LOWERING HOMOCYSTEINE TO REDUCE MYOCARDIAL ISCHEMIA

描述(申请人提供)：血清同型半胱氨酸轻度升高 水平与心肌梗死风险增加2-4倍相关 超过40%-50%的冠心病患者存在心肌梗死 动脉疾病。研究人员先前观察到硝酸根的缺陷。 正常人外周血管中的氧化物介导的血管扩张 同型半胱氨酸轻度升高的人类。最近，他们雇佣了 正电子发射断层扫描(PET)证实同型半胱氨酸 损害健康人的冠状动脉微血管扩张。降下 同型半胱氨酸水平可以很容易地通过叶酸达到。然而， 重要的问题是是否降低这些患者的同型半胱氨酸水平 个人减少冠状动脉疾病的表现残留 无人接听。 拟议的一系列调查代表了合乎逻辑的下一步，即 研究叶酸降低同型半胱氨酸的潜在益处。 这项调查的第一个目的是检验这样一种假设，即降低温和的， 常见的血清同型半胱氨酸升高改善冠状动脉 微血管扩张，使用正电子发射计算机断层扫描。这项研究的第二个目的是测试 假设降低轻度升高的同型半胱氨酸浓度会降低 运动性心肌缺血，采用运动负荷试验。这个 第三个目标是验证叶酸也能显著改善冠状动脉病变的假设 微血管扩张不依赖于其降低同型半胱氨酸的作用。 因此，这些研究将评估同型半胱氨酸在 会导致心脏病，并将评估患者是否患有 使用叶酸降低同型半胱氨酸水平可能会使冠心病受益。在……里面 除了解决临床上最重要的问题外，这 拟议的项目将成为申请者成长的关键催化剂 作为MGH和哈佛医学院(HMS)的初级教员。 此外，这一奖项将为申请者提供无价的 有机会提升对他成长为一名 对以患者为中心的临床研究和 了解冠状动脉血管生理学。

DESCRIPTION (provided by applicant): Mild elevations in serum homocysteine levels are associated with a two-four fold increased risk in myocardial infarctions and are present in over 40-50 percent of individuals with coronary artery disease. The investigators previously observed a defect in nitric oxide-mediated vasodilation in the peripheral vasculature of otherwise healthy humans with mild elevations in homocysteine. More recently, they employed positron emission tomography (PET) and demonstrated that homocysteine acutely impairs coronary microvascular dilation in healthy humans. Lowering homocysteine levels can be readily achieved with folic acid. However, the important question of whether or not lowering homocysteine levels in these individuals reduces the manifestations of coronary artery disease remains unanswered. The proposed series of investigations represent the logical next-step, by investigating the potential benefits of homocysteine-lowering with folic acid. The first aim of this investigation tests the hypothesis that lowering mild, commonly encountered elevations of serum homocysteine improves coronary microvascular dilation, using PET. The second aim of this study tests the hypothesis that lowering mildly elevated homocysteine concentrations decreases exercise-induced myocardial ischemia, using exercise stress testing. The third aim tests the hypothesis that folic acid also acutely improves coronary micro vascular dilation independently of its homocysteine-lowering effects. As such, these investigations would appraise homocysteine's role in contributing to cardiac disease, and would assess whether patients with coronary disease might benefit from homocysteine-lowering with folic acid. In addition to addressing a question of the highest clinical importance, this proposed project would serve as a critical catalyst for the applicant's growth as a junior faculty member of the MGH and Harvard Medical School (HMS). Furthermore, this award would provide the applicant with an invaluable opportunity to advance the skills that are essential for his maturation as a significant contributor to patient oriented clinical research and to the understanding of coronary vascular physiology.