Electrical Plasticity and Cardioprotection in Myocardial Ischemia—Role of Selective Sodium Channel Blockers

Abstract

The concept of electrical protection of the ischemic myocardium is in constant evolution and has recently been supported by experimental and clinical studies. Historically, antiplatelet agents, angiotensin‐converting enzyme inhibitors, β‐blockers, and statins have been all proposed as drugs conferring anti‐ischemic cardioprotection. This was supported by the evidence consistently indicating that all these drugs were capable of reducing mortality and the risk of repeat myocardial infarction. The electrical plasticity paradigm is, however, a novel concept that depicts the benefits of improved sodium channel blockade with drugs such as ranolazine and cariporide. Although it has been hypothesized that the protective role of ranolazine depends on decreased fatty acid β‐oxidation affecting preconditioning, we speculate against such a hypothesis, because inhibition of β‐oxidation requires higher concentrations of the drug, above the therapeutic range. Rather, we discuss the key role of calcium overload reduction through inhibition of the late sodium current (INa). Mechanisms driving cardioprotection involve the block of a cascade of complex ionic exchanges that can result in intracellular acidosis, excess cytosolic calcium, myocardial cellular dysfunction, and eventually cell injury and death. In this review we discuss the studies that demonstrate how electrical plasticity through sodium channel blockers can promote cardioprotection against ischemia in coronary heart disease.

Selective inhibition of physiological late Na+ current stabilizes ventricular repolarization

“…In an increasing body of literature from experimental models of proarrhythmia and in defined human pathophysiological settings, an enhanced late I Na has been identified as an important inward current that regulates the APD and contributes to disease-specific electrophysiological (proarrhythmic) phenotypes (2,8,19). For these reasons, this current is now recognized as an antiarrhythmic target (7,14,15,24). On the other hand, much less is known and published about the functional role(s) of the normal and small physiological late I Na of the mammalian cardiomyocyte.…”

KATP channels and MPTP are involved in the cardioprotection bestowed by chronic intermittent hypobaric hypoxia in the developing rat

“…Heart diseases induced by I/R, such as necrosis, heart failure and arrhythmia, are common diseases and leading causes of morbidity and mortality clinically. To date, only limited success has been achieved in preventing and treating ischemic heart diseases [1].…”