Impact of PVC prematurity on PVC-induced Cardiomyopathy

Project: Research

Investigators

  • Jose Francisco Huizar (PI)

Description

Frequent premature ventricular contractions (PVCs) can cause a non-ischemic cardiomyopathy (CM), known as PVC-induced CM. The mechanism responsible for this CM is unknown. Postulated theories include: 1) post-extra systolic potentiation (PESP), an increase in contractility that follows PVCs (due to calcium (Ca) overload), and/or 2) LV dyssynchrony due to asynchronous LV mechanical contraction. PESP is more prominent in early as compared to late PVCs, whereas, LV dyssynchrony is more prominent in late as compared to early PVCs. Our PVC-induced CM animal model found that: 1) decrease in Calcium current (ICaL), 2) reduction and disarray of pore-forming subunit (Cav1.2) of the L-type Calcium channel (LTCC), 3) impaired excitation-contraction (EC) coupling, and 4) decrease in Junctophylin-2 (JPH-2) and BIN-1 (key scaffolding proteins in EC coupling) could explain the mechanism of PVC-induced CM.Aim 1. Evaluate the impact of PVC prematurity in the development of PVC-induced CM. Aim 2. Determine the temporal molecular changes responsible for decrease in Ca-release and Junctophylin-2 (JPH-2) and their role on PVC-induced CM and recovery upon PVC cessation. Our main hypotheses include: 1) PESP rather than LV dyssynchrony is a key trigger responsible for PVC-induced CM; thus, CM (Aim 1) and cellular and molecular changes (Aim 2) are greater in early compared to late PVCs due to a more pronounced PESP; 2) Decreased JPH-2 (by increased calpain activity and/or microRNA-24) and disarray of Cav1.2 protein (by decrease in BIN1), lead to changes in EC coupling responsible for PVC-induced CM; 3) Early changes in Cav1.2 and JPH-2 pathways precede the development of this CM and the normalization of LV function during the recovery phase (Aim 2), supporting these pathways as a primary cause rather than secondary to CM.To test our hypotheses, we will compare the changes in LV function, hemodynamics, Ca-induced Ca release and temporal changes in T-tubule and EC coupling proteins after 12-week periods of PVCs and recovery phase between: 1) early PVCs (200-220ms), 2) late PVCs (320-340ms), and 3) sham (no PVCs). Comparing the early changes of Cav1.2 and JPH-2 pathways prior to CM and as LV function improves during recovery phase, will be key to support causation by these pathways. Finally, knowing the impact of different PVC prematurities will help us identify the trigger mechanism (PESP vs. LV dyssynchrony) and patients at risk to develop PVC-induced CM.
Award amount$154,000.00
Award date07/01/2016
Program typeGrant-in-Aid
Award ID16GRNT30140012
Effective start/end date07/01/201610/17/2016
StatusFinished