Showing papers by "David A. Kass published in 2012"
TL;DR: The distinctive clinical features of the major causes of HF in humans are defined and those distinctive pathological features ofHF in humans that should be present in an animal model being used to identify fundamental causes ofHF or to test preventative or reparative therapies that could reduce HF morbidity and mortality are recommended.
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality in the United States. Despite a number of important therapeutic advances for the treatment of symptomatic HF,1 the prevalence, mortality, and cost associated with HF continue to grow in the United States and other developed countries. Given the aging of our population and the prevalence of diseases such as diabetes mellitus and hypertension that predispose patients to this syndrome, it is possible that HF prevalence will increase in the next decade. Current treatments primarily slow the progression of this syndrome, and there is a need to develop novel preventative and reparative therapies. Development of these novel HF therapies requires testing of the putative therapeutic strategies in appropriate HF animal models.
The purposes of this scientific statement are to define the distinctive clinical features of the major causes of HF in humans and to recommend those distinctive pathological features of HF in humans that should be present in an animal model being used to identify fundamental causes of HF or to test preventative or reparative therapies that could reduce HF morbidity and mortality.
HF is a clinical syndrome with primary symptoms including dyspnea, fatigue, exercise intolerance, and retention of fluid in the lungs and peripheral tissues. The causes of HF are myriad, but the common fundamental defect is a decreased ability of the heart to provide sufficient cardiac output to support the normal functions of the tissues because of impaired filling and/or ejection of blood.
HF is a significant health burden in both the developed world and in emerging nations. In the United States, over a half million new diagnoses of HF occur each year, and the prevalence is 5.8 million individuals >20 years of age.1 HF has a substantial societal burden, with yearly costs in the United …
401 citations
TL;DR: Pulmonary hypertension and pulmonary fibrosis do not significantly change the hyperbolic dependence between RPA and CPA, and patient age has only minimal effects, which helps explain the difficulty of reducing total right ventricular afterload by therapies that have a modest impact on mean RPA.
Abstract: Background—Right ventricular failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (RPA) and compliance (CPA) are consistently and inversely related regardless of age, pulmonary hypertension, or interstitial fibrosis and that this relation may be changed by elevated pulmonary capillary wedge pressure, augmenting right ventricular pulsatile load. Methods and Results—Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the RPA-CPA relationship with pulmonary hypertension, pulmonary fibrosis, patient age, and varying pulmonary capillary wedge pressure. Patients with suspected or documented pulmonary hypertension (n=1009) and normal pulmonary capillary wedge pressure displayed a consistent RPA-CPA hyperbolic (inverse) dependence, CPA=0.564/(0.047+RPA), with a near-co...
363 citations
TL;DR: The current evidence for reverse remodeling by existing therapies is reviewed, and novel approaches that are rapidly moving from preclinical to clinical trials are discussed.
Abstract: Heart failure (HF) involves changes in cardiac structure, myocardial composition, myocyte deformation, and multiple biochemical and molecular alterations that impact heart function and reserve capacity. Collectively, these changes have been referred to as 'cardiac remodeling'. Understanding the components of this process with the goal of stopping or reversing its progression has become a major objective. This concept is often termed 'reverse remodeling', and is successfully achieved by inhibitors of the renin-angiotensin-aldosterone system, β-blockers, and device therapies such as cardiac resynchronization or ventricular assist devices. Not every method of reverse remodeling has long-lasting clinical efficacy. However, thus far, every successful clinical treatment with long-term benefits on the morbidity and mortality of patients with HF reverses remodeling. Reverse remodeling is defined by lower chamber volumes (particularly end-systolic volume) and is often accompanied by improved β-adrenergic and heart-rate responsiveness. At the cellular level, reverse remodeling impacts on myocyte size, function, excitation-contraction coupling, bioenergetics, and a host of molecular pathways that regulate contraction, cell survival, mitochondrial function, oxidative stress, and other features. Here, we review the current evidence for reverse remodeling by existing therapies, and discuss novel approaches that are rapidly moving from preclinical to clinical trials.
197 citations
TL;DR: Selective, functionally significant phosphorylation alterations occurred on individual residues of cardiac troponin I in heart failure, likely reflecting an imbalance in kinase/phosphatase activity.
