Heart failure (HF) is one of the most common causes of morbidity and mortality worldwide. Although many patients suffering from HF die from sudden cardiac death caused by arrhythmias, the mechanism linking HF remodeling to an increased arrhythmogenic propensity remains incomplete. Independently of the etiology of the disease, HF is typically characterized by a progressive loss of transverse tubule (T-tubule) domains, which leads to an altered distribution of L-type Calcium channels (LTCCs). Ischemic cardiomyopathy (ICM) is usually accompanied by an increase in LTCC open probability (Po) in the T-tubules which depends on the activity of protein kinase A (PKA). In dilated cardiomyopathy (DCM) on the other hand, the increased LTCC Po on the non-T-tubule sarcolemma results from enhanced calcium-calmodulin kinase II (CaMKII) modulation. Microdomain degradation also causes the disruption of the β2 adrenergic receptor (β2AR) and phosphodiesterase (PDE) signaling localizations, normally confined to the dyadic space.
The goal of this study was to analyze how these subcellular changes affect the function of LTCCs and lead to the emergence of ventricular cell-level triggers of arrhythmias. Furthermore, we aimed to compare how the two different pathways lead to different phenotypes in ICM vs. DCM.
Using computational modeling, we analyzed the behavior of the LTCC current (ICaL) under basal and sympathetic stimulation and its effect on cellular action potentials (APs). Our results showed that channels redistributed from the T-tubular membrane to the bulk of the sarcolemma displayed an altered function in their new, non-native signaling domain. The changes in LTCC current led to the development of early afterdepolarizations (EADs) in both types of HF, and triggered reentrant arrhythmias only in the DCM model.
Thus, our work shows that altered LTCC function is a potential cause for the emergence of cell-level triggers of arrhythmia, and that CaMKII, β2ARs and PDEs present useful therapeutic targets for treatment of HF and prevention of sudden cardiac death