Cardiac Activator Research Articles

Omecamtiv mecarbil: a new cardiac myosin activator for the treatment of heart failure

Introduction: Current available inotropic agents increase cardiac contractility, but are associated with myocardial ischemia, arrhythmias, and mortality. A novel selective cardiac myosin activator, omecamtiv mecarbil (CK-1827452/ AMG-423) is a small molecule that activates the sarcomere proteins directly, resulting in prolonged systolic ejection time and increased cardiac contractility.Areas covered: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of omecamtiv mecarbil. Omecamtiv mecarbil represents a novel therapeutic approach to directly improve cardiac function and is therefore proposed as a potential new treatment of patients with systolic heart failure. The authors review results of previous studies investigating the effect of omecamtiv mecarbil in heart failure animal models, healthy volunteers, and patients with acute and chronic systolic heart failure.Expert opinion: Results of phase I and phase II studies demonstrate that omecamtiv mecarbil is safe and well tolerated both as an intravenous and oral formulation. In healthy volunteers and chronic systolic heart failure patients, administration of omecamtiv mecarbil resulted in a concentration-dependent increase of left ventricular ejection time, ejection fraction, fractional shortening, and stroke volume. The first results of a double-blind, randomized, placebo-controlled phase IIb dose-finding study with the oral formulation of omecamtiv mecarbil demonstrated beneficial effects on cardiac function and N-terminal pro-brain natriuretic peptide levels. This study will provide essential dosing information for the requisite phase III trials which will investigate whether the beneficial effects of omecamtiv mecarbil translate into improved clinical outcomes.

Omecamtiv Mecarbil, a Cardiac Myosin Activator, Increases Ca2+ Sensitivity in Myofilaments With a Dilated Cardiomyopathy Mutant Tropomyosin E54K.

Apart from transplant, there are no satisfactory therapies for the severe depression in contractility in familial dilated cardiomyopathy (DCM). Current heart failure treatments that act by increasing contractility involve signaling cascades that alter calcium homeostasis and induce arrhythmias. Omecamtiv mecarbil is a promising new inotropic agent developed for heart failure that may circumvent such limitations. Omecamtiv is a direct cardiac myosin activator that promotes and prolongs the strong myosin-actin binding conformation to increase the duration of systolic elastance. We tested the effect of omecamtiv on Ca(2+) sensitivity of myofilaments of a DCM mouse model containing a tropomyosin E54K mutation. We compared tension and ATPase activity of detergent-extracted myofilaments with and without treatment with 316 nM omecamtiv at varying pCa values. When transgenic myofilaments were treated with omecamtiv, the pCa50 for activation of tension increased from 5.70 ± 0.02 to 5.82 ± 0.02 and ATPase activity increased from 5.73 ± 0.06 to 6.07 ± 0.04. This significant leftward shift restored Ca(2+) sensitivity to levels no longer significantly different from controls. Proteomic studies lacked changes in sarcomeric protein phosphorylation. Our data demonstrate that omecamtiv can potentially augment cardiac contractility in DCM by increasing Ca(2+) sensitivity. The use of direct myosin activators addresses functional defects without incurring the adverse side effects of Ca(2+)-dependent treatments.

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. Ca2+ -dependent active force production (Factive ), its Ca2+ sensitivity (pCa50 ), the kinetic characteristics of Ca2+ -regulated activation and relaxation, and Ca2+ -independent passive force (Fpassive ) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM). In permeabilized cardiomyocytes, OM increased the Ca2+ sensitivity of force production (ΔpCa50 : 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration-response relationship of the Ca2+ sensitization was bell-shaped, with maximal effects at 0.3-1 μM OM (EC50 : 0.08 ± 0.01 μM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 μM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. OM acted as a Ca2+ -sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased Fpassive production.

Population pharmacokinetic‐pharmacodynamic modeling of omecamtiv mecarbil, a cardiac myosin activator, in healthy volunteers and patients with stable heart failure

