sessler, Daniel; Villar, Juan Carlos; Berwanger, Otavio; McQueen, Matthew; Mathew, Anna; Hill, Stephen; Gibson, Simon; Berry, Colin; Yeh, Huei-Ming; Devereaux, P J

    2009-10-20

    We conducted a systematic review and meta-analysis to determine if pre-operative brain natriuretic peptide (BNP) (i.e., BNP or N-terminal pro-B-type natriuretic peptide [NT-proBNP]) is an independent predictor of 30-day adverse cardiovascular outcomes after noncardiac surgery. Pre-operative clinical cardiac risk indices have only modest predictive power. BNP predicts adverse cardiovascular outcomes in a variety of nonsurgical settings and may similarly predict these outcomes in the perioperative setting. We employed 5 search strategies (e.g., searching bibliographic databases), and we included all studies that assessed the independent prognostic value of pre-operative BNP measurement as a predictor of cardiovascular complications after noncardiac surgery. We determined study eligibility and conducted data abstraction independently and in duplicate. We calculated a pooled odds ratio using a random effects model. Nine studies met eligibility criteria, and included a total of 3,281 patients, among whom 314 experienced 1 or more perioperative cardiovascular complications. The average proportion of patients with elevated BNP was 24.8% (95% confidence interval [CI]: 20.1 to 30.4%; I(2) = 89%). All studies showed a statistically significant association between an elevated pre-operative BNP level and various cardiovascular outcomes (e.g., a composite of cardiac death and nonfatal myocardial infarction; atrial fibrillation). Data pooled from 7 studies demonstrated an odds ratio (OR) of 19.3 (95% CI: 8.5 to 43.7; I(2) = 58%). The pre-operative BNP measurement was an independent predictor of perioperative cardiovascular events among studies that only considered the outcomes of death, cardiovascular death, or myocardial infarction (OR: 44.2, 95% CI: 7.6 to 257.0, I(2) = 51.6%), and those that included other outcomes (OR: 14.7, 95% CI: 5.7 to 38.2, I(2) = 62.2%); the p value for interaction was 0.28. These results suggest that an elevated pre-operative BNP or NT

  14. Consequences of Circadian and Sleep Disturbances for the Cardiovascular System.

    PubMed

    Alibhai, Faisal J; Tsimakouridze, Elena V; Reitz, Cristine J; Pyle, W Glen; Martino, Tami A

    2015-07-01

    Circadian rhythms play a crucial role in our cardiovascular system. Importantly, there has been a recent flurry of clinical and experimental studies revealing the profound adverse consequences of disturbing these rhythms on the cardiovascular system. For example, circadian disturbance worsens outcome after myocardial infarction with implications for patients in acute care settings. Moreover, disturbing rhythms exacerbates cardiac remodelling in heart disease models. Also, circadian dyssynchrony is a causal factor in the pathogenesis of heart disease. These discoveries have profound implications for the cardiovascular health of shift workers, individuals with circadian and sleep disorders, or anyone subjected to the 24/7 demands of society. Moreover, these studies give rise to 2 new frontiers for translational research: (1) circadian rhythms and the cardiac sarcomere, which sheds new light on our understanding of myofilament structure, signalling, and electrophysiology; and (2) knowledge translation, which includes biomarker discovery (chronobiomarkers), timing of therapies (chronotherapy), and other new promising approaches to improve the management and treatment of cardiovascular disease. Reconsidering circadian rhythms in the clinical setting benefits repair mechanisms, and offers new promise for patients. Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  15. Role of Arginase in Vessel Wall Remodeling

    PubMed Central

    Durante, William

    2013-01-01

    Arginase metabolizes the semi-essential amino acid l-arginine to l-ornithine and urea. There are two distinct isoforms of arginase, arginase I and II, which are encoded by separate genes and display differences in tissue distribution, subcellular localization, and molecular regulation. Blood vessels express both arginase I and II but their distribution appears to be cell-, vessel-, and species-specific. Both isoforms of arginase are induced by numerous pathologic stimuli and contribute to vascular cell dysfunction and vessel wall remodeling in several diseases. Clinical and experimental studies have documented increases in the expression and/or activity of arginase I or II in blood vessels following arterial injury and in pulmonary and arterial hypertension, aging, and atherosclerosis. Significantly, pharmacological inhibition or genetic ablation of arginase in animals ameliorates abnormalities in vascular cells and normalizes blood vessel architecture and function in all of these pathological states. The detrimental effect of arginase in vascular remodeling is attributable to its ability to stimulate vascular smooth muscle cell and endothelial cell proliferation, and collagen deposition by promoting the synthesis of polyamines and l-proline, respectively. In addition, arginase adversely impacts arterial remodeling by directing macrophages toward an inflammatory phenotype. Moreover, the proliferative, fibrotic, and inflammatory actions of arginase in the vasculature are further amplified by its capacity to inhibit nitric oxide (NO) synthesis by competing with NO synthase for substrate, l-arginine. Pharmacologic or molecular approaches targeting specific isoforms of arginase represent a promising strategy in treating obstructive fibroproliferative vascular disease. PMID:23717309

  16. Prediction of Left Ventricular Remodeling after a Myocardial Infarction: Role of Myocardial Deformation: A Systematic Review and Meta-Analysis

    PubMed Central

    Huttin, Olivier; Coiro, Stefano; Selton-Suty, Christine; Juillière, Yves; Donal, Erwan; Magne, Julien; Sadoul, Nicolas; Zannad, Faiez; Rossignol, Patrick; Girerd, Nicolas

    2016-01-01

    Aims Left ventricular (LV) adverse or reverse remodeling after ST-segment elevation myocardial infarction (MI) is the best outcome to assess the benefit of revascularization. Speckle tracking echocardiography (STE) may accurately identify early deformation impairment, while also being predictive of LV remodeling during follow-up. This systematic analysis aimed to provide a comprehensive review of current findings on STE as a predictor of LV remodeling after MI. Methods PubMed databases were searched through December 2014 to identify studies in adults targeting the association between LV remodeling and STE. Meta-regression was performed for longitudinal analysis. Results A total of 23 prospective studies (3066 patients) were found eligible. Eleven studies reported an association between STE and adverse remodeling and twelve studies with reverse remodeling. Using peak systolic longitudinal strain, the most accurate cut-off to predict adverse remodeling and reverse remodeling ranged from -12.8% to -10.2% and from -13.7% to -9.5%, respectively. In smaller studies, assessment of circumferential strain and torsion showed additive value in predicting remodeling. Meta-regression analysis revealed that longitudinal STE was associated with adverse remodeling (pooled univariable OR = 1.27, 1.17–1.38, p<0.001; pooled multivariable OR = 1.38, 1.13–1.70, p = 0.002) while pooled ORs of longitudinal STE only tended to predict reverse remodeling (pooled OR = 0.75, 0.54–1.06, p = 0.09). Conclusions This systematic review suggests that STE is associated with changes in LV volume or function regardless of underlying mechanisms and deformation direction. Meta-regression demonstrates a strong association between peak longitudinal systolic strain and adverse remodeling. Added STE predictive value over other clinical, biological and imaging variables remains to be proven. PMID:28036335

  17. Chromatin Remodeling and Plant Immunity.

    PubMed

    Chen, W; Zhu, Q; Liu, Y; Zhang, Q

    2017-01-01

    Chromatin remodeling, an important facet of the regulation of gene expression in eukaryotes, is performed by two major types of multisubunit complexes, covalent histone- or DNA-modifying complexes, and ATP-dependent chromosome remodeling complexes. Snf2 family DNA-dependent ATPases constitute the catalytic subunits of ATP-dependent chromosome remodeling complexes, which accounts for energy supply during chromatin remodeling. Increasing evidence indicates a critical role of chromatin remodeling in the establishment of long-lasting, even transgenerational immune memory in plants, which is supported by the findings that DNA methylation, histone deacetylation, and histone methylation can prime the promoters of immune-related genes required for disease defense. So what are the links between Snf2-mediated ATP-dependent chromosome remodeling and plant immunity, and what mechanisms might support its involvement in disease resistance?

  18. Remodeling with the sun

    SciTech Connect

    Bodzin, S.

    1997-05-01

    Remodeling is the perfect time to improve daylighting, direct gain heating and shading with passive solar techniques. It can also provide the best opportunity to add solar water heating or even photoboltaics to a home. This article describes addition of such energy efficient plans to a home in terms of what is needed and what the benefits are: adding windows, North glass, east and west glass, south glass, daylighting, the roof, shingles and roofing tiles, walls and floors, solar hot water, photovoltaics. Two side bars discuss the sunplace: a passive solar room and angles and overhangs.

  19. Dual Endothelin-A/Endothelin-B Receptor Blockade and Cardiac Remodeling in Heart Failure With Preserved Ejection Fraction.

    PubMed

    Valero-Munoz, Maria; Li, Shanpeng; Wilson, Richard M; Boldbaatar, Batbold; Iglarz, Marc; Sam, Flora

    2016-11-01

    Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension. In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF. These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF. © 2016 American Heart Association, Inc.

  20. Dual Endothelin-A/Endothelin-B Receptor Blockade and Cardiac Remodeling in Heart Failure With Preserved Ejection Fraction

    PubMed Central

    Valero-Munoz, Maria; Li, Shanpeng; Wilson, Richard M.; Boldbaatar, Batbold; Iglarz, Marc; Sam, Flora

    2017-01-01

    Background Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension. Methods and Results In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF. Conclusions These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF. PMID:27810862

  1. Cardiovascular damage resulting from chronic excessive endurance exercise.

    PubMed

    Patil, Harshal R; O'Keefe, James H; Lavie, Carl J; Magalski, Anthony; Vogel, Robert A; McCullough, Peter A

    2012-01-01

    A daily routine of physical activity is highly beneficial in the prevention and treatment of many prevalent chronic diseases, especially of the cardiovascular (CV) system. However, chronic, excessive sustained endurance exercise may cause adverse structural remodeling of the heart and large arteries. An evolving body of data indicates that chronically training for and participating in extreme endurance competitions such as marathons, ultra-marathons, Iron-man distance triathlons, very long distance bicycle racing, etc., can cause transient acute volume overload of the atria and right ventricle, with transient reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which generally return to normal within seven to ten days. In veteran extreme endurance athletes, this recurrent myocardial injury and repair may eventually result in patchy myocardial fibrosis, particularly in the atria, interventricular septum and right ventricle, potentially creating a substrate for atrial and ventricular arrhythmias. Furthermore, chronic, excessive, sustained, high-intensity endurance exercise may be associated with diastolic dysfunction, large-artery wall stiffening and coronary artery calcification. Not all veteran extreme endurance athletes develop pathological remodeling, and indeed lifelong exercisers generally have low mortality rates and excellent functional capacity. The aim of this review is to discuss the emerging understanding of the cardiac pathophysiology of extreme endurance exercise, and make suggestions about healthier fitness patterns for promoting optimal CV health and longevity.

  2. Cardiac remodelling and RAS inhibition

    PubMed Central

    Ferrario, Carlos M.

    2016-01-01

    Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin–angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS. PMID:27105891

  3. Caffeine and cardiovascular health.

    PubMed

    Turnbull, Duncan; Rodricks, Joseph V; Mariano, Gregory F; Chowdhury, Farah

    2017-10-01

    This report evaluates the scientific literature on caffeine with respect to potential cardiovascular outcomes, specifically relative risks of total cardiovascular disease (CVD), coronary heart disease (CHD) and acute myocardial infarction (AMI), effects on arrhythmia, heart failure, sudden cardiac arrest, stroke, blood pressure, hypertension, and other biomarkers of effect, including heart rate, cerebral blood flow, cardiac output, plasma homocysteine levels, serum cholesterol levels, electrocardiogram (EKG) parameters, heart rate variability, endothelial/platelet function and plasma/urine catecholamine levels. Caffeine intake has been associated with a range of reversible and transient physiological effects broadly and cardiovascular effects specifically. This report attempts to understand where the delineations exist in caffeine intake and corresponding cardiovascular effects among various subpopulations. The available literature suggests that cardiovascular effects experienced by caffeine consumers at levels up to 600 mg/day are in most cases mild, transient, and reversible, with no lasting adverse effect. The point at which caffeine intake may cause harm to the cardiovascular system is not readily identifiable in part because data on the effects of daily intakes greater than 600 mg is limited. However, the evidence considered within this review suggests that typical moderate caffeine intake is not associated with increased risks of total cardiovascular disease; arrhythmia; heart failure; blood pressure changes among regular coffee drinkers; or hypertension in baseline populations. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Prolonged vasoconstriction of resistance arteries involves vascular smooth muscle actin polymerization leading to inward remodelling

    PubMed Central

    Staiculescu, Marius C.; Galiñanes, Edgar L.; Zhao, Guiling; Ulloa, Uri; Jin, Minshan; Beig, Mirza I.; Meininger, Gerald A.; Martinez-Lemus, Luis A.

    2013-01-01

    Aims Inward remodelling of the resistance vasculature is predictive of hypertension and life-threatening cardiovascular events. We hypothesize that the contractile mechanisms responsible for maintaining a reduced diameter over time in response to prolonged stimulation with vasoconstrictor agonists are in part responsible for the initial stages of the remodelling process. Here we investigated the role of vascular smooth muscle (VSM) actin polymerization on agonist-induced vasoconstriction and development of inward remodelling. Methods and results Experiments were conducted in Sprague–Dawley rat resistance vessels isolated from the cremaster and mesentery. Within blood vessels, actin dynamics of VSM were monitored by confocal microscopy after introduction of fluorescent actin monomers through electroporation and by differential centrifugation to probe globular (G) and filamentous (F) actin content. Results indicated that 4 h of agonist-dependent vasoconstriction induced inward remodelling and caused significant actin polymerization, elevating the F-/total-actin ratio. Inhibition of actin polymerization prevented vessels from maintaining prolonged vasoconstriction and developing inward remodelling. Activation of the small GTPases Rho/Rac/Cdc42 also increased the F-/total-actin ratio and induced inward remodelling, while inhibition of Rho kinase or Rac-1 prevented inward remodelling. Disruption of the actin cytoskeleton reversed the inward remodelling caused by prolonged vasoconstriction, but did not affect the passive diameter of freshly isolated vessels. Conclusion These results indicate that vasoconstriction-induced inward remodelling is in part caused by the polymerization of actin within VSM cells through activation of small GTPases. PMID:23417038

  5. Prolonged vasoconstriction of resistance arteries involves vascular smooth muscle actin polymerization leading to inward remodelling.

    PubMed

    Staiculescu, Marius C; Galiñanes, Edgar L; Zhao, Guiling; Ulloa, Uri; Jin, Minshan; Beig, Mirza I; Meininger, Gerald A; Martinez-Lemus, Luis A

    2013-06-01

    Inward remodelling of the resistance vasculature is predictive of hypertension and life-threatening cardiovascular events. We hypothesize that the contractile mechanisms responsible for maintaining a reduced diameter over time in response to prolonged stimulation with vasoconstrictor agonists are in part responsible for the initial stages of the remodelling process. Here we investigated the role of vascular smooth muscle (VSM) actin polymerization on agonist-induced vasoconstriction and development of inward remodelling. Experiments were conducted in Sprague-Dawley rat resistance vessels isolated from the cremaster and mesentery. Within blood vessels, actin dynamics of VSM were monitored by confocal microscopy after introduction of fluorescent actin monomers through electroporation and by differential centrifugation to probe globular (G) and filamentous (F) actin content. Results indicated that 4 h of agonist-dependent vasoconstriction induced inward remodelling and caused significant actin polymerization, elevating the F-/total-actin ratio. Inhibition of actin polymerization prevented vessels from maintaining prolonged vasoconstriction and developing inward remodelling. Activation of the small GTPases Rho/Rac/Cdc42 also increased the F-/total-actin ratio and induced inward remodelling, while inhibition of Rho kinase or Rac-1 prevented inward remodelling. Disruption of the actin cytoskeleton reversed the inward remodelling caused by prolonged vasoconstriction, but did not affect the passive diameter of freshly isolated vessels. These results indicate that vasoconstriction-induced inward remodelling is in part caused by the polymerization of actin within VSM cells through activation of small GTPases.

  6. Left Ventricular Structure and Risk of Cardiovascular Events: A Framingham Heart Study Cardiac Magnetic Resonance Study.

    PubMed

    Tsao, Connie W; Gona, Philimon N; Salton, Carol J; Chuang, Michael L; Levy, Daniel; Manning, Warren J; O'Donnell, Christopher J

    2015-09-15

    Elevated left ventricular mass index (LVMI) and concentric left ventricular (LV) remodeling are related to adverse cardiovascular disease (CVD) events. The predictive utility of LV concentric remodeling and LV mass in the prediction of CVD events is not well characterized. Framingham Heart Study Offspring Cohort members without prevalent CVD (n=1715, 50% men, aged 65±9 years) underwent cardiovascular magnetic resonance for LVMI and geometry (2002-2006) and were prospectively followed for incident CVD (myocardial infarction, coronary insufficiency, heart failure, stroke) or CVD death. Over 13 808 person-years of follow-up (median 8.4, range 0.0 to 10.5 years), 85 CVD events occurred. In multivariable-adjusted proportional hazards regression models, each 10-g/m(2) increment in LVMI and each 0.1 unit in relative wall thickness was associated with 33% and 59% increased risk for CVD, respectively (P=0.004 and P=0.009, respectively). The association between LV mass/LV end-diastolic volume and incident CVD was borderline significant (P=0.053). Multivariable-adjusted risk reclassification models showed a modest improvement in CVD risk prediction with the incorporation of cardiovascular magnetic resonance LVMI and measures of LV concentricity (C-statistic 0.71 [95% CI 0.65 to 0.78] for the model with traditional risk factors only, improved to 0.74 [95% CI 0.68 to 0.80] for the risk factor model additionally including LVMI and relative wall thickness). Among adults free of prevalent CVD in the community, greater LVMI and LV concentric hypertrophy are associated with a marked increase in adverse incident CVD events. The potential benefit of aggressive primary prevention to modify LV mass and geometry in these adults requires further investigation. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  7. Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

    PubMed Central

    Shi, Mingjun; Cho, Han Jun; Adams-Huet, Beverley; Paek, Jean; Hill, Kathy; Shelton, John; Amaral, Ansel P.; Faul, Christian; Taniguchi, Masatomo; Wolf, Myles; Brand, Markus; Takahashi, Masaya; Kuro-o, Makoto; Hill, Joseph A.

    2015-01-01

    Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiency—genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor–23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-β1–, angiotensin II–, or high phosphate–induced fibrosis and abolished TGF-β1– or angiotensin II–induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor–23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging. PMID:25326585

  8. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling.

    PubMed

    Hu, Ming Chang; Shi, Mingjun; Cho, Han Jun; Adams-Huet, Beverley; Paek, Jean; Hill, Kathy; Shelton, John; Amaral, Ansel P; Faul, Christian; Taniguchi, Masatomo; Wolf, Myles; Brand, Markus; Takahashi, Masaya; Kuro-O, Makoto; Hill, Joseph A; Moe, Orson W

    2015-06-01

    Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiency-genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-β1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-β1- or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging. Copyright © 2015 by the American Society of Nephrology.

  9. Effects of Obstructive Sleep Apnea and Obesity on Cardiac Remodeling: The Wisconsin Sleep Cohort Study

    PubMed Central

    Korcarz, Claudia E.; Peppard, Paul E.; Young, Terry B.; Chapman, Carrie B.; Hla, K. Mae; Barnet, Jodi H.; Hagen, Erika; Stein, James H.

    2016-01-01

    Study Objectives: To characterize the prospective associations of obstructive sleep apnea (OSA) with future echocardiographic measures of adverse cardiac remodeling Methods: This was a prospective long-term observational study. Participants had overnight polysomnography followed by transthoracic echocardiography a mean (standard deviation) of 18.0 (3.7) y later. OSA was characterized by the apnea-hypopnea index (AHI, events/hour). Echocardiography was used to assess left ventricular (LV) systolic and diastolic function and mass, left atrial volume and pressure, cardiac output, systemic vascular resistance, and right ventricular (RV) systolic function, size, and hemodynamics. Multivariate regression models estimated associations between log10(AHI+1) and future echocardiographic findings. A secondary analysis looked at oxygen desaturation indices and future echocardiographic findings. Results: At entry, the 601 participants were mean (standard deviation) 47 (8) y old (47% female). After adjustment for age, sex, and body mass index, baseline log10(AHI+1) was associated significantly with future reduced LV ejection fraction and tricuspid annular plane systolic excursion (TAPSE) ≤ 15 mm. After further adjustment for cardiovascular risk factors, participants with higher baseline log10(AHI+1) had lower future LV ejection fraction (β = −1.35 [standard error = 0.6]/log10(AHI+1), P = 0.03) and higher odds of TAPSE ≤ 15 mm (odds ratio = 6.3/log10(AHI+1), 95% confidence interval = 1.3–30.5, P = 0.02). SaO2 desaturation indices were associated independently with LV mass, LV wall thickness, and RV area (all P < 0.03) Conclusions: OSA is associated independently with decreasing LV systolic function and with reduced RV function. Echocardiographic measures of adverse cardiac remodeling are strongly associated with OSA but are confounded by obesity. Hypoxia may be a stimulus for hypertrophy in individuals with OSA. Citation: Korcarz CE, Peppard PE, Young TB, Chapman CB, Hla

  10. To Remodel or To Build?

    ERIC Educational Resources Information Center

    Rosenblum, Todd

    2009-01-01

    The question of remodeling an existing house to make it wheelchair accessible or building a new barrier-free house is a difficult decision. This article presents some initial questions and considerations followed by a list of pros and cons for remodeling an existing house vs. building a new house.

  11. To Remodel or To Build?

    ERIC Educational Resources Information Center

    Rosenblum, Todd

    2009-01-01

    The question of remodeling an existing house to make it wheelchair accessible or building a new barrier-free house is a difficult decision. This article presents some initial questions and considerations followed by a list of pros and cons for remodeling an existing house vs. building a new house.

  12. No-Regrets Remodeling, 2nd Edition

    SciTech Connect

    2013-12-01

    No-Regrets Remodeling, sponsored by Oak Ridge National Laboratory, is an informative publication that walks homeowners and/or remodelers through various home remodeling projects. In addition to remodeling information, the publication provides instruction on how to incorporate energy efficiency into the remodeling process. The goal of the publication is to improve homeowner satisfaction after completing a remodeling project and to provide the homeowner with a home that saves energy and is comfortable and healthy.

  13. CARDIOVASCULAR EFFECTS OF ULTRAFINE CARBON PARTICLES IN HYPERTENSIVE RATS (SHR)

    EPA Science Inventory

    Rationale: Epidemiological evidence suggests that ultrafine particles are associated with adverse cardiovascular effects, specifically in elderly individuals with preexisting cardiovascular disease. The objective of this study was (i) to assess cardiopulmonary responses in adult ...

  14. CARDIOVASCULAR EFFECTS OF ULTRAFINE CARBON PARTICLES IN HYPERTENSIVE RATS (SHR)

    EPA Science Inventory

    Rationale: Epidemiological evidence suggests that ultrafine particles are associated with adverse cardiovascular effects, specifically in elderly individuals with preexisting cardiovascular disease. The objective of this study was (i) to assess cardiopulmonary responses in adult ...

  15. Adverse effects of cannabis.

    PubMed

    2011-01-01

    establish a causal relationship in either direction, because of these methodological limitations. In Australia, the marked increase in cannabis use has not been accompanied by an increased incidence of schizophrenia. On the basis of the available data, we cannot reach firm conclusions on whether or not cannabis use causes psychosis. It seems prudent to inform apparently vulnerable individuals that cannabis may cause acute psychotic decompensation, especially at high doses. Users can feel dependent on cannabis, but this dependence is usually psychological. Withdrawal symptoms tend to occur within 48 hours following cessation of regular cannabis use, and include increased irritability, anxiety, nervousness, restlessness, sleep difficulties and aggression. Symptoms subside within 2 to 12 weeks. Driving under the influence of cannabis doubles the risk of causing a fatal road accident. Alcohol consumption plays an even greater role. A few studies and a number of isolated reports suggest that cannabis has a role in the occurrence of cardiovascular adverse effects, especially in patients with coronary heart disease. Numerous case-control studies have investigated the role of cannabis in the incidence of some types of cancer. Its role has not been ruled out, but it is not possible to determine whether the risk is distinct from that of the tobacco with which it is often smoked. Studies that have examined the influence of cannabis use on the clinical course of hepatitis C are inconclusive. Alcohol remains the main toxic agent that hepatitis C patients should avoid. In practice, the adverse effects of low-level, recreational cannabis use are generally minor, although they can apparently be serious in vulnerable individuals. The adverse effects of cannabis appear overall to be less serious than those of alcohol, in terms of neuropsychological and somatic effects, accidents and violence.

