Coronary Dysfunction in Hypertrophic Cardiomyopathy

肥厚型心肌病的冠状动脉功能障碍

• 批准号: 6897466
• 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/6897466
• 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.

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.