Heart failure (HF) is associated with anatomic and functional remodeling of cardiac tissues in both animal models and humans,which alters Ca2+ homeostasis, protein phosphorylation, excitation-contraction coupling, results in arrhythmias. Indeed, the electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. The changes in cellular and tissue function are regionally heterogenous particularly in the dyssynchronously contracting heart. Cardiac resynchronization therapy (CRT) is widely applied in patients with HF and dyssynchronous left ventricular (LV) contraction (DHF), but the electrophysiological consequences of CRT are not fully understood.We demonstrated the molecular and cellular basis of excitability, conduction, and electrical remodeling in DHF and its restoration by CRT using a canine tachypacing HF model. CRT partially reversed the DHFinduced downregulation of K+ current and improved Na+ channel gating and abbreviated persistent (late) Na+ current. CRT reduced Ca2+/ calmodulin protein kinase II activity and restored transverse tubular system and spatial distribution of ryanodine receptor, thus it significantly improved Ca2+ homeostasis especially in myocytes from late-activated, lateral wall and restored the DHF-induced blunted β-adrenergic receptor responsiveness. CRT abbreviated DHF-induced prolongation of APD in the lateral wall myocytes and reduced the LV regional gradient of APD and suppressed the development of early afterdepolarizations. In conclusion, CRT partially restores the DHF-induced ion channel remodeling, abnormal Ca2+ homeostasis, blunted β-adrenergic response, and regional heterogeneity of APD, thus it may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.
- Cardiac resynchronization therapy
- Heart failure
- Ion channels
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Molecular Medicine
- Pharmaceutical Science