  16. Ghrelin and the cardiovascular system.

    PubMed

    Tokudome, Takeshi; Kishimoto, Ichiro; Miyazato, Mikiya; Kangawa, Kenj

    2014-01-01

    Ghrelin is a peptide that was originally isolated from the stomach. It exerts potent growth hormone (GH)-releasing and orexigenic activities. Several studies have highlighted the therapeutic benefits of ghrelin for the treatment of cardiovascular disease. In animal models of chronic heart failure, the administration of ghrelin improved cardiac function and remodeling; these findings were replicated in human patients with heart failure. Moreover, in an animal study, ghrelin administration effectively reduced pulmonary hypertension induced by chronic hypoxia. In addition, repeated administration of ghrelin to cachectic patients with chronic obstructive pulmonary disease had positive effects on overall body function, including muscle wasting, functional capacity and sympathetic activity. The administration of ghrelin early after myocardial infarction (MI) reduced fatal arrhythmia and related mortality. In ghrelin-deficient mice, both exogenous and endogenous ghrelin were protective against fatal arrhythmia and promoted remodeling after MI. Although the mechanisms underlying the effects of ghrelin on the cardiovascular system remain unclear, there are indications that its beneficial effects are mediated through both direct physiological actions, including increased GH levels, improved energy balance and direct actions on cardiovascular cells, and regulation of autonomic nervous system activity. Therefore, ghrelin is a promising novel therapeutic agent for cardiovascular disease.

  17. Thyroid hormones and cardiovascular disease.

    PubMed

    Jabbar, Avais; Pingitore, Alessandro; Pearce, Simon H S; Zaman, Azfar; Iervasi, Giorgio; Razvi, Salman

    2017-01-01

    Myocardial and vascular endothelial tissues have receptors for thyroid hormones and are sensitive to changes in the concentrations of circulating thyroid hormones. The importance of thyroid hormones in maintaining cardiovascular homeostasis can be deduced from clinical and experimental data showing that even subtle changes in thyroid hormone concentrations - such as those observed in subclinical hypothyroidism or hyperthyroidism, and low triiodothyronine syndrome - adversely influence the cardiovascular system. Some potential mechanisms linking the two conditions are dyslipidaemia, endothelial dysfunction, blood pressure changes, and direct effects of thyroid hormones on the myocardium. Several interventional trials showed that treatment of subclinical thyroid diseases improves cardiovascular risk factors, which implies potential benefits for reducing cardiovascular events. Over the past 2 decades, accumulating evidence supports the association between abnormal thyroid function at the time of an acute myocardial infarction (MI) and subsequent adverse cardiovascular outcomes. Furthermore, experimental studies showed that thyroid hormones can have an important therapeutic role in reducing infarct size and improving myocardial function after acute MI. In this Review, we summarize the literature on thyroid function in cardiovascular diseases, both as a risk factor as well as in the setting of cardiovascular diseases such as heart failure or acute MI, and outline the effect of thyroid hormone replacement therapy for reducing the risk of cardiovascular disease.

  18. Advances in stem cell therapy for cardiovascular disease (Review)

    PubMed Central

    SUN, RONGRONG; LI, XIANCHI; LIU, MIN; ZENG, YI; CHEN, SHUANG; ZHANG, PEYING

    2016-01-01

    Cardiovascular disease constitutes the primary cause of mortality and morbidity worldwide, and represents a group of disorders associated with the loss of cardiac function. Despite considerable advances in the understanding of the pathologic mechanisms of the disease, the majority of the currently available therapies remain at best palliative, since the problem of cardiac tissue loss has not yet been addressed. Indeed, few therapeutic approaches offer direct tissue repair and regeneration, whereas the majority of treatment options aim to limit scar formation and adverse remodeling, while improving myocardial function. Of all the existing therapeutic approaches, the problem of cardiac tissue loss is addressed uniquely by heart transplantation. Nevertheless, alternative options, particularly stem cell therapy, has emerged as a novel and promising approach. This approach involves the transplantation of healthy and functional cells to promote the renewal of damaged cells and repair injured tissue. Bone marrow precursor cells were the first cell type used in clinical studies, and subsequently, preclinical and clinical investigations have been extended to the use of various populations of stem cells. This review addresses the present state of research as regards stem cell therapy for cardiovascular disease. PMID:27220939

  19. Cystatin C: an emerging biomarker in cardiovascular disease.

    PubMed

    Angelidis, Christos; Deftereos, Spyridon; Giannopoulos, Georgios; Anatoliotakis, Nikolaos; Bouras, Georgios; Hatzis, Georgios; Panagopoulou, Vasiliki; Pyrgakis, Vlasios; Cleman, Michael W

    2013-01-01

    Cystatin C (cys-C) is a small protein molecule (120 amino acid peptide chain, approximately 13kDa) produced by virtually all nucleated cells in the human body. It belongs to the family of papain-like cysteine proteases and its main biological role is the extracellular inhibition of cathepsins. It's near constant production rate, the fact that it is freely filtered from the glomerular membrane and then completely reabsorbed without being secreted from the proximal tubular cells, made it an almost perfect candidate for estimating renal function. The strong correlation between chronic kidney disease (CKD) and cardiovascular disease (CVD) along with the growing understanding of the role of cysteinyl cathepsins in the pathophysiology of CVD inspired researchers to explore the potential association of cys-C with CVD. Throughout the spectrum of CVD (peripheral arterial disease, stroke, abdominal aortic aneurysm, heart failure, coronary artery disease) adverse outcomes and risk stratification have been associated with high plasma levels of cys-C. The exact mechanisms behind the observed correlations have not been comprehensively clarified. Plausible links between high cys-C levels and poor cardiovascular outcome could be impaired renal function, atherogenesis and inflammatory mediators, remodeling of myocardial tissue and others (genetic factors, aging and social habits). The scope of the present article is to systematically review the current knowledge about cys-C biochemistry, metabolism, methods of detection and quantification and pathophysiological associations with different aspects of CVD.

  20. Psoriasis and Cardiovascular Disease.

    PubMed

    Shahwan, Kathryn T; Kimball, Alexa B

    2015-11-01

    Psoriasis is a systemic inflammatory disease that confers significant risk of metabolic derangements and adverse cardiovascular outcomes. Early detection and treatment of modifiable risk factors and modulation of the systemic inflammatory response are important treatment goals. Studies have shown that there is a significant lack of awareness of the relationship between psoriasis and cardiovascular disease, so future considerations should focus on education of and collaboration with health care providers, especially those in primary care, and development of updated, rigorous screening guidelines. In addition, targeted biologic therapies such as TNF-a inhibitors have shown immense promise in targeting the systemic inflammation associated with psoriatic disease, but whether they will impact long-term cardiovascular outcomes remains to be seen. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Obesity and carotid artery remodeling

    PubMed Central

    Kozakova, M; Palombo, C; Morizzo, C; Højlund, K; Hatunic, M; Balkau, B; Nilsson, P M; Ferrannini, E

    2015-01-01

    Background/Objective: The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions characterized by body size-dependent increase in stroke volume (SV) and blood pressure (BP). Subjects/Methods: Common carotid artery (CCA) luminal diameter (LD), IMT and CWS were measured in three different populations in order to study: (A) cross-sectional associations between SV, BP, anthropometric parameters and CCA LD (266 healthy subjects with wide range of body weight (24–159 kg)); (B) longitudinal associations between CCA LD and 3-year IMT progression rate (ΔIMT; 571 healthy non-obese subjects without increased cardiovascular (CV) risk); (C) the impact of obesity on CCA geometry and CWS (88 obese subjects without CV complications and 88 non-obese subjects matched for gender and age). Results: CCA LD was independently associated with SV that was determined by body size. In the longitudinal study, baseline LD was an independent determinant of ΔIMT, and ΔIMT of subjects in the highest LD quartile was significantly higher (28±3 μm) as compared with those in the lower quartiles (8±3, 16±4 and 16±3 μm, P=0.001, P<0.05 and P=0.01, respectively). In addition, CCA CWS decreased during the observational period in the highest LD quartile (from 54.2±8.6 to 51.6±7.4 kPa, P<0.0001). As compared with gender- and age-matched lean individuals, obese subjects had highly increased CCA LD and BP (P<0.0001 for both), but only slightly higher CWS (P=0.05) due to a significant increase in IMT (P=0.005 after adjustment for confounders). Conclusions: Our findings suggest that in obese subjects, the CCA wall thickens to compensate the luminal enlargement caused by body size-induced increase in SV, and therefore, to normalize the wall stress. CCA diameter in obesity could

  2. Understanding the chromatin remodeling code.

    PubMed

    Ha, Misook

    2013-10-01

    Remodeling a chromatin structure enables the genetic elements stored in a genome to function in a condition-specific manner and predisposes the interactions between cis-regulatory elements and trans-acting factors. A chromatin signature can be an indicator of the activity of the underlying genetic elements. This paper reviews recent studies showing that the combination and arrangements of chromatin remodeling marks play roles as chromatin code affecting the activity of genetic elements. This paper also reviews recent studies inferring the primary DNA sequence contexts associated with chromatin remodeling that suggest interactions between genetic and epigenetic factors. We conclude that chromatin remodeling, which provides accurate models of gene expression and morphological variations, may help to find the biological marks that cannot be detected by genome-wide association study or genetic study. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  3. Remodeling and Repair in Rhinosinusitis.

    PubMed

    Watelet, Jean-Baptiste; Dogne, Jean-Michel; Mullier, François

    2015-06-01

    Remodeling refers to the development of specific but potentially irreversible structural changes in tissue. Caucasian eosinophilic chronic rhinosinusitis (CRS) with polyps associated or not with cystic fibrosis was discriminated by edema from CRS without nasal polyps, characterized by extensive fibrotic fields. However, changes in epithelial and extracellular matrix structures are common findings in all types of chronic inflammatory diseases of upper airways, but rarely specific and highly variable in extend. Recent studies have shown that remodeling in CRS appears to occur in parallel, rather than purely subsequent to inflammation. Furthermore, some preferential remodeling associations can be recognized. Tremendous efforts have been put in research on coagulation factors, cytokines, growth factors, and proteases supporting all phases of upper airway remodeling. The current exploration of other CRS sub-groups and of the particular link with concomitant asthma aims to optimize the classification of CRS and its staging modes and to develop novel therapies.

  4. Building and Remodeling Synapses

    PubMed Central

    Benson, Deanna L.; Huntley, George W.

    2011-01-01

    Synaptic junctions are generated by adhesion proteins that bridge the synaptic cleft to firmly anchor pre- and postsynaptic membranes. Several cell adhesion molecule (CAM) families localize to synapses, but it is not yet completely understood how each synaptic CAM family contributes to synapse formation and/or structure, and whether or how smaller groups of CAMs serve as minimal, functionally cooperative adhesive units upon which structure is based. Synapse structure and function evolve over the course of development, and in mature animals, synapses are composed of a greater number of proteins, surrounded by a stabilizing extracellular matrix, and often contacted by astrocytic processes. Thus, in mature networks undergoing plasticity, persistent changes in synapse strength, morphology or number must be accompanied by selective and regulated remodeling of the neuropil. Recent work indicates that regulated, extracellular proteolysis may be essential for this, and rather than simply acting permissively to enable synapse plasticity, is more likely playing a proactive role in driving coordinated synaptic structural and functional modifications that underlie persistent changes in network activity. PMID:20882551

  5. Cardiovascular Health Status and Incidence of Heart Failure in the Framingham Offspring Study

    PubMed Central

    Nayor, Matthew; Enserro, Danielle M.; Vasan, Ramachandran S.; Xanthakis, Vanessa

    2015-01-01

    Background The American Heart Association Cardiovascular Health (CVH) score is inversely associated with cardiovascular disease, but its relations to cardiac remodeling traits and to heart failure (HF) incidence have not been examined. Methods and Results A 14-point score was constructed for each participant based on the presence of poor, intermediate or ideal status on each of the 7 CVH metrics (ideal score=14). We related the CVH score to echocardiographic traits cross-sectionally, and to HF incidence prospectively in the Framingham Offspring Study. In age- and sex-adjusted models, a higher CVH score was associated with lower left ventricular (LV) mass, LV wall thickness, LV diastolic dimension, and left atrial dimension (p<0.01 for all; N=2392, mean age 58 years, 56% women), and with a 12-15% lower odds of prevalent LV concentric remodeling and concentric hypertrophy, respectively (p<0.0001 for both). On follow-up (mean 12.3 years), 188 incident HF events were observed in 3201 participants (mean age 59 years, 53% women). In age- and sex-adjusted Cox proportional hazards models, the CVH score was inversely associated with HF incidence (hazards ratio [HR] per 1-point higher CVH score 0.77, 95% CI 0.72-0.83). This association was partially attenuated upon adjustment for LV mass and interim myocardial infarction (HR 0.84, 95% CI 0.76-0.93) and was consistent for HF with preserved and reduced ejection fractions. Conclusions In our community-based sample, comprised predominantly of middle-aged white individuals of European descent, better CVH was associated with lower HF incidence, in part due to a lower prevalence of adverse cardiac remodeling. PMID:26699391

  6. Role of microRNAs in Vascular Remodeling

    PubMed Central

    Fang, Y.-C.; Yeh, C.-H.

    2015-01-01

    Besides being involved in the gradual formation of blood vessels during embryonic development, vascular remodeling also contributes to the progression of various cardiovascular diseases, such as; myocardial infarction, heart failure, atherosclerosis, pulmonary artery hypertension, restenosis, aneurysm, etc. The integrated mechanisms; proliferation of medial smooth muscle cell, dysregulation of intimal endothelial cell, activation of adventitial fibroblast, inflammation of macrophage, and the participation of extracellular matrix proteins are important factors in vascular remodeling. In the recent studies, microRNAs (miRs) have been shown to be expressed in all of these cell-types and play important roles in the mechanisms of vascular remodeling. Therefore, some miRs may be involved in prevention and others in the aggravation of the vascular lesions. miRs are small, endogenous, conserved, single-stranded, non-coding RNAs; which degrade target RNAs or inhibit translation post-transcriptionally. In this paper, we reviewed the function and mechanisms of miRs, which are highly expressed in various cells types, especially endothelial and smooth muscle cells, which are closely involved in the process of vascular remodeling. We also assess the functions of these miRs in the hope that they may provide new possibilities of diagnosis and treatment choices for the related diseases. PMID:26391551

  7. Adverse effects of statins - myths and reality.

    PubMed

    Šimić, Iveta; Reiner, Željko

    2015-01-01

    Statins reduce cardiovascular mortality and morbidity as well as cardiovascular events in patients with a very high risk of cardiovascular disease (CVD) and also in subjects with high or moderate risk by reducing the levels of low-density lipoprotein cholesterol (LDL-C). Although they are considered to be drugs with a very good safety profile, because of their wide use there are many concerns that their adverse effects might compromise their proven beneficial effects. Therefore this article reviews all the data and provides an evidence- based insight what are the proven adverse effects of statins and what are the "myths" about them. The most important side effects include myopathy and rhabdomyolysis. Another side effect is increased activity of liver tests which occurs occasionally and is reversible. However, recent studies even suggest that statin therapy can improve hepatic steatosis. It is beyond any doubt that statins do slightly increase the incidence of type 2 diabetes mellitus in people with two or more components of metabolic syndrome but the cardiovascular benefits of such a treatment by far exceed this risk. Statin therapy has also been associated with some adverse renal effects, eg. acute renal failure, but recent data suggest even a possible protective effect of these drugs on renal dysfunction. Concerns that statins might increase cancer have not been proven. On the contrary, several studies have indicated a possible benefit of these drugs in patients with different types of cancer. Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven and most recent data even suggest a possible beneficial effect of statins in the prevention of dementia. Systematic reviews and clinical guidelines suggest that the cardiovascular benefits of statins by far out-weight non-cardiovascular harms in patients with cardiovascular risk.

  8. MYOCARDIAL REMODELING IN LOW-RENIN HYPERTENSION. MOLECULAR PATHWAYS TO CELLULAR INJURY IN RELATIVE ALDOSTERONISM

    PubMed Central

    Bhattacharya, Syamal K.; Gandhi, Malay S.; Kamalov, German; Ahokas, Robert A.; Sun, Yao; Gerling, Ivan C.; Weber, Karl T.

    2010-01-01

    The pathologic hypertrophy of hypertensive heart disease is related to the quality not quantity of myocardium; the presence of fibrosis is inevitably linked to structural and functional insufficiencies with increased cardiovascular risk. Inappropriate (relative to dietary Na+) elevations in plasma aldosterone, or relative aldosteronism, are accompanied by suppressed plasma renin activity, elevation in arterial pressure, and dyshomeostasis of divalent cations. The accompanying hypocalcemia, hypomagnesemia, and hypozincemia of aldosteronism contribute to the appearance of secondary hyperparathyroidism. Parathyroid hormone-mediated intracellular Ca2+ overloading of cardiac myocytes and mitochondria leads to the induction of oxidative stress and molecular pathways associated with cardiomyocyte necrosis and scarring of myocardium, while the dyshomeostasis of Zn2+ compromises antioxidant defenses. This dyshomeostasis of Ca2+ and Zn2+ is intrinsically coupled as pro- and antioxidant, respectively, raising the prospect for therapeutic strategies designed to mitigate intracellular Ca2+ overloading while enhancing Zn2+-mediated antioxidant defenses, thus preventing adverse myocardial remodeling with fibrosis, associated diastolic dysfunction, and cardiac arrhythmias. PMID:19895752

  9. Relationship between self-reported residential indoor remodeling and semen quality: a case-control study.

    PubMed

    Miao, Mao-Hua; Li, Zheng; Li, De-Kun; Yan, Bei; Liang, Hong; Zhi, Er-Lei; Du, Hong-Wei; Yuan, Wei

    2015-01-01

    The present study examined the association between residential indoor remodeling and poor semen quality. Sperm donors aged 18-45 years old were recruited in Shanghai, China. Semen specimens were collected and analyzed. An in-person interview was conducted to obtain information on the history of indoor remodeling and potential confounders. A total of 70 participants with abnormal semen quality (case group) and 68 controls were examined. A total of 20 subjects reported indoor remodeling in the recent 24 months, and among them 17 subjects reported indoor remodeling in the recent 12 months. Compared with participants with no history of indoor remodeling, participants with a history of indoor remodeling in the recent 24 months were more than three times as likely to have poor sperm quality (adjusted odds ratio = 3.8, 95% confidence interval: 1.3-12.0) after controlling for potential confounders. The association was strengthened when the analysis was restricted to those who had indoor remodeling in the recent 12 months. Our findings provide preliminary evidence that indoor remodeling has an adverse effect on semen quality.

  10. Cardiovascular Deconditioning

    NASA Technical Reports Server (NTRS)

    Charles, John B.; Fritsch-Yelle, Janice M.; Whitson, Peggy A.; Wood, Margie L.; Brown, Troy E.; Fortner, G. William

    1999-01-01

    Spaceflight causes adaptive changes in cardiovascular function that may deleteriously affect crew health and safety. Over the last three decades, symptoms of cardiovascular changes have ranged from postflight orthostatic tachycardia and decreased exercise capacity to serious cardiac rhythm disturbances during extravehicular activities (EVA). The most documented symptom of cardiovascular dysfunction, postflight orthostatic intolerance, has affected a significant percentage of U.S. Space Shuttle astronauts. Problems of cardiovascular dysfunction associated with spaceflight are a concern to NASA. This has been particularly true during Shuttle flights where the primary concern is the crew's physical health, including the pilot's ability to land the Orbiter, and the crew's ability to quickly egress and move to safety should a dangerous condition arise. The study of astronauts during Shuttle activities is inherently more difficult than most human research. Consequently, sample sizes have been small and results have lacked consistency. Before the Extended Duration Orbiter Medical Project (EDOMP), there was a lack of normative data on changes in cardiovascular parameters during and after spaceflight. The EDOMP for the first time allowed studies on a large enough number of subjects to overcome some of these problems. There were three primary goals of the Cardiovascular EDOMP studies. The first was to establish, through descriptive studies, a normative data base of cardiovascular changes attributable to spaceflight. The second goal was to determine mechanisms of cardiovascular changes resulting from spaceflight (particularly orthostatic hypotension and cardiac rhythm disturbances). The third was to evaluate possible countermeasures. The Cardiovascular EDOMP studies involved parallel descriptive, mechanistic, and countermeasure evaluations.

  11. Compensatory Effect between Aortic Stiffening and Remodelling during Ageing

    PubMed Central

    Guala, Andrea; Camporeale, Carlo; Ridolfi, Luca

    2015-01-01

    The arterial tree exhibits a complex spatio-temporal wave pattern, whose healthy behaviour depends on a subtle balance between mechanical and geometrical properties. Several clinical studies demonstrated that such a balance progressively breaks down during ageing, when the aorta stiffens and remodels by increasing its diameter. These two degenerative processes however, have different impacts on the arterial wave pattern. They both tend to compensate for each other, thus reducing the detrimental effect they would have had if they had arisen individually. This remarkable compensatory mechanism is investigated by a validated multi-scale model, with the aim to elucidate how aortic stiffening and remodelling quantitatively impact the complex interplay between forward and reflected backward waves in the arterial network. We focus on the aorta and on the pressure at the ventricular-aortic interface, which epidemiological studies demonstrate to play a key role in cardiovascular diseases. PMID:26426360

  12. [Cardiac remodeling after myocardial infarction : Clinical practice update].

    PubMed

    Ertl, G; Brenner, S; Angermann, C E

    2017-02-01

    Heart failure remains a frequent cause of death and is the leading reason for hospitalization in Germany although therapeutic options have significantly increased over the past years particularly in heart failure with reduced ejection fraction. Clinical symptoms are usually preceded by cardiac remodeling, which was originally defined only by left ventricular dilatation and depressed function but is also associated with typical cellular and molecular processes. Healing after acute myocardial infarction is characterized by inflammation, cellular migration and scar formation. Cardiac remodeling is accompanied by adaptive changes of the peripheral cardiovascular system. Since prevention is the primary goal, rapid diagnosis and treatment of myocardial infarction are mandatory. Early reperfusion therapy limits infarct size and enables the best possible preservation of left ventricular function. Standard pharmacotherapy includes angiotensin-converting enzyme inhibitors, angiotensin-1-receptor blockers and beta blockers. In addition, mineralocorticoid receptor antagonists have proven beneficial. Compounds specifically targeting infarct healing processes are currently under development.

  13. Development of Extracorporeal Shock Wave Therapy for the Treatment for Ischemic Cardiovascular Diseases

    NASA Astrophysics Data System (ADS)

    Shimokawa, Hiroaki

    Cardiovascular diseases, such as coronary artery disease and peripheral artery disease, are the major causes of death in developed countries, and the number of elderly patients has been rapidly increasing worldwide. Thus, it is crucial to develop new non-invasive therapeutic strategies for these patients. We found that a low-energy shock wave (SW) (about 10% of the energy density that is used for urolithiasis) effectively increases the expression of vascular endothelial growth factor (VEGF) in cultured endothelial cells. Subsequently, we demonstrated that extracorporeal cardiac SW therapy with low-energy SW up-regulates the expression of VEGF, enhances angiogenesis, and improves myocardial ischemia in a pig model of chronic myocardial ischemia without any adverse effects in vivo. Based on these promising results in animal studies, we have subsequently developed a new, non-invasive angiogenic therapy with low-energy SW for cardiovascular diseases. Our extracorporeal cardiac SW therapy improved symptoms and myocardial perfusion evaluated with stress-scintigraphy in patients with severe coronary artery disease without indication of percutaneous coronary intervention or coronary artery bypass surgery. Importantly, no procedural complications or adverse effects were noted. The SW therapy was also effective in ameliorating left ventricular remodeling after acute myocardial infarction in pigs and in enhancing angiogenesis in hindlimb ischemia in animals and patients with coronary artery disease. Furthermore, our recent experimental studies suggest that the SW therapy is also effective for indications other than cardiovascular diseases. Thus, our extracorporeal cardiac SW therapy is an effective, safe, and non-invasive angiogenic strategy for cardiovascular medicine.

