Targeting Inflammation to Treat Cardiovascular Aging
Condition: Vascular Stiffness; Endothelial Dysfunction; Diastolic Dysfunction
MeSH terms: Inflammation
Intervention: Salsalate; Placebo (for salsalate)
Intervention description: 4 weeks of daily salsalate; 4 week of daily placebo
Intervention MeSH terms: Salicylsalicylic acid; Sodium Salicylate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 59.0
Sex: All
Minimum age: 18 Years
Maximum age: 79 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: aortic stiffness; endothelium-dependent dilation; vascular aging; oxidative stress; inflammation; nitric oxide; nuclear factor kappa B

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Willing and able to provide written, signed informed consent after the nature of the
             study has been explained, and prior to any research-related procedures.

          -  Age is > or = 50 and < or = 79 years (older) or > or = 18 and < or = 39 years of age

          -  healthy, as determined by health history questionnaire, medical history and physical
             examination by physician or nurse practitioner, blood and urine chemistries, resting
             blood pressure and exercise 12-lead ECG

          -  blood chemistries indicative of normal renal (creatinine <2.2 mg/dl), normal liver,
             i.e., <3 times upper limit for alanine aminotransferase (ALT) and aspartate
             aminotransferase (AST), and thyroid function (TSH between 0.4 - 5.0 mU/L)

          -  If currently receiving treatment with or taking any of the following supplements, be
             willing and able to discontinue taking them for 2 weeks prior and throughout the
             treatment period: Vitamin C, E or other multivitamins containing vitamin C or E;
             nutraceuticals containing vitamin C or E

          -  No history of cardiovascular disease (e.g., heart attack, stroke, heart failure,
             valvular heart disease, cardiomyopathy), Type 2 diabetes, chronic obstructive
             pulmonary or peripheral arterial disease

          -  Middle-aged/older females will be postmenopausal at least 1 year, had tubal ligation
             at least 1 year prior to screening, or who have had a total hysterectomy.

          -  Sedentary or recreationally active defined as performs regular aerobic exercise (30
             min or more of vigorous walking, jogging, swimming, cycling, etc) less than 3
             days/week or less than 12 days/month over the last year

          -  Non-smokers, defined as no history of smoking, no smoking for at least the past 1 year

          -  Normal resting 12-lead ECG.

        Exclusion Criteria:

          -  History of cardiovascular disease such as heart angioplasty/stent or bypass surgery,
             myocardial infarction, stroke, heart failure with or without LV ejection fraction
             <40%, cardiomyopathy, valvular heart disease, cardiomyopathy, heart transplantation,
             Type 2 diabetes and Type 1 diabetes

          -  Smoking or history of smoking within past one year

          -  History of gastric ulcers, bleeding disorders, dyspepsia, severe gastroesophageal
             reflux disease (GERD), or metabolic acidosis

          -  History of asthma or lung disease (chronic obstructive pulmonary disease, COPD)

          -  Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left
             ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree atrioventricular
             (AV) block, atrial fibrillation/flutter)

          -  Serious neurologic disorders including seizures

          -  History of renal failure, dialysis or kidney transplant

          -  Serum creatinine > 2.2 mg/dL, or hepatic enzyme concentrations > 3 times the upper
             limit of normal

          -  History of HIV infection, hepatic cirrhosis, other preexisting liver disease, or
             positive HIV, Hepatitis B or C test at screening.

          -  Use of any investigational product or investigational medical device within 30 days
             prior to screening, or requirement for any investigational agent prior to completion
             of all scheduled study assessments.

          -  History of recent chicken pox, shingles or influenza (ie., risk of Reye's syndrome)
             Recent flu-like symptoms within the past 2 weeks

          -  Pregnant or breastfeeding at screening, or planning to become pregnant (self or
             partner) at any time during the study. A urinary pregnancy test will be done on all
             females. If test is positive, the subject will be excluded.

          -  Women with history of hormone replacement therapy within the past 6 months

          -  History of rheumatoid arthritis, Grave's disease, systemic lupus erythematosis, and
             Wegener's granulomatosis;

          -  Taking medications for diabetes mellitus, kidney disease, liver disease, asthma,
             sepsis or seizure disorders;

          -  Taking lipid lowering (e.g., statins, niacin), glycemic control (e.g. metformin,
             insulin), anticoagulation, anti-seizure, anti-depression or antipsychotic agents

          -  History of co-morbid condition that would limit life expectancy to < 6 months.

          -  It is unknown if Salsalate is transferred in seminal fluid of men. However, it is
             recommended that proper protection such as a condom be used during intercourse during
             the study.

          -  Concomitant treatment with: aspirin, baby aspirin, indomethacin, naproxen (Aleve),
             acetaminophen (Tylenol), ibuprofen (Advil, Motrin), any other non-steroidal
             anti-inflammatory drugs; cox-2 inhibitors (Celebrex, Vioxx, etc); allopurinol
             (Zyloprim, Lopurin, Allopurin; coumadin (Warfarin), enoxaparin (Lovenox); clopidogrel
             (Plavix); dipyridamole (Persantine); heparin; diabetic medications (Metformin,
             glyburide, insulin, etc), thiazolidinediones (Avandia, Rezulin, Actos);
             corticosteroids (prednisone); methotrexate, infliximab (Remicade), etanercept
             (Enbrel); levothyroxine (Levoxyl, Synthroid, Levoxyl, Unithroid); Levodopa;
             Phosphodiesterase (PDE) 5 inhibitors (e.g., Viagra®, Cialis®, Levitra®, or Revatio®);
             PDE 3 inhibitors (e.g., cilostazol, milrinone, or vesnarinone); lithium

          -  May participate if use of the following medications are discontinued 2 weeks prior to
             participation: salicylate medications, aspirin, antioxidants, herbal supplements,
             vitamins, omega-3 fatty acids; cox-2 inhibitors (Celebrex, Vioxx, etc)

          -  May participate if no use of the following medications in the 48 hours prior to
             experimental visits: naproxen (Aleve), acetaminophen (Tylenol), ibuprofen (Advil,
             Motrin), other any non-steroidal anti-inflammatory drugs

          -  Vulnerable populations (prisoners, etc.) are not included in this study because we are
             studying healthy middle-aged/older adults.

          -  Any condition that, in the view of the PI, places the subject at high risk of poor
             treatment compliance or of not completing the study.

          -  Hemoglobin <12 mg/dl for men; < 10 mg/dl for women

          -  History of alcohol abuse or >10 alcoholic units per week (1 unit= 1 beer, 1 glass of
             wine, 1 mixed cocktail containing 1 oz alcohol)

          -  Low platelets (<100,000 cu mm)

          -  On weight loss drugs (e.g., Xenical (orlistat), Meridia (sibutramine), Acutrim
             (phenylpropanol-amine), or similar over-the-counter medications) within 3 months of
             screening

          -  Any surgery within 30 days of screening