Pathophysiology and clinical implications of cardiac memory.

Altering the pattern of activation of the ventricle causes remodeling of the mechanical and electrical properties of the myocardium. The electrical remodeling is evident on the surface electrocardiogram as significant change in T-wave polarity following altered activation; this phenomenon is ascribed to as "T-wave memory" or "cardiac memory." The electrophysiological remodeling following altered activation is characterized by distinct changes in regions proximal (early-activated) versus distal (late-activated) to the site of altered activation. The early-activated region exhibits marked attenuation of epicardial phase 1 notch due to reduced expression of the transient outward potassium current (I(to)). This is attributed to electrotonic changes during altered activation, and angiotensin-mediated regulation of Kv4.3 (the pore-forming alpha subunit responsible for I(to)). The late-activated region exhibits the most significant action potential prolongation due to markedly increased mechanical strain through a mechano-electrical feedback mechanism. Consequently, regionally heterogeneous action potential remodeling occurs following altered activation. This enhances regional repolarization gradients that underlie the electrophysiological basis for T-wave memory. Further, recent clinical studies highlight detrimental consequences of altered activation including worsening mechanical function and increased susceptibility to arrhythmias. Future studies to identify molecular mechanisms that link electrotonic and mechanical strain-induced changes to cellular electrophysiology will provide important insights into the role of altered activation in regulating cardiac repolarization and arrhythmogenesis.