Abstract: Background—Human cardiac troponin I is known to be phosphorylated at multiple amino acid residues by several kinases. Advances in mass spectrometry allow sensitive detection of known and novel phosphorylation sites and measurement of the level of phosphorylation simultaneously at each site in myocardial samples. Methods and Results—On the basis of in silico prediction and liquid chromatography/mass spectrometry data, 14 phosphorylation sites on cardiac troponin I, including 6 novel residues (S4, S5, Y25, T50, T180, S198), were assessed in explanted hearts from end-stage heart failure transplantation patients with ischemic heart disease or idiopathic dilated cardiomyopathy and compared with samples obtained from nonfailing donor hearts (n=10 per group). Thirty mass spectrometry–based multiple reaction monitoring quantitative tryptic peptide assays were developed for each phosphorylatable and corresponding nonphosphorylated site. The results show that in heart failure there is a decrease in the extent of ph...
134 citations
TL;DR: The finding suggests that t-system status can provide an early marker of the success of this therapy, and could also guide us to an understanding of the loss and remodeling of proteins associated with the t- system.
Abstract: Rationale:Cardiac resynchronization therapy (CRT) is an established treatment for patients with chronic heart failure. However, CRT-associated structural and functional remodeling at cellular and subcellular levels is only partly understood. Objective:To investigate the effects of CRT on subcellular structures and protein distributions associated with excitation-contraction coupling of ventricular cardiomyocytes. Methods and Results:Our studies revealed remodeling of the transverse tubular system (t-system) and the spatial association of ryanodine receptor (RyR) clusters in a canine model of dyssynchronous heart failure (DHF). We did not find this remodeling in a synchronous heart failure model based on atrial tachypacing. Remodeling in DHF ranged from minor alterations in anterior left ventricular myocytes to nearly complete loss of the t-system and dissociation of RyRs from sarcolemmal structures in lateral cells. After CRT, we found a remarkable and almost complete reverse remodeling of these structure...
119 citations
TL;DR: It is reported that Hif1af/f;Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2+ lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction, they manifest rapid cardiac decompensation.
Abstract: Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O2 consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O2 homeostasis. Mouse embryos lacking expression of the O2-regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1af/f;Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2+ lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-β signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-β signaling in Hif1af/f;Tie2-Cre mice. Inhibition of TGF-β signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK–ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-β signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.
116 citations
TL;DR: In this paper, the effect of β3-adrenergic receptor (AR) activation and downstream signaling of nitric oxide synthase (NOS) isoforms on the heart from failure and hypertrophy induced by pressure overload was investigated.
109 citations
TL;DR: Endoglin is identified as a critical component of TGF&bgr;1 signaling in the cardiac fibroblast and targeting endoglin attenuates cardiac fibrosis, thereby providing a potentially novel therapeutic approach for individuals with heart failure.
Abstract: Background—Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine transforming growth factor-β1 (TGFβ1) promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a coreceptor for TGFβ1 signaling and has been studied in vascular remodeling and preeclampsia. We hypothesized that reduced endoglin expression may limit cardiac fibrosis in heart failure. Methods and Results—We first report that endoglin expression is increased in the left ventricle of human subjects with heart failure and determined that endoglin is required for TGFβ1 signaling in human cardiac fibroblasts using neutralizing antibodies and an siRNA approach. We further identified that reduced endoglin expression attenuates cardiac fibrosis, preserves left ventricular function, and improves survival in a mouse model of pressure-overload–induced heart failure. Prior studies have shown that the extracellular domain of endoglin can be cleaved and...
102 citations
TL;DR: Findings reveal direct roles for PKGIα in attenuating pressure overload–induced remodeling in vivo and as a required effector for the cardioprotective effects of sildenafil.
Abstract: Background Cyclic GMP (cGMP) signaling attenuates cardiac remodeling, but it is unclear which cGMP effectors mediate these effects and thus might serve as novel therapeutic targets. Therefore, we tested whether the cGMP downstream effector, cGMP-dependent protein kinase G Iα (PKGIα), attenuates pressure overload–induced remodeling in vivo.
