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Direct Myosin Activation by Omecamtiv Mecarbil for Heart Failure with Reduced Ejection Fraction

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Heart Failure

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 243))

Abstract

Myosin is the indispensable molecular motor that utilizes chemical energy to produce force for contraction within the cardiac myocyte. Myosin activity is gated by intracellular calcium levels which are regulated by multiple upstream signaling cascades that can be altered for clinical utility using inotropic medications. In contrast to clinically available cardiac inotropes, omecamtiv mecarbil is a novel direct myosin activator developed to augment left ventricular systolic function without the undesirable secondary effects of altered calcium homeostasis. Its identification and synthesis followed high-throughput screening of a reconstituted sarcomere, deliberate optimization, exquisite biochemical evaluation, and subsequently promising effects in animal models were demonstrated. Physiologically, it prolonged the duration of left ventricular systole in animal models, healthy adults, and patients with heart failure with reduced ejection fraction (HFrEF) without changing the velocity of pressure development, as assessed in animal models. It has been formulated for both intravenous and oral administration, and in both acute and chronic settings produced similar alterations in the duration of systole associated with beneficial increases in cardiac output, improvements in left ventricular volumes, and reductions in heart rate and often of natriuretic peptides. Small, asymptomatic increases in troponin were also observed in the absence of clinically evident ischemia. Clinically, the question remains as to whether the possible harm of this minimal troponin release is outweighed by the potential benefits of reduced neurohormonal activation, increased stroke volume and cardiac output, and improved ventricular remodeling in patients treated with omecamtiv mecarbil. The resolution of this question is being addressed by a phase III outcomes trial of this potential novel therapy for heart failure.

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Abbreviations

ACE:

Angiotensin-converting enzyme

ARB:

Angiotensin receptor blocker

ARNI:

Angiotensin receptor neprilysin inhibitors

ATP:

Adenosine triphosphate

BNP:

Brain-type natriuretic peptide

cAMP:

Cyclic adenosine monophosphate

CO:

Cardiac output

dP/dt:

Maximal rate of pressure rise during systole

FS:

Fractional shortening

HF:

Heart failure

HFrEF:

Heart failure with reduced ejection fraction

LV:

Left ventricle

LVEDP:

Left ventricular end-diastolic pressure

LVEDV:

Left ventricular end-diastolic volume

LVEF:

Left ventricular ejection fraction

LVESV:

Left ventricular end-systolic volume

MRA:

Mineralocorticoid receptor antagonists

MVO2 :

Myocardial oxygen consumption

NCX:

Sodium–calcium exchanger

OM:

Omecamtiv mecarbil

PDE:

Phosphodiesterase

Pi :

Hydrolyzed phosphate

SERCA2a:

Sarcoplasmic reticulum calcium ATPase 2a

SET:

Systolic ejection time

SR:

Sarcoplasmic reticulum

SV:

Stroke volume

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Authors and Affiliations

  1. School of Medicine, University of California San Francisco, San Francisco, CA, USA

    Mitchell A. Psotka & John R. Teerlink

  2. Section of Cardiology, 111C, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA, 94121-1545, USA

    John R. Teerlink

Authors
  1. Mitchell A. Psotka
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Correspondence to John R. Teerlink .

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Editors and Affiliations

  1. Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover Klinik für Kardiologie und Angiologie, Hannover, Niedersachsen, Germany

    Johann Bauersachs

  2. Heart Institute, Stony Brook University , Stony Brook, New York, USA

    Javed Butler

  3. Heart and Lung Diseases, Bayer Pharma Aktiengesellschaft Heart and Lung Diseases, Wuppertal, Nordrhein-Westfalen, Germany

    Peter Sandner

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Psotka, M.A., Teerlink, J.R. (2017). Direct Myosin Activation by Omecamtiv Mecarbil for Heart Failure with Reduced Ejection Fraction. In: Bauersachs, J., Butler, J., Sandner, P. (eds) Heart Failure. Handbook of Experimental Pharmacology, vol 243. Springer, Cham. https://doi.org/10.1007/164_2017_13

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