Mechanistic Insights of Premature Ventricular Contractions-induced Cardiomyopathy

室性早搏诱发的心肌病的机制见解

• 批准号: 9922678
• 负责人: Jose Francisco Huizar
• 金额: $ 65万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922678
• 关键词: Acute; Admission activity; Animal Model; Animals; Biopsy; Calpain; Cardiac; Cardiomyopathies; Caring; Chemosensitization; Chronic; Clinical; Coupled; Coupling; Development; Etiology; Evaluation; Exposure to; Financial Hardship; Frequencies; Functional disorder; Future; Healthcare; Heart; Heart failure; Ice; Impairment; Implant; Lead; MAP Kinase Gene; Mechanics; Mediator of activation protein; Methods; MicroRNAs; Molecular; Molecular Structure; Pacemakers; Pathway interactions; Patients; Phase; Prevention; Proteins; Randomized; Recovery; Research; Risk; Role; SERCA2a; Scaffolding Protein; Secondary to; Severities; Structural Protein; Structure; Testing; Time; Ventricular; Ventricular Premature Complexes; clinical phenotype; hemodynamics; high risk; improved functioning; insight; junctophilin; molecular phenotype; mortality; phospholamban; placebo group; premature; prevent; resilience; response; restoration; theories

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.

背景。频繁的室性早搏（PVCs）可引起左室功能障碍（CM）

项目成果

Outcomes of Premature Ventricular Contraction-Cardiomyopathy in the Veteran Population: A Secondary Analysis of the CHF-STAT Study.

• DOI: 10.1016/j.jacep.2020.08.028
• 发表时间: 2021-03
• 期刊: JACC-CLINICAL ELECTROPHYSIOLOGY
• 影响因子: 7
• 作者: Huizar, Jose F.;Fisher, Susan G.;Ramsey, Frederick, V;Kaszala, Karoly;Tan, Alex Y.;Moore, Hans;Koneru, Jayanthi N.;Kron, Jordana;Padala, Santosh K.;Ellenbogen, Kenneth A.;Singh, Steven N.
• 通讯作者: Singh, Steven N.

Left ventricular dyssynchrony as marker of early dysfunction in premature ventricular contraction-induced cardiomyopathy.

左心室异位障碍作为早期功能障碍的标志性，在室性过早收缩引起的心肌病中。

• DOI: 10.3389/fcvm.2022.978341
• 发表时间: 2022
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Kowlgi, Gurukripa N.;Tan, Alex Y.;Kaszala, Karoly;Kontos, Michael C.;Lozano, Pedro;Ellenbogen, Kenneth A.;Huizar, Jose F.
• 通讯作者: Huizar, Jose F.

Eccentric hypertrophy in an animal model of mid- and long-term premature ventricular contraction-induced cardiomyopathy.

• DOI: 10.1016/j.hroo.2020.12.021
• 发表时间: 2021-03
• 期刊: Heart rhythm O2
• 作者: Torrado J;Kowlgi GN;Ramirez RJ;Balderas-Villalobos J;Jovin D;Parker C;Om E;Airapetov S;Kaszala K;Tan AY;Ellenbogen KA;Huizar JF
• 通讯作者: Huizar JF