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）是美国的头号死亡原因，也是一个重要的公共卫生问题。CVD发病率的季节变化，冬季发病率高达50%，已经观察了80年，但沉淀这一季节性高峰的生理参数尚未确定。健康男性的初步数据显示，红细胞压积（Hct，血液粘度的决定因素）在秋末/初冬达到峰值，而血浆亚硝酸盐/硝酸盐（NOx，血管扩张剂分子的稳定代谢物，一氧化氮）则达到低谷。此外，氮氧化物和内皮素-1 （ET-1，一种有效的血管收缩剂）之间的不平衡可能导致血栓形成事件；然而，Hct、等离子体NOx和等离子体ET-1与已知CVD事件季节变化的潜在联系尚未得到严格的检验。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（闭塞后微循环对血流增加的反应能力）的基线数据和时间模式。具体目的是检测：1)Hct、NOx和ET-1每隔一个月，为期一年；2)微血管反应性每隔一个月，为期一年；3)Hct、NOx和ET-1的季节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。饮食摄入和身体活动将被统计控制。选取17名健康青年男性（20-30岁）、17名健康中年男性（50-60岁）和17名健康绝经后中年女性（50-60岁）作为方便样本。血浆NOx和ET-1将采用ELISA测定。在肱动脉闭塞3分钟前后用激光多普勒通量仪测量微血管反应性。使用身体活动问卷（PASE）和7天饮食记录来测量协变量。将检查Hct、NOx、ET-1和微血管反应性的季节变化、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，将帮助我们在心血管生理学的一个领域中架起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针对季节性生理量身定制的创新药理学和/或生活方式干预措施的发展奠定基础，旨在降低CVD的发病率。公共卫生相关性：冬季心血管发病率和死亡率高于夏季，但目前的干预措施并未专门针对冬季心血管事件的预防。红细胞压积、血浆亚硝酸盐（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。如果我们知道红细胞压积、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，这将是开发一种新颖和创新的方法来预防和/或治疗心血管疾病的第一步，这种方法将针对心血管疾病事件风险最高的中老年人的季节性生理。

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.