Showing papers by "David A. Kass published in 2011"
TL;DR: It is shown that omecamtiv mecarbil binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myOSin into the strongly actin-bound force-generating state.
Abstract: Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.
494 citations
TL;DR: It is shown that TGF-β suppression in cardiomyocytes was required to protect against maladaptive remodeling and involved noncanonical (non-Smad-related) signaling and non canonical pathways predominantly affecting the mal Adaptive hypertrophy/dysfunction in hearts subjected to pressure overload.
Abstract: The cardiac pathological response to sustained pressure overload involves myocyte hypertrophy and dysfunction along with interstitial changes such as fibrosis and reduced capillary density. These changes are orchestrated by mechanical forces and factors secreted between cells. One such secreted factor is TGF-β, which is generated by and interacts with multiple cell types. Here we have shown that TGF-β suppression in cardiomyocytes was required to protect against maladaptive remodeling and involved noncanonical (non–Smad-related) signaling. Mouse hearts subjected to pressure overload and treated with a TGF-β–neutralizing Ab had suppressed Smad activation in the interstitium but not in myocytes, and noncanonical (TGF-β–activated kinase 1 [TAK1]) activation remained. Although fibrosis was greatly reduced, chamber dysfunction and dilation persisted. Induced myocyte knockdown of TGF-β type 2 receptor (TβR2) blocked all maladaptive responses, inhibiting myocyte and interstitial Smad and TAK1. Myocyte knockdown of TβR1 suppressed myocyte but not interstitial Smad, nor TAK1, modestly reducing fibrosis without improving chamber function or hypertrophy. Only TβR2 knockdown preserved capillary density after pressure overload, enhancing BMP7, a regulator of the endothelial-mesenchymal transition. BMP7 enhancement also was coupled to TAK1 suppression. Thus, myocyte targeting is required to modulate TGF-β in hearts subjected to pressure overload, with noncanonical pathways predominantly affecting the maladaptive hypertrophy/dysfunction.
296 citations
TL;DR: The pathophysiology of abnormal ventriculoarterial stiffening and how it affects ventricular function, cardiovascular hemodynamics, reserve capacity, and symptoms is discussed.
247 citations
TL;DR: In this paper, the authors found that cardiac resynchronization therapy (CRT) increased ATPase activity by ≈2-fold (P < 0.05) over dyssynchronous heart failure (DHF) and this effect was recapitulated with a reducing agent.
Abstract: Rationale:Cardiac resynchronization therapy (CRT) is an effective clinical treatment for heart failure patients with conduction delay, impaired contraction, and energetics. Our recent studies have revealed that mitochondrial posttranslational modifications (PTM) may contribute to its benefits, motivating the present study of the oxidative regulation of mitochondrial ATP synthase. Objectives:We tested whether CRT alteration of ATP synthase function is linked to cysteine (Cys) oxidative PTM (Ox-PTM) of specific ATP synthase subunits. Methods and Results:Canine left ventricular myocardium was collected under conditions to preserve Ox-PTM from control, dyssynchronous heart failure (DHF), or hearts that had undergone CRT. In-gel ATPase activity showed that CRT increased ATPase activity by ≈2-fold (P<0.05) over DHF, approaching control levels, and this effect was recapitulated with a reducing agent. ATP synthase function and 3 Ox-PTM: disulfide bond, S-glutathionylation and S-nitrosation were assessed. ATP synt...
142 citations
TL;DR: New features of HNO's cardiovascular effects that when combined with its positive inotropic/lusitropic action may render HNO donors an attractive addition to the current therapeutic armamentarium for treating patients with acutely decompensated congestive heart failure are reviewed.
Abstract: The nitric oxide (NO•) sibling, nitroxyl or nitrosyl hydride (HNO), is emerging as a molecule whose pharmacological properties include providing functional support to failing hearts. HNO also preconditions myocardial tissue, protecting it against ischemia-reperfusion injury while exerting vascular antiproliferative actions. In this review, HNO's peculiar cardiovascular assets are discussed in light of its unique chemistry that distinguish HNO from NO• as well as from reactive oxygen and nitrogen species such as the hydroxyl radical and peroxynitrite. Included here is a discussion of the possible routes of HNO formation in the myocardium and its chemical targets in the heart. HNO has been shown to have positive inotropic/lusitropic effects under normal and congestive heart failure conditions in animal models. The mechanistic intricacies of the beneficial cardiac effects of HNO are examined in cellular models. In contrast to β-receptor/cyclic adenosine monophosphate/protein kinase A-dependent enhan...
