Regional Cardiac Ion Channel Heterogeneity and the Mechanisms of Fibrillatory Conduction.

Abstract

Spatial dispersion of action potential duration (APD) is a substrate for cardiac fibrillation, but the mechanisms are still poorly understood. Spatial APD dispersion has also been associated with both regional fibrillatory patterns as well as regional ionic heterogeneities in cardiac tissue. In particular, regional gradients in two major repolarizing potassium channels, hERG (IKr) and Kir2.1 (IK1), have been implicated in fibrillation. We investigated the role of spatial APD dispersion and the mechanisms by which regional heterogeneity in hERG and Kir2.1 expression contribute to fibrillation. Using a structurally uniform experimental model, neonatal rat ventricular myocyte monolayers, and a novel regional magnetofection technique, we were able to isolate the effects of regional ion channel heterogeneity on electrical propagation. In combination with computer simulations, we were able to provide crucial insights into the underlying mechanisms of arrhythmias. Regional hERG overexpression shortened APD and increased rotor incidence in the infected region. It also generated fibrillatory conduction in a frequency- and location-dependent manner. The APD gradient only generated wavebreak if activity was faster than 12.9 Hz and originated within the infected region. Simulations determined that hERG-induced transient hyperpolarization is an important factor in rotor frequency but is not significant for the generation of wavebreak. In contrast, Kir2.1 overexpression generates both APD shortening as well as a stable hyperpolarization of the resting membrane potential. Regional Kir2.1 heterogeneity results in both an APD gradient as well as bimodal spatial and frequency-dependent conduction velocity (CV) gradient. Simulations reveal the bimodal CV gradient to be the result of the balance of sodium channel availability and potassium conductance. Regional Kir2.1 overexpression generated fibrillatory conduction in a frequency and location dependent manner. However, the minimal frequency required for wavebreak was only 10.8 Hz; this suggests that tissue containing Kir2.1 gradients may be more susceptible to fibrillation than tissue containing hERG gradients. This study provides insight, at the molecular level, into the mechanisms by which both spatial APD and bimodal CV dispersion contribute to wavebreak, rotor stabilization and fibrillatory conduction.