The therapeutic potential of novel cardiotonic agents

Abstract

During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as β-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca²⁺mobilisation (upstream mechanism). These agents are associated with the risk of Ca²⁺ overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca²⁺ overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca²⁺ ions (central and/or downstream mechanisms). Novel Ca²⁺ sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca²⁺ sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.

• Ca2+ sensitisers
• cardiac E-C coupling
• levosimendan
• myofilament Ca2+ sensitivity
• novel cardiotonic agents
• PDE3 inhibitors
• pimobendan