103 citations
TL;DR: Inhibition of cGMP-targeted phosphodiesterases (PDEs) such as PDE5A is an alternative approach that appears to have more potent effects and directions for further research are suggested.
99 citations
TL;DR: More specific gold standard assessments of ventricular and arterial properties are reviewed, and how these relate to the parameters reported and utilized in practice are discussed.
83 citations
TL;DR: In this article, the authors focus on the regulatory role of dystrophin in relation to neuronal nitric oxide synthase (nNOS) and transient receptor potential canonical channels (TRPC).
Abstract: Cardiac dysfunction is a frequent manifestation of Duchenne muscular dystrophy (DMD) and a common cause of death for individuals with this condition. Early diastolic dysfunction and focal fibrosis proceed to dilated cardiomyopathy (DCM), complicated by heart failure and arrhythmia in most patients. Improvements in the management of respiratory insufficiency in DMD have improved lifespan and overall prognosis, but heart failure and sudden death continue to impact survival and quality of life for people with DMD. Since the specific mechanisms resulting in heart failure for people with DMD are poorly understood, current treatments are not targeted, but rely on approaches that are considered standard for DCM. These approaches include angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists. Data from one trial in DMD support the use of ACE inhibitors before the onset of left ventricular dysfunction. Angiotensin receptor blockers have shown similar efficacy to ACE inhibitors in numerous studies of dilated cardiomyopathy, and are a good choice for patients who cannot tolerate ACE inhibition. The pathogenesis of DMD-associated cardiomyopathy may be similar to other genetic disorders of the cytoskeletal complex of ventricular myocytes, though unique features offer targeted opportunities to impact treatment. Novel areas of investigation are focused on the regulatory role of dystrophin in relation to neuronal nitric oxide synthase (nNOS) and transient receptor potential canonical channels (TRPC). Inhibition of phosphodiesterase-5 (PDE5) addresses several aspects of regulatory dysfunction induced by dystrophin deficiency, and studies with PDE5-inhibitors have shown benefits in murine models of DMD. PDE5-inhibitors are currently under investigation in at least one study in humans. This article focuses on mechanisms of cardiac dysfunction, as well as potential targets for pharmacologic manipulation to prevent or improve cardiomyopathy in DMD.
79 citations
TL;DR: In this article, the authors identify TSP4 as myocyte-interstitial mechano-signaling molecule central to adaptive cardiac contractile responses to acute stress, which appears to play a crucial role in the transition to chronic cardiac dilatation and failure.
Abstract: Rationale: One of the physiological mechanisms by which the heart adapts to a rise in blood pressure is by augmenting myocyte stretch-mediated intracellular calcium, with a subsequent increase in contractility. This slow force response was first described over a century ago and has long been considered compensatory, but its underlying mechanisms and link to chronic adaptations remain uncertain. Because levels of the matricellular protein thrombospondin-4 (TSP4) rapidly rise in hypertension and are elevated in cardiac stress overload and heart failure, we hypothesized that TSP4 is involved in this adaptive mechanism. Objective: To determine the mechano-transductive role that TSP4 plays in cardiac regulation to stress. Methods and results: In mice lacking TSP4 ( Tsp4 −/− ), hearts failed to acutely augment contractility or activate stretch-response pathways (ERK1/2 and Akt) on exposure to acute pressure overload. Sustained pressure overload rapidly led to greater chamber dilation, reduced function, and increased heart mass. Unlike controls, Tsp4 −/− cardiac trabeculae failed to enhance contractility and cellular calcium after a stretch. However, the contractility response was restored in Tsp4 −/− muscle incubated with recombinant TSP4. Isolated Tsp4 −/− myocytes responded normally to stretch, identifying a key role of matrix-myocyte interaction for TSP4 contractile modulation. Conclusion: These results identify TSP4 as myocyte-interstitial mechano-signaling molecule central to adaptive cardiac contractile responses to acute stress, which appears to play a crucial role in the transition to chronic cardiac dilatation and failure.