Data from 3 clinical trials of omecamtiv mecarbil in healthy volunteers and patients with stable heart failure (HF) were analyzed using a nonlinear mixed-effects model to investigate omecamtiv mecarbil's pharmacokinetics and relationship between plasma concentration and systolic ejection time (SET) and Doppler-derived left ventricular outflow tract stroke volume (LVOTSV). Omecamtiv mecarbil pharmacokinetics were described by a linear 2-compartment model with a zero-order input rate for intravenous administration and first-order absorption for oral administration. Oral absorption half-life was 0.62 hours, and absolute bioavailability was estimated as 90%; elimination half-life was approximately 18.5 hours. Variability in pharmacokinetic parameters was not explained by patient baseline characteristics. Omecamtiv mecarbil plasma concentration was directly correlated with increases in SET and LVOTSV between healthy volunteers and patients with HF. The maximum increase from baseline in SET (delta SET) estimated by an Emax model was 137 milliseconds. LVOTSV increased linearly from baseline by 1.6 mL per 100 ng/mL of omecamtiv mecarbil. Model-based simulations for several immediate-release oral dose regimens (37.5, 50, and 62.5 mg dosed every 8, 12, and 24 hours) showed that a pharmacodynamic effect (delta SET ≥20 milliseconds) could be maintained in the absence of excessive omecamtiv mecarbil plasma concentrations.

New perspective in heart failure management: could myosin activators be the answer?

Heart failure is a worldwide leading cause of hospital admissions. There is a critical need for new methods of management in acute heart failure. The current drug panel available in the treatment of hemodinamically unstable patients is not only limited, but it is also associated with deleterious side effects. Discoveries in the heart failure field seemed to lack an adequate answer and a change in paradigm may be necessary. The cardiac myosin activator omecamtiv mecarbil is a new therapeutic approach that improves the myocardial contractility through an innovative mechanism, avoiding the harmful effects of currently used inotropic agents. Several studies provided us with promising results, but further scientific proofs are needed.

Mechanisms of epigenetic and cell-type specific regulation of Hey target genes in ES cells and cardiomyocytes

Hey bHLH transcription factors are critical effectors of Notch signaling. During mammalian heart development they are expressed in atrial and ventricular cardiomyocytes and in the developing endocardium. Hey knockout mice suffer from lethal cardiac defects, such as ventricular septum defects, valve defects and cardiomyopathy. Despite this functional relevance, little is known about the regulation of downstream targets in relevant cell types. The objective of this study was to elucidate the regulatory mechanisms by which Hey proteins affect gene expression in a cell type specific manner.We used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey proteins generally correlates with the extent of Hey-binding to target promoters, Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These also lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4. Ectopic Nkx2-5 overexpression in ESC blocks Hey-mediated repression of these genes.Thus, Hey proteins mechanistically repress target genes via Hdac recruitment and histone deacetylation. In CM Hey-repression is counteracted by cardiac activators, which recruit histone acetylases and prevent Hey mediated deacetylation and subsequent repression for a subset of genes.

Safety and Tolerability of Omecamtiv Mecarbil During Exercise in Patients With Ischemic Cardiomyopathy and Angina

ObjectivesThe goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time. BackgroundOmecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time. MethodsIn this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3). ResultsThe primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events. ConclusionsDoses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565)

Acute decompensated heart failure: current pharmacological approaches

Acute heart failure (AHF) represents a major burden in developed countries. However, pharmacological approaches have remained almost same for 30 years and are still based on consensus rather than evidence, given that no medical therapy has been shown to positively affect clinical outcomes. Current pharmacological approaches are still based on decongestion by using diuretics in almost all patients, plus either vasodilators or inotropic agents to hemodynamics according to perfusion status. The role of loop diuretics (furosemide) and nitrates (nitroglycerin and nitroprusside) is well established, but new agents such as vasopressin and adenosine antagonists, as well as nesiritide, have failed to show any additional value. In presence of hypoperfusion, use of inotropics must be considered despite lack of benefit in terms of survival, and use of phosphodiesterase inhibitors and levosimendan has not shown any significant advantages over catecholamines (dobutamine). AHF involves a wide spectrum of patients and syndromes, and this probably accounts for failure of trials set up to evaluate new therapeutic approaches for improving outcomes: therapies need to be tailored to specific patients. At this time, serelaxin represents a promising new agent which has a multifaceted effect, including organ protection, and has shown encouraging results when tailored for a well defined population. In addition, role of ularitide, a synthetic form of natriuretic peptide urodilatin, and new cardiac myosin activators, as a new class of inotropic agents, will be established in near future by ongoing trials. Therefore, AHF continues to be an unsolved problem and, in light of lessons learned, new pharmacological approaches should be tai- lored to well defined AHF populations, incorporating concepts such as the sooner better, improve and stabilize, and prevent organ damage, in order to be able to clinical outcomes, including both mortality and readmission rates.

