Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

Abstract

Background Frequent premature ventricular contractions (PVCs) are associated with increased risk for sudden cardiac death (SCD) and can cause secondary cardiomyopathy (CM). Objective We sought to determine the mechanism(s) responsible for prolonged refractory period and LV dysfunction demonstrated in our canine model of PVC-induced CM. Methods Single myocytes were isolated from LV free wall of PVC and control canines, and used for patch clamp recording, [Ca]i measurements and immunocytochemistry/confocal microscopy. LV tissues adjacent to area of myocyte isolation were used for immunoblot quantification of protein expression. Results In PVC group, LVEF declined from 57.6±1.5% to 30.4±3.1% after ≥ 4 months of ventricular bigeminy. Compared to control myocytes, PVC myocytes had reduced densities of both outward (Ito and IK1) and inward (ICaL) currents, but no consistent changes in IKr or IKs. The reduction in Ito, IK1 and ICaL was accompanied by decreased protein levels of their channel subunits. The degrees of reduction in Ito, IK1 and ICaL varied among PVC myocytes, creating marked heterogeneity in action potential (AP) configurations and durations. PVC myocytes showed impaired Ca-induced Ca release from SR, without increase in SR Ca leak or decrease in SR Ca store. This was accompanied by a decrease in dyad scaffolding protein, junctophilin-2, and loss of Cav1.2 registry with Ca-releasing channels (RyR2). Conclusion PVCs increase dispersion of AP configuration/duration, a risk factor for SCD, due to heterogeneous reduction in Ito, IK1 and ICaL. The E-C coupling is impaired due to decrease in ICaL and Cav1.2 misalignment with respect to RyR2.

Ablating Premature Ventricular Complexes: Justification, Techniques, and Outcomes

“…35 PVCs increased dispersion of action potential duration due to heterogeneous reduction in I to , I K1 and I CaL and caused abnormalities in myocardial calcium handling. 36 Suppression of PVCs with ablation is often required to potentially reverse the cardiomyopathy. PVCs are culpable in preventing recovery of LV dysfunction in patients with ventricular conduction abnormalities treated with cardiac resynchronization therapy (CRT).…”

Beneficial Effect of Renal Denervation on Ventricular Premature Complex Induced Cardiomyopathy

“…In addition, some studies showed that altered calcium homeostasis, including reduced inward L‐type calcium current and SERCA function, may induce contractile dysfunction, resulting in the progression of heart failure and arrhythmogenicity with electrical remodeling 22, 23, 24. In VPC‐induced cardiomyopathy models without heart failure, a recent study reported that frequent VPCs reduced inward L‐type Ca current density, but the difference of Cav1.2 protein did not reach a statistically significant level compared to control 25. In their study, Kir2.1 protein levels also did not differ statistically.…”

Outflow tract ventricular arrhythmias: An update

“…Myocytes isolated from canine left ventricular wall in a PVC-CM model show decreased current density of the inward L-type Ca current and a decrease in Ca-induced Ca release from the sarcoplasmic reticulum (SR). However, compared with controls, there is no difference in SR Ca leak or SR Ca stores [26]. A misalignment of Cav1.2, the pore-forming subunit of the slow-inward L-type calcium current, with RyR2 (calcium release (B) Following a perturbation to increase intracellular calcium (e.g., exposure to catecholamines or digoxin), rapid pacing induces a single DAD.…”

“…(Reproduced with permission from Lerman [11].) channel) is thought to underlie this mechanism, since efficient Ca-induced Ca release and EC coupling requires the juxtaposition and appropriate alignment of Cav1.2 channels in the t-tubule membrane with RyR2 channels in the junctional SR membrane [26].…”