Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study.
ABSTRACT 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.
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ABSTRACT: Acute heart failure is a common condition associated with considerable morbidity, mortality, and cost. However, evidence-based data on treating heart failure in the acute setting are limited, and current individual treatment options have variable efficacy. The healthcare team must often individualize patient care in ways that may extend beyond available clinical guidelines. In this review, we address the question, "How do you do the best you can clinically with incomplete evidence and imperfect drugs?" Expert opinion is provided to supplement guideline-based recommendations and help address the typical challenges that are involved in the management of patients with acute heart failure. Specifically, we discuss 4 key areas that are important in the continuum of patient care: differential diagnosis and risk stratification; choice and implementation of initial therapy; assessment of the adequacy of therapy during hospitalization or observation; and considerations for discharge/transition of care. A case study is presented to highlight the decision-making process throughout each of these areas. Evidence is accumulating that should help guide patients and healthcare providers on a path to better quality of care.Critical Pathways in Cardiology 03/2015; 14(1):12-24. DOI:10.1097/HPC.0000000000000031
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ABSTRACT: Heart failure remains a leading cause of morbidity, hospitalizations, and deaths. We previously showed that overexpression of the enzyme ribonucleotide reductase (RNR) in cardiomyocytes increased levels of the myosin activator, 2-deoxy-ATP, catalysed enhanced contraction, and improved cardiac performance in rodent hearts. Here we used a swine model of myocardial infarction (MI) to test preliminarily a novel gene therapy for heart failure based on delivery of the human RNR enzyme complex under the control of a cardiac-specific promoter via an adeno-associated virus serotype 6 vector-designated as BB-R12. We induced heart failure following MI in Yucatan minipigs by balloon occlusion of the left anterior descending artery. Two weeks, later, pigs received BB-R12 at one of three doses via antegrade coronary infusion. At 2 months post-treatment, LVEF and systolic LV dimension (measured by echocardiography) improved significantly in the high-dose group, despite further deterioration in the saline controls. Haemodynamic parameters including LV end-diastolic pressure, +dP/dt, and -dP/dt all trended towards improvement in the high-dose group. We observed no difference in the histopathological appearance of hearts or other organs from treated animals vs. controls, nor did we encounter any safety or tolerability concerns following BB-R12 delivery. These pilot results suggest cardiac-specific gene therapy using BB-R12 may reverse cardiac dysfunction by myosin activation in a large-animal heart failure model with no observed safety concerns. Thus further research into the therapeutic potential of BB-R12 for patients with chronic heart failure appears warranted. © 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.European Journal of Heart Failure 04/2015; DOI:10.1002/ejhf.270 · 6.58 Impact Factor
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ABSTRACT: One of the obstacles to a better understanding of the pathogenesis of human cardiomyopathies has been poor availability of heart tissue samples at early stages of disease development. This has possibly changed by the advent of patient-derived induced pluripotent stem cell (hiPSC) from which cardiomyocytes can be derived in vitro. The main promise of hiPSC technology is that by capturing the effects of thousands of individual gene variants, the phenotype of differentiated derivatives of these cells will provide more information on a particular disease than simple genotyping. This article summarizes what is known about the "human cardiomyopathy or heart failure phenotype in vitro", which constitutes the reference for modeling sarcomeric cardiomyopathies in hiPSC-derived cardiomyocytes. The current techniques for hiPSC generation and cardiac myocyte differentiation are briefly reviewed and the few published reports of hiPSC models of sarcomeric cardiomyopathies described. A discussion of promises and challenges of hiPSC-modeling of sarcomeric cardiomyopathies and individualized approaches is followed by a number of questions that, in the view of the authors, need to be answered before the true potential of this technology can be evaluated. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.Cardiovascular Research 01/2015; 105(4). DOI:10.1093/cvr/cvv017 · 5.81 Impact Factor