Background. Frequent premature ventricular contractions (PVCs) can cause LV dysfunction (CM), referred to as PVC-cardiomyopathy (PVC-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 four working hypotheses are: 1) Post-extrasystolic potentiation, associated with PVCs, is a key trigger responsible for PVC-CM. LV dysfunction (Aim 1), impaired EC coupling and dyad remodeling (Aim 2) are greater in early- rather than late-coupled PVCs since this phenomenon is more prominent in early- rather than late-coupled PVCs; 2) Impaired EC coupling in PVC-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 (Aim 2); and 4) Baseline clinical and structural / molecular phenotype can identify those animals that will develop PVC-CM when exposed to 33% PVC burden.
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-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-CM and recovery upon PVC cessation.
Aim 3. Identify baseline echocardiographic, hemodynamic and molecular features that can predict the development of, or resilience to PVC-CM despite identical ventricular ectopy. Methods. 56 animals will undergo pacemaker implant to reproduce frequent ventricular ectopy (PVCs). They will be randomized to one of 4 groups: 1) early-coupled 50% PVCs (n=13), 2) late-coupled 50% PVCs (n=13), 3) early-coupled PVCs 33% PVCs (n=18), or 4) control (n=12) groups. At the end of a 12-week PVC period, a recovery phase (disabling PVCs) will be allowed in 6 animals of each group exposed to 50% burden and sham group (Fig. 6). 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 baseline and different time points of PVC-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-CM; 2) assess the impact of PVC coupling interval in the development or severity of PVC-CM, 3) identify molecular mechanisms behind impaired EC coupling in PVC-CM and 4) identify baseline clinical and molecular phenotypes that distinguish patients at risk to develop PVC-CM. Understanding the mechanism of PVC-CM will help us to identify high-risk patients for development of PVC- CM, but most importantly find future targets to prevent and treat subjects with PVC-CM.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL139874-03
Application #
9922678
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Balijepalli, Ravi C
Project Start
2018-05-15
Project End
2021-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298