# Mechanistic Insights of Premature Ventricular Contractions-induced Cardiomyopathy

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $650,046

## Abstract

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-...

## Key facts

- **NIH application ID:** 9922678
- **Project number:** 5R01HL139874-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Jose Francisco Huizar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $650,046
- **Award type:** 5
- **Project period:** 2018-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922678

## Citation

> US National Institutes of Health, RePORTER application 9922678, Mechanistic Insights of Premature Ventricular Contractions-induced Cardiomyopathy (5R01HL139874-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9922678. Licensed CC0.

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