74 citations
TL;DR: Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure therapy to date to clinically improve acute and chronic function while also lowering mortality.
Abstract: Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving β-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and β-adrenergic receptor sarcomere and calcium responses, particularly the β2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gαi signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling (RGS2, RGS3), yielding Gαs-biased β2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum-localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased β2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored β-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.
63 citations
TL;DR: A brief review of instrumentation, the theory behind its use, and how volume signals are calibrated are discussed and elements of P-V analysis are discussed to provide a convenient summary of earlier investigations and insights for users whose primary interests lie in genetic/molecular studies rather than in biomedical engineering.
Abstract: Nearly 40 years ago, the Sagawa laboratory spawned a renaissance in the use of instantaneous ventricular pressure-volume (P-V) relations to assess cardiac function. Since then, this analysis has taken hold as the most comprehensive way to quantify ventricular chamber function and energetics and cardiovascular interactions. First studied in large mammalian hearts and later in humans employing a catheter-based method, P-V analysis was translated to small rodents in the late 1990s by the Kass laboratory. Over the past decade, this approach has become a gold standard for comprehensive examination of in vivo cardiac function in mice, facilitating a new era of molecular cardiac physiology. The catheter-based method remains the most widely used approach in mice. In this brief review, we discuss this instrumentation, the theory behind its use, and how volume signals are calibrated and discuss elements of P-V analysis. The goal is to provide a convenient summary of earlier investigations and insights for users whose primary interests lie in genetic/molecular studies rather than in biomedical engineering.
TL;DR: The dose response of daily oral synthetic sapropterin dihydrochloride on pre-established pressure-overload cardiac disease exposes a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals.
TL;DR: The pathophysiologic role of decreased BH(4) bioavailability, molecular mechanisms regulating its metabolism, and its potential therapeutic use as well as pitfalls as an NOS-modulating drug are discussed.
TL;DR: RGS2 is defined as a novel negative regulator of the β(2)AR-G(i) signaling but also provides a potential novel target for the treatment of chronic heart failure.
TL;DR: AS is associated with preserved atrial contractility and atrial synchrony, resulting in optimal LV diastolic filling, stroke volume, and LV systolic mechanics, which maximizes LV performance and the hemodynamic benefit of CRT in patients with heart failure.
Abstract: Objectives The aim of this study was to evaluate atrial and ventricular function in patients undergoing cardiac resynchronization therapy (CRT). Background Right atrial pacing (AP) in CRT induces delays in electrical and mechanical activation of the left atrium. The influence of atrial sensing (AS) versus AP on ventricular performance in CRT and the mechanisms underlying the differences between AS and AP in CRT have not been fully elucidated. Methods Fifty-five patients with heart failure undergoing CRT for 9 ± 12.5 months and 22 control subjects without heart failure were enrolled. Conventional and tissue Doppler echocardiography was performed to examine atrial and ventricular mechanics and hemodynamic status. Results The optimal atrioventricular interval was shorter in AS compared with AP mode (126 ± 19 ms vs. 155 ± 20 ms, p Conclusions AS is associated with preserved atrial contractility and atrial synchrony, resulting in optimal LV diastolic filling, stroke volume, and LV systolic mechanics. This pacing mode maximizes LV performance and the hemodynamic benefit of CRT in patients with heart failure.
TL;DR: Well into the mid 2000s, PDE5 was thought to be expressed in selective vascular beds, lung and corpus cavernosum being dominant, and to have a minor cardiovascular profile elsewhere, with a negligible role in the heart.