Cardiomyopathy Ctnt Mutation in Patient Derived Cardiomyocytes from Induced Pluripotent Stem Cells Affects Sarcomere Structure and Function

Cardiomyocytes derived from human induced pluripotent stem cells (hIPS-CM) are useful to understand basic structural and functional characteristics of normal and diseased human heart cells. We investigated mechanical properties of hIPS-CM derived from unaffected and affected members of a family harboring a dilated cardiomyopathy (DCM) mutation in cardiac troponin T (cTnT), the tropomyosin binding unit of troponin. Patients with a cTnT point mutation (R173W) develop DCM, which commonly leads to diastolic and systolic dysfunction and progressive heart failure. To study the shortening and shortening velocity of normal and cTnT mutant hIPS-CM cells, cells were plated on substrates with a relatively soft stiffness (160 kPa) molded from polydimethylsiloxane and measured using a line scan method. Data were collected using a Zeiss 710 confocal microscope. Visual observation of cells after 5 days maturity on the PDMS substrates indicate a smaller percent of mutant (8%) compared to normal (87%) hIPS-CM were spontaneously beating. Immunohistochemistry showed that myofibril structure was better developed in normal compared to cTnT mutation cells. Day 5 line scans revealed normal hIPS-CM cells shorten more (0.47 μm) than mutant cTnT cells (0.32 μm); shortening velocity was faster in normal (1.42 μm/s) compared to mutant cTnT cells (0.67 μm/s). Acute treatment (1 dose with a 10 min activation dwell time) with omecamtiv mecarbil (200nM), a cardiac myosin activator, increased the shortening and shortening velocity of normal (0.78 μm at 1.85 μm/s) but not cTnT mutant (0.32 μm at 0.70 μm/s) hIPS-CM cells. Although more studies are necessary, these results suggest that cTnT may affect development of sarcomeres and the regulation of contractility. Furthermore, the myosin activator omecamtiv mecarbil may not be sufficient to rescue dysfunction in the cTnT mutation R173W. [Funding: NIH T32HL07692, PO1HL62426]

The Efficacy and Tolerability of Azilsartan in Obese Insulin-Resistant Mice with Left Ventricular Pressure Overload

Angiotensin II receptor blockers (ARBs) are used widely for the treatment of heart failure. However, their use in obese and insulin-resistant patients remains controversial. To clarify their potential efficacy in these conditions, we administered azilsartan medoxomil (azilsartan), a prodrug of an angiotensin II receptor blocker to mice fed a high-fat diet (HFD) with left ventricular (LV) pressure overload (aortic banding). LV fibrosis (hydroxyproline), cardiac plasminogen activator inhibitor-1 (PAI-1; a marker of profibrosis), and creatine kinase (a marker of myocardial viability and energetics) were assessed. LV wall thickness and cardiac function were assessed echocardiographically. Mice given a HFD were obese and insulin resistant. Their LV hypertrophy was accompanied by greater LV PAI-1 and reduced LV creatine kinase compared with normal diet controls. Drug treatment reduced LV wall thickness, hypertrophy, and PAI-1 and increased cardiac output after aortic banding compared with results in HFD vehicle controls. Thus, azilsartan exerted favorable biological effects on the hearts of obese insulin-resistant mice subjected to LV pressure overload consistent with its potential utility in patients with analogous conditions.

A New Approach to Inotropic Therapy in the Treatment of Heart Failure

Systolic heart failure remains a leading cause of death and disability, and available pharmacologic treatments for heart failure are limited in both safety and effectiveness. Existing drugs focus on diverse mechanisms related to the pathophysiology of heart failure, yet none directly target the central feature of systolic heart failure, decreased cardiac contractility. Cardiac myosin activators, specifically omecamtiv mecarbil (formerly CK-1827452), directly activate the enzymatic pathway within the cardiac myocyte leading to ventricular contraction. This unique inotropic agent has been shown in preclinical and clinical studies to be effective in improving cardiac contractility by increasing systolic ejection time without the unwanted effects of the currently available indirect inotropic drugs. Cardiac myosin activators show great promise and may prove to be a safer and more effective therapeutic approach for the treatment of systolic heart failure.

Emerging Pharmacotherapies: The Future of Heart Failure Management

Patients with heart failure (HF) often remain symptomatic and have a poor prognosis despite treatment with existing therapies [Cleland JG et al. Lancet 2011]. Several new therapeutic options are currently emerging for HF, including direct renin inhibitors, neprilysin inhibitors, selective If channel inhibitors, cardiac myosin activators, vasopressin receptor antagonists, and phosphodiesterase type 5 inhibitors. This article discusses clinical trial data for direct renin inhibitors and neprilysin inhibitors.

