Conditions: Heart Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: yes

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.

Arms:
arm 1: Control arm 2: Heart Failure

Interventions: intervention 1: BQ-123
Intervention descriptions: intervention 1: Endothelin subtype A antagonist

Protocol document:
Prot_SAP_000.pdf: 
Title: Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure 
NCT Number: NCT02124824 
Date: December 17, 2021 
 
 


Study Objective: To compare the effect of Endothelin-1 on limb blood flow in patients with heart 
failure and healthy, age matched controls.  
 
Study Design: Single arm, unblinded. Limb blood flow will be determined in patients with heart 
failure and healthy, age-matched controls.     
 
Study Methods:  
Limb Blood Flow: An ultrasound Doppler system (Logiq 7, GE Medical Systems, Milwaukee, 
Wisconsin, USA) equipped with a linear array transducer operating at an imaging frequency of 7-
8 MHz and a Doppler frequency of 4-5 MHz will be used for determination of femoral artery 
diameter and blood velocity. 
Study drug: The ETA selective antagonist BQ-123 (0.6 mcg/dl/min) will be administered intra-
arterially (common femoral artery) rest and during knee extensor exercise (0, 5, 10, and 15 Watts).   
 
Statistical Analysis: Mixed model with repeated measures, with drug infusion at each work load 
is the dependent variable and HF (yes, no) and work load are the major predictor variables, with 
age and gender as additional explanatory variables. In a case where multivariate analysis is 
ultimately deemed appropriate and of interest, but the data do not satisfy the assumptions of 
normal distribution, we will invoke the central limit theorem and perform the bootstrap technique 
to estimate the bias and variation in the data and then correct accordingly. Because of the 
importance of ensuring a potential positive finding is not missed, no statistical adjustment will be 
made for multiple primary comparisons.