Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)
Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)
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.
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.
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.