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Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified October 2014 by Department of Veterans Affairs
University of Utah
Information provided by (Responsible Party):
Department of Veterans Affairs Identifier:
First received: February 11, 2014
Last updated: October 28, 2014
Last verified: October 2014

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.

Condition Intervention Phase
Heart Failure
Drug: BQ-123
Phase 0

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Basic Science
Official Title: Contribution of Endothelin-1 to Exercise Intolerance in HF

Resource links provided by NLM:

Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Blood Flow [ Time Frame: two years ] [ Designated as safety issue: No ]
    Ultrasound Doppler

Estimated Enrollment: 40
Study Start Date: September 2014
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Drug: BQ-123
Endothelin subtype A antagonist
Experimental: 2
Heart Failure
Drug: BQ-123
Endothelin subtype A antagonist

Detailed Description:

Specific Aim 1 will determine the direct effect of vascular endothelin-1 (ET-1) on skeletal muscle vasoconstriction in HF and age-matched controls. Intra-arterial infusion of the ETA subtype receptor will be undertaken to pharmacologically probe disease-related changes in the ET-1 pathway at rest and during exercise. It is hypothesized that ET-1-mediated vasoconstriction will be elevated in HF compared to controls at rest, such that ETA receptor blockade will augment blood flow in HF patients to a greater degree than age-matched controls. During exercise, we anticipate that inhibition of the ETA receptor will augment skeletal muscle blood flow in HF patients compared to age-matched controls, leading to improved exercise tolerance and reduced skeletal muscle fatigue in this patient group. Specific Aim 2 will determine the potentiating effect of vascular endothelin-1 (ET-1) on sympathetic vasoconstriction in HF and age-matched controls. At rest, we hypothesize that infusion of a sympathomimetic drug (norepinephrine, NE) will produce greater vasoconstriction in HF patients compared to age-matched controls, demonstrating a hypersensitivity of the alpha-adrenergic receptors. Inhibition of the ETA receptor will reduce "sensitivity" of NE-mediated vasoconstriction in HF patients towards that of age-matched controls, identifying ET-1 as a contributor to alpha adrenergic hypersensitivity in HF. During exercise, it is anticipated that NE-mediated vasoconstriction will be greater in HF patients compared to age-matched controls. Inhibition of the ETA receptor will reduce NE-mediated vasoconstriction during exercise. This will augment skeletal muscle blood flow, leading to improved exercise tolerance and reduced skeletal muscle fatigue in HF patients. We anticipate that findings from the proposed work with ET-1 inhibition could thus provide a "missing link" of information in our understanding of skeletal muscle blood flow regulation and exercise tolerance in HF, ultimately leading to enhanced quality of life in this cohort.


Ages Eligible for Study:   45 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes

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
  • We 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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02124824

Contact: David W Wray, PhD (858) 205-3078
Contact: Russell Richardson, PhD (801) 582-1565 ext 4344

United States, Utah
VA Salt Lake City Health Care System, Salt Lake City, UT Not yet recruiting
Salt Lake City, Utah, United States, 84148
Contact: David W Wray, PhD    858-205-3078   
Contact: Douglas S Capps, BS    (801) 582-1565 ext 4414   
Principal Investigator: David W. Wray, PhD         
Sponsors and Collaborators
University of Utah
Principal Investigator: David W. Wray, PhD VA Salt Lake City Health Care System, Salt Lake City, UT
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs Identifier: NCT02124824     History of Changes
Other Study ID Numbers: F1418-P
Study First Received: February 11, 2014
Last Updated: October 28, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Additional relevant MeSH terms:
Heart Failure
Cardiovascular Diseases
Heart Diseases processed this record on November 25, 2014