Methods and Results The effect of transaortic constriction (TAC)–induced left ventricular (LV) pressure overload was examined in mice with selective mutations in the PKGIα leucine zipper interaction domain. Compared with wild-type littermate controls, in response to TAC, these Leucine Zipper Mutant (LZM) mice developed significant LV systolic and diastolic dysfunction by 48 hours (n=6 WT sham, 6 WT TAC, 5 LZM sham, 9 LZM TAC). In response to 7-day TAC, the LZM mice developed increased pathologic hypertrophy compared with controls (n=5 WT sham, 4 LZM sham, 8 WT TAC, 11 LZM TAC). In WT mice, but not in LZM mice, phosphodiesterase 5 (PDE5) inhibition with sildenafil (Sil) significantly inhibited TAC-induced cardiac hypertrophy and LV systolic dysfunction in WT mice, but this was abolished in the LZM mice (n=3 WT sham, 4 LZM sham, 3 WT TAC vehicle, 6 LZM TAC vehicle, 4 WT TAC Sil, 6 LZM TAC Sil). And in response to prolonged, 21-day TAC (n=8 WT sham, 7 LZM sham, 21 WT TAC, 15 LZM TAC), the LZM mice developed markedly accelerated mortality and congestive heart failure. TAC induced activation of JNK, which inhibits cardiac remodeling in vivo, in WT, but not in LZM, hearts, identifying a novel signaling pathway activated by PKGIα in the heart in response to LV pressure overload.
Conclusions These findings reveal direct roles for PKGIα in attenuating pressure overload–induced remodeling in vivo and as a required effector for the cardioprotective effects of sildenafil.
69 citations
TL;DR: In this paper, the role of heme-oxidation and altered intracellular compartmentation of sGC as potential mechanisms for reduced NO-coupled sGC activity was investigated.
Abstract: Rationale: Soluble guanylyl cyclase (sGC) generates cyclic guanosine monophophate (cGMP) upon activation by nitric oxide (NO). Cardiac NO–sGC-cGMP signaling blunts cardiac stress responses, including pressure-overload–induced hypertrophy. The latter itself depresses signaling through this pathway by reducing NO generation and enhancing cGMP hydrolysis. Objective: We tested the hypothesis that the sGC response to NO also declines with pressure-overload stress and assessed the role of heme-oxidation and altered intracellular compartmentation of sGC as potential mechanisms. Methods and Results: C57BL/6 mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and dysfunction. NO-stimulated sGC activity was markedly depressed, whereas NO- and heme-independent sGC activation by BAY 60–2770 was preserved. Total sGCα 1 and β 1 expression were unchanged by TAC; however, sGCβ 1 subunits shifted out of caveolin-enriched microdomains. NO-stimulated sGC activity was 2- to 3-fold greater in Cav3-containing lipid raft versus nonlipid raft domains in control and 6-fold greater after TAC. In contrast, BAY 60–2770 responses were >10 fold higher in non-Cav3 domains with and without TAC, declining about 60% after TAC within each compartment. Mice genetically lacking Cav3 had reduced NO- and BAY-stimulated sGC activity in microdomains containing Cav3 for controls but no change within non–Cav3-enriched domains. Conclusions: Pressure overload depresses NO/heme-dependent sGC activation in the heart, consistent with enhanced oxidation. The data reveal a novel additional mechanism for reduced NO-coupled sGC activity related to dynamic shifts in membrane microdomain localization, with Cav3-microdomains protecting sGC from heme-oxidation and facilitating NO responsiveness. Translocation of sGC out of this domain favors sGC oxidation and contributes to depressed NO-stimulated sGC activity.
67 citations
TL;DR: It is concluded that preconditioning by inhibition of PDE‐5 can be a powerful novel approach to improve stem cell therapy following myocardial infarction.
