Mechanisms of Improved Diastolic Function in Human Heart

描述（由申请人提供）：作为许多不同类型心血管疾病的终点，心力衰竭（HF）是美国死亡率和发病率的主要原因。尽管一些HF患者具有完整的收缩功能，但几乎所有HF患者都具有异常的舒张功能和响应生理应激（包括运动）增加心脏性能的能力受损。 在运动过程中，心肌对心率增加和肾上腺素能刺激的反应通常涉及心脏充盈增强（需要舒张储备）和射血增强（需要收缩储备）。 在细胞水平，松弛储备，本申请的重点，需要细胞内钙（Ca）瞬变的更快衰减和肌丝Ca敏感性的降低。 通常，这两个过程通过β-肾上腺素能刺激触发关键Ca调节蛋白和肌丝蛋白的PKA介导的磷酸化而增强。 然而，舒张储备和舒张储备的肾上腺素能调节在衰竭的心脏是异常的。 认识到钙循环动力学本身在衰竭心肌中是异常的，所提出的研究的广泛目标是以解释这些心脏中存在的钙循环缺陷的方式来检查β-肾上腺素能/PKA介导的对衰竭人类心脏的舒张储备的调节。 我们的工作假设是，肾上腺素能信号传导缺陷导致钙摄取率的β-肾上腺素能增强受损和降低肌丝钙敏感性的能力降低。 从机制上讲，我们假设磷酸化受磷蛋白和肌钙蛋白I的能力降低，导致cAMP和PKA依赖性信号传导能力受损，分别增加肌浆网Ca摄取和降低肌丝Ca敏感性。 我们的具体目标是：1）检查患有收缩期和舒张期HF的患者中舒张储备的β-肾上腺素能调节; 2）检查人心肌中cAMP诱导的舒张储备和Ca摄取的调节; 3）检查人心肌中肌丝Ca敏感性的PKA依赖性调节;和4）确定Ca循环缺陷或PKA对肌钙蛋白I的靶向降低是否限制PKA依赖性舒张储备调节。 这些研究将有助于开发和验证动态非侵入性成像策略，用于HF患者关系储备的临床评估。

DESCRIPTION (provided by applicant): As an endpoint for many different types of cardiovascular disease, heart failure (HF) is a leading cause of mortality and morbidity in the U.S. Though some patients with HF have intact systolic function, virtually all patients with HF have abnormal diastolic function and an impaired ability to increase cardiac performance in response to physiologic stress, including exercise. During exercise, myocardial responses to increased heart rate and adrenergic stimulation normally involve augmentation of cardiac filling (requiring relaxation reserve) and enhanced ejection (requiring contractility reserve). At the cellular level, relaxation reserve, the focus of this application, requires faster decay of the intracellular calcium (Ca) transient and a decrease in myofilament Ca sensitivity. Ordinarily, both processes are enhanced by beta- adrenergic stimulation triggering PKA-mediated phosphorylation of key Ca regulatory and myofilament proteins. However, both relaxation reserved and adrenergic modulation of relaxation reserve are abnormal in failing hearts. Recognizing that Ca cycling dynamics are themselves abnormal in failing myocardium, the broad objective of the proposed studies is to examine beta-adrenergic/PKA-mediated modulation of relaxation reserve in failing human hearts in a manner that accounts for the defects in Ca cycling present in these hearts. Our working hypothesis is that adrenergic signaling defects result in an impaired beta-adrenergic augmentation of Ca uptake rates and a reduced ability to decrease myofilament Ca sensitivity. Mechanistically, we hypothesize that a reduced ability to phosphorylate phospholamban and troponin I cause an impaired ability of cAMP and PKA-dependent signaling to augment sarcoplasmic reticulum Ca uptake and reduce myofilament Ca sensitivity, respectively. Our specific aims are to: 1) examine beta-adrenergic modulation of relaxation reserve in patients with systolic an diastolic HF; 2) examine cAMP-induced modulation of relaxation reserve and Ca uptake in human myocardium; 3) examine PKA-dependent modulation of myofilament Ca sensitivity in human myocardium; and 4) determine whether Ca cycling defects or reduced targeting of PKA to troponin I limit PKA-dependent modulation of relaxation reserve. While defining mechanisms of impaired relaxation, these studies will help develop and validate dynamic noninvasive imaging strategies for clinical assessment of relation reserve in patients with HF.