Mechanistic Insights of Premature Ventricular Contractions-induced Cardiomyopathy

背景频繁的室性早搏（PVC）可导致LV功能障碍（CM）， 称为PVC心肌病（PVC-CM）。PVC偶联间隔的影响及机理 （早产儿）不清楚。可疑的触发因素是期外收缩后增强和LV不同步。 假设。我们的四个工作假设是：1）与PVC相关的期外收缩后增强，是一种 负责PVC-CM的关键触发器。LV功能障碍（目的1）、EC偶联受损和二分体重构（目的 2)早-而不是晚-耦合PVC更大，因为这种现象在早- 而不是晚偶联的PVC; 2）PVC-CM中EC偶联受损是由于JPH-2和Cav1.2的变化。 二分体、JPH-2和Cav1.2通路的早期变化先于CM的发展 以及PVC停止后LV功能的恢复，提供证据表明这些变化是主要的 CM的原因（目的2）;和4）基线临床和结构/分子表型可以识别这些动物 当暴露于33%的PVC负荷时，将形成PVC-CM。 目标1.评价期外收缩后增强和PVC偶联间期在以下发展中的影响 与慢性暴露于频繁PVC（PVC-CM）相关的LV功能障碍。 目标2.确定导致Ca2+释放减少的时间结构和分子变化， Junctophylin-2及其在PVC-CM病理生理学和PVC停止后恢复中的作用。 目标3.确定基线超声心动图、血流动力学和分子特征， 尽管有相同的心室异位，但仍发生或恢复PVC-CM。 方法. 56只动物将接受起搏器植入术，以重现频繁的心室异位（PVC）。他们 将被随机分配至4组之一：1）早期偶联50% PVC（n = 13），2）晚期偶联50% PVC（n = 13）， 3)早期偶联PVC 33%PVC（n = 18），或4）对照组（n = 12）。在12周PVC期结束时， 将允许暴露于50%负荷和假手术的每组6只动物进入恢复期（致残性PVC） 组（图6）。连续心脏评估和活检将使我们能够评估LV功能，二分体结构，Ca2 + 瞬变（EC偶联），JPH-2和Cav1.2表达、功能和分布的变化及其 所有组在基线和PVC-CM的不同时间点的介质。 意义本研究将：1）提供对期外收缩后增强和LV PVC-CM机制中的不同步性; 2）评估PVC偶联间期在发育中的影响 3）确定PVC-CM中EC偶联受损背后的分子机制，以及4） 确定基线临床和分子表型，以区分有发生PVC-CM风险的患者。 了解PVC-CM的机制将有助于我们识别发生PVC的高危患者， CM，但最重要的是找到预防和治疗PVC-CM受试者的未来目标。

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.