LOWERING HOMOCYSTEINE TO REDUCE MYOCARDIAL ISCHEMIA

描述（由申请方提供）：血清同型半胱氨酸轻度升高 水平与心肌梗死的风险增加2 - 4倍有关。 心肌梗死，并且存在于超过40- 50%的患有冠状动脉粥样硬化的个体中。 动脉疾病 调查人员先前观察到一个缺陷， 氧化物介导的血管舒张在外周血管系统，否则健康 同型半胱氨酸轻度升高的人。 最近，他们雇用了 正电子发射断层扫描（PET），并证明同型半胱氨酸急性 损害健康人的冠状动脉微血管扩张。 降低 高半胱氨酸水平可以用叶酸容易地达到。 但 重要的问题是是否降低同型半胱氨酸水平， 冠状动脉疾病的症状有哪些 无人回应 拟议的一系列调查代表了合乎逻辑的下一步， 研究叶酸降低同型半胱氨酸的潜在益处。 本研究的第一个目的是检验降低轻度， 常见的血清同型半胱氨酸升高可改善冠状动脉 微血管扩张，使用PET。 本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 运动诱发的心肌缺血，使用运动负荷试验。 的 第三个目的是检验叶酸也能明显改善冠状动脉粥样硬化的假设。 微血管扩张独立于其同型半胱氨酸降低作用。 因此，这些研究将评估同型半胱氨酸在以下方面的作用： 有助于心脏病，并将评估患者是否与 冠心病可能受益于叶酸降低同型半胱氨酸。 在 除了解决临床上最重要的问题外， 拟议的项目将作为申请人成长的关键催化剂 作为MGH和哈佛医学院（HMS）的初级教员。 此外，该奖项将为申请人提供一个宝贵的 有机会提高他作为一个成熟的人所必需的技能， 对以患者为导向的临床研究和 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.