Targeting Inflammation to Treat Cardiovascular Aging in Humans

描述（由申请人提供）：心血管疾病（CVD）是美国死亡的主要原因，其中年龄较大是主要危险因素。鉴于到2030年，美国65岁以上的成年人数量将翻一番，达到近7000万，未来老年人中与心血管疾病相关的疾病仍然是一个主要的公共卫生问题。老年人心血管疾病风险的增加在很大程度上归因于与正常衰老相关的心血管结构和功能的三个基本改变：大弹性中央动脉（如主动脉）硬化，血管内皮功能降低，心脏左室舒张功能下降。随着年龄的增长，导致这些生理变化的机制尚不完全清楚，但强有力的证据表明，炎症和氧化应激可能是它们之间共同的机制联系。我们的主要工作假设是慢性血管炎症通过氧化应激介导的心血管功能恶化在心血管疾病的发展中起着核心作用。该项目的长期目标是确定水杨酸盐是否能抑制慢性炎症

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in the U.S. of which older age is a primary risk factor. Given that the number of adults >65 years of age in the U.S. will double to almost 70 million by 2030, future CVD-related illness in older adults remains a major public health concern. The increased risk of CVD in older adults has been attributed in large part to three fundamental alterations in cardiovascular structure and function associated with normal aging: stiffening of the large elastic central arteries (e.g., aort), reduction in vascular endothelial function, and decreased cardiac left ventricular (LV) diastolic function. The mechanisms responsible for these physiological changes with aging are not completely understood, but strong evidence suggests that inflammation and oxidative stress may be common mechanistic links between them. Our central working hypothesis is that chronic vascular inflammation plays a central role in the development of CVD with aging, through an oxidative stress-mediated deterioration in cardiovascular function. The broad, long-term objective of this project is to determine whether chronic inhibition of inflammation with salsalate (8 weeks; 3-4 g/day), a non-acetylated salicylate commonly used clinically to treat chronic inflammatory diseases (e.g., rheumatoid arthritis), is effective in improving or restoring impaired cardiovascular function in older adults through an oxidative stress-dependent mechanism. In a group of older adults (age 60-79 years) without CVD, we will test the following three specific aims in a randomized, placebo-controlled, double-blind, pilot study: Aim 1 will test the hypothesis that chronic inhibition of inflammation will improve aortic wall stiffness (carotid- femoral artery pulse wave velocity; proximal aortic characteristic impedance); Aim 2 will test the hypothesis that chronic inhibition of inflammation will improve vascular endothelial function (brachial artery flow-mediated endothelium-dependent vasodilation); and Aim 3 will test the hypothesis that chronic inhibition of inflammation will improve LV diastolic relaxation and filling dynamics (diastolic LV mitral annular velocity, E' via Tissue Doppler imaging). We predict that the mechanism for the improvement in aortic stiffness, endothelial function, and LV diastolic function from inhibition of inflammation will be mediated in part by suppression of oxidative stress. The goals of this application are consistent with NIA's Strategic Direction that includes investigating "the role that inflammation plays in the aging process" and the current R21 funding announcement (PAS -11-280) testing "novel interventions for prevention and treatment of age related conditions." The study will have a significant impact on the field by: 1) establishing the efficacy of a FDA-approved anti-inflammatory drug on key physiological markers of cardiovascular aging strongly linked to clinical CVD risk; 2) offering preliminary insight into mechanisms of action by which salsalate has its effect on cardiovascular function in older adults, and 3) providing the scientific basis for future larger studies extending salsalate therapy to older adults with age-related co-morbidities (e.g., hypertension, diabetes) and/or with clinical CVD.