Novel Pharmacologic Therapies in Development for Acute Decompensated Heart Failure

Acute heart failure is a public health issue with morbidity and mortality exceeding that of myocardial infarction. Novel compounds for the treatment of acute heart failure are clearly needed and fall into the general categories of inotropic, vasodilatory and other compounds in phase I to III of development. Furthest along are omecamtiv mecarbil (a cardiac myosin activator), ularitide (a natriuretic and diuretic peptide) and relaxin (a vasodilator). Each compound has a unique set of assets and liabilities that will aid in the understanding of the syndrome and application to the right patients at the right time in this heterogeneous syndrome. This review will explore current and future novel pharmacologic therapies for the treatment of acute heart failure.

Different cardiac tissue plasminogen activator release patterns by local stimulation of the endothelium and sympathetic nerves in pigs

Myocardial ischemia induces cardiac tissue plasminogen activator (tPA) release, declining by repeated periods of ischemia. However, the mechanisms and cellular sources are unknown. Sympathetic nerve stimulation (SS) and bradykinin (BK), an endogenous inducer of endothelial tPA release, may play roles, potentially involving different sources or mechanisms revealed by different release patterns. Therefore, we compared the cardiac tPA release patterns during repeated coronary BK infusions and SS, both with an ensuing period of local myocardial ischemia/reperfusion (I/R). Nine pigs were subjected to four periods of coronary BK infusion (4 min) and another nine animals to four periods of SS (4 min). Finally, 10 min of I/R was induced in both groups. The single-peaked BK-induced tPA release declined toward baseline by repeated infusions, but tPA release reappeared during I/R. In contrast, total tPA release during repeated SS and subsequent I/R was more stable, and SS-induced total tPA and norepinephrine (NE) releases were strongly correlated. Surprisingly, the instantaneous SS-induced tPA release was biphasic with a stable first peak, and a second peak declining toward baseline by repeated stimulations. The fluctuations in cardiac release of plasminogen activator inhibitor-1 and the endogenous BK inhibitor angiotensin-converting enzyme, could not explain the diverging tPA release patterns. Different tPA release patterns were demonstrated during SS and BK stimulation, as well as diverging responses to repeated stimulations and subsequent I/R. This study demonstrates strong association between tPA and NE during SS and possibly two different sources or mechanisms for SS-induced tPA release.

Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II–induced cardiac, renal, and vascular injury

Angiotensin II causes cardiovascular injury in part by aldosterone-induced mineralocorticoid receptor activation, and it can also activate the mineralocorticoid receptor in the absence of aldosterone in vitro. Here we tested whether endogenous aldosterone contributes to angiotensin II/salt-induced cardiac, vascular, and renal injury by the mineralocorticoid receptor. Aldosterone synthase knockout mice and wild type littermates were treated with angiotensin II or vehicle plus the mineralocorticoid receptor antagonist spironolactone or regular diet while drinking 0.9- saline. Angiotensin II/salt caused hypertension in both the knockout and wild type mice; an effect significantly blunted in the knockout mice. Either genetic aldosterone deficiency or mineralocorticoid receptor antagonism reduced cardiac hypertrophy, aortic remodeling, and albuminuria, as well as cardiac, aortic, and renal plasminogen activator inhibitor-1 mRNA expression during angiotensin II treatment. Mineralocorticoid receptor antagonism reduced angiotensin II/salt-induced glomerular hypertrophy, but aldosterone deficiency did not. Combined mineralocorticoid receptor antagonism and aldosterone deficiency reduced blood urea nitrogen and restored nephrin immunoreactivity. Angiotensin II/salt also promoted glomerular injury through the mineralocorticoid receptor in the absence of aldosterone. Thus, mineralocorticoid antagonism may have protective effects in the kidney beyond aldosterone synthase inhibition.

Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study

Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study

First-in-human studies with cardiac myosin activators

First-in-human studies with cardiac myosin activators

Cardiac myosin activator shows promise in phase II trial

A novel, small-molecule, sarcomere-directed activator of cardiac myosin, omecamtiv mecarbil, is well tolerated in healthy individuals, and significantly improves cardiac function in patients with stable heart failure (HF), according to two reports published in The Lancet. Professor John Cleland, from the University of Hull, UK, is “excited about the possibility of a new molecule that could improve cardiac function not only by a fundamentally different molecular mechanism, but also a very different physiological principle (prolongation of contraction rather than increased velocity of contraction).”

The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial

Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. Cytokinetics Inc.

Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study

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 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; 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. Cytokinetics Inc.