Pathophysiology and clinical implications of cardiac memory

Abstract

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.

Figure 1. Time course of cardiac memory

Surface ECG leads I and avF from a canine model of ventricular pacing to induce memory is illustrated. ECG’s and VCG’s recorded before onset of pacing, during pacing and at 7, 21 days after ventricular pacing are illustrated. The arrows indicate the change in T-wave vector which follows the vector of the paced QRS indicative of memory (adapted from Yu et al.)

Figure 2. Action potential remodeling in cardiac memory

The top panel illustrates action potentials recorded using optical imaging from unpaced dogs. The action potentials from anterior and posterior walls are similar with minimal regional action potential gradients. In contrast, following memory there is marked action potential prolongation in late-activated region. Also note the significant attenuation of epicardial phase1 notch limited to the early-activated region (arrow). This heterogeneous action potential remodeling causes regional repolarization gradients which underlies the electrophysiological basis for T-wave memory.

Figure 3. Summary of current understanding of pathophysiology and mechanisms that regulate cardiac memory

The common sources of altered activation include diseases that affect the cardiac conduction system, accessory pathways and ventricular pacing. Two distinct anatomical regions are affected based on proximity to origin of altered activation. Early-activated region, i.e. region proximal to the site of altered activation exhibits attenuation of epicardial phase1 notch due to reduced I_to, reduced I_Ca/I_Kr and reduced connexin43 expression. This is attributed to electronic changes and Angiotensin II medicated signaling. The late-activated region exhibits marked action potential prolongation due to enhanced mechanical strain.