  14. Cardiovascular and other effects of salt consumption

    PubMed Central

    Cappuccio, Francesco P

    2013-01-01

    Salt is one of the most important determinants of high blood pressure and increased cardiovascular risk worldwide. However, a high salt intake has other adverse effects beyond those involving the cardiovascular system, so that there is renewed interest in the relationships between high salt intake and other diseases. PMID:25019010

  15. Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes

    PubMed Central

    Tate, Mitchel; Chong, Aaron; Robinson, Emma; Green, Brian D; Grieve, David J

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the CVS where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting is limited, although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1-based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes. PMID:25231355

  16. Stress and atherosclerotic cardiovascular disease.

    PubMed

    Inoue, Nobutaka

    2014-01-01

    Recent major advances in medical science have introduced a wide variety of treatments against atherosclerosis-based cardiovascular diseases, which has led to a significant reduction in mortality associated with these diseases. However, atherosclerosis-based cardiovascular disease remains a leading cause of death. Furthermore, progress in medical science has demonstrated the pathogenesis of cardiovascular disease to be complicated, with a wide variety of underlying factors. Among these factors, stress is thought to be pivotal. Several types of stress are involved in the development of cardiovascular disease, including oxidative stress, mental stress, hemodynamic stress and social stress. Accumulating evidence indicates that traditional risk factors for atherosclerosis, including diabetes, hyperlipidemia, hypertension and smoking, induce oxidative stress in the vasculature. Oxidative stress is implicated in the pathogenesis of endothelial dysfunction, atherogenesis, hypertension and remodeling of blood vessels. Meanwhile, mental stress is a well-known major contributor to the development of cardiovascular disease. The cardiovascular system is constantly exposed to hemodynamic stress by the blood flow and/or pulsation, and hemodynamic stress exerts profound effects on the biology of vascular cells and cardiomyocytes. In addition, social stress, such as that due to a lack of social support, poverty or living alone, has a negative impact on the incidence of cardiovascular disease. Furthermore, there are interactions between mental, oxidative and hemodynamic stress. The production of reactive oxygen species is increased under high levels of mental stress in close association with oxidative stress. These stress responses and their interactions play central roles in the pathogenesis of atherosclerosis-based cardiovascular disease. Accordingly, the pathophysiological and clinical implications of stress are discussed in this article.

  17. Metabolic remodeling in hypertrophied and failing myocardium: a review.

    PubMed

    Peterzan, Mark A; Lygate, Craig A; Neubauer, Stefan; Rider, Oliver J

    2017-09-01

    The energy starvation hypothesis proposes that maladaptive metabolic remodeling antedates, initiates, and maintains adverse contractile dysfunction in heart failure (HF). Better understanding of the cardiac metabolic phenotype and metabolic signaling could help identify the role metabolic remodeling plays within HF and the conditions known to transition toward HF, including "pathological" hypertrophy. In this review, we discuss metabolic phenotype and metabolic signaling in the contexts of pathological hypertrophy and HF. We discuss the significance of alterations in energy supply (substrate utilization, oxidative capacity, and phosphotransfer) and energy sensing using observations from human and animal disease models and models of manipulated energy supply/sensing. We aim to provide ways of thinking about metabolic remodeling that center around metabolic flexibility, capacity (reserve), and efficiency rather than around particular substrate preferences or transcriptomic profiles. We show that maladaptive metabolic remodeling takes multiple forms across multiple energy-handling domains. We suggest that lack of metabolic flexibility and reserve (substrate, oxidative, and phosphotransfer) represents a final common denominator ultimately compromising efficiency and contractile reserve in stressful contexts. Copyright © 2017 the American Physiological Society.

  18. Myocardial Tissue Remodeling in Adolescent Obesity

    PubMed Central

    Shah, Ravi V.; Abbasi, Siddique A.; Neilan, Tomas G.; Hulten, Edward; Coelho‐Filho, Otavio; Hoppin, Alison; Levitsky, Lynne; de Ferranti, Sarah; Rhodes, Erinn T.; Traum, Avram; Goodman, Elizabeth; Feng, Henry; Heydari, Bobak; Harris, William S.; Hoefner, Daniel M.; McConnell, Joseph P.; Seethamraju, Ravi; Rickers, Carsten; Kwong, Raymond Y.; Jerosch‐Herold, Michael

    2013-01-01

    Background Childhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue‐level markers within the myocardium that precede organ‐level alterations have not been described. Methods and Results We studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m2, including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m2) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size‐adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high‐sensitivity C‐reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum. Conclusions Obese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function. PMID:23963758

  19. [Age characteristics of the cardiovascular system, depending on the thyroid function in type 2 diabetes mellitus].

    PubMed

    Ignateva, P A; Ballyuzek, M F; Shpakov, A O

    2015-01-01

    To study the features of cardiovascular system in patients with diabetes mellitus type 2 considering the thyroid pathology and age, 264 patients were examined. They were divided into three groups: 1st - patients with diffuse-nodular changes in the thyroid gland, 2nd - patients with autoimmune thyroid disease, 3rd - a control group of patients without thyroid disease. The patients of different ages were examined in each of these groups. All patients were in euthyroid state. It was established that identified in diabetes mellitus type 2 thyroid pathology and the thyroid disease contribute special features to the clinical picture for combined diabetic and cardiovascular pathology even in a euthyroid state including the age features. The laboratory and instrumental researches showed that the patients with combined diabetes and thyroid pathology have a higher incidence of atrial fibrillation, ischemic heart disease, and ventricular arrhythmias of high grades. They also were noticed to have a more adverse form of the left ventricle remodeling, also the combination of diastolic and systolic dysfunctions were found to be more frequent. It was concluded about the necessity of early diagnosis and correction of the cardiovascular disorders and thyroid systems in type 2 diabetes mellitus patients, including euthyroid patients.

  20. Hydrogen sulfide depletion contributes to microvascular remodeling in obesity.

    PubMed

    Candela, Joseph; Velmurugan, Gopal V; White, Carl

    2016-05-01

    Structural remodeling of the microvasculature occurs during obesity. Based on observations that impaired H2S signaling is associated with cardiovascular pathologies, the current study was designed to test the hypothesis that altered H2S homeostasis is involved in driving the remodeling process in a diet-induced mouse model of obesity. The structural and passive mechanical properties of mesenteric resistance arterioles isolated from 30-wk-old lean and obese mice were assessed using pressure myography, and vessel H2S levels were quantified using the H2S indicator sulfidefluor 7-AM. Remodeling gene expression was assessed using quantitative RT-PCR, and histological staining was used to quantify vessel collagen and elastin. Obesity was found to be associated with decreased vessel H2S concentration, inward hypertrophic remodeling, altered collagen-to-elastin ratio, and reduced vessel stiffness. In addition, mRNA levels of fibronectin, collagen types I and III, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 1 were increased and elastin was decreased by obesity. Evidence that decreased H2S was responsible for the genetic changes was provided by experiments in which H2S levels were manipulated, either by inhibition of the H2S-generating enzyme cystathionine γ-lyase with dl-propargylglycine or by incubation with the H2S donor GYY4137. These data suggest that, during obesity, depletion of H2S is involved in orchestrating the genetic changes underpinning inward hypertrophic remodeling in the microvasculature. Copyright © 2016 the American Physiological Society.

  1. Sex differences in cardiovascular ageing.

    PubMed

    Merz, Allison A; Cheng, Susan

    2016-06-01

    Despite recent progress in identifying and narrowing the gaps in cardiovascular outcomes between men and women, general understanding of how and why cardiovascular disease presentations differ between the sexes remains limited. Sex-specific patterns of cardiac and vascular ageing play an important role and, in fact, begin very early in life. Differences between the sexes in patterns of age-related cardiac remodelling are associated with the relatively greater prevalence in women than in men of heart failure with preserved ejection fraction. Similarly, sex variation in how vascular structure and function change with ageing contributes to differences between men and women in how coronary artery disease manifests typically or atypically over the adult life course. Both hormonal and non-hormonal factors underlie sex differences in cardiovascular ageing and the development of age-related disease. The midlife withdrawal of endogenous oestrogen appears to augment the age-related increase in cardiovascular risk seen in postmenopausal compared with premenopausal women. However, when compared with intrinsic biological differences between men and women that are present throughout life, this menopausal transition may not be as substantial an actor in determining cardiovascular outcomes. 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/

  2. Vaccine Adverse Events

    MedlinePlus

    ... Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products Vaccines, Blood & Biologics Home Vaccines, Blood & Biologics Safety & Availability ( ... Center for Biologics Evaluation & Research Vaccine Adverse Events Vaccine Adverse Events Share Tweet Linkedin Pin it More ...

  3. Echocardiographic Predictors for Left Ventricular Remodeling after Acute ST Elevation Myocardial Infarction with Low Risk Group: Speckle Tracking Analysis

    PubMed Central

    Na, Hyun-Min; Lee, Joo Myung; Cha, Myung-Jin; Yoon, Yeonyee E.; Lee, Seung-Pyo; Kim, Hyung-Kwan; Kim, Yong-Jin; Sohn, Dae-Won

    2016-01-01

    Background We sought to assess echocardiographic predictors of left ventricular (LV) adverse remodeling after successfully reperfused acute ST elevation myocardial infarction (STEMI). LV remodeling is commonly found in STEMI patients and it may suggest adverse outcome in acute myocardial infarction. We sought to identify whether 2D strain and torsion be independent parameters for prediction of LV adverse remodeling. Methods We investigated 208 patients with low-risk STEMI patients who had follow up echocardiography at 6 or more months. After clinical assessments, all patients received revascularization according to current guideline. LV remodeling was defined as > 20% increase in end-diastolic volume (EDV) at follow up. Results During the follow-up (11.9 ± 5.3 months), 53 patients (25.5%) showed LV remodeling. In univariate analysis, EDV, end-systolic volume, deceleration time (DT), CK-MB, and global longitudinal strain (GLS) were associated with LV remodeling. In multivariate analysis, EDV [hazard ratio (HR): 0.922, 95% confidence interval (CI): 0.897–0.948, p< 0.001], GLS (HR: 0.842, 95% CI: 0.728–0.974, p = 0.020), DT (HR: 0.989, 95% CI: 0.980–0.998, p = 0.023) and CK-MB (HR: 1.003, 95% CI: 1.000–1.005, p = 0.033) independently predicted LV remodeling. However, global circumferential strain, net twist, and twist or untwist rate were not associated with remodeling. Conclusion Of various parameters of speckle strain, only GLS predicted adverse remodeling in STEMI patients. PMID:27358705

  4. Cardiovascular consequences of metabolic syndrome.

    PubMed

    Tune, Johnathan D; Goodwill, Adam G; Sassoon, Daniel J; Mather, Kieren J

    2017-01-09

    The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiological mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review, we highlight current knowledge regarding the pathophysiological consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiological and molecular mechanisms that may contribute to these adverse outcomes.

  5. Arsenic and cardiovascular disease.

    PubMed

    States, J Christopher; Srivastava, Sanjay; Chen, Yu; Barchowsky, Aaron

    2009-02-01

    Chronic arsenic exposure is a worldwide health problem. Although arsenic-induced cancer has been widely studied, comparatively little attention has been paid to arsenic-induced vascular disease. Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease. In addition, studies suggest that susceptibility to arsenic-induced vascular disease may be modified by nutritional factors in addition to genetic factors. Recently, animal models for arsenic-induced atherosclerosis and liver sinusoidal endothelial cell dysfunction have been developed. Initial studies in these models show that arsenic exposure accelerates and exacerbates atherosclerosis in apolipoprotein E-knockout mice. Microarray studies of liver mRNA and micro-RNA abundance in mice exposed in utero suggest that a permanent state of stress is induced by the arsenic exposure. Furthermore, the livers of the arsenic-exposed mice have activated pathways involved in immune responses suggesting a pro-hyperinflammatory state. Arsenic exposure of mice after weaning shows a clear dose-response in the extent of disease exacerbation. In addition, increased inflammation in arterial wall is evident. In response to arsenic-stimulated oxidative signaling, liver sinusoidal endothelium differentiates into a continuous endothelium that limits nutrient exchange and waste elimination. Data suggest that nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide or its derivatives are essential second messengers in the signaling pathway for arsenic-stimulated vessel remodeling. The recent findings provide future directions for research into the cardiovascular effects of arsenic exposure.

  6. Risk of Bias in Systematic Reviews of Non-Randomized Studies of Adverse Cardiovascular Effects of Thiazolidinediones and Cyclooxygenase-2 Inhibitors: Application of a New Cochrane Risk of Bias Tool

    PubMed Central

    Bilandzic, Anja; Fitzpatrick, Tiffany; Rosella, Laura; Henry, David

    2016-01-01

    Background Systematic reviews of the effects of healthcare interventions frequently include non-randomized studies. These are subject to confounding and a range of other biases that are seldom considered in detail when synthesizing and interpreting the results. Our aims were to assess the reliability and usability of a new Cochrane risk of bias (RoB) tool for non-randomized studies of interventions and to determine whether restricting analysis to studies with low or moderate RoB made a material difference to the results of the reviews. Methods and Findings We selected two systematic reviews of population-based, controlled non-randomized studies of the relationship between the use of thiazolidinediones (TZDs) and cyclooxygenase-2 (COX-2) inhibitors and major cardiovascular events. Two epidemiologists applied the Cochrane RoB tool and made assessments across the seven specified domains of bias for each of 37 component studies. Inter-rater agreement was measured using the weighted Kappa statistic. We grouped studies according to overall RoB and performed statistical pooling for (a) all studies and (b) only studies with low or moderate RoB. Kappa scores across the seven bias domains ranged from 0.50 to 1.0. In the COX-2 inhibitor review, two studies had low overall RoB, 14 had moderate RoB, and five had serious RoB. In the TZD review, six studies had low RoB, four had moderate RoB, four had serious RoB, and two had critical RoB. The pooled odds ratios for myocardial infarction, heart failure, and death for rosiglitazone versus pioglitazone remained significantly elevated when analyses were confined to studies with low or moderate RoB. However, the estimate for myocardial infarction declined from 1.14 (95% CI 1.07–1.24) to 1.06 (95% CI 0.99–1.13) when analysis was confined to studies with low RoB. Estimates of pooled relative risks of cardiovascular events with COX-2 inhibitors compared with no nonsteroidal anti-inflammatory drug changed little when analyses were

  7. Regulation of chromatin structure in the cardiovascular system.

    PubMed

    Rosa-Garrido, Manuel; Karbassi, Elaheh; Monte, Emma; Vondriska, Thomas M

    2013-01-01

    It has been appreciated for some time that cardiovascular disease involves large-scale transcriptional changes in various cell types. What has become increasingly clear only in the past few years, however, is the role of chromatin remodeling in cardiovascular phenotypes in normal physiology, as well as in development and disease. This review summarizes the state of the chromatin field in terms of distinct mechanisms to regulate chromatin structure in vivo, identifying when these modes of regulation have been demonstrated in cardiovascular tissues. We describe areas in which a better understanding of chromatin structure is leading to new insights into the fundamental biology of cardiovascular disease. 

  8. Ventricular remodeling in heart failure: the role of myocardial collagen.

    PubMed

    Janicki, J S; Brower, G L; Henegar, J R; Wang, L

    1995-01-01

    Collagen which is present in the myocardium in relatively small amounts is the most abundant structural protein of the connective tissue network. Its structural organization consists of a complex weave of collagen fibers that surrounds and interconnects myocytes, groups of myocytes, muscle fibers and muscle bundles. The conformation of interstitial fibrillar collagen makes it highly resistant to degradation by all proteinases other than specific collagenases. In hearts with myocardial damage secondary to myocardial infarction, chronic ischemia, inflammation, or cardiomyopathy, a complex sequence of compensatory events occur that eventually result in an adverse left ventricular remodeling. This continual state of remodeling is characterized by persistent collagenase activity, fibrillar collagen degradation, and progressive myocyte loss. The net effect is a shift in the balance between collagen synthesis and degradation which leads to an inadequate fibrillar collagen matrix, progressive ventricular dilatation and sphericalization with wall thinning and eventual congestive heart failure.

  9. Cardiovascular drugs-induced oral toxicities: A murky area to be revisited and illuminated.

    PubMed

    Balakumar, Pitchai; Kavitha, Muthu; Nanditha, Suresh

    2015-12-01

    Oral health is an imperative part of overall human health. Oral disorders are often unreported, but are highly troublesome to human health in a long-standing situation. A strong association exists between cardiovascular drugs and oral adverse effects. Indeed, several cardiovascular drugs employed clinically have been reported to cause oral adverse effects such as xerostomia, oral lichen planus, angioedema, aphthae, dysgeusia, gingival enlargement, scalded mouth syndrome, cheilitis, glossitis and so forth. Oral complications might in turn worsen the cardiovascular disease condition as some reports suggest an adverse correlation between periodontal oral disease pathogenesis and cardiovascular disease. These are certainly important to be understood for a better use of cardiovascular medicines and control of associated oral adverse effects. This review sheds lights on the oral adverse effects pertaining to the clinical use of cardiovascular drugs. Above and beyond, an adverse correlation between oral disease and cardiovascular disease has been discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Cardiovascular safety of antipsychotics: a clinical overview.

    PubMed

    Polcwiartek, Christoffer; Kragholm, Kristian; Schjerning, Ole; Graff, Claus; Nielsen, Jimmi

    2016-05-01

    Although antipsychotics have been associated with sudden cardiac death (SCD), they still remain a cornerstone in the treatment of psychiatric patients. Most antipsychotics have an unfavorable cardiovascular adverse effect profile, and SCD may occur even in patients with no cardiovascular risk factors. This clinical overview summarizes the cardiovascular safety of antipsychotics by focusing on the wide range of associated adverse effects. In addition, we also discuss current guidelines regarding routine electrocardiogram (ECG) monitoring. As SCD in psychiatric patients is multifactorial, the contribution from antipsychotic treatment remains largely unknown. Cardiovascular adverse effects of antipsychotics vary substantially, even when used in therapeutic doses. Currently, most clinical concern focuses on antipsychotic-induced corrected QT prolongation, as this may increase risk of Torsades de Pointes and eventually SCD. However, other serious cardiovascular adverse effects of antipsychotics also include Brugada syndrome phenotype, myocardial infarction, and myocarditis. Increased awareness of the cardiovascular safety of antipsychotics can allow physicians to better manage and monitor high-risk patients. In this patient group, ECG monitoring may be warranted and other examinations symptom driven. Prescription of antipsychotics should always be a balance between the perceived clinical effect and the burden of adverse effects.

  11. Exercise and the cardiovascular system.

    PubMed

    Golbidi, Saeid; Laher, Ismail

    2012-01-01

    There are alarming increases in the incidence of obesity, insulin resistance, type II diabetes, and cardiovascular disease. The risk of these diseases is significantly reduced by appropriate lifestyle modifications such as increased physical activity. However, the exact mechanisms by which exercise influences the development and progression of cardiovascular disease are unclear. In this paper we review some important exercise-induced changes in cardiac, vascular, and blood tissues and discuss recent clinical trials related to the benefits of exercise. We also discuss the roles of boosting antioxidant levels, consequences of epicardial fat reduction, increases in expression of heat shock proteins and endoplasmic reticulum stress proteins, mitochondrial adaptation, and the role of sarcolemmal and mitochondrial potassium channels in the contributing to the cardioprotection offered by exercise. In terms of vascular benefits, the main effects discussed are changes in exercise-induced vascular remodeling and endothelial function. Exercise-induced fibrinolytic and rheological changes also underlie the hematological benefits of exercise.

  12. Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation

    PubMed Central

    Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah; Lee, JuYong; Yang, Yongyao; Mehrzad, Raman; Onufrak, Jillian; Song, Jin; Enderling, Heiko; Agarwal, Akhil; Rahimi, Layla; Morgan, James; Wilson, Paul F.; Carrozza, Joseph; Walsh, Kenneth; Kishore, Raj; Goukassian, David A.

    2014-01-01

    Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton (1H; 0.5 Gy, 1 GeV) and iron ion (56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy. PMID:25337914

  13. Cardiovascular risks associated with low dose ionizing particle radiation.

    PubMed

    Yan, Xinhua; Sasi, Sharath P; Gee, Hannah; Lee, JuYong; Yang, Yongyao; Mehrzad, Raman; Onufrak, Jillian; Song, Jin; Enderling, Heiko; Agarwal, Akhil; Rahimi, Layla; Morgan, James; Wilson, Paul F; Carrozza, Joseph; Walsh, Kenneth; Kishore, Raj; Goukassian, David A

    2014-01-01

    Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton ((1)H; 0.5 Gy, 1 GeV) and iron ion ((56)Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in (56)Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, (56)Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.

  14. Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation

    DOE PAGES

    Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah; ...

    2014-10-22

    Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton (1H; 0.5 Gy, 1 GeV) and iron ion (56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initiallymore » improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Finally, understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.« less

  15. Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation

    SciTech Connect

    Yan, Xinhua; Sasi, Sharath P.; Gee, Hannah; Lee, JuYong; Yang, Yongyao; Mehrzad, Raman; Onufrak, Jillian; Song, Jin; Enderling, Heiko; Agarwal, Akhil; Rahimi, Layla; Morgan, James; Wilson, Paul F.; Carrozza, Joseph; Walsh, Kenneth; Kishore, Raj; Goukassian, David A.

    2014-10-22

    Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton (1H; 0.5 Gy, 1 GeV) and iron ion (56Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in 56Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, 56Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Finally, understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.

  16. Oral disease in adults treated with hemodialysis: prevalence, predictors, and association with mortality and adverse cardiovascular events: the rationale and design of the ORAL Diseases in hemodialysis (ORAL-D) study, a prospective, multinational, longitudinal, observational, cohort study.

