Old and New Intravenous Inotropic Agents in the Treatment of Advanced Heart Failure

Abstract

Inotropic agents are administered to improve cardiac output and peripheral perfusion in patients with systolic dysfunction and low cardiac output. However, there is evidence of increased mortality and adverse effects associated with current inotropic agents. These adverse outcomes may be ascribed to patient selection, increased myocardial energy expenditure and oxygen consumption, or to specific mechanisms of action. Both sympathomimetic amines and type III phosphodiesterase inhibitors act through an increase in intracellular cyclic adenosine monophoshate and free calcium concentrations, mechanisms that increase oxygen consumption and favor arrhythmias. Concomitant peripheral vasodilation with some agents (phosphodiesterase inhibitors and levosimendan) may also lower coronary perfusion pressure and favor myocardial damage. New agents with different mechanisms of action might have a better benefit to risk ratio and allow an improvement in tissue and end-organ perfusion with less untoward effects. We have summarized the characteristics of the main inotropic agents for heart failure treatment, the data from randomized controlled trials, and future perspectives for this class of drugs. (Prog Cardiovasc Dis 2011;54:97-106)

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

“…For the past 30 years or more, the quest to develop treatments that directly improve systolic performance of the failing heart while also conferring long-term survival benefits has been met with disappointment (1). Agents that stimulate the β1-adrenergic receptor or enhance cyclic AMP (e.g., PDE3 inhibitors) work in the short term, but have worsened chronic outcomes.…”

“…Interestingly, while CRT substantially improves resting myocyte function throughout the ventricle, this is not consistently matched by increases in the calcium transient (17,20), suggesting CRT may also enhance myofilament responses to calcium. This is intriguing, as small molecule HF therapies that target the myofilament are of growing interest (1,(21)(22)(23)). …”

Inotropes and vasopressors

“…Their positive inotropic effects are independent of β1 adrenergic receptors. Therefore, since the number of β adrenoreceptors is reduced in patients with heart failure, PDEi are theoretically more effective in treatment of those patients (1,11). PDEi also have unique vasodilatory actions independent of endothelial function or nitrovasodilators (12).…”

“…Increased cardiac output produced by PDEi is a result of positive inotropy and afterload reduction. Net effect is a decrease in myocardial wall tension, which is an important contrast with most sympathomimetic agents (11). Inotropic agents that do not depend on cAMP form a diverse group of which the most important are cardiac glycosides and calcium sensitizers.Cardiac glycosides (digoxin) improve myocardial contractility by inhibiting Na+/K+ ATPase.…”

Comparative Evaluation of Calcium-Sensitizing Agents, Pimobendan and SCH00013, on the Myocardial Function of Canine Pacing–Induced Model of Heart Failure

“…Inotropic agents have been indicated for the treatment of congestive heart failure (CHF) with reduced cardiac output and peripheral hypo-perfusion (1,2). Classic inotropic agents, including cardiac glycosides, catecholamines, and phosphodiesterase (PDE) III inhibitors, improve impaired cardiac pump function by elevating intracellular calcium concentration in myocardial cells to directly improve the myocardial contractility (2 -4).…”