Calcium and Cardiac Arrhythmias: DADs, EADs, and Alternans

Abstract

Rapid progress has been made in understanding the molecular mechanisms by which calcium ions mediate certain cardiac arrhythmias. Principal advances include imaging of cytosolic calcium in isolated cells and in intact tissues, use of fluorescent indicators and monophasic action potentials to record membrane potentials in isolated tissue, and sequencing of the genes that encode critical ion channel proteins. In this review, five types of arrhythmias are discussed where calcium ion currents, or currents controlled by calcium, appear to be responsible for arrythmogenesis. These include: (1) the delayed afterpotential that occurs in conditions of intracellular calcium overload such as digitalis toxicity; (2) the early afterdepolarization that occurs when action potential duration is prolonged; (3) the slowly conducted calcium-dependent action potential (the slow response) in the SA and AV nodes; (4) the phenomenon of calcium transient alternans during ischemia, which is related to action potential duration alternans and t-wave alternans; (5) catecholamine-induced cardiac arrhythmias in families with mutations of the sarcoplasmic reticulum calcium-release channel. For each type of arrhythmia, the clinical implications of emerging knowledge are discussed. An especially important issue is whether ventricular fibrillation during acute coronary artery occlusion is due to calcium transient alternans. Ventricular fibrillation due to acute ischemia is an important subset of the 400,000 sudden cardiac deaths that occur annually in the U.S. Certain drugs, including beta blockers, fish oils, verapamil, and diltiazem, seem to specifically prevent ventricular fibrillation in this setting, and in most cases an effect of the drug on cytosolic calicum appears to be involved.

Neuronal Nitric Oxide Synthase Protects Against Myocardial Infarction-Induced Ventricular Arrhythmia and Mortality in Mice

“…Although primarily used clinically for supraventricular arrhythmias, verapamil is also known to prevent VF caused by ischemia in patients with coronary artery disease and may reduce ventricular tachyarrhythmias associated with I/R. 24,25 As expected, verapamil treatment significantly reduced I/R-induced ventricular tachyarrhythmia and reduced the incidence of VF after MI. These data suggest a role for altered Ca 2ϩ handling in the increased cardiac arrhythmia in nNOS Ϫ/Ϫ mice after MI.…”

Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function

“…In addition, the prolonged phase of Ca 2+ release that gives rise to EADs helps to unload Ca 2+ from the SR, preventing SR overfilling. The ionic mechanisms of EADs are diverse and can involve Ca 2+ -dependent and Ca 2+ -independent processes (23,24). Because Ca 2+ release is decreased in RyR2-A4860G +/− cells (Fig.…”

Exendin-4 attenuates ischemia-induced ventricular arrhythmias in rats

“…In this study, we found that 5-HD, a specific inhibitor of mitochondrial K ATP channels could abo- lish the anti-arrhythmic effect of Ex-4, indicating that mitochondrial K ATP channels may be involved in the anti-arrhythmic effect of Ex-4. Many studies showed that activation of mitochondrial K ATP channels could limit mitochondrial Ca 2+ overload and maintain mitochondrial Ca 2+ homeostasis during MI [16,17]; mitochondrial Ca 2+ homeostasis plays a fundamental role in cytosolic free Ca 2+ homeostasis and could prevent ischemia-induced cytosolic free Ca 2+ overload [18,19] which plays an important role in ischemia-induced ventricular arrhythmias [20]. Thus, mitochondrial K ATP channels was involved in the anti-arrhythmic effect of Ex-4 during MI.…”