    PubMed

    Strippoli, Giovanni F M; Palmer, Suetonia C; Ruospo, Marinella; Natale, Patrizia; Saglimbene, Valeria; Craig, Jonathan C; Pellegrini, Fabio; Petruzzi, Massimo; De Benedittis, Michele; Ford, Pauline; Johnson, David W; Celia, Eduardo; Gelfman, Ruben; Leal, Miguel R; Torok, Marietta; Stroumza, Paul; Bednarek-Skublewska, Anna; Dulawa, Jan; Frantzen, Luc; Ferrari, Juan Nin; del Castillo, Domingo; Hegbrant, Jorgen; Wollheim, Charlotta; Gargano, Letitzia

    2013-04-19

    People with end-stage kidney disease treated with dialysis experience high rates of premature death that are at least 30-fold that of the general population, and have markedly impaired quality of life. Despite this, interventions that lower risk factors for mortality (including antiplatelet agents, epoetins, lipid lowering, vitamin D compounds, or dialysis dose) have not been shown to improve clinical outcomes for this population. Although mortality outcomes may be improving overall, additional modifiable determinants of health in people treated with dialysis need to be identified and evaluated. Oral disease is highly prevalent in the general population and represents a potential and preventable cause of poor health in dialysis patients. Oral disease may be increased in patients treated with dialysis due to their lower uptake of public dental services, as well as increased malnutrition and inflammation, although available exploratory data are limited by small sample sizes and few studies evaluating links between oral health and clinical outcomes for this group, including mortality and cardiovascular disease. Recent data suggest periodontitis may be associated with mortality in dialysis patients and well-designed, larger studies are now required. The ORAL Diseases in hemodialysis (ORAL-D) study is a multinational, prospective (minimum follow-up 12 months) study. Participants comprise consecutive adults treated with long-term in-center hemodialysis. Between July 2010 and February 2012, we recruited 4500 dialysis patients from randomly selected outpatient dialysis clinics in Europe within a collaborative network of dialysis clinics administered by a dialysis provider, Diaverum, in Europe (France, Hungary, Italy, Poland, Portugal, and Spain) and South America (Argentina). At baseline, dental surgeons with training in periodontology systematically assessed the prevalence and characteristics of oral disease (dental, periodontal, mucosal, and salivary) in all participants

  17. Oral disease in adults treated with hemodialysis: prevalence, predictors, and association with mortality and adverse cardiovascular events: the rationale and design of the ORAL Diseases in hemodialysis (ORAL-D) study, a prospective, multinational, longitudinal, observational, cohort study

    PubMed Central

    2013-01-01

    Background People with end-stage kidney disease treated with dialysis experience high rates of premature death that are at least 30-fold that of the general population, and have markedly impaired quality of life. Despite this, interventions that lower risk factors for mortality (including antiplatelet agents, epoetins, lipid lowering, vitamin D compounds, or dialysis dose) have not been shown to improve clinical outcomes for this population. Although mortality outcomes may be improving overall, additional modifiable determinants of health in people treated with dialysis need to be identified and evaluated. Oral disease is highly prevalent in the general population and represents a potential and preventable cause of poor health in dialysis patients. Oral disease may be increased in patients treated with dialysis due to their lower uptake of public dental services, as well as increased malnutrition and inflammation, although available exploratory data are limited by small sample sizes and few studies evaluating links between oral health and clinical outcomes for this group, including mortality and cardiovascular disease. Recent data suggest periodontitis may be associated with mortality in dialysis patients and well-designed, larger studies are now required. Methods/design The ORAL Diseases in hemodialysis (ORAL-D) study is a multinational, prospective (minimum follow-up 12 months) study. Participants comprise consecutive adults treated with long-term in-center hemodialysis. Between July 2010 and February 2012, we recruited 4500 dialysis patients from randomly selected outpatient dialysis clinics in Europe within a collaborative network of dialysis clinics administered by a dialysis provider, Diaverum, in Europe (France, Hungary, Italy, Poland, Portugal, and Spain) and South America (Argentina). At baseline, dental surgeons with training in periodontology systematically assessed the prevalence and characteristics of oral disease (dental, periodontal, mucosal, and

  18. Anxiety Disorders and Cardiovascular Disease.

    PubMed

    Celano, Christopher M; Daunis, Daniel J; Lokko, Hermioni N; Campbell, Kirsti A; Huffman, Jeff C

    2016-11-01

    Anxiety and its associated disorders are common in patients with cardiovascular disease and may significantly influence cardiac health. Anxiety disorders are associated with the onset and progression of cardiac disease, and in many instances have been linked to adverse cardiovascular outcomes, including mortality. Both physiologic (autonomic dysfunction, inflammation, endothelial dysfunction, changes in platelet aggregation) and health behavior mechanisms may help to explain the relationships between anxiety disorders and cardiovascular disease. Given the associations between anxiety disorders and poor cardiac health, the timely and accurate identification and treatment of these conditions is of the utmost importance. Fortunately, pharmacologic and psychotherapeutic interventions for the management of anxiety disorders are generally safe and effective. Further study is needed to determine whether interventions to treat anxiety disorders ultimately impact both psychiatric and cardiovascular health.

  19. Notch signaling in the developing cardiovascular system.

    PubMed

    Niessen, Kyle; Karsan, Aly

    2007-07-01

    The Notch proteins encompass a family of transmembrane receptors that have been highly conserved through evolution as mediators of cell fate. Recent findings have demonstrated a critical role of Notch in the developing cardiovascular system. Notch signaling has been implicated in the endothelial-to-mesenchymal transition during development of the heart valves, in arterial-venous differentiation, and in remodeling of the primitive vascular plexus. Mutations of Notch pathway components in humans are associated with congenital defects of the cardiovascular system such as Alagille syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and bicuspid aortic valves. This article focuses on the role of the Notch pathway in the developing cardiovascular system and congenital human cardiovascular diseases.

  20. Cell death in the cardiovascular system

    PubMed Central

    Clarke, Murray; Bennett, Martin; Littlewood, Trevor

    2007-01-01

    Cell death is important for both development and tissue homeostasis in the adult. As such, it is tightly controlled and deregulation is associated with diverse pathologies; for example, regulated cell death is involved in vessel remodelling during development or following injury, but deregulated death is implicated in pathologies such as atherosclerosis, aneurysm formation, ischaemic and dilated cardiomyopathies and infarction. We describe the mechanisms of cell death and its role in the normal physiology and various pathologies of the cardiovascular system. PMID:16547202

  1. Correction of hyperphosphatemia suppresses cardiac remodeling in uremic rats.

    PubMed

    Yamazaki-Nakazawa, Ai; Mizobuchi, Masahide; Ogata, Hiroaki; Kumata, Chiaki; Kondo, Fumiko; Ono, Naoko; Koiwa, Fumihiko; Uda, Susumu; Kinugasa, Eriko; Akizawa, Tadao

    2014-02-01

    Hyperphosphatemia is associated with cardiovascular disease in patients with chronic kidney disease. To examine the effects of correction of hyperphosphatemia, we investigated the association between phosphate metabolism and cardiac remodeling in uremic rats. Four groups were studied for 8 weeks: (1) control (sham), (2) 5/6 nephrectomized (Nx) rats fed a normal phosphate regular diet (Nx + NP), (3) Nx rats fed a high phosphate (1.2 %) diet (Nx + HP), and (4) Nx rats fed a high phosphate diet containing 2 % lanthanum carbonate (Nx + HP + La). The relationship between phosphate metabolism and cardiac remodeling was analyzed. Nx + HP rats showed a significant increase in serum phosphate and PTH compared with Nx + NP rats, while Nx + HP + La rats showed slight decreases in these levels. Both Nx + HP and Nx + HP + La rats showed a significant increase in fibroblast growth factor-23 (FGF23) compared with Nx + NP rats. Urinary phosphate excretion showed a similar trend to that of FGF23. Nx + HP rats showed a significant increase in LV weight and matrix deposition compared with Nx + NP rats, and this increase was also significantly suppressed in Nx + HP + La rats. Serum phosphate levels and PTH were significantly correlated with LV weight and matrix deposition, but FGF23 levels did not show the correlation. FGF23 had a high correlation with urinary phosphate excretion. These results suggest that correction of hyperphosphatemia by lanthanum carbonate could suppress cardiac remodeling independently of changes in FGF23.

  2. The angiotensin receptor blocker losartan reduces coronary arteriole remodeling in type 2 diabetic mice.

    PubMed

    Husarek, Kathryn E; Katz, Paige S; Trask, Aaron J; Galantowicz, Maarten L; Cismowski, Mary J; Lucchesi, Pamela A

    2016-01-01

    Cardiovascular complications are a leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM) and are associated with alterations of blood vessel structure and function. Although endothelial dysfunction and aortic stiffness have been documented, little is known about the effects of T2DM on coronary microvascular structural remodeling. The renin-angiotensin-aldosterone system plays an important role in large artery stiffness and mesenteric vessel remodeling in hypertension and T2DM. The goal of this study was to determine whether the blockade of AT1R signaling dictates vascular smooth muscle growth that partially underlies coronary arteriole remodeling in T2DM. Control and db/db mice were given AT1R blocker losartan via drinking water for 4 weeks. Using pressure myography, we found that coronary arterioles from 16-week db/db mice undergo inward hypertrophic remodeling due to increased wall thickness and wall-to-lumen ratio with a decreased lumen diameter. This remodeling was accompanied by decreased elastic modulus (decreased stiffness). Losartan treatment decreased wall thickness, wall-to-lumen ratio, and coronary arteriole cell number in db/db mice. Losartan treatment did not affect incremental elastic modulus. However, losartan improved coronary flow reserve. Our data suggest that Ang II-AT1R signaling mediates, at least in part, coronary arteriole inward hypertrophic remodeling in T2DM without affecting vascular mechanics, further suggesting that targeting the coronary microvasculature in T2DM may help reduce cardiac ischemic events.

  3. Remodeling of ribosomal genes in somatic cells by Xenopus egg extract

    SciTech Connect

    Ostrup, Olga; Hyttel, Poul; Klaerke, Dan A.; Collas, Philippe

    2011-09-02

    Highlights: {yields} Xenopus egg extract remodels nuclei and alter cell growth characteristics. {yields} Ribosomal genes are reprogrammed within 6 h after extract exposure. {yields} rDNA reprogramming involves promoter targeting of SNF2H remodeling complex. {yields} Xenopus egg extract does not initiate stress-related response in somatic cells. {yields} Aza-cytidine elicits a stress-induced response in reprogrammed cells. -- Abstract: Extracts from Xenopus eggs can reprogram gene expression in somatic nuclei, however little is known about the earliest processes associated with the switch in the transcriptional program. We show here that an early reprogramming event is the remodeling of ribosomal chromatin and gene expression. This occurs within hours of extract treatment and is distinct from a stress response. Egg extract elicits remodeling of the nuclear envelope, chromatin and nucleolus. Nucleolar remodeling involves a rapid and stable decrease in ribosomal gene transcription, and promoter targeting of the nucleolar remodeling complex component SNF2H without affecting occupancy of the transcription factor UBF and the stress silencers SUV39H1 and SIRT1. During this process, nucleolar localization of UBF and SIRT1 is not altered. On contrary, azacytidine pre-treatment has an adverse effect on rDNA remodeling induced by extract and elicits a stress-type nuclear response. Thus, an early event of Xenopus egg extract-mediated nuclear reprogramming is the remodeling of ribosomal genes involving nucleolar remodeling complex. Condition-specific and rapid silencing of ribosomal genes may serve as a sensitive marker for evaluation of various reprogramming methods.

  4. Adrenal Androgen Dehydroepiandrosterone Sulfate Inhibits Vascular Remodeling Following Arterial Injury

    PubMed Central

    Ii, Masaaki; Hoshiga, Masaaki; Negoro, Nobuyuki; Fukui, Ryosuke; Nakakoji, Takahiro; Kohbayashi, Eiko; Shibata, Nobuhiko; Furutama, Daisuke; Ishihara, Tadashi; Hanafusa, Toshiaki; Losordo, Douglas W.; Ohsawa, Nakaaki

    2009-01-01

    Recent epidemiologic studies have suggested that serum dehydroepiandrosterone sulfate (DHEAS) levels have a significant inverse correlation with the incidence of cardiovascular diseases. However, direct evidence for the association with DHEAS and vascular disorders has not yet been explored. DHEAS significantly reduced neointima formation 28 days after surgery without altering other serum metabolite levels in a rabbit carotid balloon injury model. Immunohistochemical analyses revealed the reduction of proliferating cell nuclear antigen (PCNA) index and increase of TdT-mediated dUTP-biotin Nick End Labeling (TUNEL) index, expressing differentiated vascular smooth muscle cell (VSMC) markers in the media 7 days after surgery. In vitro, DHEAS exhibited inhibitory effects on VSMC proliferation and migration activities, inducing G1 cell cycle arrest with upregulation of one of the cyclin dependent kinase (CDK) inhibitors p16INK4a and apoptosis with activating peroxisome proliferator-activated receptor (PPAR)-α in VSMCs. DHEAS inhibits vascular remodeling reducing neointima formation after vascular injury via its effects on VSMC phenotypic modulation, functions and apoptosis upregulating p16INK4a/activating PPARα. DHEAS may play a pathophysiological role for vascular remodeling in cardiovascular disease. PMID:19298964

  5. Research into Specific Modulators of Vascular Sex Hormone Receptors in the Management of Postmenopausal Cardiovascular Disease.

    PubMed

    do Nascimento, Graciliano R A; Barros, Yaskara V R; Wells, Amanda K; Khalil, Raouf A

    2009-11-01

    Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Studies on the vasculature have identified estrogen receptors ERα, ERβ and a novel estrogen binding membrane protein GPR30, that mediate genomic and/or non-genomic effects. Estrogen promotes endothelium-dependent relaxation by inducing the production/activity of nitric oxide, prostacyclin, and hyperpolarizing factor, and inhibits the mechanisms of vascular smooth muscle contraction including [Ca(2+)](i), protein kinase C, Rho kinase and mitogen-activated protein kinase. Additional effects of estrogen on the cytoskeleton, matrix metalloproteinases and inflammatory factors contribute to vascular remodeling. However, the experimental evidence did not translate into vascular benefits of menopausal hormone therapy (MHT), and the HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events. The discrepancy has been partly related to delayed MHT and potential changes in the vascular ER amount, integrity, affinity, and downstream signaling pathways due to the subjects' age and preexisting CVD. The adverse vascular effects of MHT also highlighted the need of specific modulators of vascular sex hormone receptors. The effectiveness of MHT can be improved by delineating the differences in phramcokinetics and pharmacodynamics of natural, synthetic, and conjugated equine estrogens. Estriol, "hormone bioidenticals" and phytoestrogens are potential estradiol substitutes. The benefits of low dose MHT, and transdermal or vaginal estrogens over oral preparations are being evaluated. Specific ER modulators (SERMs) and ER agonists are being developed to maximize the effects on vascular ERs. Also, the effects of estrogen are being examined in the context of the whole body hormonal environment and the levels of progesterone and androgens. Thus, the experimental vascular benefits of estrogen can be translated to

  6. Research into Specific Modulators of Vascular Sex Hormone Receptors in the Management of Postmenopausal Cardiovascular Disease

    PubMed Central

    do Nascimento, Graciliano R. A.; Barros, Yaskara V. R.; Wells, Amanda K.; Khalil, Raouf A.

    2010-01-01

    Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Studies on the vasculature have identified estrogen receptors ERα, ERβ and a novel estrogen binding membrane protein GPR30, that mediate genomic and/or non-genomic effects. Estrogen promotes endothelium-dependent relaxation by inducing the production/activity of nitric oxide, prostacyclin, and hyperpolarizing factor, and inhibits the mechanisms of vascular smooth muscle contraction including [Ca2+]i, protein kinase C, Rho kinase and mitogen-activated protein kinase. Additional effects of estrogen on the cytoskeleton, matrix metalloproteinases and inflammatory factors contribute to vascular remodeling. However, the experimental evidence did not translate into vascular benefits of menopausal hormone therapy (MHT), and the HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events. The discrepancy has been partly related to delayed MHT and potential changes in the vascular ER amount, integrity, affinity, and downstream signaling pathways due to the subjects' age and preexisting CVD. The adverse vascular effects of MHT also highlighted the need of specific modulators of vascular sex hormone receptors. The effectiveness of MHT can be improved by delineating the differences in phramcokinetics and pharmacodynamics of natural, synthetic, and conjugated equine estrogens. Estriol, “hormone bioidenticals” and phytoestrogens are potential estradiol substitutes. The benefits of low dose MHT, and transdermal or vaginal estrogens over oral preparations are being evaluated. Specific ER modulators (SERMs) and ER agonists are being developed to maximize the effects on vascular ERs. Also, the effects of estrogen are being examined in the context of the whole body hormonal environment and the levels of progesterone and androgens. Thus, the experimental vascular benefits of estrogen can be translated to

  7. Matrix remodeling during endochondral ossification.

    PubMed

    Ortega, Nathalie; Behonick, Danielle J; Werb, Zena

    2004-02-01

    Endochondral ossification, the process by which most of the skeleton is formed, is a powerful system for studying various aspects of the biological response to degraded extracellular matrix (ECM). In addition, the dependence of endochondral ossification upon neovascularization and continuous ECM remodeling provides a good model for studying the role of the matrix metalloproteases (MMPs) not only as simple effectors of ECM degradation but also as regulators of active signal-inducers for the initiation of endochondral ossification. The daunting task of elucidating their specific role during endochondral ossification has been facilitated by the development of mice deficient for various members of this family. Here, we discuss the ECM and its remodeling as one level of molecular regulation for the process of endochondral ossification, with special attention to the MMPs.

  8. Neural remodeling in retinal degeneration.

    PubMed

    Marc, Robert E; Jones, Bryan W; Watt, Carl B; Strettoi, Enrica

    2003-09-01

    Mammalian retinal degenerations initiated by gene defects in rods, cones or the retinal pigmented epithelium (RPE) often trigger loss of the sensory retina, effectively leaving the neural retina deafferented. The neural retina responds to this challenge by remodeling, first by subtle changes in neuronal structure and later by large-scale reorganization. Retinal degenerations in the mammalian retina generally progress through three phases. Phase 1 initiates with expression of a primary insult, followed by phase 2 photoreceptor death that ablates the sensory retina via initial photoreceptor stress, phenotype deconstruction, irreversible stress and cell death, including bystander effects or loss of trophic support. The loss of cones heralds phase 3: a protracted period of global remodeling of the remnant neural retina. Remodeling resembles the responses of many CNS assemblies to deafferentation or trauma, and includes neuronal cell death, neuronal and glial migration, elaboration of new neurites and synapses, rewiring of retinal circuits, glial hypertrophy and the evolution of a fibrotic glial seal that isolates the remnant neural retina from the surviving RPE and choroid. In early phase 2, stressed photoreceptors sprout anomalous neurites that often reach the inner plexiform and ganglion cell layers. As death of rods and cones progresses, bipolar and horizontal cells are deafferented and retract most of their dendrites. Horizontal cells develop anomalous axonal processes and dendritic stalks that enter the inner plexiform layer. Dendrite truncation in rod bipolar cells is accompanied by revision of their macromolecular phenotype, including the loss of functioning mGluR6 transduction. After ablation of the sensory retina, Müller cells increase intermediate filament synthesis, forming a dense fibrotic layer in the remnant subretinal space. This layer invests the remnant retina and seals it from access via the choroidal route. Evidence of bipolar cell death begins in

  9. Regeneration and Remodeling of Materials

    DTIC Science & Technology

    2012-08-01

    Turchyn (Chem) Brett Krull (MatSE) Concepts and Motivation Regeneration and Remodeling in biology: Tree skink lizard Linckia starfish Human Bone...Damage Fill Pumping Regime Microchannels in Specimen Overhead Camera Damage Regeneration Setup 45mm 2mm Pressurized Delivery 5.0 mm gap with bi...phase resin 4.0 mm gap (PDMS healing system) 3.5 mm gap (PDMS healing system) Damage Filling Results Maximum Fill Size PDMS Pre-mixed Epoxy 3mm

  10. Frontiers in growth and remodeling

    PubMed Central

    Menzel, Andreas; Kuhl, Ellen

    2012-01-01

    Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID:22919118

  11. Vascular Remodeling in Pulmonary Hypertension

    PubMed Central

    Shimoda, Larissa A; Laurie, Steven S.

    2013-01-01

    Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions and the appearance of cells expressing smooth muscle specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular trans-differentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting. PMID:23334338

  12. Calcium remodeling in colorectal cancer.

    PubMed

    Villalobos, Carlos; Sobradillo, Diego; Hernández-Morales, Miriam; Núñez, Lucía

    2017-06-01

    Colorectal cancer (CRC) is the third most frequent form of cancer and the fourth leading cause of cancer-related death in the world. Basic and clinical data indicate that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) may prevent colon cancer but mechanisms remain unknown. Aspirin metabolite salicylate and other NSAIDs may inhibit tumor cell growth acting on store-operated Ca(2+) entry (SOCE), suggesting an important role for this pathway in CRC. Consistently, SOCE is emerging as a novel player in different forms of cancer, including CRC. SOCE and store-operated currents (SOCs) are dramatically enhanced in CRC while Ca(2+) stores are partially empty in CRC cells. These features may contribute to CRC hallmarks including enhanced cell proliferation, migration, invasion and survival. At the molecular level, enhanced SOCE and depleted stores are mediated by overexpression of Orai1, Stromal interaction protein 1 (STIM1) and Transient receptor protein channel 1 (TRPC1) and downregulation of STIM2. In normal colonic cells, SOCE is mediated by Ca(2+)-release activated Ca(2+) channels made of STIM1, STIM2 and Orai1. In CRC cells, SOCE is mediated by different store-operated currents (SOCs) driven by STIM1, Orai1 and TRPC1. Loss of STIM2 contributes to depletion of Ca(2+) stores and enhanced resistance to cell death in CRC cells. Thus, SOCE is a novel key player in CRC and inhibition by salicylate and other NSAIDs may contribute to explain chemoprevention activity. Colorectal cancer (CRC) is the third most frequent form of cancer worldwide. Recent evidence suggests that intracellular Ca(2+) remodeling may contribute to cancer hallmarks. In addition, aspirin and other NSAIDs might prevent CRC acting on remodeled Ca(2+) entry pathways. In this review, we will briefly describe 1) the players involved in intracellular Ca(2+) homeostasis with a particular emphasis on the mechanisms involved in SOCE activation and inactivation, 2) the evidence that aspirin

  13. A review on cardiovascular diseases originated from subclinical hypothyroidism.

    PubMed

    Mansourian, Azad Reza

    2012-01-15

    Thyroid hormones play an important role on the cardiovascular systems and thyroid disorder ultimately have a profound adverse effects on myocardium and vascular functions. There are extensive reports on the role of overt thyroid dysfunction which adversely can modify the cardiovascular metabolism but even at the present of some controversial reports, the subclinical thyroid disorders are able also to manipulate cardiovascular system to some extent. The aim of this study is to review the cardiovascular disorders accompanied with subclinical hypothyroidism. It is concluded that adverse effect of thyroid malfunction on myocardium and vascular organs are through the direct role of thyroid hormone and dyslipidemia on heart muscle cells at nuclear level and vascular system, respectively. It seems many cardiovascular disorders initially would not have been occurred in the first place if the thyroid of affected person had functioned properly, therefore thyroid function tests should be one of a prior laboratory examinations in cardiovascular disorders.

  14. Depression and cardiovascular disease.

    PubMed

    Glassman, A

    2008-11-01

    This manuscript reviews the evidence that depression is associated with increased risk of mortality and explores the evidence that treating depression reduces that risk. The thought that depression and death are linked is ancient, but scientifically it has been difficult to prove. After the World War II, type "A" personality appeared capable of identifying cardiac patients at increased risk of death. By the mid 1970s that evidence appeared to weaken and may have been altered by the changing treatment of cardiovascular disease. At the same time, research began to focus on a diagnosis of depression as a predictor but it was 25 years before the association was firmly established. Originally examined in medically healthy in-dividuals followed for long periods of time, in the early 1990s epidemiological research began examining the influence of depression in patients with overt cardiovascular disease. That focus has been primarily on post-MI depression and the obvious question was if treating depression would reduce the risk. Such studies require a very large sample and initially there was no safety data available with any antidepressant drug. Gradually evidence has accumulated that SSRI antidepressants were safe and effective and there is a suggestion that they reduce not only depression but medical adverse events as well. However, that evidence is not definitive and the reason behind the association between depression and cardiovascular morbidity and mortality remains uncertain.

  15. Pleiotropic Effects of Neutrophils on Myocyte Apoptosis and Left Ventricular Remodeling During Early Volume Overload

    PubMed Central

    Kolpakov, Mikhail A; Seqqat, Rachid; Rafiq, Khadija; Xi, Hang; Margulies, Kennneth B; Libonati, Joseph R; Powel, Pamela; Houser, Steven R; Dell'italia, Louis J; Sabri, Abdelkarim

    2009-01-01

    Most of the available evidence on the role of neutrophils on pathological cardiac remodeling has been pertained after acute myocardial infarction. However, whether neutrophils directly contribute to the pathogenesis of cardiac remodeling after events other than acute myocardial infarction remains unknown. Here we show that acute eccentric hypertrophy induced by aorto-caval fistula (ACF) in the rats induced an increase in the inflammatory response characterized by activation of the STAT pathway and increased infiltration of neutrophils in the myocardium. This early inflammation was associated with a decrease in interstitial collagen accumulation and an increase in myocyte apoptosis. Neutrophil infiltration blockade attenuated MMP activation, ECM degradation, and myocyte apoptosis induced by ACF at 24hrs and attenuated the development of eccentric hypertrophy induced by ACF at 2- and 3-weeks, suggesting a causal relationship between neutrophils and the ACF-induced cardiac remodeling. In contrast, sustained neutrophil depletion over 4-weeks resulted in adverse cardiac remodeling with further increase in cardiac dilatation and macrophage infiltration, but with no change in myocyte apoptosis level. These data support a functional role for neutrophils in MMP activation, ECM degradation, and myocyte apoptosis during eccentric cardiac hypertrophy and underscore the adverse effects of chronic anti-neutrophil therapy on cardiac remodeling induced by early VO. PMID:19716828

  16. Mechanisms of arterial remodeling: lessons from genetic diseases

    PubMed Central

    van Varik, Bernard J.; Rennenberg, Roger J. M. W.; Reutelingsperger, Chris P.; Kroon, Abraham A.; de Leeuw, Peter W.; Schurgers, Leon J.

