Targeting Inflammation to Treat Cardiovascular Aging (TIVA)

April 30, 2018 updated by: Gary L. Pierce

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

59

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 79 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Salsalate
Salsalate capsule 1.5 g/day twice per day by mouth for 4 weeks
Drug: Salsalate
4 weeks of daily salsalate
Other Names:
  • Disalcid
  • Mono-Gesic
  • Salflex
  • Salsitab
Placebo Comparator: Placebo
Placebo capsule twice per day by mouth for 4 weeks
Drug: Placebo (for salsalate)
4 week of daily placebo
Other Names:
  • Placebo capsule sugar pill to mimic salsalate
No Intervention: Young Control
No intervention; Baseline measurements only

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Carotid-femoral Pulse Wave Velocity (CFPWV)
Time Frame: Change in CFPWV from baseline at 4 weeks
Aortic stiffness
Change in CFPWV from baseline at 4 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brachial Artery Flow-mediated Dilation (FMD)
Time Frame: Change from baseline brachial artery FMD at 4 weeks
Endothelial function
Change from baseline brachial artery FMD at 4 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Tissue Doppler Left Ventricular Relaxation Velocity (E')
Time Frame: Change from baseline E' at 4 weeks
Left ventricular diastolic dysfunction
Change from baseline E' at 4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gary L. Pierce

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2012

Primary Completion (Actual)

February 1, 2016

Study Completion (Actual)

February 1, 2016

Study Registration Dates

First Submitted

January 4, 2013

First Submitted That Met QC Criteria

January 22, 2013

First Posted (Estimate)

January 25, 2013

Study Record Updates

Last Update Posted (Actual)

May 31, 2018

Last Update Submitted That Met QC Criteria

April 30, 2018

Last Verified

April 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201201739

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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