Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: A first-in-man study
Section of Cardiology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA 94121-1545, USA. The Lancet
(Impact Factor: 45.22).
08/2011; 378(9792):667-75. DOI: 10.1016/S0140-6736(11)61219-1
Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings.
In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223.
The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15  mL), fractional shortening (8% ), and ejection fraction (7% ; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time.
These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure.
Available from: Farid Moussavi-Harami
- "However, this medication increases the duration of cardiomyocyte twitches, increases systolic ejection time, and decreases time in diastole. Furthermore, there is concern that Omecamtiv mecarbil decreases coronary perfusion and coronary filling  . Our approach to treating heart failure is myofilament specific, and we have previously shown that the nucleotide dATP can transfer from one cell to another via gap junctions  so elevation of ribonucleotide reductase need not be accomplished throughout the myocardium. "
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ABSTRACT: We are developing a novel treatment for heart failure by increasing myocardial 2 deoxy-ATP (dATP). Our studies in rodent models have shown that substitution of dATP for adenosine triphosphate (ATP) as the energy substrate in vitro or elevation of dATP in vivo increases myocardial contraction and that small increases in the native dATP pool of heart muscle are sufficient to improve cardiac function. Here we report, for the first time, the effect of dATP on human adult cardiac muscle contraction. We measured the contractile properties of chemically-demembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure. Isometric force was increased at both saturating and physiologic Ca(2+) concentrations with dATP compared to ATP. This resulted in an increase in the Ca(2+) sensitivity of force (pCa50) by 0.06 pCa units. The rate of force redevelopment (ktr) in demembranated wall muscle was also increased, as was the rate of contractile activation (kACT) in isolated myofibrils, indicating increased cross-bridge binding and cycling compared with ATP in failing human myocardium. These data suggest that dATP could increase dP/dT and end systolic pressure in failing human myocardium. Importantly, even though the magnitude and rate of force development were increased, there was no increase in the time to 50% and 90% myofibril relaxation. These data, along with our previous studies in rodent models, show the promise of elevating myocardial dATP to enhance contraction and restore cardiac pump function. These data also support further pre-clinical evaluation of this new approach for treating heart failure.
Copyright © 2014. Published by Elsevier Ltd.
Available from: onlinelibrary.wiley.com
- "Cardiac sarcoplasmic reticulum Ca 2+ -ATPase2a (SERCA2a) gene therapy is one of a number of promising therapies that target specific protein derangements in HF. Others include myosin activators (Teerlink et al., 2011), ryanodine receptor (RyR) stabilizers (Wehrens et al., 2005) and Ca 2+ /calmodulin kinase (CaMKII) inhibition (Anderson et al., 1998), but a detailed description of these is beyond the scope of this article. "
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ABSTRACT: Therapeutic options which directly enhance cardiomyocyte contractility in chronic heart failure (HF) therapy are currently limited and do not improve prognosis. In fact, most positive inotropic agents, such as β-adrenoreceptor agonists and phosphodiesterase inhibitors, which have been assessed in HF patients cause increased mortality as a result of arrhythmia and sudden cardiac death. Cardiac sarcoplasmic reticulum Ca(2+) ATPase2a (SERCA2a) is a key protein involved in sequestration of Ca(2+) into the sarcoplasmic reticulum (SR) during diastole. There is a reduction of SERCA2a protein level and function in HF, which has been successfully targeted via viral transfection of the SERCA2a gene into cardiac tissue in-vivo. This has enhanced cardiac contractility and reduced mortality in several preclinical models of HF. Theoretical concerns have been raised regarding the possibility of arrhythmogenic adverse effects of SERCA2a gene therapy due to enhanced SR Ca(2+) load and induction of SR Ca(2+) leak as a result. Contrary to these concerns SERCA2a gene therapy in a wide variety of pre-clinical models, including acute ischaemia/reperfusion, chronic pressure overload, and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias. The potential mechanisms for this unexpected beneficial effect, as well as mechanisms of enhancement of cardiac contractile function, are reviewed in this article.
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ABSTRACT: We use functions of a bicomplex variable to unify the existing constructions of harmonic morphisms from a 3-dimensional Euclidean or pseudo-Euclidean space to a Riemannian or Lorentzian surface. This is done by using the notion of complex-harmonic morphism between complex-Riemannian manifolds and showing how these are given by bicomplex-holomorphic functions when the codomain is one-bicomplex dimensional. By taking real slices, we recover well-known compactifications for the three possible real cases. On the way, we discuss some interesting conformal compactifications of complex-Riemannian manifolds by interpreting them as bicomplex manifolds.
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