An editorial¹ reviewing options for circulatory support in patients with cardiogenic shock argues that traditional inotrope therapy may be replaced by newer alternatives that have a less detrimental effect on myocardial oxygen demand.
Newer inotropic agents include levosimendan, istaroxime, and omecamtiv mecarbil. Mechanical therapies include intra-aortic balloon pumps (IABP), ventricular assist devices (VAD), and extracorporeal membrane oxygenation (ECMO).

Levosimendan is an inodilator, with the following characteristics:

• stabilises the myocardial calcium-troponin C complex
• activates adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle and cardiac mitochondria,
• acts as a traditional phosphodiesterase inhibitor at higher doses
• improved cardiac output and a reduction in filling pressures compared with dobutamine
• may also improve diastolic function by increasing relaxation rate
• modulates the neuroendocrine response to heart failure by reducing brain natriuretic peptide levels
• has anti-apoptotic and anti-inflammatory effects
• renal function may also improve
• is associated with a similar risk of ventricular arrhythmias to dobutamine
• increases risk of new onset atrial fibrillation
• has conflicting literature surrounding mortality
• has shown a lack of consistent outcome benefits in studies
• may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively².

Istaroxime, a novel inotrope with positive lusitropic (cardiac relaxant) effects³:

• is an inhibitor of the sodium-potassium-ATPase (resulting, like digoxin, in elevated intracellular calcium) with additional stimulatory effects on the sarcoplasmic reticulum calcium pump (SERCA)
• provides a dose-dependant increase in cardiac output without significant change in heart rate or arrhythmia
• in one study reducesd pulmonary capillary wedge pressure, increased systolic blood pressure, and reduced heart rate and left ventricular end-diastolic volume
• requires further clinical evaluation.

Omecamtiv mecarbil is a cardiac myosin activator. This new drug:

• improves myocardial contraction by increasing the hydrolysis of ATP by myosin ATPase
• this produces the power stroke between actin and myosin and subsequent shortening of sarcomere length
• in phase-2a studies in patients with systolic heart failure it demonstrated improved stroke volume without an increase in heart rate, although cardiac ischaemia emerged at high plasma concentrations^4,5.

1. Do inotropes really have a future?
Anaesthesia. 2011 Nov;66(11):972-6.
2. Inotropes in cardiac patients: update 2011
Curr Opin Crit Care. 2010 Oct;16(5):432-41
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PURPOSE OF REVIEW: ICU patients frequently develop low output syndromes due to cardiac dysfunction, myocardial injury, and inflammatory activation. Conventional inotropic agents seem to be useful in restoring hemodynamic parameters and improving peripheral organ perfusion, but can increase short-term and long-term mortality in these patients. Novel inotropes may be promising in the management of ICU patients, having no serious adverse effects. This review summarizes all the current knowledge about the use of conventional and new inotropic agents in various clinical entities of critically ill patients.

RECENT FINDINGS: In recent European Society of Cardiology guidelines, inotropic agents are administered in patients with low output syndrome due to impaired cardiac contractility, and signs and symptoms of congestion. The most recommended inotropes in this condition are levosimendan and dobutamine (both class of recommendation: IIa, level of evidence: B). Recent data indicate that levosimendan may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively. Furthermore, calcium sensitizing by levosimendan can be effectively used for weaning of mechanical ventilation in postcardiac surgery patients and has also cardioprotective effect as expressed by the absence of troponin release in this patient population. Finally, new agents, such as istaroxime and cardiac myosin activators may be safe and improve central hemodynamics in experimental models of heart failure and heart failure patients in phase II clinical trials; however, large-scale randomized clinical trials are required.

SUMMARY: In an acute cardiac care setting, short-term use of inotropic agents is crucial for the restoration of arterial blood pressure and peripheral tissue perfusion, as well as weaning of cardiosurgery. New promising agents should be tested in randomized clinical trials.

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3. Combining SERCA2a activation and Na-K ATPase inhibition: a promising new approach to managing acute heart failure syndromes with low cardiac output.
Discov Med. 2011 Aug;12(63):141-51 Free Full Text
[EXPAND Abstract]

Heart failure (HF) patients are a medically complex and heterogeneous population with multiple cardiac and non-cardiac comorbidities. Although there are a multitude of etiologic substrates and initiating and amplifying mechanisms contributing to disease progression, these pathophysiologic processes ultimately all lead to impaired myocardial function. The myocardium must both pump oxygenated, nutrient-rich blood throughout the body (systolic function) and receive deoxygenated, nutrient-poor blood returning from the periphery (diastolic function). At the molecular level, it is well-established that Ca2+ plays a central role in excitation-contracting coupling with action potentials stimulating the opening of L-type Ca2+ in the plasma membrane and ryanodine receptor 2 (RyR2) in the sarcoplasmic reticulum (SR) membrane during systole and the Na-Ca2+ exchanger and SERCA2a returning Ca2+ to the extracellular space and SR, respectively, during diastole. However, there is increasing recognition that impaired Ca2+ cycling may contribute to myocardial dysfunction. Preclinical studies and clinical trials indicate that combining SERCA2a activation and Na-K ATPase inhibition may increase contractility (inotropy) and facilitate active relaxation (lusitropy), improving both systolic and diastolic functions. Istaroxime, a novel luso-inotrope that activates SERCA2a and inhibits the Na-K ATPase, is currently in phase II clinical development and has been shown to improve systolic and diastolic functions and central hemodynamics, increase systolic but not diastolic blood pressure, and decrease substantially heart rate. Irrespective of its clinical utility, the development of istaroxime has evolved our understanding of the clinical importance of inhibiting the Na-K ATPase in order to obtain a clinically significant effect from SERCA2a activation in the setting of myocardial failure.

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4. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study
Lancet. 2011 Aug 20;378(9792):667-75
[EXPAND Abstract]

BACKGROUND: 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.

METHODS: 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.

FINDINGS: 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.
INTERPRETATION: 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.

FUNDING: Cytokinetics Inc.

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5. 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
Lancet. 2011 Aug 20;378(9792):676-83
[EXPAND Abstract]

BACKGROUND: 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.

METHODS: 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.

FINDINGS: T45 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.

INTERPRETATION: 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.

FUNDING: Cytokinetics Inc.

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