istaroxime and omecamtiv-mecarbil

Treatment with inotropic agents is one of the most controversial topics in heart failure. Initial enthusiasm, based on strong pathophysiological rationale and apparent empirical efficacy, has been progressively limited by results of controlled trials and registries showing poorer outcomes of the patients on inotropic therapy. The use of these agents remains, however, potentially indicated in a significant proportion of patients with low cardiac output, peripheral hypoperfusion and end-organ dysfunction caused by heart failure. Limitations of inotropic therapy seem to be mainly related to their mechanisms of action entailing arrhythmogenesis, peripheral vasodilation, myocardial ischemia and damage, and possibly due to their use in patients without a clear indication, rather than to the general principle of inotropic therapy itself. This review will discuss the characteristics of the patients with a potential indication for inotropic therapy, the main data from registries and controlled trials, the mechanism of the untoward effects of these agents on outcomes and, lastly, perspectives with new agents with novel mechanisms of action.

Topics: Acute Disease; Cardiotonic Agents; Digoxin; Dobutamine; Etiocholanolone; Exercise Test; Heart Failure; Hemodynamics; Hospitals, Group Practice; Humans; Hydrazones; Prognosis; Pyrazines; Pyridazines; Quinolines; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan; Treatment Outcome; Urea; Vasodilator Agents

Acute heart failure represents an increasingly common cause of hospitalization, and may require the use of inotropic drugs in patients with low cardiac output and evidence of organ hypoperfusion. However, currently available therapies may have deleterious effects and increase mortality. An ideal inotropic drug should restore effective tissue perfusion by enhancing myocardial contractility without causing adverse effects. Such a drug is not available yet. New agents with different biological targets are under clinical development. In particular, istaroxime seems to dissociate the inotropic effect exerted by digitalis (inhibition of the membrane sodium/potassium adenosine triphosphatase) from the arrhythmic effect and to ameliorate diastolic dysfunction (via sarcoendoplasmic reticulum calcium adenosine triphosphatase activation). Additionally, the myosin activator omecamtiv mecarbil appears to have promising characteristics, while genetic therapy has been explored in animal studies only. Further investigations are needed to confirm and expand the effectiveness and safety of these agents in patients with acute heart failure and low cardiac output.

Topics: Acute Disease; Animals; Cardiac Output; Cardiotonic Agents; Clinical Trials as Topic; Digoxin; Dobutamine; Etiocholanolone; Genetic Therapy; Heart Failure; Humans; Hydrazones; Pyridazines; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan; Sodium-Potassium-Exchanging ATPase; Urea