Coronary Dysfunction in Hypertrophic Cardiomyopathy

肥厚型心肌病的冠状动脉功能障碍

• 批准号: 6769968
• 负责人: LIH KUO
• 金额: $ 36.38万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769968
• 关键词: adenosine; coronary disorder; exercise; genetically modified animals; hypertrophic myocardiopathy; in situ hybridization; laboratory mouse; myocardial ischemia /hypoxia; polymerase chain reaction; potassium channel; purinergic receptor; renin angiotensin system; vasodilatation; vasodilators; western blottings

DESCRIPTION (provided by applicant): Hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young during exercise, exhibits cardiac pathophysiology, ischemia and impaired metabolic coronary flow regulation. Although the altered cardiac pathophysiology has been well documented, the impaired coronary vasomotor function has not been systematically characterized and the underlying mechanism responsible for this dysfunction has not been elucidated. Therefore, the long-term goals of this study are to understand the coronary vascular dysfunction associated with HCM and to elucidate the cellular and molecular mechanisms involved in this impairment. To achieve these goals, a recently developed transgenic mouse model resembling the cardiac pathophysiology observed in HCM patients will be used to test the central hypothesis that coronary microvascular reactivity to metabolic vasodilator adenosine is altered in HCM. Because adenosine receptors, vascular ATP-sensitive potassium (KATP) channels and endothelial release of nitric oxide (NO) are known to be involved in the coronary arteriolar dilation to adenosine and in metabolic regulation of coronary blood flow, we will examine whether the impairment of these pathways are responsible for the coronary microvascular dysfunction associated with HCM. More specifically, we will pursue the following specific aims to achieve these goals: (1) characterizing coronary vascular dysfunction in response to metabolic vasodilator adenosine. We will test the hypothesis that the downregulation of specific adenosine receptors, reduction of endothelial release of NO, and impairment of vascular KATP channels contribute to the vascular dysfunction associated with HCM; and (2) determining the role of vascular renin-angiotensin system in coronary vascular dysfunction. We will test the hypothesis that upregulation of renin-angiotensin system (e.g., renin, ACE, ANG-II and angiotensin receptors) is the underlying mechanism contributing to the impairment of vasodilation to adenosine via the inhibition of KATP channel function and the activation of oxidative stress. The results of these studies could enhance our understanding of coronary vascular dysfunction associated with HCM and may help to develop a therapeutic strategy to improve coronary function and to alleviate myocardial ischemia, which is known to aggravate the already impaired cardiac function in HCM.

描述（由申请人提供）：肥厚性心肌病（HCM）是年轻人运动时心源性猝死的最常见原因，表现出心脏病理生理学、缺血和代谢性冠状动脉血流调节受损。 尽管心脏病理生理学的改变已得到充分记录，但尚未系统地表征受损的冠状血管舒缩功能，并且尚未阐明导致这种功能障碍的潜在机制。 因此，本研究的长期目标是了解与肥厚型心肌病相关的冠状血管功能障碍，并阐明与这种损伤相关的细胞和分子机制。 为了实现这些目标，最近开发的转基因小鼠模型类似于在 HCM 患者中观察到的心脏病理生理学，将用于测试中心假设，即 HCM 中冠状动脉微血管对代谢性血管扩张剂腺苷的反应性发生了改变。 由于已知腺苷受体、血管 ATP 敏感钾 (KATP) 通道和内皮释放一氧化氮 (NO) 参与冠状动脉向腺苷的扩张以及冠状动脉血流的代谢调节，因此我们将检查这些通路的损伤是否与 HCM 相关的冠状微血管功能障碍有关。 更具体地说，我们将追求以下具体目标来实现这些目标：（1）表征代谢性血管扩张剂腺苷反应的冠状血管功能障碍。 我们将检验以下假设：特定腺苷受体的下调、内皮细胞 NO 释放的减少以及血管 KATP 通道的损伤导致与 HCM 相关的血管功能障碍； (2)确定血管肾素-血管紧张素系统在冠状血管功能障碍中的作用。 我们将检验以下假设：肾素-血管紧张素系统（例如，肾素、ACE、ANG-II 和血管紧张素受体）的上调是通过抑制 KATP 通道功能和激活氧化应激来损害腺苷血管舒张功能的潜在机制。 这些研究的结果可以增强我们对与 HCM 相关的冠状血管功能障碍的理解，并可能有助于制定改善冠状动脉功能和减轻心肌缺血的治疗策略，众所周知，心肌缺血会加剧 HCM 中已经受损的心脏功能。