Cardiac Autonomic Function in Women

描述（由申请人提供）：微血管冠状动脉功能障碍（MCD）在大约50%的有心肌缺血症状和体征的女性中普遍存在，但没有阻塞性冠状动脉疾病（CAD），并且具有与阻塞性CAD相当的不良心血管（CV）预后。先前被认为是良性的并被标记为“心脏综合征X”（CSX），与无症状的女性相比，无阻塞性CAD的女性主要不良心脏事件（MACE）增加了3倍。传统的心血管危险因素难以预测MCD；治疗方法还不发达。虽然动物和人类的数据表明心脏自主神经系统（ANS）在心肌缺血和心源性猝死的机制通路中的重要性，但尚未在具有明确的冠状动脉血流和心肌缺血测量的MCD中进行研究。患有MCD的女性有低心率/精神压力相关的心绞痛、心肌梗死，并与“心碎综合征”（Takotsubo心肌病）有关。我们假设以交感优势为特征的心脏ANS交感迷走神经平衡与MCD的存在和严重程度呈正相关。为了进一步测试ANS作为MCD的机制途径，我们假设随机分配到有节奏呼吸的MCD受试者将有益地改变ANS交感迷走神经平衡并改善作为MCD标志的缺血性症状。比较三组：(1)患有MCD的女性；(2) CSX女性（无MCD的症状对照）；(3)对照女性（无症状正常对照）。受试者将从正在进行的NIH-NHLBI资助的女性缺血综合征评估(WISE) -冠状动脉血管功能障碍研究（R01 HL090957, PI: Bairey Merz）中招募，以测试以下目的：1)通过（1a）通过123碘-甲氧苄基胍（MIBG）单光子发射计算机断层扫描（SPECT）成像测量心脏交感神经活动，以及（1b）通过心理应激测试和外周血管测试检测低心率应激对三组患者ANS交感神经平衡的影响，研究MCD患者与CSX对照组相比心脏ANS交感神经迷走神经平衡的关系；2)使用基于设备的有节奏呼吸来测试ANS交感迷走神经平衡作为MCD的机制途径。我们建议研究包括CSX受试者在内的三组没有MCD证据的女性，因为CSX先前的工作表明ANS平衡的作用，但没有将其与MCD（冠状动脉血流和缺血）的测量联系起来，留下了一个重要的知识空白，关于ANS平衡是MCD的机制途径还是仅仅是症状的良性后果。解决这一知识差距将为ANS是否应该作为临床试验的机制途径提供指导，旨在降低这一高危MCD人群的MACE。

DESCRIPTION (provided by applicant): Microvascular coronary dysfunction (MCD) is prevalent in approximately 50% of women with signs and symptoms of myocardial ischemia but no obstructive coronary artery disease (CAD) and carries an adverse cardiovascular (CV) prognosis, comparable to obstructive CAD. Previously thought to be benign and labeled "Cardiac Syndrome X" (CSX), there is a 3-fold increase in major adverse cardiac events (MACE) in women with no obstructive CAD compared to asymptomatic women. Traditional CV risk factors poorly predict MCD; therapeutics are poorly developed. While animal and human data demonstrate the importance of the cardiac autonomic nervous system (ANS) in the mechanistic pathways for myocardial ischemia and sudden cardiac death, this has not been studied in MCD with well-defined measures of coronary blood flow and myocardial ischemia. Women with MCD have low heart rate/mental stress-related angina, myocardial infarctions, and links to "broken heart syndrome" (Takotsubo cardiomyopathy). We hypothesize that cardiac ANS sympathovagal balance characterized by sympathetic predominance is positively associated with the presence and severity of MCD. To further test ANS as a mechanistic pathway of MCD, we hypothesize that MCD subjects randomized to paced breathing will have beneficially altered ANS sympathovagal balance and improved ischemic symptoms as a marker of MCD. Three groups will be compared: (1) Women with MCD; (2) Women with CSX (symptomatic controls without MCD); (3) Reference Control women (asymptomatic normal controls). Subjects will be recruited from the on-going NIH-NHLBI funded Women's Ischemia Syndrome Evaluation (WISE) - Coronary Vascular Dysfunction study (R01 HL090957, PI: Bairey Merz) to test the following Aims: 1) To characterize the association between cardiac ANS sympathovagal balance in MCD compared to CSX and reference control subjects by (1a) measuring cardiac sympathetic activity by 123iodine-metaiodobenzylguanidine (MIBG) single photon emission computed tomography (SPECT) imaging, and (1b) testing the effect of low heart rate stress on ANS sympathovagal balance in the three groups via mental stress testing and peripheral vascular testing; 2) To test ANS sympathovagal balance as a mechanistic pathway in MCD using device- based paced breathing. We propose to study three groups of women including CSX subjects without evidence of MCD because prior work in CSX has suggested a role for ANS balance but has not linked this to measures of MCD (coronary flow and ischemia), leaving an important knowledge gap regarding whether ANS balance is a mechanistic pathway in MCD or simply a benign consequence of symptoms. Addressing this knowledge gap will provide guidance regarding whether the ANS should be targeted as a mechanistic pathway in clinical trials designed to reduce MACE in this at-risk MCD population.