Targeting Inflammation to Treat Cardiovascular Aging
Condition: Vascular Stiffness; Endothelial Dysfunction; Diastolic Dysfunction
MeSH terms: Inflammation
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Salsalate; Placebo (for salsalate)
Intervention type(s): Drug; Drug
Intervention description(s): 4 weeks of daily salsalate; 4 week of daily placebo
Other intervention name(s): Disalcid; Mono-Gesic; Salflex; Salsitab; Placebo capsule sugar pill to mimic salsalate
Intervention MeSH terms: Salicylsalicylic acid; Sodium Salicylate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: aortic stiffness; endothelium-dependent dilation; vascular aging; oxidative stress; inflammation; nitric oxide; nuclear factor kappa B