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，并且在应对生理应激（包括运动）时提高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包括心脏充盈增加（需要松弛储备）和射血增强（需要收缩储备）。在细胞水平上，松弛储备，这一应用的重点，需要更快的细胞内钙（Ca）瞬态衰变和肌丝钙敏感性的降低。通常，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磷酸化，从而增强这两个过程。然而，松弛储备和松弛储备的肾上腺素能调节在衰竭心脏中都是异常的。认识到钙循环动力学本身在衰竭心肌中是异常的，提出的研究的广泛目的是检查β -肾上腺素能/ pka介导的松弛储备在衰竭人类心脏中的调节，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钙摄取速率的β -肾上腺素能增强受损，并降低肌丝钙敏感性的能力。在机制上，我们假设磷酸化磷蛋白和肌钙蛋白I的能力降低导致cAMP和pka依赖的信号传导能力受损，从而分别增加肌浆网钙摄取和降低肌丝钙敏感性。我们的具体目的是：1)检查收缩期和舒张期心衰患者的舒张储备的β -肾上腺素能调节；2)观察camp对心肌松弛储备和钙摄取的调节作用；3)检测心肌肌丝钙敏感性的pka依赖性调节；4)确定钙循环缺陷或PKA对肌钙蛋白I靶向降低是否限制了PKA依赖性的松弛储备调节。在确定松弛受损机制的同时，这些研究将有助于开发和验证动态无创成像策略，用于心衰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.