Abstract: In 1998, the world was formally introduced to Viagra (sildenafil), the first oral agent to be approved in the United States for the treatment of erectile dysfunction. Developed by Pfizer chemists, sildenafil inhibited phosphodiesterase type 5 (PDE5), one of the 11-member superfamily of enzymes that hydrolyze cyclic nucleotide monophosphates and among the first discovered that was selective for cGMP. PDE5 had been identified more than 2 decades earlier, first as a protein that bound cGMP and later as one that hydrolyzed it (the binding function turning out to be a mechanism to regulate activity).1 Sildenafil induces vasorelaxation by blocking PDE5-cGMP hydrolysis, raising cGMP levels in smooth muscle to activate protein kinase G (also known as cGK). In platelets, this blunts thrombosis; together, the effects suggested a potential use for coronary vascular disease and hypertension. Pfizer initiated trials targeting coronary ischemia, but, although antianginal effects were disappointing, the study gave a whole new meaning to the term “side effect,” effectively hijacking sildenafil from cardiovascular development to a rather different indication.
Article see p 8
There were still some cardiovascular studies performed, but essentially all were limited assessments of volunteer populations, mostly normal and at rest and some with cardiovascular disease; the results were interpreted to support safety for patients taking the drug. In particular, blood pressure changes were slight if present at all, and cardiac function appeared unaltered. Well into the mid 2000s, PDE5 was thought to be expressed in selective vascular beds, lung and corpus cavernosum being dominant, and to have a minor cardiovascular profile elsewhere, with a negligible role in the heart.
Sildenafil reemergence as …
Journal Article•
TL;DR: The hypothesis that Eng and sEng mediate opposing effects on cardiac fibrosis in heart failure was tested and reduced LV fibrosis was observed in Eng+/− mice, while LV mass, cardiomyoc...
Abstract: Transforming growth factor beta-1 (TGFb1) promotes cardiac fibrosis. The transmembrane co-receptor Endoglin (Eng; CD105) facilitates TGFb1 signaling via SMAD effector proteins. In contrast, a circulating form of soluble endoglin (sEng) inhibits TGFb1 signaling in vascular endothelium. We recently reported that increased sEng levels in human serum correlate with clinical indices of heart failure severity. Therefore, we tested the hypothesis that Eng and sEng mediate opposing effects on cardiac fibrosis in heart failure. In male, wild-type mice (WT), Eng expression increased in the left ventricle (LV) after 2, 4, and 10 weeks of thoracic aortic constriction (TAC) accompanied by progressive LV fibrosis and hypertrophy. In contrast to WT mice, Eng haploinsufficient (Eng+/−) mice had preserved LV function (FS%: 78±4 vs 22±16, Eng+/− vs WT, p<0.01) and improved survival [88%(7/8) vs 50%(4/8), Eng+/− vs WT, p<0.001) after 10 weeks of TAC. Reduced LV fibrosis was observed in Eng+/− mice, while LV mass, cardiomyoc...
Journal Article•
TL;DR: It is shown that calcium sensitivity is significantly decreased with dyssynchrony, but is improved with cardiac resynchronization therapy (CRT) using trabeculae from the right ventricle with improved results with CRT.
Abstract: We have previously shown that calcium sensitivity is significantly decreased with dyssynchrony, but is improved with cardiac resynchronization therapy (CRT) using trabeculae from the right ventricl...
TL;DR: This study explored JNK activation in LZM mouse hearts in response to various durations of TAC, and hypothesized that PKGIa inhibits TACinduced remodeling through activation of JNK in the heart.
Abstract: Background cGMP signaling inhibits pathologic cardiac hypertrophy and remodeling in vivo In prior studies, we explored the role of the cGMP-dependent protein kinase I alpha (PKGIa) in regulating cardiac remodeling by studying mice with mutations in the PKGIa leucine zipper (LZ) domain [1], in which PKGIa kinase activity is retained but LZ-mediated protein-protein interactions are abolished These mice (termed leucine zipper mutant, or LZM, mice) develop accelerated contractile dysfunction, and increased hypertrophy and mortality in response to LV pressure overload induced by Transaortic constriction, (TAC) [2], supporting a critical role for PKGIa in inhibiting remodeling in vivo The specific myocardial signaling pathways regulated through PKGIa LZ-mediated interactions remain unknown Cardiac JNK activation is required for normal LV compensation to TAC, and in vitro studies support a role of PKGIa in activating JNK in the cardiac myocyte We hypothesized that PKGIa inhibits TACinduced remodeling through activation of JNK in the heart To test this, we explored JNK activation in LZM mouse hearts in response to various durations of TAC