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Background: A growing population of patients with end-stage heart failure (HF) with reduced ejection fraction has limited treatment options to improve their quality and quantity of life. Although positive inotropes have failed to show survival benefit, these agents may enhance patient-reported health status, that is, symptoms, functional status, and health-related quality of life. We sought to review the available clinical trial data on positive inotrope use in patients with end-stage HF and to summarize evidence supporting the use of these agents to improve health status of patients with end-stage HF., Methods: A literature review of randomized controlled trials examining the use of positive inotropy in HF with reduced ejection fraction was conducted. We searched MEDLINE, SCOPUS, and Web of Science between January 1980 to December 2018 for randomized controlled trials that used as their main outcome measures the effects of inotrope therapy on (1) morbidity/mortality, (2) symptoms, (3) functional status, or (4) health-related quality of life. Inotropes of interest included adrenergic agents, phosphodiesterase inhibitors, calcium sensitizers, myosin activators, and SERCA2a (sarcoplasmic reticulum Ca 2+ -ATPase) modulators., Results: Twenty-two out of 26 inotrope randomized controlled trials measured the effect of inotropes on at least one patient-reported health status domain. Among the 22 studies with patient-related health status outcomes, 11 (50%) gauged symptom response, 15 (68%) reported functional capacity changes, and 12 (54%) reported health-related quality of life measures. Fourteen (64%) of these trials noted positive outcomes in at least one health status domain measured; 11 (79%) of these positive studies used agents that worked through phosphodiesterase inhibition., Conclusions: There has been a lack of standardization surrounding measurement of patient-centered outcomes in studies of inotropes for end-stage HF with reduced ejection fraction. The degree to which positive inotropes can improve patient-reported health status and the adverse risk they pose remains unknown.

The term "inotrope" is familiar and intimately connected with pharmaceuticals clinically used for treatment of low cardiac output with cardiogenic shock. Traditional inotropic agents exert their effect by modulating calcium signaling in the myocardium. Their use is associated with poor long-term outcomes. Newer molecules in development intend to break from calcium mediation and the associated detrimental long-term effects by targeting distinct mechanisms of action to improve cardiac performance. Thus, "inotropy" does not sufficiently describe the range of potential novel pharmaceutical products. To enhance communication around and evaluation of current, emerging, and potential therapies, this review proposes a novel nuanced and holistic framework to categorize pharmacological agents that improve myocardial performance based on 3 myocardial mechanisms: calcitropes, which alter intracellular calcium concentrations; myotropes, which affect the molecular motor and scaffolding; and mitotropes, which influence energetics. Novel chemical entities can easily be incorporated into this structure, distinguishing themselves based on their mechanisms and clinical outcomes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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.