Targeting Inflammation to Treat Cardiovascular Aging in Humans

University Of Iowa, Iowa City IA

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Abstract

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.