Modulation of p-adrenergic and myofilament responses by Cardiac Resynchronization

心脏再同步化治疗（CRT）是新千年以来心力衰竭治疗的主要新进展。它使用双心室起搏刺激来抵消传导延迟，从而改善受影响患者的收缩协调性。它在急性和慢性改善休息和储备收缩功能的治疗中是独一无二的，因为它也提高了生存率。该PPG的总体主题是，通过了解这是如何在细胞和分子水平上完成的，将为最佳使用CRT和更广泛的心力衰竭治疗提供重要的新见解。我们最近的研究表明，心肌细胞休息和β -肾上腺素能刺激功能在非同步性心力衰竭（DHF）中明显下降，而CRT极大地增强了这两种功能。其机制包括β -1受体数量的适度增加，腺苷酸环化酶活性的增强，以及抑制性g蛋白偶联的明显抑制，这可能与g偶联信号蛋白3的调节负调控有关。新的数据显示，肌丝钙响应性的增强也与CRT有关，并伴有几种调节细丝蛋白的磷酸化变化。这些变化在发生心力衰竭并始终同步收缩的心脏中也没有观察到，但在先前DHF的心脏中，同步恢复似乎是特有的。该项目的目的是确定CRT诱导的肌丝-钙和β -肾上腺素能/ gi偶联改变介导的收缩储备改善的机制。目的1在我们的犬模型中研究肌丝敏感性改变的机制，测试其与ATP利用的耦合，以及翻译后变化在皮肤肌肉和肌细胞制备中的作用。目的2和3测试CRT如何独特调节β - ar储备，重点关注RGS蛋白对Gi信号的抑制作用和β - β 2激活效应的变化。这项工作使用狗模型，以及新的DHF和CRT小鼠模型，使研究普遍缺乏RGS2， -3或-4的小鼠能够更直接地测试这种调节的影响。这些数据可能为适合CRT的心脏提供新的潜在生物标志物，并为成功的治疗方法提供新的见解，这可能会影响更广泛的患者群体的心力衰竭治疗。

Cardiac resynchronization therapy (CRT) is the major new advance in heart failure treatment in the new millennium. It uses bi-ventricular pacing stimulation to offset conduction delay and thereby improve contraction coordination in affected patients. It is unique among treatments that acutely and chronically improve rest and reserve systolic function, as it also improves survival. The overall theme ofthis PPG is that by understanding how this is accomplished at the cellular and molecular level will yield important new insights into optimally using CRT, and for heart failure therapy more generally. Our recent work showed myocyte rest and beta-adrenergic stimulated function are markedly depressed in dyssynchronous heart failure (DHF) and both are greatly enhanced by CRT. Mechanisms included a modest rise in beta-1 receptor number, enhanced adenylate cyclase activity, and a marked suppression of inhibitory G-protein coupling potentially linked to negative modulation by regulator of G-coupled signaling protein 3. New data shows enhanced myofilament calcium responsiveness with CRT also contributes, and is accompanied by phosphorylation changes in several regulatory thin filament proteins. These changes are not observed in hearts that develop failure with always synchronous contraction either, but appear specific to having synchrony restored in a previously DHF heart. The goal of this project is to determine the mechanisms underlying improved contractile reserve mediated by myofilament-calcium and beta-adrenergic/Gi-coupled changes induced by CRT. Aim 1 studies the mechanisms of altered myofilament sensitivity in our canine models, testing its coupling to ATP utilization, and role of post-translational changes in skinned muscle and myocyte-preparations. Aims 2 and 3 test how CRT uniquely modulates beta-AR reserve, focusing on the role of RGS protein suppression of Gi signaling and changes in betai-beta2 activation effects. This work uses the dog model, as well as a new mouse model of DHF and CRT to enable studies of mice generically lacking RGS2, -3, or -4 to more directly test the impact of this regulation. These data may yield novel potential biomarkers for hearts amenable to CRT, and provide novel insights into a successful therapy that could impact heart failure treatment in the broader patient population.