Mechanisms linking hot flashes to cardiovascular risk

描述(申请人提供)：随着年龄的增长，女性面临的两个主要健康问题是心血管疾病(CVD)和更年期潮热。心血管疾病是女性死亡的主要原因。许多中年女性都会经历潮热，30%的女性潮热是频繁或严重的。虽然潮热传统上被认为是一种良性的中年症状，但最近的研究发现，潮热的高负担与心血管疾病的风险有关。几项大型试验表明，使用激素发生心血管事件的最大风险似乎集中在报告中度至重度潮热的女性中。我们的研究表明，在报告频繁潮热的女性中，亚临床心血管疾病增加。将潮热的高负荷与心血管疾病风险联系起来的重要机制可能是内皮功能、炎症/凝血和心脏迷走神经控制的变化。然而，将潮热与心血管风险联系起来的研究结果才刚刚出现。这些研究都不是为了检查潮热和心血管风险之间的关系。大多数都有明显的局限性，包括依赖于对潮热的粗略、自我报告的测量，容易受到多种偏见的影响。这项研究的目的是检查与没有潮热的女性相比，每天有潮热的女性是否有心血管风险的不利指标，包括内皮功能较差，颈动脉内膜中层厚度较高，心脏迷走神经控制较低，以及不良的炎症和止血特征。假设这些差异将独立于传统的心血管疾病风险因素。次要目标包括测试潮热期间心脏迷走神经控制的急性变化，并检查与这些联系有关的关键通路。建议的样本包括300名年龄在40-60岁的围绝经期和绝经后女性，其中一半每天有潮热，另一半没有潮热。参与者将是非吸烟者，没有心脏病，没有接受过糖尿病或高血压治疗，也没有影响潮热的药物。所有女性都将接受为期3天的生理性潮热监测，其中24小时将包括用于测量心脏迷走神经控制(高频心率变异性)的动态心电图，用于测量内皮功能(血流介导的扩张)的臂动脉超声，用于测量内膜中层厚度的颈动脉超声，以及用于评估炎症/止血标志物和雌二醇浓度的血液样本。潮热和心血管风险指标之间的关系将使用线性回归和线性混合模型进行检验。这项研究是专门研究潮热和心血管疾病风险之间关系的第一项研究，也是更好地了解潮热和心血管疾病风险之间联系的重要的第一步。解决这些目标可能有助于更好地理解潮热的生理学，并支持开发一种新的中年女性心血管风险标记物。这项工作有可能挑战研究人员、临床医生和妇女对这种可能是良性更年期症状的理解方式。

DESCRIPTION (provided by applicant): Two major health issues facing women as they age are cardiovascular disease (CVD) and menopausal hot flashes. CVD is the leading cause of death among women. Hot flashes are experienced by many midlife women, and for 30% of women, they are frequent or severe. Although hot flashes are traditionally regarded as a benign midlife symptom, recent research has linked a high burden of hot flashes to CVD risk. Several large trials have indicated that the greatest risk of cardiovascular events with hormone use appears concentrated among women reporting moderate to severe hot flashes. Our research shows elevated subclinical CVD among women reporting frequent hot flashes. Important mechanisms linking a high burden of hot flashes to CVD risk may be changes in endothelial function, inflammation/coagulation and cardiac vagal control. However, findings linking hot flashes to cardiovascular risk are just emerging. None of these studies was designed to examine associations between hot flashes and cardiovascular risk. Most have notable limitations, including the reliance upon crude, self-report measures of hot flashes vulnerable to multiple biases. The aim of this investigation is to examine whether women with daily hot flashes have adverse indicators of cardiovascular risk, including poorer endothelial function, higher carotid intima media thickness, lower cardiac vagal control, and an adverse inflammatory and hemostatic profile, relative to women without hot flashes. It is hypothesized that these differences will be independent of traditional CVD risk factors. Secondary aims include testing acute changes in cardiac vagal control during hot flashes and examining key pathways involved in these associations. The proposed sample includes 300 perimenopausal and postmenopausal women aged 40-60, half with daily hot flashes and half without hot flashes. Participants will be nonsmokers, free of heart disease and treated diabetes or hypertension, and free of medications impacting hot flashes. All women will undergo 3 days of physiologic hot flash monitoring, 24 hours of which will include ambulatory electrocardiography for measurement of cardiac vagal control (high frequency heart rate variability), a brachial artery ultrasound for measurement of endothelial function (flow mediated dilation), a carotid artery ultrasound for measurement of intima media thickness, and a blood sample for assessment of inflammatory/hemostatic markers and estradiol concentrations. Relations between hot flashes and cardiovascular risk indicators will be examined using linear regression and linear mixed models. This study represents the first study specifically designed to examine relations between hot flashes and CVD risk, and is an important first step in better understanding links between hot flashes and CVD risk. Addressing these aims may inform a better understanding of the physiology of hot flashes and support the development of a novel marker of cardiovascular risk among midlife women. This work has the potential to challenge the way that this presumably benign menopausal symptom is understood by researchers, clinicians, and women.