Endothelial Dysfunction Clinical Trial
Official title:
Targeting Inflammation to Treat Cardiovascular Aging in Humans (TIVA Study)
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States with older age being a primary risk factor. The number of adults greater than age 65 years will almost double to 70 million by 2030, therefore identifying therapeutic strategies for treating or preventing age-related disorders in humans is of major biomedical importance. Cardiovascular aging, defined as a reduction in vascular and cardiac functions with normal aging, occurs even in the absence of CVD risk factors and overt CVD. A key feature of cardiovascular aging is stiffening of the large elastic central arteries such as the aorta. This is important because aortic stiffness directly contributes to clinical problems such as increased blood pressure, reduced blood flow to the heart muscle, and thickening of the heart muscle. Therefore, these clinical consequences are hypothesized to mediate a substantial proportion of the increase in CVD risk in older adults. However, effective drug treatments for aortic stiffness are not currently available and the biological reasons (mechanisms) involved in causing aortic stiffening remain undefined. In addition, the inability of smaller blood vessels to relax, impairment of the heart to relax during the filling phase of the heart cycle (i.e., diastole), and increased blood pressure variability, have all been linked to aortic stiffness. Furthermore, chronic low-grade inflammation with advancing age has been proposed to be a common mechanistic link (i.e., biological reason) between these reductions in cardiovascular function in older adults. Therefore, the investigators propose that inflammation could be a novel therapeutic target to treat cardiovascular aging in older adults. Our central hypothesis is that inflammation mediates the age-related deterioration in cardiovascular functions observed with advancing age through the development of oxidative stress (i.e., imbalance between damaging oxygen free radicals vs. protective antioxidants). Our hypothesis predicts that chronic inhibition of inflammation with Salsalate, an FDA-approved anti-inflammatory drug similar to aspirin that is used to treat rheumatoid arthritis pain and known to inhibit the 'master' regulator of inflammation in the cell (i.e., nuclear factor kappa B), will improve cardiovascular function in older adults. In addition, the investigators hypothesize that the mechanism for the improvement in cardiovascular function during inhibition of inflammation will be by suppressing oxidative stress. To test our hypothesis, the investigators will randomize older healthy adults (age 50-79 years) to 3 g/day of salsalate or placebo (i.e., pill with inactive substance) pills for 4 weeks and have cardiovascular function measured at baseline and again after 4 weeks.
Aim 1: To measure aortic wall stiffness and circulating biomarkers of oxidative stress during
both acute (IV) intravenous infusions of saline and then the antioxidant vitamin C at
baseline and after 4 weeks of salsalate or placebo in healthy older adults. Hypothesis 1:
Inhibition of inflammation in older adults will decrease aortic wall stiffness in part by
reductions in oxidative stress.
Aim 2: To measure brachial artery endothelium-dependent vasodilation (EDV) and circulating
markers of oxidative stress during acute intravenous infusions of saline and then the vitamin
C at baseline and after 4 weeks of salsalate or placebo in healthy older adults. Hypothesis
2: Inhibition of inflammation in older adults will improve vascular endothelial vasodilatory
function in older adults in part by reductions in oxidative stress.
Aim 3: To measure left ventricular (LV) diastolic relaxation and filling dynamics and
circulating markers of oxidative stress during both acute intravenous infusions of saline and
then vitamin C at baseline and after 4 weeks of Salsalate or placebo in healthy older adults.
Hypothesis 3: Inhibition of inflammation in older adults will improve LV diastolic function
in part by reductions in oxidative stress.
Exploratory Aim: To measure 24-hour pressure variability and short-term baroreflex
sensitivity before and after 4 weeks of oral Salsalate or placebo treatment in older adults.
Exploratory hypothesis: Inhibition of inflammation in older adults will improve
cardiovascular autonomic dysregulation in older healthy adults.
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