    2012-01-01

    Vascular disease is still the leading cause of morbidity and mortality in the Western world, and the primary cause of myocardial infarction, stroke, and ischemia. The biology of vascular disease is complex and still poorly understood in terms of causes and consequences. Vascular function is determined by structural and functional properties of the arterial vascular wall. Arterial stiffness, that is a pathological alteration of the vascular wall, ultimately results in target-organ damage and increased mortality. Arterial remodeling is accelerated under conditions that adversely affect the balance between arterial function and structure such as hypertension, atherosclerosis, diabetes mellitus, chronic kidney disease, inflammatory disease, lifestyle aspects (smoking), drugs (vitamin K antagonists), and genetic abnormalities [e.g., pseudoxanthoma elasticum (PXE), Marfan's disease]. The aim of this review is to provide an overview of the complex mechanisms and different factors that underlie arterial remodeling, learning from single gene defect diseases like PXE, and PXE-like, Marfan's disease and Keutel syndrome in vascular remodeling. PMID:23248645

  17. ENDOTHELIAL INJURY IN PARTICULATE MATTER (PM)-INDUCED CARDIOVASCULAR INJURY: KINETIC ANALYSIS OF GENE EXPRESSION PROFILES

    EPA Science Inventory

    Numerous epidemiological studies established positive associations between ambient fine PM and cardiovascular morbidity and mortality. The biological basis for these adverse health effects is yet to be elucidated. Cardiovascular toxicity of fine PM and its toxic constituents may ...

  18. A Case control study of cardiovascular disease and arsenic exposure in Inner Mongolia, China

    EPA Science Inventory

    Background: Millions of people are at risk from the adverse effects of waterborne arsenic. Although the cardiovascular effects of high exposures to arsenic have been well documented, few individual level prospective studies have assessed cardiovascular risk at moderate exposures....

  19. Fish oil and olive oil-rich diets modify ozone-induced cardiovascular effect in rats

    EPA Science Inventory

    Rationale: Air pollution exposure has been associated with adverse cardiovascular health effects. Our clinical studies suggest that fish oil (FO) and olive oil (OO) supplementations attenuate the cardiovascular responses to inhaled concentrated ambient particles. This study was...

  20. A Case control study of cardiovascular disease and arsenic exposure in Inner Mongolia, China

    EPA Science Inventory

    Background: Millions of people are at risk from the adverse effects of waterborne arsenic. Although the cardiovascular effects of high exposures to arsenic have been well documented, few individual level prospective studies have assessed cardiovascular risk at moderate exposures....

  1. Incidence and economic burden of suspected adverse events and adverse event monitoring during AF therapy.

    PubMed

    Kim, M H; Lin, J; Hussein, M; Battleman, D

    2009-12-01

    Rhythm- and rate-control therapies are an essential part of atrial fibrillation (AF) management; however, the use of existing agents is often limited by the occurrence of adverse events. The aim of this study was to evaluate suspected adverse events and adverse event monitoring, and associated medical costs, in patients receiving AF rhythm-control and/or rate-control therapy. This retrospective cohort study used claims data from the Integrated Healthcare Information Systems National Managed Care Benchmark Database from 2002-2006. Patients hospitalized for AF (primary diagnosis), and who had at least 365 days' enrollment before and after the initial (index) AF hospitalization, were included in the analysis. Suspected AF therapy-related adverse events and function tests for adverse event monitoring were identified according to pre-specified diagnosis codes/procedures, and examined over the 12 months following discharge from the index hospitalization. Events/function tests had to have occurred within 90 days of a claim for AF therapy to be considered a suspected adverse event/adverse event monitoring. Of 4174 AF patients meeting the study criteria, 3323 received AF drugs; 428 received rhythm-control only (12.9%), 2130 rate-control only (64.1%), and 765 combined rhythm/rate-control therapy (23.0%). Overall, 50.1% of treated patients had a suspected adverse event and/or function test for adverse event monitoring (45.5% with rate-control, 53.5% with rhythm-control, and 61.2% with combined rhythm/rate-control). Suspected cardiovascular adverse events were the most common events (occurring in 36.1% of patients), followed by pulmonary (6.1%), and endocrine events (5.9%). Overall, suspected adverse events/function tests were associated with mean annual per-patient costs of $3089 ($1750 with rhythm-control, $2041 with rate control, and $6755 with combined rhythm/rate-control). As a retrospective analysis, the study is subject to potential selection bias, while its reliance on

  2. Recent insights and therapeutic perspectives of angiotensin-(1-9) in the cardiovascular system.

    PubMed

    Ocaranza, Maria Paz; Michea, Luis; Chiong, Mario; Lagos, Carlos F; Lavandero, Sergio; Jalil, Jorge E

    2014-11-01

    Chronic RAS (renin-angiotensin system) activation by both AngII (angiotensin II) and aldosterone leads to hypertension and perpetuates a cascade of pro-hypertrophic, pro-inflammatory, pro-thrombotic and atherogenic effects associated with cardiovascular damage. In 2000, a new pathway consisting of ACE2 (angiotensin-converting enzyme2), Ang-(1-9) [angiotensin-(1-9)], Ang-(1-7) [angiotensin-(1-7)] and the Mas receptor was discovered. Activation of this novel pathway stimulates vasodilation, anti-hypertrophy and anti-hyperplasia. For some time, studies have focused mainly on ACE2, Ang-(1-7) and the Mas receptor, and their biological properties that counterbalance the ACE/AngII/AT1R (angiotensin type 1 receptor) axis. No previous information about Ang-(1-9) suggested that this peptide had biological properties. However, recent data suggest that Ang-(1-9) protects the heart and blood vessels (and possibly the kidney) from adverse cardiovascular remodelling in patients with hypertension and/or heart failure. These beneficial effects are not modified by the Mas receptor antagonist A779 [an Ang-(1-7) receptor blocker], but they are abolished by the AT2R (angiotensin type 2 receptor) antagonist PD123319. Current information suggests that the beneficial effects of Ang-(1-9) are mediated via the AT2R. In the present review, we summarize the biological effects of the novel vasoactive peptide Ang-(1-9), providing new evidence of its cardiovascular-protective activity. We also discuss the potential mechanism by which this peptide prevents and ameliorates the cardiovascular damage induced by RAS activation.

  3. Vascular Remodelling Relates to an Elevated Oscillatory Shear Index and Relative Residence Time in Spontaneously Hypertensive Rats.

    PubMed

    Chen, Zhiyan; Yu, Haiyi; Shi, Yue; Zhu, Minjia; Wang, Yueshen; Hu, Xi; Zhang, Youyi; Chang, Yu; Xu, Ming; Gao, Wei

    2017-05-17

    Haemodynamic disorders are common clinical findings in hypertension and lead to adverse cardiovascular events. However, the haemodynamic conditions in hypertension models are poorly understood. This study aimed to observe the characteristics of haemodynamics in spontaneously hypertensive rats (SHRs) and antihypertensive-treated SHRs. Twenty-four adult male SHRs and Wistar-Kyoto rats (WKYs) were randomly divided into four groups and treated for 7 days as follows: WKY-CON (WKYs + saline), WKY-NIF (WKYs + nifedipine, 50 mg/kg/day), SHR-CON (SHRs + saline), and SHR-NIF (SHRs + nifedipine). Aortic computational fluid dynamics (CFD) models were simulated to obtain the haemodynamic parameters. We found that in the hypertensive (SHR-CON) and blood pressure-controlled (SHR-NIF) groups, the oscillatory shear index (OSI) and relative residence time (RRT), which are key haemodynamics indices, were markedly elevated. Furthermore, there was a correlation between both the elevated OSI and RRT with the vascular wall thickening in regions near the inner wall of the aortic arch. Our research demonstrates that haemodynamics remains disturbed even if the blood pressure is normalized. In addition, vascular remodelling may play an important role in maintaining elevated OSI and RRT values.

  4. Cardiovascular Disease

    USDA-ARS?s Scientific Manuscript database

    Cardiovascular disease (CVD), particularly CHD (coronary heart disease) and stroke, remain the leading causes of death of women in America and most developed countries. In recent years the rate of CVD has declined in men but not in women. This is contributed to by an under-recognition of women’s C...

  5. Traditional Chinese Medication Qiliqiangxin attenuates cardiac remodeling after acute myocardial infarction in mice

    PubMed Central

    Tao, Lichan; Shen, Sutong; Fu, Siyi; Fang, Hongyi; Wang, Xiuzhi; Das, Saumya; Sluijter, Joost P. G.; Rosenzweig, Anthony; Zhou, Yonglan; Kong, Xiangqing; Xiao, Junjie; Li, Xinli

    2015-01-01

    In a multicenter randomized double-blind study we demonstrated that Qiliqiangxin (QLQX), a traditional Chinese medicine, had a protective effect in heart failure patients. However, whether and via which mechanism QLQX attenuates cardiac remodeling after acute myocardial infarction (AMI) is still unclear. AMI was created by ligating the left anterior descending coronary artery in mice. Treating the mice in the initial 3 days after AMI with QLQX did not change infarct size. However, QLQX treatment ameliorated adverse cardiac remodeling 3 weeks after AMI including better preservation of cardiac function, decreased apoptosis and reduced fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) was down-regulated in control animals after AMI and up-regulated by QLQX administration. Interestingly, expression of AKT, SAPK/JNK, and ERK was not altered by QLQX treatment. Inhibition of PPARγ reduced the beneficial effects of QLQX in AMI remodeling, whereas activation of PPARγ failed to provide additional improvement in the presence of QLQX, suggesting a key role for PPARγ in the effects of QLQX during cardiac remodeling after AMI. This study indicates that QLQX attenuates cardiac remodeling after AMI by increasing PPARγ levels. Taken together, QLQX warrants further investigation as as a therapeutic intervention to mitigate remodeling and heart failure after AMI. PMID:25669146

  6. Cardiovascular effects of bariatric surgery.

    PubMed

    Beamish, Andrew J; Olbers, Torsten; Kelly, Aaron S; Inge, Thomas H

    2016-12-01

    Obesity is a major global health problem, and its multisystem effects are inextricably linked with elevated cardiovascular risk and adverse outcomes. The cardiovascular benefits of reversing obesity in adults are well-established. Compared with other weight-loss strategies, programmes that incorporate bariatric surgery for weight loss are beneficial for sustained BMI reduction. A marked improvement in cardiovascular risk factors, including hypertension, dyslipidaemia, inflammation, and type 2 diabetes mellitus, has been observed after bariatric surgery. This broad improvement in cardiovascular risk profile has led to substantial reductions in the risk of myocardial infarction, stroke, and death. As with all procedures, the benefits of bariatric surgery must be weighed against its potential risks. Modern bariatric surgery has an excellent safety profile, but important limitations remain, including the potential for surgical complications and nutritional deficiencies, and the lifelong requirement for nutritional supplementation. Surgery should be considered in patients with severe obesity, especially those with cardiovascular comorbidities. In this Review, we summarize the current management options for patients with obesity, and discuss the effects of bariatric surgery on cardiovascular risk factors and outcomes.

  7. The Role and Molecular Mechanism of Non-Coding RNAs in Pathological Cardiac Remodeling

    PubMed Central

    Gao, Jinning; Xu, Wenhua; Wang, Jianxun; Wang, Kun; Li, Peifeng

    2017-01-01

    Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Studies show that ncRNAs are not only involved in cell proliferation, apoptosis, differentiation, metabolism and other physiological processes, but also involved in the pathogenesis of diseases. Cardiac remodeling is the main pathological basis of a variety of cardiovascular diseases. Many studies have shown that the occurrence and development of cardiac remodeling are closely related with the regulation of ncRNAs. Recent research of ncRNAs in heart disease has achieved rapid development. Thus, we summarize here the latest research progress and mainly the molecular mechanism of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), in cardiac remodeling, aiming to look for new targets for heart disease treatment. PMID:28287427

  8. Pulsatile Fluid Shear in Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Frangos, John A.

    1997-01-01

    The objective of this investigation was to elucidate the sensitivity to transients in fluid shear stress in bone remodeling. Bone remodeling is clearly a function of the local mechanical environment which includes interstitial fluid flow. Traditionally, load-induced remodeling has been associated with low frequency (1-2 Hz) signals attributed to normal locomotion. McLeod and Rubin, however, demonstrated in vivo remodeling events associated with high frequency (15-30 Hz) loading. Likewise, other in vivo studies demonstrated that slowly applied strains did not trigger remodeling events. We therefore hypothesized that the mechanosensitive pathways which control bone maintenance and remodeling are differentially sensitive to varying rates of applied fluid shear stress.

  9. Faces of adversity.

    PubMed

    Bunkers, Sandra Schmidt

    2008-04-01

    This column introduces ideas for a nursing curriculum addressing living with adversity. The question is posed: How do we educate professional nurses to be with others in compassionate and helpful ways at times of calamitous or disastrous experiences? To answer this question the following possibilities for curriculum development are presented: (a) undergird nursing knowledge with value-laden nursing theory, (b) provide "away experiences" for both undergraduate and graduate students in nursing; (c) include theoretical literature on adversity in the curriculum; and (d) develop programs of research addressing phenomena of health experienced by those living with adversity. The column concludes with a personal story of an "away experience" by Vickie Britson.

  10. Erythrocyte Stiffness during Morphological Remodeling Induced by Carbon Ion Radiation

    PubMed Central

    Zhang, Baoping; Liu, Bin; Zhang, Hong; Wang, Jizeng

    2014-01-01

    The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new

  11. Regional myocardial three-dimensional principal strains during postinfarction remodeling.

    PubMed

    Pilla, James J; Koomalsingh, Kevin J; McGarvey, Jeremy R; Witschey, Walter R T; Dougherty, Larry; Gorman, Joseph H; Gorman, Robert C

    2015-03-01

    The purpose of this study was to quantify myocardial three-dimensional (3D) principal strains as the left ventricle (LV) remodels after myocardial infarction (MI). Serial quantification of myocardial strains is important for understanding the mechanical response of the LV to MI. Principal strains convert the 3D LV wall-based strain matrix with three normal and three shear elements, to a matrix with three nonzero normal elements, thereby eliminating the shear elements, which are difficult to physically interpret. The study was designed to measure principal strains of the remote, border zone, and infarct regions in a porcine model of post-MI LV remodeling. Magnetic resonance imaging was used to measure function and strain at baseline, 1 week, and 4 weeks after infarct. Principal strain was measured using 3D acquisition and the optical flow method for displacement tracking. Principal strains were altered as the LV remodeled. Maximum principal strain magnitude decreased in all regions, including the noninfarcted remote, while maximum principal strain angles rotated away from the radial direction in the border zone and infarct. Minimum principal strain magnitude followed a similar pattern; however, strain angles were altered in all regions. Evolution of principal strains correlated with adverse LV remodeling. Using a state-of-the-art imaging and optical flow method technique, 3D principal strains can be measured serially after MI in pigs. Results are consistent with progressive infarct stretching as well as with decreased contractile function in the border zone and remote myocardial regions. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  12. Energy Remodeling, Mitochondrial Disorder and Heart Failure.

    PubMed

    Wang, Peng; Xu, Lei; Sun, Aijun

    2016-01-01

    Heart failure (HF) is a major global problem in public health with no curative treatment currently available. Energy remodeling is one of the features in HF, preceding cardiac structure remodeling. As an important energy organelle, mitochondrion plays critical roles in the progress of HF. This review focuses on the potential mechanisms linking mitochondrial functions and energy remodeling in HF including the energy starvation theory and energy substrate metabolism. It also highlights the potentials of novel drugs targeting HF energy metabolism.

  13. Regeneration and Remodeling of Composite Materials

    DTIC Science & Technology

    2015-08-27

    AFRL-AFOSR-VA-TR-2015-0263 REGENERATION AND REMODELING OF COMPOSITE MATERIALS Scott White UNIVERSITY OF ILLINOIS Final Report 08/27/2015 DISTRIBUTION...Remodeling of Composite Materials 5a. CONTRACT NUMBER FA9550-10-1-0255 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) White, Scott R., Sottos...distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The Regeneration and Remodeling of Composite Materials (Regeneration) Program was

  14. Microtissues in Cardiovascular Medicine: Regenerative Potential Based on a 3D Microenvironment

    PubMed Central

    Günter, Julia; Wolint, Petra; Bopp, Annina; Steiger, Julia; Cambria, Elena; Hoerstrup, Simon P.; Emmert, Maximilian Y.

    2016-01-01

    More people die annually from cardiovascular diseases than from any other cause. In particular, patients who suffer from myocardial infarction may be affected by ongoing adverse remodeling processes of the heart that may ultimately lead to heart failure. The introduction of stem and progenitor cell-based applications has raised substantial hope for reversing these processes and inducing cardiac regeneration. However, current stem cell therapies using single-cell suspensions have failed to demonstrate long-lasting efficacy due to the overall low retention rate after cell delivery to the myocardium. To overcome this obstacle, the concept of 3D cell culture techniques has been proposed to enhance therapeutic efficacy and cell engraftment based on the simulation of an in vivo-like microenvironment. Of great interest is the use of so-called microtissues or spheroids, which have evolved from their traditional role as in vitro models to their novel role as therapeutic agents. This review will provide an overview of the therapeutic potential of microtissues by addressing primarily cardiovascular regeneration. It will accentuate their advantages compared to other regenerative approaches and summarize the methods for generating clinically applicable microtissues. In addition, this review will illustrate the unique properties of the microenvironment within microtissues that makes them a promising next-generation therapeutic approach. PMID:27073399

  15. Translational Success Stories: Role of Mineralocorticoid Receptor Antagonists in Cardiovascular Disease

    PubMed Central

    Ferrario, Carlos M; Schiffrin, Ernesto L

    2014-01-01

    Aldosterone exerts its best known sodium homeostasis actions by controlling sodium excretion at the level of the distal tubules via activation of the apical epithelial sodium channel (ENaC) and the basolateral Na+/K+ ATPase pump. Recently, this mineralocorticoid hormone has been demonstrated to act on the heart and blood vessels. Excess release of aldosterone in relation to the salt status induces both genomic and non-genomic effects that by promoting endothelial dysfunction, and vascular and cardio-renal adverse remodeling, contribute to the target organ damage found in hypertension, heart failure, myocardial infarction and chronic renal failure. Mineralocorticoid receptor blockers have been shown to be highly effective in resistant hypertension and to slow down heart failure progression, and in experimental animals, the development of atherosclerosis. Blockade of the action of aldosterone and potentially other mineralocorticoid steroids has been increasingly demonstrated to be an extremely beneficial therapy in different forms of cardiovascular disease. This review provides a summary of the knowledge that exists regarding aldosterone actions in the cardiovascular system and, in providing the translational impact of this knowledge to the clinical arena, illustrates how much more needs to be achieved in exploring the use of mineralocorticoid receptor blockers in less advanced stages of heart, renal, and vascular disease. PMID:25552697

  16. The remodeling transient and the calcium economy.

    PubMed

    Aloia, J F; Arunabh-Talwar, S; Pollack, S; Yeh, J K

    2008-07-01

    The remodeling transient describes a change in bone mass that lasts one remodeling cycle following an intervention that disturbs the calcium economy. We demonstrated the transient in a study of the response of bone density to calcium/vitamin D3 supplementation and show the hazards of misinterpretation if the transient is not considered. The remodeling transient describes a change in bone mass that lasts for one remodeling cycle following an intervention that disturbs the calcium economy. We report an intervention with calcium and vitamin D supplementation in 208 postmenopausal African-American women where the remodeling transient was considered a priori in the study design. Both groups (calcium alone vs. calcium + 20 microg (800 IU) vitamin D3) were ensured a calcium intake in excess of 1200 mg/day. There were no differences between the two groups in changes in BMD over time. These BMD changes were therefore interpreted to reflect increased calcium intake in both groups but not any influence of vitamin D. A transient increase in bone mineral density was observed during the first year of study, followed by a decline. The remodeling period was estimated at about 9 months, which is similar to histomorphometric estimates. It is problematic to draw conclusions concerning interventions that influence the calcium economy without considering the remodeling transient in study design. Studies of agents that effect bone remodeling must be carried out for at least two remodeling cycles and appropriate techniques must be used in data analysis.

  17. RAMCO Remodel America Corp.Information Sheet

    EPA Pesticide Factsheets

    RAMCO Remodel America Corp. (the Company) is located in Memphis, Tennessee. The settlement involves renovation activities conducted at a property constructed prior to 1978, located in Memphis, Tennessee.

  18. Age-associated Pro-inflammatory Remodeling and Functional Phenotype in the Heart and Large Arteries

    PubMed Central

    Wang, Mingyi; Shah, Ajay M

    2015-01-01

    The aging population is increasing dramatically. Aging–associated stress simultaneously drives proinflammatory remodeling, involving angiotensin II and other factors, in both the heart and large arteries. The structural remodeling and functional changes that occur with aging include cardiac and vascular wall stiffening, systolic hypertension and suboptimal ventricular-arterial coupling, features that are often clinically silent and thus termed a silent syndrome. These age-related effects are the result of responses initiated by cardiovascular proinflammatory cells. Local proinflammatory signals are coupled between the heart and arteries due to common mechanical and humoral messengers within a closed circulating system. Thus, targeting proinflammatory signaling molecules would be a promising approach to improve age-associated suboptimal ventricular-arterial coupling, a major predisposing factor for the pathogenesis of clinical cardiovascular events such as heart failure. PMID:25665458

  19. Social factors and cardiovascular morbidity.

    PubMed

    Brunner, Eric John

    2017-03-01

    Recent progress in population health at aggregate level, measured by life expectancy, has been accompanied by lack of progress in reducing the difference in health prospects between groups defined by social status. Cardiovascular disease is an important contributor to this undesirable situation. The stepwise gradient of higher risk with lower status is accounted for partly by social gradients in health behaviors. The psychosocial hypothesis provides a stronger explanation, based on social patterning of living and working environments and psychological assets that individuals develop during childhood. Three decades of research based on Whitehall II and other cohort studies provide evidence for psychosocial pathways leading to cardiovascular morbidity and mortality. Job stress is a useful paradigm because exposure is long term and depends on occupational status. Studies of social-biological translation implicate autonomic and neuroendocrine function among the biological systems that mediate between chronic adverse psychosocial exposures and increased cardiometabolic risk and cardiovascular disease incidence.

  20. Radiotherapy-induced right ventricular remodelling: The missing piece of the puzzle.

    PubMed

    Tadic, Marijana; Cuspidi, Cesare; Hering, Dagmara; Venneri, Lucia; Grozdic-Milojevic, Isidora

    2017-02-01

    The number of studies demonstrating that right ventricular structure, function and mechanics are valuable predictors of cardiovascular and total morbidity and mortality in patients with a wide range of cardiovascular conditions is constantly increasing. Most studies that evaluated the influence of radiotherapy on the heart focused on left ventricular remodelling, which is why current guidelines only recommend detailed assessment of the left ventricle. Data regarding right ventricular changes in cancer patients treated with radiotherapy are scarce. Given that radiotherapy more often induces late cardiac impairment - unlike chemotherapy-induced cardiotoxicity, which is usually acute - it is quite reasonable to follow these patients echocardiographically for a long time (even for 20years after initiation of radiotherapy). Investigations that have followed cancer survivors for at least 10years after radiotherapy agree that right ventricular structure, systolic/diastolic function and mechanics are significantly impaired. The mechanisms of radiation-induced right ventricular remodelling are still unclear, but it is thought that fibrosis is the dominant factor in myocardial remodelling and vascular changes. Many factors may contribute to right ventricular impairment during and after radiotherapy: cumulative radiation dose; dose per treatment; delivery technique; radiation target (chest and mediastinum); and co-morbidities. In this review, we aim to provide a comprehensive overview of the potential mechanisms of radiation-induced right ventricular remodelling, and to summarize clinical studies involving radiotherapy-treated cancer patients.

