Mechanisms and use of calcium-sensitizing agents in the failing heart.

Depressed cardiac contractility is central to many forms of cardiac disease and reflects the heart’s inability to generate adequate force despite being provided physiological activator calcium and chamber load. Yet, successful methods to enhance cardiac contractility have remained elusive. Agents such as dobutamine or milrinone that work through the -receptor–cAMP–protein kinase A pathway are used to manage acute hemodynamic decompensation, but short-term and, particularly, long-term use can increase risks of arrhythmia and worsen outcome. These and other data have led to the conclusion that successful heart failure management should probably avoid the targeting of contractility improvement. Leading hypotheses for the failure of existing inotropic therapies is that they increase activator calcium, worsen arrhythmia, activate maladaptive Ca -dependent signaling cascades, and increase myocardial oxygen consumption, making hearts less efficient. An alternative approach to avoid such complications would be to directly influence the manner by which intracellular calcium is transduced into muscle force. The class of molecules that achieve this are often termed “calcium sensitizers” and have attracted growing clinical interest for more than 20 years.1 The mechanisms by which such effects are achieved vary widely and include direct activators of motor proteins such as myosin, enhancers of force generated by a cross-bridge, and agents that augment Ca –troponin C (TnC) binding and its consequences. To date, many such drugs have had additional effects, such as inhibiting cAMP phosphodiesterase (PDE3a), that likely contributed to their vasodilation/venodilation and Ca dependent increases in heart rate and contractility. Other agents, such as levosimendan, also inhibit ATP-sensitive potassium channels, which can induce further effects. This review discusses basic molecular mechanisms for drugs that alter the myofilament response to calcium, how such agents affect muscle and whole-organ physiology, and what their clinical testing has revealed. In doing so, we attempted to bridge the gap between existing reductionist reviews to those that have focused largely on clinical outcome trials.