Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT02124824
• Collaborator: University of Utah (Other)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 54.9
• Patients Per Site Per Month: 0.5

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: BQ-123	Early Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: Contribution of Endothelin-1 to Exercise Intolerance in HF
• Actual Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Mar 31, 2019
• Actual Study Completion Date: Mar 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: Control Control	Drug: BQ-123; Endothelin subtype A antagonist
Experimental: Arm 2: Heart Failure Heart Failure	Drug: BQ-123; Endothelin subtype A antagonist

Outcome Measures

Primary Outcome Measures

1. Blood Flow [two years]

   Ultrasound Doppler

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 75 Years
• Sexes Eligible for Study: All
• 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

• 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Salt Lake City Health Care System, Salt Lake City, UT	Salt Lake City	Utah	United States	84148

Sponsors and Collaborators

• VA Office of Research and Development
• University of Utah

Investigators

• Principal Investigator: David W. Wray, PhD, VA Salt Lake City Health Care System, Salt Lake City, UT

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 17, 2021

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02124824
• Other Study ID Numbers: F1418-P
• First Posted: Apr 28, 2014
• Last Update Posted: Dec 20, 2021
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Heart Failure; cyclo(Trp-Asp-Pro-Val-Leu)

Study Results

Participant Flow

Arm/Group Title	Arm 1: Control	Arm 2: Heart Failure
Arm/Group Description	Control BQ-123: Endothelin subtype A antagonist	Heart Failure BQ-123: Endothelin subtype A antagonist
Period Title: Overall Study
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm 1: Control	Arm 2: Heart Failure	Total
Arm/Group Description	Control BQ-123: Endothelin subtype A antagonist	Heart Failure BQ-123: Endothelin subtype A antagonist	Total of all reporting groups
Overall Participants	15	15	30
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 100%	15 100%	30 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64 (4)	59 (6)	62 (4)
Sex: Female, Male (Count of Participants)
Female	2 13.3%	2 13.3%	4 13.3%
Male	13 86.7%	13 86.7%	26 86.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.7%	1 6.7%	2 6.7%
Not Hispanic or Latino	11 73.3%	12 80%	23 76.7%
Unknown or Not Reported	3 20%	2 13.3%	5 16.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 6.7%	1 3.3%
Native Hawaiian or Other Pacific Islander	2 13.3%	3 20%	5 16.7%
Black or African American	1 6.7%	1 6.7%	2 6.7%
White	12 80%	9 60%	21 70%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 6.7%	1 3.3%
Region of Enrollment (Count of Participants)
United States	15 100%	15 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	Blood Flow
Description	Ultrasound Doppler
Time Frame	two years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Control	Arm 2: Heart Failure
Arm/Group Description	Control BQ-123: Endothelin subtype A antagonist	Heart Failure BQ-123: Endothelin subtype A antagonist
Measure Participants	15	15
Mean (Standard Error) [ml/min]	300 (50)	275 (45)

Adverse Events

Time Frame	2 years
Arm/Group Title	Arm 1: Control		Arm 2: Heart Failure
Arm/Group Description	Control BQ-123: Endothelin subtype A antagonist		Heart Failure BQ-123: Endothelin subtype A antagonist
All Cause Mortality
	Arm 1: Control		Arm 2: Heart Failure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Arm 1: Control		Arm 2: Heart Failure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1: Control		Arm 2: Heart Failure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.