Targeting Inflammation to Treat Cardiovascular Aging in Humans

简介(申请人提供)：心血管疾病(CVD)是美国主要的死亡原因，老年是主要的危险因素。鉴于到2030年，美国65岁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变化：大的弹性中心动脉(例如，主动脉瓣)硬化，血管内皮功能下降，以及心脏左室(LV)舒张期功能下降。导致这些随年龄增长的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常见的机制联系。我们的中心工作假设是，慢性血管炎症通过氧化应激介导的心血管功能恶化，在随着年龄增长的心血管疾病的发展中发挥核心作用。该项目的广泛、长期目标是确定水杨酸盐对炎症的慢性抑制作用 (8周，3-4g/天)，临床上常用于治疗慢性炎症性疾病(如类风湿性关节炎)的非乙酰水杨酸盐，在改善或恢复受损方面有效 老年人通过氧化应激依赖机制的心血管功能。在一组没有心血管疾病的老年人(年龄60-79岁)中，我们将在一项随机、安慰剂对照、双盲的先导研究中测试以下三个特定目标：目标1将检验慢性抑制炎症将改善主动脉壁僵硬的假说(颈动脉-股动脉脉搏波速度；近端主动脉特征阻抗)；目标2将检验慢性抑制炎症将改善血管内皮功能(肱动脉血流介导的内皮依赖性血管扩张)的假说；目标3将检验慢性抑制炎症将改善左室舒张期松弛和充盈的假说。 血流动力学指标(二尖瓣环舒张期血流速度、组织多普勒E‘)。我们预测，通过抑制炎症改善主动脉僵硬、内皮功能和左室舒张功能的机制将部分通过抑制氧化应激来实现。这项申请的目标与NIA的战略方向一致，战略方向包括调查“炎症在衰老过程中扮演的角色”，以及目前的R21资金公告(PAS-11-280)测试“预防和治疗与年龄相关疾病的新干预措施”。这项研究将在该领域产生重大影响：1)建立一种FDA批准的抗炎药物对心血管衰老的关键生理指标的有效性，这些指标与临床心血管疾病风险密切相关；2)初步了解水杨酸盐对老年人心血管功能的作用机制；3)为未来扩大水杨酸盐疗法的更大规模研究提供科学基础 对于患有与年龄相关的共病(如高血压、糖尿病)和/或有临床症状的老年人 心血管疾病。

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.