Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy

Abstract

Despite a clear association between left ventricular (LV) mechanical dysfunction in end-stage heart failure and the incidence of arrhythmias, the majority of sudden cardiac deaths occur at earlier stages of disease development. The mechanisms by which structural, mechanical, and molecular alterations predispose to arrhythmias at the tissue level before the onset of LV dysfunction remain unclear. In a rat model of pressure overload hypertrophy (PoH) produced by ascending aortic banding, we correlated mechanical and structural changes measured in vivo with key electrophysiological changes measured ex vivo in the same animals. We found that action potential prolongation, a hallmark of electrical remodeling at the tissue level, is highly correlated with changes in LV wall thickness but not mechanical function. In contrast, conduction delays are not predicted by either mechanical or structural changes during disease development. Moreover, disrupted Cx43 phosphorylation at intermediate (increased) and late (decreased) stages of PoH are associated with moderate and severe conduction delays, respectively. Interestingly, the level of interaction between Cx43 and the cytoskeletal protein ZO-1 is exclusively decreased at the late stage of PoH. Closely coupled action potentials consistent with afterdepolarization-mediated triggered beats were readily observed in 6 of 15 PoH hearts but never in controls. Similarly, PoH (8/15) but not control hearts exhibited sustained episodes of ventricular tachycardia after rapid stimulation. The initiation and early maintenance of arrhythmias in PoH were formed by rapid and highly uniform activation wavefronts emanating from sites distal to the former site of stimulation. In conclusion, repolarization but not conduction delays are predicted by structural remodeling in PoH. Cx43 phosphorylation is disrupted at intermediate (increased) and late (decreased) stages, which are associated with conduction delays. Dephosphorylation of Cx43 is associated with loss of interaction with ZO-1 and severe conduction delays. Remodeling at all stages of PoH predisposes to triggers and focal arrhythmias.

Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs

“…Hearts were positioned in a custom-built chamber with their anterior surface gently pressed against a glass imaging window by a customized U-shaped piston, as described in detail elsewhere (21,28). Movement was suppressed using 10 M blebbistatin (Tocris Bioscience) mixed in Tyrode solution for 10 min.…”

“…Conduction abnormalities underlie the initiation and maintenance of reentrant arrhythmias in common structural heart diseases, including ischemia (23), myocardial infarction (44), hypertrophy (21), and heart failure (4,18,35). Of interest, Shimoni and colleagues (39) identified conduction changes in hearts of STZ-injected rats.…”

FGF‐23 dysregulates calcium homeostasis and electrophysiological properties in HL‐1 atrial cells

“…Cardiac hypertrophy is associated with a high risk of cardiac arrhythmias, which play a critical role in cardiovascular mortality [8][9][10]. Abnormal calcium regulation can induce cardiac …”

Gene therapies for arrhythmias in heart failure

“…In fact, the pro-arrhythmic tendency of some pharmacological agents has resulted in the premature termination of the Cardiac Arrhythmia Suppression Trial (CAST), after a substantial increase in arrhythmic deaths was noted in post myocardial infarction (MI) patients treated with encanide or flecainide compared to placebo [22]. These pro-arrhythmic effects may arise from the heterogeneity of ion channel expression and function across regions and layers of the heart [4, 61], the nonspecific nature of most pharmacological agents used to target ion channels, the complex cross-talk between individual ion channels, and the dynamic nature of remodeling that occurs in the context of left ventricular (LV) dysfunction [33]. In this article, we review advances in our understanding of arrhythmia mechanisms in the failing heart and illustrate how improved knowledge of the molecular basis of these arrhythmias can be translated into novel gene-based therapeutic approaches.…”