Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure

• Status: Completed
• Trial end date: 2019-03-31
• Target enrollment: 0
• Participant gender: All

Summary

Heart disease is the leading cause of death in the United States, accounting for one in every four deaths in 2010 and costing over $300 billion annually in health care, medication, and lost productivity. Heart failure (HF), a clinical syndrome that develops as a consequence of heart disease, is characterized by the worsening of symptoms, such as dyspnea and fatigue, upon exertion, collectively defined as "exercise intolerance". Surprisingly, exercise intolerance does not correlate with the degree of cardiac contractile (ventricular) dysfunction, suggesting that changes in the peripheral circulation may be to blame for exercise intolerance in this cohort. Though there are a host of factors that may contribute to this impairment, disease-related increases in circulating endothelin-1 (ET-1) may be a significant factor in the sequelae of exercise intolerance in HF. Thus, the overall purpose of this Small Projects in Rehabilitation Research (SPiRE) proposal is to explore the contribution of ET-1 to chronic vasoconstriction in HF patients, and to examine whether inhibition of this pathway could improve vasodilatory ability, and thus exercise tolerance, in Veterans with HF.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: VA Office of Research and Development
• Collaborator: University of Utah
• Treatments: cyclo(Trp-Asp-Pro-Val-Leu)

Criteria

Inclusion Criteria:

General Inclusion/Exclusion Criteria:

• The study group will include subjects with a history of stable cardiomyopathy (ischemic and non-ischemic, >3 months duration, ages 45-75 yrs) despite a minimum of 6 weeks of optimal treatment.

• Optimal therapy will be according to AHA/ACC and HFSA HF guidelines, including treatment with ACE and -blocker therapy (for at least 6 weeks), or have documented reason for variation, including medication intolerance, contraindication, patient preference, or personal physician's judgment.

• Patient enrollment will be limited to those individuals with NYHA class II and III symptoms, LVEF<35%, with no or minimal smoking history (<15 pk yrs), and without pacemakers.

Exclusion Criteria:

• Patients with atrial fibrillation or HF believed to be secondary to atrial fibrillation will be excluded.

• Patients with HF secondary to significant uncorrected primary valvular disease (except mitral regurgitation secondary to left ventricular dysfunction) will also be excluded.

• Patients will be sedentary, defined here as no regular physical activity for at least the prior 6 months and current activity level will be documented by an activity questionnaire.

• Patients must have no orthopedic limitations that would prohibit them from performing knee-extensor exercise.

• Due to the typical age of patients with HF, all women will be postmenopausal (either natural or surgical) defined as a cessation of menses for at least 2 years, and in women without a uterus, follicle stimulating hormone (FSH) >40 IU/L.

• Women currently taking hormone replacement therapy (HRT) will be excluded from the proposed studies due to the direct vascular effects of HRT Comorbidity Exclusion Criteria: Patients with significant non-cardiac comorbidities, which if present could alter the study results, will be excluded.

• These include a diagnosis of Dementia

• Severe COPD

• Peripheral Vascular Disease

• Anemia

• Sleep-related Breathing Disorder

• Severe Valvular Heart Disease

• Diabetes (if on insulin therapy)

• or End-stage Malignancy

• The investigators will also exclude morbidly obese patients (BMI >35), patients with uncontrolled Hypertension (>160/100), Anemia (Hgb<9) and Severe Renal Insufficiency (individuals with creatinine clearance <30 by the Cockcroft-Gault formula).