  1. Physiological cardiac remodelling in response to endurance exercise training: cellular and molecular mechanisms.

    PubMed

    Ellison, Georgina M; Waring, Cheryl D; Vicinanza, Carla; Torella, Daniele

    2012-01-01

    Exercise training fosters the health and performance of the cardiovascular system, and represents nowadays a powerful tool for cardiovascular therapy. Exercise exerts its beneficial effects through reducing cardiovascular risk factors, and directly affecting the cellular and molecular remodelling of the heart. Traditionally, moderate endurance exercise training has been viewed to determine a balanced and revertible physiological growth, through cardiomyocyte hypertrophy accompanied by appropriate neoangiogenesis (the Athlete's Heart). These cellular adaptations are due to the activation of signalling pathways and in particular, the IGF-1/IGF-1R/Akt axis appears to have a major role. Recently, it has been shown that physical exercise determines cardiac growth also through new cardiomyocyte formation. Accordingly, burgeoning evidence indicates that exercise training activates circulating, as well as resident tissue-specific cardiac, stem/progenitor cells. Dissecting the mechanisms for stem/progenitor cell activation with exercise will be instrumental to devise new effective therapies, encompassing myocardial regeneration for a large spectrum of cardiovascular diseases.

  2. The Role of Cardiolipin in Cardiovascular Health

    PubMed Central

    Shen, Zheni; Ye, Cunqi; McCain, Keanna; Greenberg, Miriam L.

    2015-01-01

    Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is crucial for both mitochondrial function and cellular processes outside of the mitochondria. The importance of CL in cardiovascular health is underscored by the life-threatening genetic disorder Barth syndrome (BTHS), which manifests clinically as cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation. BTHS is caused by mutations in the gene encoding tafazzin, the transacylase that carries out the second CL remodeling step. In addition to BTHS, CL is linked to other cardiovascular diseases (CVDs), including cardiomyopathy, atherosclerosis, myocardial ischemia-reperfusion injury, heart failure, and Tangier disease. The link between CL and CVD may possibly be explained by the physiological roles of CL in pathways that are cardioprotective, including mitochondrial bioenergetics, autophagy/mitophagy, and mitogen activated protein kinase (MAPK) pathways. In this review, we focus on the role of CL in the pathogenesis of CVD as well as the molecular mechanisms that may link CL functions to cardiovascular health. PMID:26301254

  3. Beneficial effects of grape seed proanthocyanidin extract on arterial remodeling in spontaneously hypertensive rats via protecting against oxidative stress.

    PubMed

    Liang, Ying; Wang, Jian; Gao, Haiqing; Wang, Quanzhen; Zhang, Jun; Qiu, Jie

    2016-10-01

    Arterial remodeling is a pathogenic occurrence during hypertension and, in turn, is closely associated with the development and complications of hypertension. Grape seed proanthocyanidin extract (GSPE) has been reported to exhibit a protective effect on cardiovascular disease, however its effect on arterial remodeling remains to be fully elucidated. In the present study, the effects of GSPE on arterial remodeling were analyzed by treating spontaneously hypertensive rats (SHRs) with GSPE (250 mg/kg·day). Arterial remodeling was quantified through morphological methods; thoracic aortas were stained with hematoxylin-eosin or sirius red‑victoria blue. The arterial ultrastructure was imaged using transmission electron microscopy. The content of nitric oxide (NO) and endothelin‑1 (ET‑1) were examined to determine endothelial function. Oxidative stress was assessed by malondialdehyde (MDA) levels and the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Administration of GSPE markedly alleviated hypertension‑induced arterial remodeling, which was not associated with blood pressure control. ET‑1 production was reduced, while NO production was increased in the GSPE group, which exhibited improved endothelial function. In addition, treatment with GSPE significantly ameliorated oxidative stress by improving SOD and CAT activities and reducing MDA formation. In conclusion, GSPE may attenuate hypertension‑induced arterial remodeling by repressing oxidative stress and is recommended as a potential anti‑arterial remodeling agent for patients with hypertensive vascular diseases.

  4. [Cardiovascular pharmacogenomics].

    PubMed

    Scibona, Paula; Angriman, Federico; Simonovich, Ventura; Heller, Martina M; Belloso, Waldo H

    2014-01-01

    Cardiovascular disease remains a major cause of morbidity and mortality worldwide. Current medical practice takes into account information based on population studies and benefits observed in large populations or cohorts. However, individual patients present great differences in both toxicity and clinical efficacy that can be explained by variations in adherence, unknown drug to drug interactions and genetic variability. The latter seems to explain from 20% up to 95% of patient to patient variability. Treating patients with cardiovascular disorders faces the clinician with the challenge to include genomic analysis into daily practice. There are several examples within cardiovascular disease of treatments that can vary in toxicity or clinical usefulness based on genetic changes. One of the main factors affecting the efficacy of Clopidogrel is the phenotype associated with polymorphisms in the gene CYP 2C9. Furthermore, regarding oral anticoagulants, changes in CYP2C9 and VKORC1 play an important role in changing the clinical response to anticoagulation. When analyzing statin treatment, one of their main toxicities (myopathy) can be predicted by the SLCO1B1 polymorphism. The potential for prediction of toxicity and clinical efficacy from the use of genetic analysis warrants further studies aiming towards its inclusion in daily clinical practice.

  5. The adverse health effects of chronic cannabis use.

    PubMed

    Hall, Wayne; Degenhardt, Louisa

    2014-01-01

    This paper summarizes the most probable of the adverse health effects of regular cannabis use sustained over years, as indicated by epidemiological studies that have established an association between cannabis use and adverse outcomes; ruled out reverse causation; and controlled for plausible alternative explanations. We have also focused on adverse outcomes for which there is good evidence of biological plausibility. The focus is on those adverse health effects of greatest potential public health significance--those that are most likely to occur and to affect a substantial proportion of regular cannabis users. These most probable adverse effects of regular use include a dependence syndrome, impaired respiratory function, cardiovascular disease, adverse effects on adolescent psychosocial development and mental health, and residual cognitive impairment.

  6. Bone remodeling after renal transplantation.

    PubMed

    Bellorin-Font, Ezequiel; Rojas, Eudocia; Carlini, Raul G; Suniaga, Orlando; Weisinger, José R

    2003-06-01

    Several studies have indicated that bone alterations after transplantation are heterogeneous. Short-term studies after transplantation have shown that many patients exhibit a pattern consistent with adynamic bone disease. In contrast, patients with long-term renal transplantation show a more heterogeneous picture. Thus, while adynamic bone disease has also been described in these patients, most studies show decreased bone formation and prolonged mineralization lag-time faced with persisting bone resorption, and even clear evidence of generalized or focal osteomalacia in many patients. Thus, the main alterations in bone remodeling are a decrease in bone formation and mineralization up against persistent bone resorption, suggesting defective osteoblast function, decreased osteoblastogenesis, or increased osteoblast death rates. Indeed, recent studies from our laboratory have demonstrated that there is an early decrease in osteoblast number and surfaces, as well as in reduced bone formation rate and delayed mineralization after transplantation. These alterations are associated with an early increase in osteoblast apoptosis that correlates with low levels of serum phosphorus. These changes were more frequently observed in patients with low turnover bone disease. In contrast, PTH seemed to preserve osteoblast survival. The mechanisms of hypophosphatemia in these patients appear to be independent of PTH, suggesting that other phosphaturic factors may play a role. However, further studies are needed to determine the nature of a phosphaturic factor and its relationship to the alterations of bone remodeling after transplantation.

  7. Adrenocortical Zonation, Renewal, and Remodeling

    PubMed Central

    Pihlajoki, Marjut; Dörner, Julia; Cochran, Rebecca S.; Heikinheimo, Markku; Wilson, David B.

    2015-01-01

    The adrenal cortex is divided into concentric zones. In humans the major cortical zones are the zona glomerulosa, zona fasciculata, and zona reticularis. The adrenal cortex is a dynamic organ in which senescent cells are replaced by newly differentiated ones. This constant renewal facilitates organ remodeling in response to physiological demand for steroids. Cortical zones can reversibly expand, contract, or alter their biochemical profiles to accommodate needs. Pools of stem/progenitor cells in the adrenal capsule, subcapsular region, and juxtamedullary region can differentiate to repopulate or expand zones. Some of these pools appear to be activated only during specific developmental windows or in response to extreme physiological demand. Senescent cells can also be replenished through direct lineage conversion; for example, cells in the zona glomerulosa can transform into cells of the zona fasciculata. Adrenocortical cell differentiation, renewal, and function are regulated by a variety of endocrine/paracrine factors including adrenocorticotropin, angiotensin II, insulin-related growth hormones, luteinizing hormone, activin, and inhibin. Additionally, zonation and regeneration of the adrenal cortex are controlled by developmental signaling pathways, such as the sonic hedgehog, delta-like homolog 1, fibroblast growth factor, and WNT/β-catenin pathways. The mechanisms involved in adrenocortical remodeling are complex and redundant so as to fulfill the offsetting goals of organ homeostasis and stress adaptation. PMID:25798129

  8. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction.

    PubMed

    Solomon, Scott D; Shin, Sung Hee; Shah, Amil; Skali, Hicham; Desai, Akshay; Kober, Lars; Maggioni, Aldo P; Rouleau, Jean L; Kelly, Roxzana Y; Hester, Allen; McMurray, John J V; Pfeffer, Marc A

    2011-05-01

    Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system (RAAS) at the most proximal, specific, and rate-limiting step. We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following acute myocardial infarction receiving stable, individually optimized therapy, including another inhibitor of the RAAS. We randomly assigned 820 patients between ∼2 and 8 weeks following acute myocardial infarction, with the left ventricular ejection fraction (LVEF) ≤45%, and regional wall motion abnormalities (≥20% akinetic area), to receive aliskiren (n = 423), titrated to 300 mg, or matched placebo (n = 397), added to the standard therapy. All patients were required to be on a stable dose of an ACE-inhibitor or ARB, and beta-blocker unless contraindicated or not tolerated. Echocardiograms were obtained at baseline, and following 26-36 weeks of treatment. The primary endpoint was change in left ventricular end-systolic volume from baseline to 36 weeks, and was evaluable in 329 patients in the placebo group and 343 patients in the aliskiren group. We observed no difference in the primary endpoint of end-systolic volume change between patients randomized to aliskiren (-4.4 ± 16.8 mL) or placebo (-3.5 ± 16.3 mL), or in secondary measures of end-diastolic volume, or LVEF. We also observed no differences in a composite endpoint of cardiovascular death, hospitalization for heart failure, or reduction in LVEF >6 points. There were more investigator reported adverse events in the aliskiren group, including hypotension, increases in creatinine and hyperkalaemia. Adding the direct renin inhibitor aliskiren to the standard therapy, including an inhibitor of the RAAS, in high-risk post-MI patients did not result in further attenuation of left ventricular remodelling, and was associated with more adverse effects. These findings do not suggest that dual RAAS blockade with

  9. Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling.

    PubMed

    Zhu, Baoling; Liu, Kai; Yang, Chengzhi; Qiao, Yuhui; Li, Zijian

    2016-12-01

    Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro-Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.

  10. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer.

    PubMed

    Cox, Thomas R; Erler, Janine T

    2011-03-01

    Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.

  11. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer

    PubMed Central

    Cox, Thomas R.; Erler, Janine T.

    2011-01-01

    Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM. PMID:21324931

  12. Classification and Prognostic Evaluation of Left Ventricular Remodeling in Patients With Asymptomatic Heart Failure.

    PubMed

    Pugliese, Nicola Riccardo; Fabiani, Iacopo; La Carrubba, Salvatore; Conte, Lorenzo; Antonini-Canterin, Francesco; Colonna, Paolo; Caso, Pio; Benedetto, Frank; Santini, Veronica; Carerj, Scipione; Romano, Maria Francesca; Citro, Rodolfo; Di Bello, Vitantonio

    2017-01-01

    Patients with asymptomatic heart failure (HF; stage A and B) are characterized by maladaptive left ventricular (LV) remodeling. Classic 4-group classification of remodeling considers only LV mass index and relative wall thickness as variables. Complex remodeling classification (CRC) includes also LV end-diastolic volume index. Main aim was to assess the prognostic impact of CRC in stage A and B HF. A total of 1,750 asymptomatic subjects underwent echocardiographic examination as a screening evaluation in the presence of cardiovascular risk factors. LV dysfunction, both systolic (ejection fraction) and diastolic (transmitral flow velocity pattern), was evaluated, together with LV remodeling. We considered a composite end point: all-cause death, myocardial infarction, coronary revascularizations, cerebrovascular events, and acute pulmonary edema. CRC was suitable for 1,729 patients (men 53.6%; age 58.3 ± 13 years). Two hundred thirty-eight patients presented systolic dysfunction (ejection fraction <50%) and 483 diastolic dysfunction. According to the CRC, 891 patients were normals or presented with physiologic hypertrophy, 273 concentric remodeling, 47 eccentric remodeling, 350 concentric hypertrophy, 29 mixed hypertrophy, 86 dilated hypertrophy, and 53 eccentric hypertrophy. Age and gender distribution was noticed (p <0.001). After a median follow-up of 21 months, Kaplan-Meier analysis showed different survival distribution (p <0.001) of the CRC patterns. In multivariate Cox regression (adjusted for age, gender, history of stable ischemic heart disease, classic remodeling classification, systolic, and diastolic dysfunction), CRC was independent predictor of primary end point (p = 0.044, hazard ratio 1.101, 95% CI 1.003 to 1.21), confirmed in a logistic regression (p <0.03). In conclusion, CRC could help physicians in prognostic stratification of patients in stage A and B HF. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Chromatin remodeling: nucleosomes bulging at the seams.

    PubMed

    Peterson, Craig L

    2002-04-02

    ATP-dependent chromatin remodeling enzymes, such as SWI/SNF, hydrolyze thousands of ATPs to regulate gene expression on chromatin fibers. Recent mechanistic studies suggest that these enzymes generate localized changes in DNA topology that drive formation of multiple, remodeled nucleosomal states.

  14. Remodeling, Renovation, & Conversion of Educational Facilities.

    ERIC Educational Resources Information Center

    Association of Physical Plant Administrators of Universities and Colleges, Washington, DC.

    Based on a series of workshops, this collection of papers provides a framework for thought--emphasizing planning within time, flexibility, and maintenance constraints--as well as a practical guide for actual engineering of remodeling/renovation/conversion projects. Is remodeling always less expensive than new construction? Should high initial…

  15. An Analysis of the Residential Remodeling Occupation.

    ERIC Educational Resources Information Center

    Scruggs, Kenneth

    The general purpose of the occupational analysis is to provide workable, basic information dealing with the many and varied duties performed in the residential remodeling occupation. The analysis only briefly covers the many areas of residential remodeling. The document opens with a brief introduction followed by a job description. The bulk of the…

  16. Cervical Remodeling during Pregnancy and Parturition

    PubMed Central

    Timmons, Brenda; Akins, Meredith; Mahendroo, Mala

    2010-01-01

    Appropriate and timely cervical remodeling is key for successful birth. Premature cervical opening can result in preterm birth which occurs in 12.5% of pregnancies. Research focused on the mechanisms of term and preterm cervical remodeling is essential to prevent prematurity. This review highlights recent findings that better define molecular processes driving progressive disorganization of the cervical extracellular matrix. This includes studies that redefine the role of immune cells and identify diverse functions of the cervical epithelia and hyaluronan in remodeling. New investigations proposing that infection-induced premature cervical remodeling is distinct from the normal process are presented. Recent advances in our understanding of term and preterm cervical remodeling provide new directions for investigation and compel investigators to reevaluate currently accepted models. PMID:20172738

  17. Nucleosome dynamics during chromatin remodeling in vivo.

    PubMed

    Ramachandran, Srinivas; Henikoff, Steven

    2016-01-01

    Precise positioning of nucleosomes around regulatory sites is achieved by the action of chromatin remodelers, which use the energy of ATP to slide, evict or change the composition of nucleosomes. Chromatin remodelers act to bind nucleosomes, disrupt histone-DNA interactions and translocate the DNA around the histone core to reposition nucleosomes. Hence, remodeling is expected to involve nucleosomal intermediates with a structural organization that is distinct from intact nucleosomes. We describe the identification of a partially unwrapped nucleosome structure using methods that map histone-DNA contacts genome-wide. This alternative nucleosome structure is likely formed as an intermediate or by-product during nucleosome remodeling by the RSC complex. Identification of the loss of histone-DNA contacts during chromatin remodeling by RSC in vivo has implications for the regulation of transcriptional initiation.

  18. Adverse reactions to sulfites

    PubMed Central

    Yang, William H.; Purchase, Emerson C.R.

    1985-01-01

    Sulfites are widely used as preservatives in the food and pharmaceutical industries. In the United States more than 250 cases of sulfite-related adverse reactions, including anaphylactic shock, asthmatic attacks, urticaria and angioedema, nausea, abdominal pain and diarrhea, seizures and death, have been reported, including 6 deaths allegedly associated with restaurant food containing sulfites. In Canada 10 sulfite-related adverse reactions have been documented, and 1 death suspected to be sulfite-related has occurred. The exact mechanism of sulfite-induced reactions is unknown. Practising physicians should be aware of the clinical manifestations of sulfite-related adverse reactions as well as which foods and pharmaceuticals contain sulfites. Cases should be reported to health officials and proper advice given to the victims to prevent further exposure to sulfites. The food industry, including beer and wine manufacturers, and the pharmaceutical industry should consider using alternative preservatives. In the interim, they should list any sulfites in their products. PMID:4052897

  19. [Cardiovascular screening].

    PubMed

    Pellizzari, Barbara; Siddu, Andrea; Ferro, Antonio; Colonna, Manuela; Mantovani, William; Valsecchi, Massimo; Marensi, Lorenzo; Moro, Alessandro; Brusaferro, Silvio; Cinquetti, Sandro

    2014-01-01

    To evaluate, through active call, lifestyles of an asymptomatic population in order to identify hyperglycaemic subjects and/or high-blood pressure sufferers to dispatch to their GP to perform suitable checking, and subjects to invite to a cardiovascular disease prevention programme because of their lifestyles. Between April 2011 and March 2013, all healthy residents in 6 Local Health Authorities of Regione Veneto aged 45-59 years were invited to join a cardiovascular disease prevention programme. All participants were evaluated through an administered lifestyle questionnaire. Parameters such as blood pressure (BP), glycemia, waist circumference and body mass index were collected and recorded. Participants also received counseling, informational materials on lifestyle and were invited to individual or group health promotion initiatives in relation to personal risk factors. Among the invited, 60.84%(10,346/17,004) adhered. Subjects without risks factors were 23.95%. Subjects with lifestyle risk factors but normal BP and glycemia were 56.59%, while those with altered values for BP and glycemia were 13.9%. The 5.55% of the respondents was not eligible for the study. The results confirmthat a preventive programme based on the citizens active call by the Department of prevention could be an effective tool to identify asymptomatic individuals with unknown hypertension and/or hyperglycaemia and to offer lifestyle interventions to lower the risk of cardiovascular diseases. Since the results were positive, the the Regional Veneto Centre for Disease Prevention and Control (CCMR - Veneto) presented a similar project to the Ministry of Health, involving 12 Italian Regions.

  20. 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

  1. 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.

  2. Ghrelin signaling in heart remodeling of adult obese mice.

    PubMed

    Lacerda-Miranda, Glauciane; Soares, Vivian M; Vieira, Anatalia K G; Lessa, Juliana G; Rodrigues-Cunha, Alessandra C S; Cortez, Erika; Garcia-Souza, Erica P; Moura, Anibal S

    2012-05-01

    Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology, content and phosphorilation of cardiac proteins: ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK) and actin were achieved by Western blotting. GHSR-1a gene expression was analyzed by Real Time-PCR. We observed hyperglycemia and higher liver and visceral fat weight in obese when compared to control group. Obese mice presented a marked increase in heart weight/tibia length, indicating an enlarged heart size or a remodeling process. Obese mice had increased GHSR-1a content and expression in the heart associated to PI3K content and increased AKT content and phosphorylation. In contrast, AMPK content and phosphorylation in heart was not different between experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. Our data suggest that remodeled myocardial in adult obese mice overnourished in early life are associated with higher phosphorylation of GHSR-1a, PI3K and AKT but not with AMPK.

  3. Cardiovascular Autonomic Dysfunction in Chronic Kidney Disease: a Comprehensive Review.

    PubMed

    Salman, Ibrahim M

    2015-08-01

    Cardiovascular autonomic dysfunction is a major complication of chronic kidney disease (CKD), likely contributing to the high incidence of cardiovascular mortality in this patient population. In addition to adrenergic overdrive in affected individuals, clinical and experimental evidence now strongly indicates the presence of impaired reflex control of both sympathetic and parasympathetic outflow to the heart and vasculature. Although the principal underlying mechanisms are not completely understood, potential involvements of altered baroreceptor, cardiopulmonary, and chemoreceptor reflex function, along with factors including but not limited to increased renin-angiotensin-aldosterone system activity, activation of the renal afferents and cardiovascular structural remodeling have been suggested. This review therefore analyzes potential mechanisms underpinning autonomic imbalance in CKD, covers results accumulated thus far on cardiovascular autonomic function studies in clinical and experimental renal failure, discusses the role of current interventional and therapeutic strategies in ameliorating autonomic deficits associated with chronic renal dysfunction, and identifies gaps in our knowledge of neural mechanisms driving cardiovascular disease in CKD.

  4. Calcium signalling remodelling and disease.

    PubMed

    Berridge, Michael J

    2012-04-01

    A wide range of Ca2+ signalling systems deliver the spatial and temporal Ca2+ signals necessary to control the specific functions of different cell types. Release of Ca2+ by InsP3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca2+ signals being set either too high or too low. Such subtle dysregulation of Ca2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease.

  5. Zika Virus Induced Cellular Remodeling.

    PubMed

    Rossignol, Evan D; Peters, Kristen N; Connor, John H; Bullitt, Esther

    2017-03-20

    Zika virus (ZIKV) has been associated with morbidities such as Guillain-Barré, infant microcephaly, and ocular disease. The spread of this positive-sense, single-stranded RNA virus and its growing public health threat underscore gaps in our understanding of basic ZIKV virology. To advance knowledge of the virus replication cycle within mammalian cells, we use serial section three-dimensional electron tomography to demonstrate the widespread remodeling of intracellular membranes upon infection with ZIKV. We report extensive structural rearrangements of the endoplasmic reticulum and reveal stages of the ZIKV viral replication cycle. Structures associated with RNA genome replication and virus assembly are observed integrated within the endoplasmic reticulum, and we show viruses in transit through the Golgi apparatus for viral maturation, and subsequent cellular egress. This study characterizes in detail the three-dimensional ultrastructural organization of the ZIKV replication cycle stages. Our results show close adherence of the ZIKV replication cycle to the existing flavivirus replication paradigm.

  6. [Ventricular "remodeling" after myocardial infarction].

    PubMed

    Cohen-Solal, A; Himbert, D; Guéret, P; Gourgon, R

    1991-06-01

    Cardiac failure is the principal medium-term complication of myocardial infarction. Changes in left ventricular geometry are observed after infarction, called ventricular remodeling, which, though compensatory initially, cause ventricular failure in the long-term. Experimental and clinical studies suggest that early treatment by coronary recanalisation, trinitrin and angiotensin converting enzyme inhibitors may prevent or limit the expansion and left ventricular dilatation after infarction, so improving ventricular function, and, at least in the animal, reduce mortality. Large scale trials with converting enzyme inhibitors are currently under way to determine the effects of this new therapeutic option. It would seem possible at present, independently of any reduction in the size of the infarction, to reduce or delay left ventricular dysfunction by interfering with the natural process of dilatation and ventricular modeling after infarction.