Abstract: The rationale of this article is enhancing the therapeutic potential of stem cells in ischemic microenvironments by novel preconditioning strategies is critical for improving cellular therapy. We tested the hypothesis that inhibition of phosphodiesterase-5 (PDE-5) with sildenafil (Viagra) or knockdown with a silencing vector in adipose-derived stem cells (ASCs) would improve their survival and enhance cardiac function following myocardial implantation in vivo. ASCs were treated with sildenafil or PDE-5 silencing vector short hairpin RNA (shRNA(PDE-5)) and subjected to simulated ischemia/reoxygenation in vitro. Both sildenafil and shRNA(PDE-5) significantly improved viability, decreased necrosis, apoptosis, and enhanced the release of growth factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and insulin-like growth factor. Inhibition of protein kinase G reversed these effects. To show the beneficial effect of preconditioned ASCs in vivo, adult male CD-1 mice underwent myocardial infarction. Preconditioned ASCs (4 × 10(5)) were directly injected intramyocardially. Preconditioned ASC-treated hearts showed consistently superior cardiac function when compared with nonpreconditioned ASCs after 4 weeks of treatment. This was associated with significantly reduced fibrosis, increased vascular density, and decreased resident myocyte apoptosis when compared with mice receiving nonpreconditioned ASCs. VEGF, b-FGF, and Angiopoietin-1 were also significantly elevated 4 weeks after cell therapy with preconditioned ASCs. We conclude that preconditioning by inhibition of PDE-5 can be a powerful novel approach to improve stem cell therapy following myocardial infarction.
TL;DR: New insights are detailed regarding how these PDEs modulate cGMP and cGK-1 to influence heart function and chronic stress responses, and how their inhibition may provide potential therapeutic benefits.
Abstract: The cyclic nucleotide cGMP and its corresponding activated kinase cGK-1 serve as a counterbalance to acute and chronic myocardial stress. cGMP hydrolysis by several members of the phosphodiesterase (PDE) superfamily, PDE1, PDE2, and PDE5, regulate this signaling in the heart. This review details new insights regarding how these PDEs modulate cGMP and cGK-1 to influence heart function and chronic stress responses, and how their inhibition may provide potential therapeutic benefits.
TL;DR: In this paper, the authors hypothesized that PDE5 substrate selectivity is retargeted to blunt natriuretic peptide (NP) stimulated guanylyl cyclase.
Abstract: BackgroundIn the normal heart, phosphodiesterase type 5 (PDE5) hydrolyzes cGMP coupled to nitric oxide– (specifically from nitric oxide synthase 3) but not natriuretic peptide (NP)–stimulated guanylyl cyclase. PDE5 is upregulated in hypertrophied and failing hearts and is thought to contribute to their pathophysiology. Because nitric oxide signaling declines whereas NP-derived cGMP rises in such diseases, we hypothesized that PDE5 substrate selectivity is retargeted to blunt NP-derived signaling. Methods and ResultsMice with cardiac myocyte inducible PDE5 overexpression (P5+) were crossed to those lacking nitric oxide synthase 3 (N3−), and each model, the double cross, and controls were subjected to transaortic constriction. P5+ mice developed worse dysfunction and hypertrophy and enhanced NP stimulation, whereas N3− mice were protected. However, P5+/N3− mice behaved similarly to P5+ mice despite the lack of nitric oxide synthase 3–coupled cGMP generation, with protein kinase G activity suppressed in both...
TL;DR: Sunitinib exposure significantly decreased sarcomere shortening and Ca2+ transients, while ROS levels were significantly increased after exposure to the drug as discussed by the authors, indicating that these side effects are more frequently found in patients with a lower body mass index.
Abstract: Study Type – Aetiology (case control)
Level of Evidence 2b
What's known on the subject? and What does the study add?
The multikinase inhibitor sunitinib causes cardiotoxic side effects in a substantial number of treated patients. Previously, data from clinical studies suggested that these side effects are more frequently found in patients with a lower body mass index, but the reasons for this toxic effect remain elusive.
In this study we determined, in a human multicellular model, that sunitinib causes an impairment of the contractile function of cardiomyocytes in a dose-dependent manner. Furthermore, we found that sunitinib induces alterations in calcium homeostasis in cardiomyocytes. In addition, an increased production of reactive oxygen species after exposure of cardiomyocytes to this drug was detected. These findings suggest that measurement of plasma concentration might help to control cardiotoxic side effects and optimize a more personalized application of this drug.
OBJECTIVES
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To examine the acute effects of sunitinib on inotropic function, intracellular Ca2+ transients, myofilament Ca2+ sensitivity and generation of reactive oxygen species (ROS) in human multicellular myocardium and isolated mouse cardiomyocytes.
