Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure
Condition: Heart Failure
MeSH terms: Heart Failure
Study type: Interventional
Phase: Early Phase 1

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.
    

Intervention name(s): BQ-123
Intervention type(s): Drug
Intervention description(s): Endothelin subtype A antagonist
Intervention MeSH terms: cyclo(Trp-Asp-Pro-Val-Leu)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science