  7. Metabolic Remodeling in early development and cardiomyocyte maturation

    PubMed Central

    Kreipke, Rebecca; Wang, Yuliang; Miklas, Jason Wayne; Mathieu, Julie; Ruohola-Baker, Hannele

    2016-01-01

    Aberrations in metabolism contribute to a large number of diseases, such as diabetes, obesity, cancer, and cardiovascular diseases, that have a substantial impact on the mortality rates and quality of life worldwide. However, the mechanisms leading to these changes in metabolic state – and whether they are conserved between diseases – is not well understood. Changes in metabolism similar to those seen in pathological conditions are observed during normal development in a number of different cell types. This provides hope that understanding the mechanism of these metabolic switches in normal development may provide useful insight in correcting them in pathological cases. Here, we focus on the metabolic remodeling observed both in early stage embryonic stem cells and during the maturation of cardiomyocytes. PMID:26912118

  8. Vascular remodelling and molecular biology: new concepts and therapeutic possibilities.

    PubMed

    Agrotis, A; Bobik, A

    1996-05-01

    1. Over the past decade major advances in molecular cell biology have greatly increased our understanding of the way in which many growth factor genes are expressed and regulated. This knowledge is currently being translated into investigations of the cardiovascular system. 2. Two growth factor families appear to play particularly important roles, the fibroblast growth factors and the transforming growth factors-beta. These are multifunctional growth factors capable of remodelling the vasculature through their effects on cell migration, proliferation and matrix formation. 3. An understanding of their regulation, properties and nature of their receptors is providing novel insights into the physiology and pathobiology of the vasculature. It is also providing highly specific targets for future therapy.

  9. Tissue remodelling in pulmonary fibrosis.

    PubMed

    Knudsen, Lars; Ruppert, Clemens; Ochs, Matthias

    2017-03-01

    Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease. The current concept suggests an ongoing injury of the alveolar epithelium, an impaired regeneration capacity, alveolar collapse and, finally, a fibroproliferative response. The origin of lung injury remains elusive but a diversity of factors, which will be discussed in this article, has been shown to be associated with IPF. Alveolar epithelial type II (AE2) cells play a key role in lung fibrosis and their crucial role for epithelial regeneration, stabilisation of alveoli and interaction with fibroblasts, all known to be responsible for collagen deposition, will be illustrated. Whereas mechanisms of collagen deposition and fibroproliferation are the focus of many studies in the field, the awareness of other mechanisms in this disease is currently limited to biochemical and imaging studies including quantitative assessments of lung structure in IPF and animal models assigning alveolar collapse and collapse induration crucial roles for the degradation of the lung resulting in de-aeration and loss of surface area. Dysfunctional AE2 cells, instable alveoli and mechanical stress trigger remodelling that consists of collapsed alveoli absorbed by fibrotic tissue (i.e., collapse induration).

  10. Cardiac remodeling and physical training post myocardial infarction

    PubMed Central

    Garza, Michael A; Wason, Emily A; Zhang, John Q

    2015-01-01

    After myocardial infarction (MI), the heart undergoes extensive myocardial remodeling through the accumulation of fibrous tissue in both the infarcted and noninfarcted myocardium, which distorts tissue structure, increases tissue stiffness, and accounts for ventricular dysfunction. There is growing clinical consensus that exercise training may beneficially alter the course of post-MI myocardial remodeling and improve cardiac function. This review summarizes the present state of knowledge regarding the effect of post-MI exercise training on infarcted hearts. Due to the degree of difficulty to study a viable human heart at both protein and molecular levels, most of the detailed studies have been performed by using animal models. Although there are some negative reports indicating that post-MI exercise may further cause deterioration of the wounded hearts, a growing body of research from both human and animal experiments demonstrates that post-MI exercise may beneficially alter the course of wound healing and improve cardiac function. Furthermore, the improved function is likely due to exercise training-induced mitigation of renin-angiotensin-aldosterone system, improved balance between matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1, favorable myosin heavy chain isoform switch, diminished oxidative stress, enhanced antioxidant capacity, improved mitochondrial calcium handling, and boosted myocardial angiogenesis. Additionally, meta-analyses revealed that exercise-based cardiac rehabilitation has proven to be effective, and remains one of the least expensive therapies for both the prevention and treatment of cardiovascular disease, and prevents re-infarction. PMID:25717353

  11. Structural Stability and Functional Remodeling of High-Density Lipoproteins

    PubMed Central

    Gursky, Olga

    2015-01-01

    Lipoproteins are protein-lipid nanoparticles that transport lipids in circulation and are central in atherosclerosis and other disorders of lipid metabolism. Apolipoproteins form flexible structural scaffolds and important functional ligands on the particle surface and direct lipoprotein metabolism. Lipoproteins undergo multiple rounds of metabolic remodeling that is crucial to lipid transport. Important aspects of this remodeling, including apolipoprotein dissociation and particle fusion, are mimicked in thermal or chemical denaturation and are modulated by free energy barriers. Here we review our biophysical studies that revealed kinetic mechanism of lipoprotein stabilization and unraveled its structural basis. The main focus is on high-density lipoprotein (HDL). An inverse correlation between stability and functions of various HDLs in cholesterol transport suggests functional role of structural disorder. A mechanism for conformational adaptation of the major HDL proteins, apoA-I and apoA-II, to the increasing lipid load is proposed. Together, these studies help understand why HDL form discrete subclasses separated by kinetic barriers, which have distinct composition, conformation and functional properties. Understanding these properties may help improve HDL quality and develop novel therapies for cardiovascular disease. PMID:25749369

  12. Left ventricular structure and remodeling in patients with COPD

    PubMed Central

    Pelà, Giovanna; Li Calzi, Mauro; Pinelli, Silvana; Andreoli, Roberta; Sverzellati, Nicola; Bertorelli, Giuseppina; Goldoni, Matteo; Chetta, Alfredo

    2016-01-01

    Background Data on cardiac alterations such as left ventricular (LV) hypertrophy, diastolic dysfunction, and lower stroke volume in patients with COPD are discordant. In this study, we investigated whether early structural and functional cardiac changes occur in patients with COPD devoid of manifest cardiovascular disease, and we assessed their associations with clinical and functional features. Methods Forty-nine patients with COPD belonging to all Global Initiative for Chronic Obstructive Lung Disease (GOLD) classes were enrolled and compared with 36 controls. All subjects underwent clinical history assessment, lung function testing, blood pressure measurement, electrocardiography, and conventional and Doppler tissue echocardiography. Patients were also subjected to computed tomography to quantify emphysema score. Results Patients with COPD had lower LV cavity associated with a marked increase in relative wall thickness (RWT), suggesting concentric remodeling without significant changes in LV mass. RWT was significantly associated with ratio of the forced expiratory volume in 1 second to the forced vital capacity and emphysema score and was the only cardiac parameter that – after multivariate analysis – significantly correlated with COPD conditions in all individuals. Receiver operating characteristic curve analysis showed that RWT (with a cutoff point of 0.42) predicted the severity of COPD with 83% specificity and 56% sensitivity (area under the curve =0.69, 95% confidence interval =0.59–0.81). Patients with COPD showed right ventricular to be functional but no structural changes. Conclusion Patients with COPD without evident cardiovascular disease exhibit significant changes in LV geometry, resulting in concentric remodeling. In all individuals, RWT was significantly and independently related to COPD. However, its prognostic role should be determined in future studies. PMID:27257378

  13. Scientists Trace Adversity's Toll

    ERIC Educational Resources Information Center

    Sparks, Sarah D.

    2012-01-01

    The stress of a spelling bee or a challenging science project can enhance a student's focus and promote learning. But the stress of a dysfunctional or unstable home life can poison a child's cognitive ability for a lifetime, according to new research. Those studies show that stress forms the link between childhood adversity and poor academic…

  14. Scientists Trace Adversity's Toll

    ERIC Educational Resources Information Center

    Sparks, Sarah D.

    2012-01-01

    The stress of a spelling bee or a challenging science project can enhance a student's focus and promote learning. But the stress of a dysfunctional or unstable home life can poison a child's cognitive ability for a lifetime, according to new research. Those studies show that stress forms the link between childhood adversity and poor academic…

  15. Mineral metabolism and cardiovascular disease in CKD.

    PubMed

    Fujii, Hideki; Joki, Nobuhiko

    2017-03-01

    The mineral bone disorder of CKD, called Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), has a major role in the etiology and progression of cardiovascular disease in CKD patients. Since the main emphasis in CKD-MBD is on three categories (bone abnormalities, laboratory abnormalities, and vascular calcifications), we have routinely accepted ectopic cardiovascular calcifications as a central risk factor in the pathophysiology of CKD-MBD for cardiac events. However, recent compelling evidence suggests that some CKD-MBD-specific factors other than vascular calcification might contribute to the onset of cardiovascular disease. Most notable is fibroblast growth factor-23 (FGF23), which is thought to be independently associated with cardiac remodeling. Slow progression of cardiac disorders, such as vascular calcification and cardiac remodeling, characterizes cardiac disease due to CKD-MBD. In contrast, fatal arrhythmia may be induced when QT prolongation occurs with CKD-MBD treatment, such as with lower Ca dialysate or the use of calcimimetics. Sudden onset of fatal cardiac events, such as heart failure and sudden cardiac death, due to fatal arrhythmia would be another distinctive phenomenon of CKD-MBD. This may be defined as CKD-MBD-specific cardiac complex syndrome.

  16. EMBRYONIC VASCULAR DISRUPTION ADVERSE OUTCOMES: LINKING HIGH THROUGHPUT SIGNALING SIGNATURES WITH FUNCTIONAL CONSEQUENCES

    EPA Science Inventory

    Embryonic vascular disruption is an important adverse outcome pathway (AOP) given the knowledge that chemical disruption of early cardiovascular system development leads to broad prenatal defects. High throughput screening (HTS) assays provide potential building blocks for AOP d...

  17. Rheumatoid Arthritis is Associated with Left Ventricular Concentric Remodeling: Results of a Population-based Cross-sectional Study

    PubMed Central

    Myasoedova, Elena; Davis, John M.; Crowson, Cynthia S.; Roger, Véronique L.; Karon, Barry L.; Borgeson, Daniel D.; Therneau, Terry M.; Matteson, Eric L.; Rodeheffer, Richard J.; Gabriel, Sherine E.

    2014-01-01

    Objective To study left ventricular (LV) geometry in patients with rheumatoid arthritis (RA) who have no heart failure (HF) versus subjects without either RA or HF, and to determine the impact of RA on LV remodeling. Methods A cross-sectional, community-based study was conducted among adult (≥50 years) RA patients and age- and sex-matched non-RA subjects without a history of HF. All participants underwent a standard 2D/Doppler echocardiography. LV geometry was classified into four categories based on relative wall thickness and sex-specific cut-offs for LV mass index: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, or normal geometry. Results The study included 200 RA patients and 600 matched non-RA subjects (mean age 65; 74% female in both cohorts). RA patients were significantly more likely to have abnormal LV geometry than non-RA subjects (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.03, 2.00), adjusting for cardiovascular risk factors and comorbidities. Among those with abnormal LV geometry, RA patients had significantly increased odds of concentric LV remodeling (OR 4.73; 95% CI 2.85, 7.83). In linear regression analyses, LV mass index appeared to be lower in RA patients currently using corticosteroids (Beta +/− standard error: −0.082 +/− 0.027; p=0.002), adjusting for cardiovascular risk factors and comorbidities. Conclusion RA was strongly associated with abnormal LV remodeling, particularly, with concentric LV remodeling, among patients without HF. This association was significant beyond adjustment for cardiovascular risk factors and comorbidities. RA disease related factors may promote changes in LV geometry. The biological mechanisms underlying LV remodeling warrant further investigation. PMID:23553738

  18. Alcohol Reduces Arterial Remodeling by Inhibiting Sonic Hedgehog-Stimulated Sca1(+) Progenitor Stem Cell Expansion.

    PubMed

    Fitzpatrick, Emma; Han, Xu; Liu, Weimin; Corcoran, Eoin; Burtenshaw, Denise; Alshamrani, Maryam; Morrow, David; Helt, Jay-Christian; Cahill, Paul A; Redmond, Eileen M

    2017-09-18

    Cell and molecular mechanisms mediating the cardiovascular effects of alcohol are not fully understood. Our aim was to determine the effect of moderate Ethanol (EtOH) on Sonic Hedgehog (SHh) signaling in regulating possible Sca1(+) progenitor stem cell involvement during pathologic arterial remodeling. Partial ligation or sham-operation of the left carotid artery was performed in transgenic Sca1-eGFP mice gavaged with or without 'daily moderate' EtOH. The EtOH group had reduced adventitial thickening and less neo-intimal formation, compared to ligated controls. There was expansion of eGFP expressing (i.e., Sca1(+) ) cells in remodeled vessels post-ligation (14d), especially in the neo-intima. Ethanol treatment reduced the number of Sca1(+) cells in ligated vessel cross-sections concomitant with diminished remodeling, compared to control ligated vessels. Moreover, EtOH attenuated SHh signaling in injured carotids as determined by immunohistochemical analysis of the target genes patched 1 (Ptch1) and Gli2, and RT-PCR of whole vessel Gli2 mRNA levels. Intraperitoneal injection of ligated Sca1 - eGFP mice with the SHh signaling inhibitor cyclopamine diminished hedgehog target gene expression, reduced the number of Sca1(+) cells, and ameliorated carotid remodeling. EtOH treatment of purified Sca1(+) adventitial progenitor stem cells in vitro inhibited SHh signaling, and their rSHh-induced differentiation to vascular smooth muscle cells. EtOH reduces SHh - responsive Sca1(+) progenitor cell myogenic differentiation/expansion in vitro and during arterial remodeling in response to ligation injury in vivo. Regulation of vascular Sca1(+) progenitor cells in this way may be an important novel mechanism contributing to alcohol's cardiovascular protective effects. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. Sex Differences in the Developmental Origins of Cardiovascular Disease

    PubMed Central

    Intapad, Suttira; Ojeda, Norma B.; Dasinger, John Henry

    2014-01-01

    The Developmental Origins of Health and Disease (DOHaD) proposes that adverse events during early life program an increased risk for cardiovascular disease. Experimental models provide proof of concept but also indicate that insults during early life program sex differences in adult blood pressure and cardiovascular risk. This review will highlight the potential mechanisms that contribute to the etiology of sex differences in the developmental programming of cardiovascular disease. PMID:24583768

  20. How May Proton Pump Inhibitors Impair Cardiovascular Health?

    PubMed

    Sukhovershin, Roman A; Cooke, John P

    2016-06-01

    Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastroesophageal disorders and are usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article, we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health.

  1. Airway remodeling in asthma: what really matters.

    PubMed

    Fehrenbach, Heinz; Wagner, Christina; Wegmann, Michael

    2017-03-01

    Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and "endotyped" human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

  2. Adverse health effects of non-medical cannabis use.

    PubMed

    Hall, Wayne; Degenhardt, Louisa

    2009-10-17

    For over two decades, cannabis, commonly known as marijuana, has been the most widely used illicit drug by young people in high-income countries, and has recently become popular on a global scale. Epidemiological research during the past 10 years suggests that regular use of cannabis during adolescence and into adulthood can have adverse effects. Epidemiological, clinical, and laboratory studies have established an association between cannabis use and adverse outcomes. We focus on adverse health effects of greatest potential public health interest-that is, those that are most likely to occur and to affect a large number of cannabis users. The most probable adverse effects include a dependence syndrome, increased risk of motor vehicle crashes, impaired respiratory function, cardiovascular disease, and adverse effects of regular use on adolescent psychosocial development and mental health.

  3. Adverse Events of Monoclonal Antibodies Used for Cancer Therapy

    PubMed Central

    Guan, Mei; Zhou, Yan-Ping; Sun, Jin-Lu; Chen, Shu-Chang

    2015-01-01

    In 1997, the first monoclonal antibody (MoAb), the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug administration for use in cancer patients. Since then, the panel of MoAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has continued to expand, currently encompassing a stunning amount of 20 distinct molecules for 11 targets. We provide a brief scientific background on the use of MoAbs in cancer therapy, review all types of monoclonal antibodies-related adverse events (e.g., allergy, immune-related adverse events, cardiovascular adverse events, and pulmonary adverse events), and discuss the mechanism and treatment of adverse events. PMID:26075239

  4. Maternal Uterine Vascular Remodeling During Pregnancy

    PubMed Central

    Osol, George; Mandala, Maurizio

    2009-01-01

    Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodeling of the entire uterine circulation, as well as the creation of a new fetal vascular organ: the placenta. The process of remodeling involves a number of cellular processes, including hyperplasia and hypertrophy, rearrangement of existing elements, and changes in extracellular matrix. In this review, we provide information on uterine blood flow increases during pregnancy, the influence of placentation type on the distribution of uterine vascular resistance, consideration of the patterns, nature, and extent of maternal uterine vascular remodeling during pregnancy, and what is known about the underlying cellular mechanisms. PMID:19196652

  5. Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling

    PubMed Central

    2013-01-01

    Background The late cardiotoxic effects of anthracycline chemotherapy influence morbidity and mortality in the growing population of childhood cancer survivors. Even with lower anthracycline doses, evidence of adverse cardiac remodeling and reduced exercise capacity exist. We aim to examine the relationship between cardiac structure, function and cardiovascular magnetic resonance (CMR) tissue characteristics with chemotherapy dose and exercise capacity in childhood cancer survivors. Methods Thirty patients (15 ± 3 years), at least 2 years following anthracycline treatment, underwent CMR, echocardiography, and cardiopulmonary exercise testing (peak VO2). CMR measured ventricular function, mass, T1 and T2 values, and myocardial extracellular volume fraction, ECV, a measure of diffuse fibrosis based on changes in myocardial T1 values pre- and post-gadolinium. Cardiac function was also assessed with conventional and speckle tracking echocardiography. Results Patients had normal LVEF (59 ± 7%) but peak VO2 was 17% lower than age-predicted normal values and were correlated with anthracycline dose (r = −0.49). Increased ECV correlated with decreased mass/volume ratio (r = −0.64), decreased LV wall thickness/height ratio (r = −0.72), lower peak VO2(r = −0.52), and higher cumulative dose (r = 0.40). Echocardiographic measures of systolic and diastolic function were reduced compared to normal values (p < 0.01), but had no relation to ECV, peak VO2 or cumulative dose. Conclusions Myocardial T1 and ECV were found to be early tissue markers of ventricular remodeling that may represent diffuse fibrosis in children with normal ejection fraction post anthracycline therapy, and are related to cumulative dose, exercise capacity and myocardial wall thinning. PMID:23758789

  6. Cardiovascular group

    NASA Technical Reports Server (NTRS)

    Blomqvist, Gunnar

    1989-01-01

    As a starting point, the group defined a primary goal of maintaining in flight a level of systemic oxygen transport capacity comparable to each individual's preflight upright baseline. The goal of maintaining capacity at preflight levels would seem to be a reasonable objective for several different reasons, including the maintenance of good health in general and the preservation of sufficient cardiovascular reserve capacity to meet operational demands. It is also important not to introduce confounding variables in whatever other physiological studies are being performed. A change in the level of fitness is likely to be a significant confounding variable in the study of many organ systems. The principal component of the in-flight cardiovascular exercise program should be large-muscle activity such as treadmill exercise. It is desirable that at least one session per week be monitored to assure maintenance of proper functional levels and to provide guidance for any adjustments of the exercise prescription. Appropriate measurements include evaluation of the heart-rate/workload or the heart-rate/oxygen-uptake relationship. Respiratory gas analysis is helpful by providing better opportunities to document relative workload levels from analysis of the interrelationships among VO2, VCO2, and ventilation. The committee felt that there is no clear evidence that any particular in-flight exercise regimen is protective against orthostatic hypotension during the early readaptation phase. Some group members suggested that maintenance of the lower body muscle mass and muscle tone may be helpful. There is also evidence that late in-flight interventions to reexpand blood volume to preflight levels are helpful in preventing or minimizing postflight orthostatic hypotension.

  7. Adverse cardiac events to monoclonal antibodies used for cancer therapy

    PubMed Central

    Kounis, Nicholas G; Soufras, George D; Tsigkas, Grigorios; Hahalis, George

    2014-01-01

    Monoclonal antibodies are currently used in the treatment of neoplastic, hematological, or inflammatory diseases, a practice that is occasionally associated with a variety of systemic and cutaneous adverse events. Cardiac adverse events include cardiomyopathy, ventricular dysfunction, arrhythmias, arrests, and acute coronary syndromes, such as acute myocardial infarction and vasospastic angina pectoris. These events generally follow hypersensitivity reactions including cutaneous erythema, pruritus chills, and precordial pain. Recently, IgE specific for therapeutic monoclonal antibodies have been detected, pointing to the existence of hypersensitivity and Kounis hypersensitivity-associated syndrome. Therefore, the careful monitoring of cardiovascular events is of paramount importance in the course of monoclonal antibody-based therapies. Moreover, further studies are needed to elucidate the pathophysiology of cardiovascular adverse events elicited by monoclonal antibodies and to identify preventive, protective, and therapeutic measures. PMID:25340003

  8. Simulations of trabecular remodeling and fatigue: is remodeling helpful or harmful?

    PubMed

    van Oers, René F M; van Rietbergen, Bert; Ito, Keita; Huiskes, Rik; Hilbers, Peter A J

    2011-05-01

    Microdamage-targeted resorption is paradoxal, because it entails the removal of bone from a region that was already overloaded. Under continued intense loading, resorption spaces could potentially cause more damage than they remove. To investigate this problem, we incorporated damage algorithms in a computer-simulation model for trabecular remodeling. We simulated damage accumulation and bone remodeling in a trabecular architecture, for two fatigue regimens, a 'moderate' regimen, and an 'intense' regimen with a higher number of loading cycles per day. Both simulations were also performed without bone remodeling to investigate if remodeling removed or exacerbated the damage. We found that remodeling tends to remove damage under the 'moderate' fatigue regimen, but it exacerbates damage under the 'intense' regimen. This harmful effect of remodeling may play a role in the development of stress fractures.

  9. Adverse drug reactions.

    PubMed

    O'Reilly-Foley, Georgina

    2017-04-05

    What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article defined the different types of adverse drug reactions (ADRs) and explored when they can occur. It emphasised the importance of being knowledgeable about medications, considering patient safety when patients are taking medications, being alert to the possibility of ADRs, and recognising and responding to suspected ADRs.