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To search for microRNAs as suitable biomarkers for indicating toxic cardiac effects.
PATIENTS AND METHODS
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After exposure to sunitinib (0.1–10 µg/mL) developed force, diastolic tension and kinetic variables were assessed in isolated human myocardium.
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Changes in myocyte sarcomere length, whole-cell calcium transients, myofilament force-Ca2+ relationship, and ROS generation were examined in isolated ventricular mouse cardiomyocytes.
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Microarray and realtime-PCR were used to screen for differentially expressed microRNAs in cultured cardiomyocytes that were exposed for 24 h to sunitinib.
RESULTS
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We found that higher concentrations of sunitinib (1 and 10 µg/mL) decreased developed force at 30 minutes 76.9 + 2.8 and 54.5 + 6.3%, compared to 96.1 + 2.6% in controls (P < 0.01).
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Sunitinib exposure significantly decreased sarcomere shortening and Ca2+ transients.
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Myofilament Ca2+ sensitivity was not altered, while ROS levels were significantly increased after exposure to the drug.
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MicroRNA expression patterns were not altered by sunitinib.
CONCLUSIONS
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Sunitinib elicits a dose-dependent negative inotropic effect in myocardium, accompanied by a decline in intracellular Ca2+ and increased ROS generation.
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In clinical practice, these cardiotoxic effects should be considered in cases where cardiac concentrations of sunitinib could be increased.
TL;DR: Recent developments in the field of cyclic guanosine monophosphate and its primary signaling kinase, protein kinase G, play an important role in counterbalancing stress remodeling in the heart, highlighting basic science and clinical studies.
Abstract: Cyclic guanosine monophosphate (cGMP) and its primary signaling kinase, protein kinase G, play an important role in counterbalancing stress remodeling in the heart. Growing evidence supports a positive impact on a variety of cardiac disease conditions from the suppression of cGMP hydrolysis. The latter is regulated by members of the phosphodiesterase (PDE) superfamily, of which cGMP-selective PDE5 has been best studied. Inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischemic injury, and cardiotoxicity. Clinical trials have begun exploring their potential to benefit dilated cardiomyopathy and heart failure with a preserved ejection fraction. This review discusses recent developments in the field, highlighting basic science and clinical studies.
TL;DR: A strong correlation between cardiac functional impairment and extent of SIV replication in the myocardium is demonstrated, suggesting that persistent viral replication in myocardial macrophages induces cardiomyocyte damage manifest as diastolic dysfunction.
Abstract: Objective:To establish the relationship between HIV-induced cardiac diastolic dysfunction, immune responses, and virus replication in the heart using the simian immunodeficiency virus (SIV)/macaque model.Design:Cardiac diastolic dysfunction is common in HIV-infected individuals including asymptomati
TL;DR: How high-throughput technologies including gene expression profiling and proteomics have helped in understanding of the pathophysiology of electromechanical dyssynchrony and the molecular mechanisms by which cardiac resynchronization therapy (CRT) exerts its beneficial effects is focused on.
Abstract: Cardiac resynchronization therapy reduces morbidity and mortality in patients with symptomatic systolic heart failure (New York Heart Association class III or IV) and ventricular conduction delay. The current review focuses on how high-throughput technologies including gene expression profiling and proteomics have helped in our understanding of the pathophysiology of electromechanical dyssynchrony and the molecular mechanisms by which cardiac resynchronization therapy (CRT) exerts its beneficial effects. Comparing gene expression changes in early-activated anterior vs. late-activated lateral left ventricular myocardium in a large animal model of dyssynchronous heart failure, we demonstrated a profound effect of electromechanical dyssynchrony on the regional cardiac transcriptome, as changes in gene expression were primarily observed in the early-activated anterior left ventricular myocardium. This increase in regional heterogeneity of gene expression within the left ventricle was reversed by CRT. Specifically, CRT remodeled transcripts with metabolic and cell signaling function, which was corroborated by protein data. In addition, high-throughput or “omic” techniques also hold great promise to identify key pathways and biomarkers that are regulated differentially in CRT responders vs. nonresponders.
TL;DR: In conclusion, β-receptor gene variants significantly influence inotropic and chronotropic responses to β-agonist exposure in patients on β-blocker therapy.
