Vitamin D, Subclinical Cardiovascular Disease, and Orthostatic Hypotension in Older Adults

每年，近三分之一的65岁或以上成年人都会跌倒，而美国的福尔斯跌倒率为 升中国老年人经常不能从福尔斯跌倒中恢复，导致永久性残疾和过早死亡。 鉴于美国人口老龄化，确定福尔斯发生的机制和预防福尔斯的干预措施 是公认的公共卫生优先事项。该提案的重点是一个创新的假设，即未被发现或 亚临床心血管疾病（CVD），一种在老年人中高度流行的疾病，可能导致福尔斯跌倒， 老年人我们的科学前提是基于我们最近发表的关于中年人的工作，其中 表明亚临床CVD与直立性低血压（跌倒的危险因素）密切相关。 鉴于心血管系统在支持肌肉和中枢神经系统功能方面的重要作用， 神经系统，我们认为CVD可能会促进福尔斯在几个方面超越直立，包括肌肉 力量、步态速度和平衡，亚临床CVD标志物的升高与 更高的跌倒风险。然而，这些途径尚未在老年人群体中进行过测试。 本补充建议旨在（1）确定亚临床CVD对心血管疾病发病机制的贡献， 通过直立性低血压引起的福尔斯，以及（2）确定维生素D3补充的影响， 对于福尔斯，亚临床心血管疾病。我们将通过两个可靠的和 心血管损伤和应变的高灵敏度标志物：高灵敏度心肌肌钙蛋白I（hs-cTnI）和N- NIA资助试验（STURDY）储存标本中的末端B型利钠肽原（NT-proBNP）。 STURDY测试了维生素D3补充剂对70岁及以上高危成人福尔斯跌倒的影响， 包括肌肉力量、步态速度和平衡沿着的详细评估， 直立性低血压的评估，继发于Juraschek博士的K23辅助建议。此外，委员会认为， STURDY的随机设计，其中包括四种维生素D3剂量中的一种， 维生素D不足或缺乏，提供了一个巨大的机会来确定的直接影响， 适当剂量的维生素D3对亚临床CVD的影响。 这项创新的建议汇集了（1）一个由STURDY研究人员组成的直立位专家团队， 低血压、补充剂和CVD生物标志物的测量（Drs. Juraschek，阿佩尔，Christenson），（2） 与西门子持续的行业合作伙伴关系，显著降低了分析成本，（3）令人难以置信的独特 建立了NIA研究群体;（4）生产力的良好记录。 这一建议有可能改变直立性低血压的理解和建立的范式 亚临床CVD作为后续跌倒预防策略的关键重点。此外，我们的建议将 提供明确的证据，是否一个秋天的干预，维生素D3补充，减少亚临床 CVD。这些目标将共同为未来的干预研究提供信息，这些研究重点是亚临床CVD，以预防 直立性低血压和防止老年人福尔斯跌倒。

Each year, nearly one third of adults aged 65 years or older experiences a fall and the rate of falls in the US is rising. Older adults frequently do not recover from falls, resulting in permanent disability and premature death. Given the aging US population, identifying mechanisms by which falls occur and interventions to prevent falls are recognized public health priorities. This proposal focuses on an innovative hypothesis that undetected or subclinical cardiovascular disease (CVD), a condition highly prevalent in older adults, may contribute to falls in older adults. Our scientific premise is based on our recently published work in middle-aged adults, which demonstrated that subclinical CVD was strongly associated with orthostatic hypotension, a fall risk factor. Given the essential role of the cardiovascular system to support functions of both muscle and the central nervous system, we believe that CVD might promote falls in several ways beyond orthostasis, including muscle strength, gait speed, and balance, and that elevations in markers of subclinical CVD would be associated with a higher risk of falling. However, these pathways have not been tested in a population of older adults. This supplement proposal aims to (1) determine the contribution of subclinical CVD toward the pathogenesis of falls via orthostatic hypotension, and (2) determine the impact of vitamin D3 supplementation, an intervention for falls, on subclinical CVD. We will accomplish these aims by measuring subclinical CVD via two reliable and highly sensitive markers of cardiovascular injury and strain: high sensitivity cardiac troponin I (hs-cTnI) and N- terminal pro b-type natriuretic peptide (NT-proBNP) in stored specimens of the NIA-funded trial (STURDY). STURDY tests the effects of vitamin D3 supplementation on falls in high-risk adults, age 70 and older, and includes detailed assessments of muscle strength, gait speed, and balance along with comprehensive assessments of orthostatic hypotension, secondary to Dr. Juraschek's K23 ancillary proposal. Furthermore, STURDY's randomized design, which involves one of four vitamin D3 doses administered to adults with insufficient or deficient vitamin D, affords a tremendous opportunity to determine the direct effects of appropriately dosed vitamin D3 on subclinical CVD. This innovative proposal brings together (1) an expert team of STURDY investigators on orthostatic hypotension, supplements, and the measurement of CVD biomarkers (Drs. Juraschek, Appel, Christenson), (2) an ongoing industry partnership with Siemens which significantly reduces assay costs, (3) an incredibly unique and established NIA study population, and (4) a remarkable track record of productivity. This proposal has the potential to shift paradigms in how orthostatic hypotension is understood and establish subclinical CVD as a critical focus of subsequent fall prevention strategies. Furthermore, our proposal will provide definitive evidence as to whether one fall intervention, vitamin D3 supplementation, reduces subclinical CVD. Together these aims will inform future intervention studies focused on subclinical CVD to prevent orthostatic hypotension and prevent falls in older adults.