  10. PPARγ and Its Role in Cardiovascular Diseases

    PubMed Central

    Chandra, Mini

    2017-01-01

    Peroxisome proliferator-activated receptor Gamma (PPARγ), a ligand-activated transcription factor, has a role in various cellular functions as well as glucose homeostasis, lipid metabolism, and prevention of oxidative stress. The activators of PPARγ are already widely used in the treatment of diabetes mellitus. The cardioprotective effect of PPARγ activation has been studied extensively over the years making them potential therapeutic targets in diseases associated with cardiovascular disorders. However, they are also associated with adverse cardiovascular events such as congestive heart failure and myocardial infarction. This review aims to discuss the role of PPARγ in the various cardiovascular diseases and summarize the current knowledge on PPARγ agonists from multiple clinical trials. Finally, we also review the new PPARγ agonists under development as potential therapeutics with reduced or no adverse effects. PMID:28243251

  11. Reverse remodeling and recovery from cachexia in rats with aldosteronism.

    PubMed

    Cheema, Yaser; Zhao, Wenyuan; Zhao, Tieqiang; Khan, M Usman; Green, Kelly D; Ahokas, Robert A; Gerling, Ivan C; Bhattacharya, Syamal K; Weber, Karl T

    2012-08-15

    The congestive heart failure (CHF) syndrome with soft tissue wasting, or cachexia, has its pathophysiologic origins rooted in neurohormonal activation. Mechanical cardiocirculatory assistance reveals the potential for reverse remodeling and recovery from CHF, which has been attributed to device-based hemodynamic unloading whereas the influence of hormonal withdrawal remains uncertain. This study addresses the signaling pathways induced by chronic aldosteronism in normal heart and skeletal muscle at organ, cellular/subcellular, and molecular levels, together with their potential for recovery (Recov) after its withdrawal. Eight-week-old male Sprague-Dawley rats were examined at 4 wk of aldosterone/salt treatment (ALDOST) and following 4-wk Recov. Compared with untreated, age-/sex-/strain-matched controls, ALDOST was accompanied by 1) a failure to gain weight, reduced muscle mass with atrophy, and a heterogeneity in cardiomyocyte size across the ventricles, including hypertrophy and atrophy at sites of microscopic scarring; 2) increased cardiomyocyte and mitochondrial free Ca(2+), coupled to oxidative stress with increased H(2)O(2) production and 8-isoprostane content, and increased opening potential of the mitochondrial permeability transition pore; 3) differentially expressed genes reflecting proinflammatory myocardial and catabolic muscle phenotypes; and 4) reversal to or toward recovery of these responses with 4-wk Recov. Aldosteronism in rats is accompanied by cachexia and leads to an adverse remodeling of the heart and skeletal muscle at organ, cellular/subcellular, and molecular levels. However, evidence presented herein implicates that these tissues retain their inherent potential for recovery after complete hormone withdrawal.

  12. Lead Poisoning in Remodeling of Old Homes

    ERIC Educational Resources Information Center

    Barnes, Bart

    1973-01-01

    An article based on Dr. Muriel D. Wolf's study of elevated blood lead levels in children and adults present during the remodeling of old homes. Lead poisoning examples, symptoms, and precautions are given. (ST)

  13. Raise the Floor When Remodeling Science Labs

    ERIC Educational Resources Information Center

    Nation's Schools, 1972

    1972-01-01

    A new remodeling idea adopts the concept of raised floor covering gas, water, electrical, and drain lines. The accessible floor has removable panels set into an adjustable support frame 24 inches above a concrete subfloor. (Author)

  14. B.B. Contracting & Remodeling Information Sheet

    EPA Pesticide Factsheets

    B.B. Contracting & Remodeling (the Company) is located in St. Louis, Missouri. The settlement involves renovation activities conducted at property constructed prior to 1978, located in St. Louis, Missouri.

  15. Impact of microvascular obstruction on semiautomated techniques for quantifying acute and chronic myocardial infarction by cardiovascular magnetic resonance

    PubMed Central

    Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; Bhuva, Anish N; Treibel, Thomas A; Fontana, Marianna; Weinmann, Shane; Sirker, Alex; Herrey, Anna S; Manisty, Charlotte; Moon, James C; Hausenloy, Derek J

    2016-01-01

    Aims The four most promising semiautomated techniques (5-SD, 6-SD, Otsu and the full width half maximum (FWHM)) were compared in paired acute and follow-up cardiovascular magnetic resonance (CMR), taking into account the impact of microvascular obstruction (MVO) and using automated extracellular volume fraction (ECV) maps for reference. Furthermore, their performances on the acute scan were compared against manual myocardial infarct (MI) size to predict adverse left ventricular (LV) remodelling (≥20% increase in end-diastolic volume). Methods 40 patients with reperfused ST segment elevation myocardial infarction (STEMI) with a paired acute (4±2 days) and follow-up CMR scan (5±2 months) were recruited prospectively. All CMR analysis was performed on CVI42. Results Using manual MI size as the reference standard, 6-SD accurately quantified acute (24.9±14.0%LV, p=0.81, no bias) and chronic MI size (17.2±9.7%LV, p=0.88, no bias). The performance of FWHM for acute MI size was affected by the acquisition sequence used. Furthermore, FWHM underestimated chronic MI size in those with previous MVO due to the significantly higher ECV in the MI core on the follow-up scans previously occupied by MVO (82 (75–88)% vs 62 (51–68)%, p<0.001). 5-SD and Otsu were precise but overestimated acute and chronic MI size. All techniques were performed with high diagnostic accuracy and equally well to predict adverse LV remodelling. Conclusions 6-SD was the most accurate for acute and chronic MI size and should be the preferred semiautomatic technique in randomised controlled trials. However, 5-SD, FWHM and Otsu could also be used when precise MI size quantification may be adequate (eg, observational studies). PMID:28008358

  16. Ventricular remodeling in global ischemia.

    PubMed

    Anversa, P; Zhang, X; Li, P; Olivetti, G; Cheng, W; Reiss, K; Sonnenblick, E H; Kajstura, J

    1995-06-01

    To determine the effects of chronic constriction of the left coronary artery on the function and structure of the heart, coronary artery narrowing was surgically induced in rats and ventricular pump performance, extent and distribution of myocardial damage, and the hypertrophic and hyperplastic response of myocytes were examined. Alterations in cardiac hemodynamics were found in all rats, but the characteristics of the physiological properties of the heart allowed a separation of the animals into two groups which exhibited left ventricular dysfunction and failure, respectively. Left ventricular hypertrophy occurred in both groups and was characterized by ventricular dilatation and wall thinning which were more severe in the failing animals. Multiple foci of myocardial damage across the wall were seen in all animals but tissue injury was more prominent in the endomyocardium and in failing rats. The anatomical and hemodynamic changes resulted in a significant increase in diastolic wall stress which paralleled the depression in ventricular performance. Myocyte cell loss and myocyte cellular hypertrophy were more severe with ventricular failure than with dysfunction. Finally, diastolic overload appeared to be coupled with activation of the DNA synthetic machinery of myocytes and nuclear mitotic division. In conclusion, a fixed lesion of the left coronary artery leads to abnormalities in cardiac dynamics with marked increases in diastolic wall stress and extensive ventricular remodeling in spite of compensatory myocyte cellular hypertrophy and hyperplasia in the remaining viable tissue.

  17. Minireview: Nuclear Receptor Regulation of Osteoclast and Bone Remodeling

    PubMed Central

    Jin, Zixue; Li, Xiaoxiao

    2015-01-01

    Osteoclasts are bone-resorbing cells essential for skeletal remodeling and regeneration. However, excessive osteoclasts often contribute to prevalent bone degenerative diseases such as osteoporosis, arthritis, and cancer bone metastasis. Osteoclast dysregulation is also associated with rare disorders such as osteopetrosis, pycnodysostosis, Paget's disease, and Gorham-Stout syndrome. The nuclear receptor (NR) family of transcription factors functions as metabolic sensors that control a variety of physiological processes including skeletal homeostasis and serves as attractive therapeutic targets for many diseases. In this review, we highlight recent findings on the new players and the new mechanisms for how NRs regulate osteoclast differentiation and bone resorption. An enhanced understanding of NR functions in osteoclastogenesis will facilitate the development of not only novel osteoprotective medicine but also prudent strategies to minimize the adverse skeletal effects of certain NR-targeting drugs for a better treatment of cancer and metabolic diseases. PMID:25549044

  18. Ghrelin and the Cardiovascular System.

    PubMed

    Lilleness, Brian M; Frishman, William H

    Ghrelin is a small peptide released primarily from the stomach. It is a potent stimulator of growth hormone secretion from the pituitary gland and is well known for its regulation of metabolism and appetite. There is also a strong relationship between ghrelin and the cardiovascular system. Ghrelin receptors are present throughout the heart and vasculature and have been linked with molecular pathways, including, but not limited to, the regulation of intracellular calcium concentration, inhibition of proapoptotic cascades, and protection against oxidative damage. Ghrelin shows robust cardioprotective effects including enhancing endothelial and vascular function, preventing atherosclerosis, inhibiting sympathetic drive, and decreasing blood pressure. After myocardial infarction, exogenous administration of ghrelin preserves cardiac function, reduces the incidence of fatal arrhythmias, and attenuates apoptosis and ventricular remodeling, leading to improvements in heart failure. It ameliorates cachexia in end-stage congestive heart failure patients and has shown clinical benefit in pulmonary hypertension. Nonetheless, since ghrelin's discovery is relatively recent, there remains a substantial amount of research needed to fully understand its clinical significance in cardiovascular disease.

  19. Remodeling kitchens: A smorgasbord of energy savings

    SciTech Connect

    Sullivan, B.

    1995-09-01

    The kitchen is often the busiest room in the house and is most likely to remodeled repeatedly over the life of a house. The kitchen also represents a concentration of household energy use. Remodeling a kitchen can mean introducing a host of new energy-saving features or making major energy blunders. This article discusses ways to utilized the best features: layout and design; appliances; lighting; windows and skylights; ventilation; insulation and air sealing; water; household recycling; green building materials.

  20. Laser therapy in cardiovascular disease

    NASA Astrophysics Data System (ADS)

    Rindge, David

    2009-02-01

    Cardiovascular disease is the number one cause of death worldwide. It is broadly defined to include anything which adversely affects the heart or blood vessels. One-third of Americans have one or more forms of it. By one estimate, average human life expectancy would increase by seven years if it were eliminated. The mainstream medical model seeks mostly to "manage" cardiovascular disease with pharmaceuticals or to surgically bypass or reopen blocked vessels via angioplasty. These methods have proven highly useful and saved countless lives. Yet drug therapy may be costly and ongoing, and it carries the risk of side effects while often doing little or nothing to improve underlying health concerns. Similarly, angioplasty or surgery are invasive methods which entail risk. Laser therapy1 regenerates tissue, stimulates biological function, reduces inflammation and alleviates pain. Its efficacy and safety have been increasingly well documented in cardiovascular disease of many kinds. In this article we will explore the effects of laser therapy in angina, atherosclerosis, coronary artery disease, hypertension, hyperlipidemia, myocardial infarction, stroke and other conditions. The clinical application of various methods of laser therapy, including laserpuncture and transcutaneous, supravascular and intravenous irradiation of blood will be discussed. Implementing laser therapy in the treatment of cardiovascular disease offers the possibility of increasing the health and wellbeing of patients while reducing the costs and enhancing safety of medical care.

  1. Diagnostic tools assessing airway remodelling in asthma.

    PubMed

    Manso, L; Reche, M; Padial, M A; Valbuena, T; Pascual, C

    2012-01-01

    Asthma is an inflammatory disease of the lower airways characterised by the presence of airway inflammation, reversible airflow obstruction and airway hyperresponsiveness and alterations on the normal structure of the airways, known as remodelling. Remodelling is characterised by the presence of metaplasia of mucous glands, thickening of the lamina reticularis, increased angiogenesis, subepithelial fibrosis and smooth muscle hypertrophy/hyperplasia. Several techniques are being optimised at present to achieve a suitable diagnosis for remodelling. Diagnostic tools could be divided into two groups, namely invasive and non-invasive methods. Invasive techniques bring us information about bronchial structural alterations, obtaining this information directly from pathological tissue, and permit measure histological modification placed in bronchi layers as well as inflammatory and fibrotic cell infiltration. Non-invasive techniques were developed to reduce invasive methods disadvantages and measure airway remodelling-related markers such as cytokines, inflammatory mediators and others. An exhaustive review of diagnostic tools used to analyse airway remodelling in asthma, including the most useful and usually employed methods, as well as the principal advantages and disadvantages of each of them, bring us concrete and summarised information about all techniques used to evaluate alterations on the structure of the airways. A deep knowledge of these diagnostic tools will make an early diagnosis of airway remodelling possible and, probably, early diagnosis will play an important role in the near future of asthma. Copyright © 2011 SEICAP. Published by Elsevier Espana. All rights reserved.

  2. Bone remodeling as a spatial evolutionary game.

    PubMed

    Ryser, Marc D; Murgas, Kevin A

    2017-04-07

    Bone remodeling is a complex process involving cell-cell interactions, biochemical signaling and mechanical stimuli. Early models of the biological aspects of remodeling were non-spatial and focused on the local dynamics at a fixed location in the bone. Several spatial extensions of these models have been proposed, but they generally suffer from two limitations: first, they are not amenable to analysis and are computationally expensive, and second, they neglect the role played by bone-embedded osteocytes. To address these issues, we developed a novel model of spatial remodeling based on the principles of evolutionary game theory. The analytically tractable framework describes the spatial interactions between zones of bone resorption, bone formation and quiescent bone, and explicitly accounts for regulation of remodeling by bone-embedded, mechanotransducing osteocytes. Using tools from the theory of interacting particle systems we systematically classified the different dynamic regimes of the spatial model and identified regions of parameter space that allow for global coexistence of resorption, formation and quiescence, as observed in physiological remodeling. In coexistence scenarios, three-dimensional simulations revealed the emergence of sponge-like bone clusters. Comparison between spatial and non-spatial dynamics revealed substantial differences and suggested a stabilizing role of space. Our findings emphasize the importance of accounting for spatial structure and bone-embedded osteocytes when modeling the process of bone remodeling. Thanks to the lattice-based framework, the proposed model can easily be coupled to a mechanical model of bone loading.

  3. Remodelling chromatin to shape development of plants.

    PubMed

    Gentry, Matthew; Hennig, Lars

    2014-02-01

    Establishment and dynamic regulation of a higher order chromatin structure is an essential component of development. Chromatin remodelling complexes such as the SWI2/SNF2 family of ATP-dependent chromatin remodellers can alter chromatin architecture by changing nucleosome positioning or substituting histones with histone variants. These remodellers often act in concert with chromatin modifiers such as the polycomb group proteins which confer repressive states through modification of histone tails. These mechanisms are highly conserved across the eukaryotic kingdom although in plants, owing to the maintenance of dedifferentiated cell states that allow for post-embyronic changes in development, strict control of chromatin remodelling is even more paramount. Recent and ongoing studies in the model plant Arabidopsis thaliana have found that while the major families of the SWI2/SNF2 ATPase chromatin remodellers are represented, a number of redundancies and divergent functions have emerged that show a break from the roles of their metazoan counterparts. This review focusses on the SNF2 and CHD families of ATP-dependent remodellers and their roles in plant development. © 2013 Published by Elsevier Inc.

  4. Adverse reactions to vaccines.

    PubMed

    Martin, Bryan L; Nelson, Michael R; Hershey, Joyce N; Engler, Renata J M

    2003-06-01

    (The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.) Immunization healthcare is becoming increasingly complex as the number and types of vaccines have continued to expand. Like all prescription drugs, vaccines may be associated with adverse events. The majority of these reactions are self-limited and not associated with prolonged disability. The media, Internet and public advocacy groups have focused on potentially serious vaccine-associated adverse events with questions raised about causal linkages to increasing frequencies of diseases such as autism and asthma. Despite a lack of evidence of a causal relationship to a variety of vaccine safety concerns, including extensive reviews by the Institute of Medicine, questions regarding vaccine safety continue to threaten the success of immunization programs. Risk communication arid individual risk assessment is further challenged by the public health success of vaccine programs creating the perception that certain vaccines are no longer necessary or justified because of the rare reaction risk. There is a need for improved understanding of true vaccine contraindications and precautions as well as host factors and disease threat in order to develop a patient specific balanced risk communication intervention. When they occur, vaccine related adverse events must be treated, documented and reported through the VAERS system. The increasing complexity of vaccination health care has led the Center of Disease Control and Prevention (CDC) to identify Vaccine Safety Assessment and Evaluation as a potential new specialty.

  5. [Remodeling of the aging heart : Sinus node dysfunction and atrial fibrillation].

    PubMed

    Weirich, Jörg

    2017-03-01

    The incidence of both sinus node dysfunction (SND) and atrial fibrillation (AF) increases with age. SND and AF frequently coexist. Likewise, they are often associated with cardiovascular diseases. Both arrhythmias share similar pathomechanisms such as structural and functional remodeling, i. e., degenerative fibrosis and altered Ca(2+) handling, respectively. A growing body of evidence suggests an important role for the CamKII (Ca(2+)/calmodulin-dependent protein kinase II) in structural as well as in functional remodeling. In the sinus node, remodeling leads to degenerative fibrosis and as a consequence to sinus node arrest or to reentry (brady/tachycardia). In the atrium, remodeling sets the conditions for reentry and its triggering mechanisms, especially the conditions for triggered activity on the basis of delayed afterdepolarizations (DAD). Thus, SND and AF seem to be different phenotypes of related pathophysiological mechanisms. On the other hand, it remains controversial as to whether SND causes AF or vice versa.

  6. [Adverse reactions to vaccines].

    PubMed

    Eseverri, J L; Ranea, S; Marin, A

    2003-01-01

    Adverse reactions to vaccines are highly varied, ranging from mild local reactions to fatal outcomes. In the last few years many adverse reactions have been attributed to vaccines, often without justification. In agreement with the World Health Organization, these reactions can be classified as follows, depending on the cause: vaccination-induced reactions (due to an effect of the vaccine itself or to an idiosyncrasy); reactions due to errors in storage, manipulation and/or administration; and coincidental reactions (no causal relationship with the vaccine). Hypersensitivity reactions fall into six categories, depending on the causative agent: reactions due to some component of the infectious agent or one of its products; reactions due to adjuvants: aluminium hydroxide; reactions due to stabilizers: gelatin; reactions due to preservatives: thiomersal; reactions due to antibiotics: neomycin; and reactions due to a biological culture medium: chicken embryo cells. Allergic children should not be excluded from the normal vaccine calendar. Immunologically, allergic individuals are more susceptible to infection and to microbial and viral diseases, which often play an aggravating role. Rubella, whooping cough, and influenza usually exacerbate respiratory allergies. Non-vaccination carries a marked risk of contracting serious diseases such as poliomyelitis, tetanus, and diphtheria, etc. In a not too distant future, the techniques of genetic recombination and monoclonal antibody production will allow the creation of vaccines from organisms that cannot be cultivated in the laboratory or that produce small quantities of antigen. These techniques will also lead to identification of the antigens with the greatest immunogenic power and, consequently, to extremely pure vaccines. The adverse reactions to vaccines referred to our service account for between 0.59 % and 1.27 % of first visits in the last three years. We recorded a total of 48 adverse reactions to vaccines. Of

  7. A natural product telomerase activator as part of a health maintenance program: metabolic and cardiovascular response.

    PubMed

    Harley, Calvin B; Liu, Weimin; Flom, Peter L; Raffaele, Joseph M

    2013-10-01

    A short average telomere length is associated with low telomerase activity and certain degenerative diseases. Studies in animals and with human cells confirm a causal mechanism for cell or tissue dysfunction triggered by critically short telomeres, suggesting that telomerase activation may be an approach to health maintenance. Previously, we reported on positive immune remodeling in humans taking a commercial health maintenance program, PattonProtocol-1, composed of TA-65® (a natural product-derived telomerase activator) and other dietary supplements. In over a 5-year period and an estimated 7000 person-years of use, no adverse events or effects have been attributed to TA-65 by physicians licensed to sell the product. Here we report on changes in metabolic markers measured at baseline (n=97-107 subjects) and every 3-6 months (n=27-59 subjects) during the first 12 months of study. Rates of change per year from baseline determined by a multi-level model were -3.72 mg/dL for fasting glucose (p=0.02), -1.32 mIU/mL for insulin (p=0.01), -13.2 and -11.8 mg/dL for total cholesterol and low-density lipoprotein cholesterol (LDL-C) (p=0.002, p=0.002, respectively), -17.3 and -4.2 mmHg for systolic and diastolic blood pressure (p=0.007 and 0.001, respectively), and -3.6 μmole/L homocysteine (p=0.001). In a subset of individuals with bone mineral density (BMD) measured at baseline and 12 months, density increased 2.0% in the spine (p=0.003). We conclude that in addition to apparent positive immune remodeling, PattonProtocol-1 may improve markers of metabolic, bone, and cardiovascular health.

  8. Vascular remodeling in transplant vasculopathy.

    PubMed

    Mitchell, Richard N; Libby, Peter

    2007-04-13

    As therapeutic strategies to prevent acute rejection progressively improve, transplant vasculopathy (TV) constitutes the single most important limitation for long-term functioning of solid organ allografts. In TV, allograft arteries characteristically develop severe, diffuse intimal hyperplastic lesions that eventually compromise luminal flow and cause ischemic graft failure. Traditional immunosuppressive strategies that check acute allograft rejection do not prevent TV; indeed 50% of transplant recipients will have significant disease within five years of organ transplantation, and 90% will have significant TV a decade after their surgery. TV can involve the entire length of the transplanted arterial bed, including penetrating intraorgan arterioles. Indeed, the luminal narrowing of such penetrating vessels may be the most functionally significant because arterioles represent the major contributors to tissue vascular resistance. Because of the diffuseness of TV involvement in the allograft vascular bed, the only currently definitive therapy requires re-transplantation. Nevertheless, as we better understand the pathogenesis and critical mediators of these lesions, pharmacological advances can be anticipated. Other articles in this thematic review series focus on the specifics of the inciting injury, the cytokines and chemokines that drive TV development, and the nature of the recruited cells in TV lesions, as well as the pathogenic similarities between TV and other vascular lesions such as atherosclerosis. This review focuses on the mechanisms of vascular wall remodeling in TV, including the intimal accumulation of smooth muscle-like cells and associated extracellular matrix, medial smooth muscle cell degeneration, and adventitial fibrosis. A brief overview highlights the aneurysmal changes that can accrue when vessel wall inflammation has a cytokine profile distinct from the typical proinflammatory interferon-gamma-dominated milieu.

  9. Associations of Left Ventricular Hypertrophy and Geometry with Adverse Outcomes in Patients with CKD and Hypertension.

    PubMed

    Paoletti, Ernesto; De Nicola, Luca; Gabbai, Francis B; Chiodini, Paolo; Ravera, Maura; Pieracci, Laura; Marre, Sonia; Cassottana, Paolo; Lucà, Sergio; Vettoretti, Simone; Borrelli, Silvio; Conte, Giuseppe; Minutolo, Roberto

    2016-02-05

    Left ventricular hypertrophy (LVH) and abnormal left ventricular (LV) geometry predict adverse outcomes in the general and hypertensive populations, but findings in CKD are still inconclusive. We enrolled 445 patients with hypertension and CKD stages 2-5 in two academic nephrology clinics in 1999-2003 who underwent both echocardiography and ambulatory BP monitoring. LVH (LV mass >100 g/m(2) [women] and >131 g/m(2) [men]) and relative wall thickness (RWT) were used to define LV geometry: no LVH and RWT≤0.45 (normal), no LVH and RWT>0.45 (remodeling), LVH and RWT≤0.45 (eccentric), and LVH and RWT>0.45 (concentric). We evaluated the prognostic role of LVH and LV geometry on cardiovascular (CV; composite of fatal and nonfatal events) and renal outcomes (composite of ESRD and all-cause death). Age was 64.1±13.8 years old; 19% had diabetes, and 22% had CV disease. eGFR was 39.9±20.2 ml/min per 1.73 m(2). LVH was detected in 249 patients (56.0%); of these, 125 had concentric LVH, and 124 had eccentric pattern, whereas 71 patients had concentric remodeling. Age, women, anemia, and nocturnal hypertension were independently associated with both concentric and eccentric LVH, whereas diabetes and history of CV disease associated with eccentric LVH only, and CKD stages 4 and 5 associated with concentric LVH only. During follow-up (median, 5.9 years; range, 0.04-15.3), 188 renal deaths (112 ESRD) and 103 CV events (61 fatal) occurred. Using multivariable Cox analysis, concentric and eccentric LVH was associated with higher risk of CV outcomes (hazard ratio [HR], 2.59; 95% confidence interval [95% CI], 1.39 to 4.84 and HR, 2.79; 95% CI, 1.47 to 5.26, respectively). Similarly, greater risk of renal end point was detected in concentric (HR, 2.33; 95% CI, 1.44 to 3.80) and eccentric (HR, 2.30; 95% CI, 1.42 to 3.74) LVH. Sensitivity analysis using LVH and RWT separately showed that LVH but not RWT was associated with higher cardiorenal risk. In patients with CKD, LVH is a

  10. Adverse Effects of GLP-1 Receptor Agonists

    PubMed Central

    Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have