Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction
Overview
- Phase
- Not Applicable
- Intervention
- Dobutamine
- Conditions
- Heart Failure With Preserved Ejection Fraction
- Sponsor
- University of Wisconsin, Madison
- Enrollment
- 14
- Locations
- 1
- Primary Endpoint
- Change in pulse wave velocity
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of heart failure cases in the United States, affecting a primarily elderly population. No treatment has been shown to affect mortality in HFpEF, which is more than 50% at five years a hospitalization. This project explores the underlying cardiovascular physiology of patients with HFpEF with the goal of identifying new therapeutic targets that would allow improved treatment of this devastating disease.
Detailed Description
Heart failure with preserved ejection fraction (HFpEF) is a difficult disease to diagnose due to nonspecific symptoms and clinical findings. The disease occurs in the elderly, who often have other illnesses and signs of aging that make diagnosis of heart failure more difficult. Recently, it has been suggested that HFpEF, which has primarily been thought to be a diastolic disease, is in fact multifactorial, with elements of abnormal systolic function and increased vascular stiffness playing a role in disease pathology. No treatment has been shown to reduce the high mortality of the disease. However, few studies have evaluated this population of patients during periods of increased physiologic stress, despite the consistent clinical presentation of impaired exercise tolerance with few symptoms at rest. This study explores the multifactorial physiology of HFpEF, with a detailed investigation of the specificity of abnormalities in contractile reserve and vascular stiffness for this disease, and exploration of the modifiability of these abnormalities. The techniques used are non-invasive, involving echocardiographic evaluation of cardiac function, and measurement of arterial stiffness using tonometry. The first aim of the study is to explore the specificity of a potential diagnostic test for HFpEF by investigating the change in ejection fraction before and after β-adrenergic stimulation with low-dose dobutamine in HFpEF compared to other groups important to distinguish clinically, specifically patients with shortness of breath due to pulmonary disease, and those with hypertension and left ventricular hypertrophy without clinical heart failure. In the second aim, the study will investigate the ability of the calcium channel blocker, amlodipine, to restore normal contractile responses of the myocardium. In the third aim, the role of arterial stiffness in drug responses in HFpEF will be explored. It is anticipated that improved understanding of the complex physiology of this multifactorial disease gained through this study will lead to more rational design of large clinical trials studying promising agents for HFpEF that impact not only diastolic function, but contractile reserve and arterial properties as well.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female; Age 18 or older.
- •Left ventricular ejection fraction ≥ 50%.
- •Symptomatic heart failure or appropriate comparator group criteria
- •Informed consent signed by the subject
Exclusion Criteria
- •Symptoms of active ischemia.
- •Moderate or severe mitral or aortic stenosis, or severe aortic insufficiency.
- •Serum creatinine \> 3.0 or chronic hemodialysis.
- •Known chronic hepatic disease; defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels \> 3.0 times the upper limit of normal as read at the local lab.
- •Severe renal dysfunction, i.e. glomerular filtration rate (GFR) \<30 ml/min.
- •Atrial fibrillation
- •Myocardial infarction within the last year
- •Coronary bypass surgery within the last 6 months
- •Stroke within the last 6 months
- •Known aortic aneurysm
Arms & Interventions
HFpEF
25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF \> 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease. Subjects will receive amlodipine, oral administration for a period of 12 weeks.
Intervention: Dobutamine
HFpEF
25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF \> 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease. Subjects will receive amlodipine, oral administration for a period of 12 weeks.
Intervention: Amlodipine
Pulmonary Disease
20 patients with pulmonary disease and no clinical evidence of cardiovascular disease
Intervention: Dobutamine
LVH/HTN
20 subjects with known left ventricular hypertrophy and clinically diagnosed hypertension without the diagnosis of heart failure.
Intervention: Dobutamine
HFpEF placebo
25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF \> 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease. Subjects will be administered a placebo for a period of 12 weeks.
Intervention: Dobutamine
Outcomes
Primary Outcomes
Change in pulse wave velocity
Time Frame: 12 week study visit
Change in carotid-femoral pulse wave velocity (PWV) with 12 weeks of therapy with amlodipine or placebo will be the primary outcome variable.
Change in ejection fraction with 5mcg/kg/min dobutamine
Time Frame: day 0 and 12 week study visit
The primary outcome variable in this analysis will be change in ejection fraction from baseline at the 5 mcg dobutamine dose.