Rational strategy to stop arrhythmias: Early afterdepolarizations and L-type Ca2+ current

Unlike the brief action potentials (APs) in skeletal myo­ cytes or neurons, the human cardiac AP takes 100s of milliseconds to repolarize the cell. This slow repolar­ ization is essential for proper excitation–contraction coupling in cardiac muscle, and precise control of AP duration contributes to electrical stability. Under vari­ ous pathological conditions, often when the AP dura­ tion is prolonged, repolarization can transiently fail with a sudden transient depolarization of membrane poten­ tial (Fig. 1). If such an early afterdepolarization (EAD) reaches threshold, it can trigger a premature AP and thereby initiate potentially fatal ventricular arrhythmias such as torsades de pointes (TdP) and ventricular fibril­ lation (Cranefield and Aronson, 1991). Thus, understand­ ing the causes of EADs and how one might block them is of significant clinical importance. The physiology underlying EADs is complex, involving multiple inward and outward ionic currents, changes in intracellular ion concentrations, and rapid regulation of ion channels. An EAD occurs when there is a reversal of the normal repolarization during phase 2 or 3 of the cardiac AP and is associated with a reduction in what has been referred to as " repolarization reserve " (Roden, 1998). Repolarization reserve is determined by the dy­ namic balance of outward currents and inward currents present during repolarization of the AP and implies redundancy of ionic currents in the normal heart to ensure appropriate repolarization. If there is a decrease in normal repolarization reserve, then a regenerative increase in an inward current can overcome and poten­ tially reverse repolarization, leading to an EAD. The first hint of a diminution of repolarization reserve is frequently an increase in AP duration. Conditions as­ sociated with prolongation of the AP are collectively re­ ferred to as long QT syndrome (LQTS), reflecting the longer than normal QT interval observed on the surface electrocardiogram. Both acquired and congenital forms of LQTS have been identified. Acquired LQTS occurs in the presence of certain electrolyte abnormalities, most commonly hypokalemia, as well as in response to ische­ mia, oxidative stress, and certain drugs. In the case of hypokalemia and QT­prolonging drugs, the reduction in repolarization reserve is primarily caused by a reduc­ tion in I Kr carried by the hERG K channel. Alternatively, oxidative stress, such as that experimentally induced by H 2 O 2 exposure, increases inward currents, including I NaL (late sodium current) and I Ca,L , to reduce repolar­ ization reserve (Xie et …