Impact of Seasonal Variation in Hematocrit, NOx & ET-1 on Vascular Reactivity

描述（由申请人提供）：心血管疾病（CVD）是美国的头号死因，也是一个重要的公共卫生问题。CVD发病率的季节性变化，冬季发病率高出50%，已经观察了80年，但沉淀这个季节性高峰的生理参数尚未确定。健康男性的初步数据表明，红细胞压积（Hct，血液粘度的决定因素）峰值，而血浆亚硝酸盐/硝酸盐（NOx，血管扩张分子一氧化氮的稳定代谢物）低谷在深秋/初冬。此外，NOx和内皮素-1（ET-1，一种有效的血管收缩剂）之间的失衡可能导致血栓形成事件;然而，尚未严格检查Hct、血浆NOx和血浆ET-1与CVD事件中已知季节性变化的潜在联系。这项R-21提案的总体目的是首先在健康成人中建立Hct、NOx、ET-1和微血管反应性（微循环对阻塞后流量增加的反应能力）的基线数据和时间模式。具体目的是：1）Hct、NOx和ET-1每隔一个月检查一年，2）微血管反应性每隔一个月检查一年，3）Hct、NOx和ET-1的季节性变化对微血管反应性的影响。本研究将采用3组前瞻性纵向设计，重复测量Hct、NOx、ET-1和微血管反应性。将对饮食摄入量和体力活动进行统计学控制。将招募17名健康青年男性（20-30岁）、17名健康中年男性（50-60岁）和17名健康中年绝经后女性（50-60岁）的方便样本。将使用ELISA测量血浆NOx和ET-1。在肱动脉闭塞3分钟之前和之后，将使用激光多普勒通量测定法测量微血管反应性。体力活动问卷（PASE）和7天饮食记录将用于测量协变量。将检查Hct、NOx、ET-1和微血管反应性的季节性变化、年龄差异、性别差异以及变量之间的关系。这项研究是我们多学科团队的一个新的研究方向，将有助于我们在心血管生理学的一个领域中建立基础科学和应用科学的桥梁。了解这些重要心血管参数的季节性节律将为未来开发针对季节性生理学的创新药理学和/或生活方式干预措施奠定基础，旨在降低CVD的发病率。公共卫生相关性：冬季心血管疾病发病率和死亡率高于夏季，但目前的干预措施并没有专门针对冬季心血管事件的预防。血细胞比容、血浆亚硝酸盐/硝酸盐（NOx）和/或血浆内皮素-1（ET-1）是影响微血管反应性的重要心血管物质。如果已知血细胞比容、血浆NOx和/或血浆ET-1与冬季微血管反应性的改变有关，那么，这将是开发一种预防和/或治疗心血管疾病的新颖和创新方法的第一步，该方法将针对中老年人群的季节性生理学，这是心血管疾病事件风险最大的人群。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the number one cause of death in the United States and an important public health problem. Seasonal variation in CVD morbidity, with up to a 50% higher winter occurrence, has been observed for 80 years, yet the physiological parameters that precipitate this seasonal peak have not been defined. Preliminary data in healthy men suggest that hematocrit (Hct, a determinant of blood viscosity) peaks while plasma nitrite/nitrate (NOx, a stable metabolite of the vasodilator molecule, nitric oxide) troughs in late fall/early winter. Additionally, an imbalance between NOx and endothelin-1 (ET-1, a potent vasoconstrictor) may lead to a thrombotic event; yet, Hct, plasma NOx and plasma ET-1 have not been examined rigorously for potential links to the known seasonal variation in CVD events. The overall purpose of this R-21 proposal is to establish, first, in healthy adults, baseline data and temporal patterns for Hct, NOx, ET-1 and microvascular reactivity (ability of the microcirculation to respond to increased flow following occlusion). The specific aims are to examine: 1) Hct, NOx, and ET-1 at one month intervals for one year, 2) microvascular reactivity at one month intervals for one year, and 3) the impact of seasonal variation of Hct, NOx, and ET-1 on microvascular reactivity. This study will employ a 3 group, prospective, longitudinal design with repeated measures of Hct, NOx, ET-1, and microvascular reactivity. Dietary intake and physical activity will be controlled statistically. A convenience sample of 17 healthy young men (20-30 yrs old), 17 healthy middle-aged men (50-60 yrs old) and 17 healthy middle-aged post-menopausal women (50-60 yrs old) will be recruited. Plasma NOx and ET-1 will be measured using ELISA. Microvascular reactivity will be measured using laser Doppler fluxmetry before and after 3 min of brachial artery occlusion. A physical activity questionnaire (PASE) and a 7-day diet record will be used to measure the covariates. Hct, NOx, ET-1, and microvascular reactivity will be examined for seasonal variation, differences by age, differences by gender and relationships between the variables. This study, which is a new research direction for our multidisciplinary team, will assist us to bridge basic and applied science in one area of cardiovascular physiology. An understanding of the seasonal rhythms of these important cardiovascular parameters will lay the foundation for the development of future innovative pharmacologic and/or lifestyle interventions tailored to seasonal physiology and designed to decrease the incidence of CVD. PUBLIC HEALTH RELEVANCE: Cardiovascular morbidity and mortality are higher in the winter than the summer, but current interventions do not specifically target the prevention of cardiovascular events during the winter. Hematocrit, plasma nitrite/nitrate (NOx) and/or plasma endothelin-1 (ET-1) are important cardiovascular substances that impact microvascular reactivity. If it were known that hematocrit, plasma NOx and/or plasma ET-1 were related to altered microvascular reactivity during the winter, then, that would be the first step toward developing a novel and innovative approach to prevention and/or treatment of cardiovascular disease that would tailored to the seasonal physiology of middle-aged and older adults, the group at greatest risk for a cardiovascular disease event.