Contribution of Endothelin-1 to Exercise Intolerance in Heart Failure
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 45 - 75 |
| Updated: | 11/18/2018 |
| Start Date: | September 1, 2014 |
| End Date: | September 1, 2019 |
| Contact: | David W Wray, PhD |
| Email: | walter.wray@hsc.utah.edu |
| Phone: | (801) 582-1565 |
Contribution of Endothelin-1 to Exercise Intolerance in HF
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.
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.
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.
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.
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).
We found this trial at
1
site
Salt Lake City, Utah 84148
Principal Investigator: David W. Wray, PhD
Phone: 801-582-1565
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