Cellular mechanisms of arrhythmogenic cardiac alternans

Despite the strong association between mechanical dysfunction of the heart and sudden death due to arrhythmias, the causal relationship is not well understood. Cardiac alternans has been linked to arrhythmogenesis and can be mediated by intracellular calcium handling. Given the integral role intracellular calcium plays in contractile function, calcium-mediated alternans may represent an important mechanistic link between mechanical dysfunction and electrical instability. This relationship, however, is not well understood due to complex feedback between membrane currents, intracellular calcium, and contraction. This manuscript describes the cellular mechanisms of cardiac alternans. Through several pathways, calcium transient alternans is coupled to repolarization alternans that can form a substrate for reentrant excitation. Abnormal intracellular calcium cycling, either impaired release or impaired reuptake of sarcoplasmic reticulum calcium, is a cellular mechanism of calcium transient alternans. Thus, cardiac alternans is an important mechanistic link between mechanical dysfunction and sudden cardiac death.