Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)
| Status: | Completed |
|---|---|
| Conditions: | High Blood Pressure (Hypertension), Cardiology, Orthopedic, Pulmonary |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Pulmonary / Respiratory Diseases, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | April 2011 |
| End Date: | December 2013 |
Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction
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.
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.
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.
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.
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
- Contra-indication to withdrawal of beta blocker or antihypertensive medications
- Resting or orthostatic hypotension (SBP < 90 mmHg)
- Any gastrointestinal disorder which would interfere with drug absorption
- Any significant valvular heart disease, including prior multiple valve replacement.
- Pericardial Disease
- Infiltrative or hypertrophic cardiomyopathy
- Cor pulmonale
- Unstable coronary disease
- Pregnancy
- Any condition which may prevent the subject from adhering to the study protocol, as
determined by the investigator
Heart Failure with Preserved Ejection Fraction
- Clinical evidence of heart failure with preserved ejection fraction, as manifest by
at least 2 symptoms or signs, including dyspnea on exertion or at rest, orthopnea,
jugular venous distention or hepatojugular reflux, rales or edema.
- Controlled systolic BP (< 150 mmHg on the day of study)
Pulmonary Disease Group
- Known obstructive airways disease with objective documentation of an isolated
obstructive defect by pulmonary function testing.
- No history of heart failure.
- No history of cardiovascular disease, with the exception of hypertension or
hyperlipidemia
- History and physical examination free of signs and symptoms of heart failure,
including elevated jugular venous pressure, hepatojugular reflux, rales or edema.
- Baseline echocardiographic examination without evidence of heart failure, including
systolic dysfunction of the LV or RV, or evidence of more than mild diastolic
dysfunction on non-invasive assessment.
HTN/LVH Group
- Known history of hypertension.
- Echocardiographic evidence of left ventricular hypertrophy and diastolic dysfunction.
- No history or physical examination evidence of heart failure, including excessive
dyspnea on exertion, dyspnea at rest, orthopnea, PND, jugular venous distention,
hepatojugular reflux, rales or edema.
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