Mechanisms of Improved Diastolic Function in Human Heart

描述(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患者的收缩功能完整，但几乎所有HF患者都有异常的舒缩功能，以及在包括运动在内的生理性应激下提高心功能的能力受损。在运动中，心肌对心率加快和肾上腺素能刺激的反应通常包括心脏充盈增加(需要松弛储备)和射血增加(需要收缩储备)。在细胞水平上，松弛储备，这一应用的重点，需要细胞内钙瞬变的更快衰减和肌丝钙敏感性的降低。通常，这两个过程都是通过β-肾上腺素能刺激触发PKA介导的关键钙调节蛋白和肌丝蛋白的磷酸化而增强的。然而，在衰竭的心脏中，松弛储备和松弛储备的肾上腺素能调节都是异常的。认识到钙循环动力学在衰竭心肌中本身是异常的，建议的研究的广泛目标是研究β-肾上腺素能/PKA介导的对衰竭心脏松弛储备的调节，以解释这些心脏中存在的钙循环缺陷。我们的工作假设是，肾上腺素能信号缺陷导致β-肾上腺素能钙摄取率受损，并降低肌丝钙敏感性的能力降低。从机制上，我们假设磷酸化蛋白和肌钙蛋白I的能力降低分别导致cAMP和PKA依赖的信号增强肌浆网钙摄取和降低肌丝钙敏感性的能力受损。我们的具体目标是：1)研究收缩和舒张性心衰患者的β-肾上腺素能对松弛储备的调节；2)研究cAMP对人心肌松弛储备和钙摄取的调节；3)研究PKA对人心肌肌丝钙敏感性的调节；以及4)确定钙循环缺陷或PKA对肌钙蛋白I靶向减少是否限制了PKA依赖的松弛储备的调节。在明确松弛受损机制的同时，这些研究将有助于开发和验证动态非侵入性成像策略，用于临床评估心力衰竭患者的关系储备。

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.