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Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure

Primary Purpose

Heart Failure

Status

Completed

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

BQ-123

About this trial

This is an interventional basic science trial for Heart Failure

Eligibility Criteria

45 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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).

Sites / Locations

VA Salt Lake City Health Care System, Salt Lake City, UT

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm 1: Control

Arm 2: Heart Failure

Arm Description

Control

Heart Failure

Outcomes

Primary Outcome Measures

Blood Flow

Ultrasound Doppler

Secondary Outcome Measures

Full Information

NCT ID

NCT02124824

First Posted

February 11, 2014

Last Updated

December 17, 2021

Sponsor

VA Office of Research and Development

Collaborators

University of Utah

1. Study Identification

Unique Protocol Identification Number

NCT02124824

Brief Title

Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure

Official Title

Contribution of Endothelin-1 to Exercise Intolerance in HF

Study Type

Interventional

2. Study Status

Record Verification Date

December 2021

Overall Recruitment Status

Completed

Study Start Date

September 1, 2014 (Actual)

Primary Completion Date

March 31, 2019 (Actual)

Study Completion Date

March 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

VA Office of Research and Development

Collaborators

University of Utah

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief 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.

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, the investigators 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, the investigators 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. The investigators anticipate that findings from the proposed work with ET-1 inhibition could thus provide a "missing link" of information in the investigators' understanding of skeletal muscle blood flow regulation and exercise tolerance in HF, ultimately leading to enhanced quality of life in this cohort.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure

7. Study Design

Primary Purpose

Basic Science

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Randomized

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1: Control

Arm Type

Experimental

Arm Description

Control

Arm Title

Arm 2: Heart Failure

Arm Type

Experimental

Arm Description

Heart Failure

Intervention Type

Drug

Intervention Name(s)

BQ-123

Intervention Description

Endothelin subtype A antagonist

Primary Outcome Measure Information:

Title

Blood Flow

Description

Ultrasound Doppler

Time Frame

two years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

45 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility 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).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David W. Wray, PhD

Organizational Affiliation

VA Salt Lake City Health Care System, Salt Lake City, UT

Official's Role

Principal Investigator

Facility Information:

Facility Name

VA Salt Lake City Health Care System, Salt Lake City, UT

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84148

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure

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