Levosimendan: dual mechanisms for acute heart failure...and beyond?

Levosimendan is a novel compound recently approved for the management of acute heart failure in Sweden and several European countries. Levosimendan exerts dual mechanisms of action associated with dose-dependent increases in cardiac output and decreases in pulmonary capillary wedge pressures. A positive inotropic effect is achieved through calcium sensitization, an effect of levosimendan binding to troponin C in a calcium-dependent manner. This mode of enhanced contractile force generation is achieved without an increase in myocardial oxygen consumption, intracellular calcium concentrations, or an adverse effect on diastolic function. The vasodilatory effect observed in cardiac, pulmonary and systemic vasculature occurs as a result of K-ATP channel activation, a mechanism which may also confer anti-ischemic properties. It remains unclear whether calcium sensitization or K-ATP channel activation is of greater clinical significance. Clinical studies utilizing fixed-dose infusions of 6 to 24 h in patients with left ventricular systolic dysfunction demonstrate greater safety and hemodynamic efficacy than placebo or dobutamine. This has translated into improved comparative survival at 31 days and potentially 180 days. Two additional prospective, outcome studies are being completed to confirm the beneficial effect on morbidity and mortality. Hypo-tension and decreased hematologic indices are the most common adverse effects requiring monitoring. No relevant drug interactions have been noted with chronic oral heart failure medications. Levosimendan's unique safety and efficacy profile suggests it is a rationale alternative to conventional inotropes, and potentially a useful first line agent for management of acute decompensated heart failure. Its role in other clinical scenarios, such as for cardiac surgery, diastolic dysfunction and outpatient infusion therapy, continues to evolve.