Background. Frequent premature ventricular contractions (PVCs) can cause LV dysfunction (CM), referred to as PVC-induced cardiomyopathy (CM). The mechanism responsible and the impact of PVC coupling interval (prematurity) are unclear. Suspected triggers are post-extrasystolic potentiation and LV dyssynchrony. Hypotheses. Our working hypotheses are: 1) Post-extrasystolic potentiation, associated with PVCs, is a key trigger responsible for PVC-induced CM. LV dysfunction (Aim 1), impaired EC coupling and dyad remodeling (Aim 2) are greater in short- rather than long- coupled PVCs since this phenomenon is more prominent in short- rather than long-coupled PVCs. 2) Impaired EC coupling in PVC-induced CM is due to changes in JPH-2 and Cav1.2 pathways (Fig.1). 3) Early changes in dyad, JPH-2 and Cav1.2 pathways precede the development of this CM and the recovery of LV function after PVC cessation, providing evidence that these changes are a primary cause of CM. 4) Decrease in post-extrasystolic potentiation (less Ca2+ overload) with diltiazem (LTCC blocker) results in a lesser dyad remodeling, thereby preventing or minimizing impaired EC-coupling and PVC-induced CM.
Aim 1. Evaluate the impact of post-extrasystolic potentiation and PVC coupling interval in the development of LV dysfunction associated with chronic exposure to frequent PVCs (PVC-induced CM).
Aim 2. Determine the temporal structural and molecular changes responsible for decrease in Ca2+ release and Junctophylin-2, and their role on the pathophysiology of PVC-induced CM and recovery upon PVC cessation.
Aim 3. Assess the impact of reducing post-extrasystolic potentiation with L-type Ca2+ channel blocker to prevent abnormal Ca2+ release and EC-coupling in PVC-induced CM. Methods. Fifty four canines will undergo pacemaker implant to reproduce 50% PVCs (ventricular bigeminy). They will be randomized to one of 4 groups: 1) short-coupled PVC (n=14), 2) long-coupled PVCs (n=14), 3) short-coupled PVCs + diltiazem (n=14), or 4) control (n=12) groups. At the end of a 12-week PVC period, a recovery phase (disabling PVCs) will be allowed in 50% of animals. Serial cardiac evaluation and biopsies will allow us to assess LV function, dyad structure, Ca2+ transients (EC coupling), changes in JPH-2 and Cav1.2 expression, function and distribution and their mediators at different time points of CM in all groups. Significance. This study will: 1) provide an understanding of the role of post-extrasystolic potentiation and LV dyssynchrony in the mechanism of PVC-induced CM; 2) assess the impact of PVC coupling interval in the development or severity of PVC-induced CM, 3) identify molecular mechanisms behind impaired EC coupling in PVC-induced CM and 4) assess the benefit of LTCC blockers to prevent or minimize PVC-induced CM. Understanding the mechanism of PVC-induced CM will help us to identify high-risk patients for development of PVC-induced CM, but most importantly find future targets to prevent and treat subjects with PVC-induced CM.
Premature heart beats, so called ?PVCs?, are commonly seen in patients with heart failure. PVCs have been recognized to debilitate the heart and cause heart failure, called 'PVC?induced cardiomyopathy (CM)'. This cardiomyopathy also carries significant financial burden in the care of our patients. We anticipate that this study will help us understand the mechanism of this heart condition, leading to better prevention and treatment of PVC-induced CM and identification of high-risk patients with significant impact in heart failure admission, mortality and healthcare spending.