Abstract: Previous studies have demonstrated that β-adrenergic receptor polymorphisms affect outcomes in patients with heart failure or after an acute coronary syndrome. Whether β-adrenergic polymorphisms influence catecholamine responses in patients with cardiovascular disease is not known. Cardiovascular responses to the β1-receptor agonist dobutamine and the β2-receptor agonist terbutaline were studied using gated blood pool scintigraphy in 21 patients on long-term β-blocker therapy. Heart rate (HR), stroke volume (SV), and cardiac output (CO) increased, and end-systolic volume decreased with dobutamine and terbutaline. Changes in HR and CO with dobutamine were higher for those with ≥1 β1 Arg389 allele than those homozygous for the Gly389 allele (change in HR 15 vs 1 beat/min, p = 0.02; change in CO 2.4 vs 1.0 L/min, p = 0.02). Increases in HR, CO, and SV with terbutaline were greater for those homozygous for the β2 Glu27 allele than those with ≥1 Gln27 allele (change in HR 13.7 vs 4.8 beats/min, p = 0.048; change in CO 3.1 vs 1.6 L/min, p = 0.034; change in SV 28.3 vs 14.8 ml, p = 0.045). Changes in CO and volume with terbutaline were greater in those with an ejection fraction <40% than in those with an ejection fraction ≥40%. In conclusion, β-receptor gene variants significantly influence inotropic and chronotropic responses to β-agonist exposure in patients on β-blocker therapy.
TL;DR: Current heart failure therapies are fairly defensive; blocking neuro-humoral stimuli and hemodynamic overload, however, adaptive/offensive strategies are advancing, including those aimed at enhancing metabolism, vascular supply, and cell regeneration, and those activating molecular signaling to counter maladaptation.
Abstract: The pathologically hypertrophied and failing heart is a battlefield in a war that would make even George Lucas proud. On the one side, you have hemodynamic, neurohormonal, morphologic, and cellular/molecular dark forces urging the ventricle towards decompensation and ultimate demise. On the other, Jedi signaling cascades valiantly try to stave off the impending disaster. Alas, unlike the movies, the dark side often wins, and we need better-equipped counter forces to change this. Current heart failure therapies are fairly defensive; blocking neuro-humoral stimuli and hemodynamic overload. However, adaptive/offensive strategies are advancing, including those aimed at enhancing metabolism, vascular supply, and cell regeneration, and those activating molecular signaling to counter maladaptation. (SELECT FULL TEXT TO CONTINUE)
TL;DR: These processes are discussed, including how one measures systolic function, the molecular mechanisms underlying its load and frequency dependence, and post-translational regulation of the proteins that dictate the strength of contraction.
Abstract: With each heart beat, cardiac muscle cycles between a passive state and one reflecting the consequence of active cross-bridge formation in the sarcomere. The process can be remarkably stable from cycle to cycle, but is also exquisitely sensitive to changes in the load imposed on the muscle by the venous and arterial loading systems, changes in cycle frequency, and a multitude of signaling pathways that impact how the sarcomere will perform. New advances in the ability to manipulate the individual molecular components of this process both in vitro and in intact animals have yielded important insights regarding how contractility is regulated in health and disease. This chapter discusses these processes, including how one measures systolic function, the molecular mechanisms underlying its load and frequency dependence, and post-translational regulation of the proteins that dictate the strength of contraction.
01 Jan 2012
TL;DR: Animal Models of Heart Failure : A Scientific Statement From the American Heart Association is published online May 17, 2012; Circ Res.
Abstract: Francis, Sumanth D. Prabhu, Howard A. Rockman, David A. Kass, Jeffery D. Molkentin, Mark Steven R. Houser, Kenneth B. Margulies, Anne M. Murphy, Francis G. Spinale, Gary S. Association Animal Models of Heart Failure : A Scientific Statement From the American Heart Print ISSN: 0009-7330. Online ISSN: 1524-4571 Copyright © 2012 American Heart Association, Inc. All rights reserved. is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation Research published online May 17, 2012; Circ Res. http://circres.ahajournals.org/content/early/2012/05/17/RES.0b013e3182582523.citation World Wide Web at: The online version of this article, along with updated information and services, is located on the