Heart Failure (HF) affects ~2% of the western population and ~10% of individuals aged >75 years. Not only is HF already an epidemic, but with the aging of the population, a dramatic further increase in its prevalence is expected. Approximately 50% of patients with HF have a normal ejection fraction (HF with preserved ejection fraction, HFpEF), often called """"""""diastolic"""""""" HF. Many therapeutic interventions are available for HF with reduced ejection fraction, but there is currently no effective intervention available for HFpEF. Given the enormous public health, clinical and societal burden of HFpEF, finding effective therapies for this condition is a top priority in the field. Based on a series of animal experimental and human observational studies that link arterial wave reflections to abnormal left ventricular relaxation, left ventricular remodeling (hypertrophy) and HF risk, we propose a pilot randomized double-blind controlled clinical trial designed to assess whether reducing arterial wave reflections with either isosorbide dinitrate or the combination of isosorbide dinitrate and hydralazine administered for 24 weeks will improve diastolic function, LV remodeling and clinically-relevant endpoints (physical fitness, quality of life) among 42 patients with HFpEF. We therefore aim to: 1) Test whether prolonged nitrate therapy (24 weeks) exerts sustained effects on wave reflections and whether the addition of hydralazine enhances the effect of nitrate therapy on wave reflections in patients with HFpEF. 2) Test whether long-term vasoactive therapy with nitrates + hydralazine results in regression of LV hypertrophy (reduction in LV mass) and LV fibrosis in patients with HFpEF.3) Assess whether nitrate + hydralazine therapy improves diastolic relaxation in patients with HFpEF. 4) Assess whether nitrate + hydralazine therapy results in an improvement in endpoints with immediate clinical relevance (physical fitness and quality of life) in patients with HFpEF. We will also assess whether the effects of vasoactive therapy on LV remodeling, diastolic relaxation, physical fitness and quality of life can be explained by a reduction in arterial wave reflections. If our interventin improves ventricular remodeling, diastolic function and physical fitness, this would introduce a new paradigm in the field and provide a foundation for justifying, designing and powering a more definitive hard endpoint-driven clinical trial in which this approach will be tested as a strategy o improve the outcomes of patients with HFpEF.

Public Health Relevance

Heart Failure with preserved ejection is a highly prevalent condition in the elderly associated with high morbidity and mortality for which no effective therapies are available. This randomized trial will test the hypothesis that reducing arterial wave reflections with vasoactive therapy will improve diastolic function, LV remodeling, physical fitness and quality of life in patients with HFpEF.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG043802-01
Application #
8430125
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Zieman, Susan
Project Start
2013-06-15
Project End
2015-05-31
Budget Start
2013-06-15
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$280,000
Indirect Cost
$105,000
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zamani, Payman; Tan, Victor; Soto-Calderon, Haideliza et al. (2017) Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction. Circ Res 120:1151-1161
Zamani, Payman; Akers, Scott; Soto-Calderon, Haideliza et al. (2017) Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc 6:
Chirinos, Julio A; Phan, Timothy S; Syed, Amer A et al. (2017) Late Systolic Myocardial Loading Is Associated With Left Atrial Dysfunction in Hypertension. Circ Cardiovasc Imaging 10:e006023
Chirinos, Julio A; Londono-Hoyos, Francisco; Zamani, Payman et al. (2017) Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction. Eur J Heart Fail 19:1507-1515
Chirinos, Julio A (2017) Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): Clinical and Therapeutic Considerations. J Cardiovasc Transl Res 10:261-274
Sardana, Mayank; Syed, Amer Ahmed; Hashmath, Zeba et al. (2017) Beta-Blocker Use Is Associated With Impaired Left Atrial Function in Hypertension. J Am Heart Assoc 6:
Phan, Timothy S; Li, John K-J; Segers, Patrick et al. (2016) Misinterpretation of the Determinants of Elevated Forward Wave Amplitude Inflates the Role of the Proximal Aorta. J Am Heart Assoc 5:
Phan, Timothy S; Li, John K-J; Segers, Patrick et al. (2016) Aging is Associated With an Earlier Arrival of Reflected Waves Without a Distal Shift in Reflection Sites. J Am Heart Assoc 5:
Zamani, Payman; Lilly, Scott M; Segers, Patrick et al. (2016) Pulsatile Load Components, Resistive Load and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis (MESA). J Card Fail 22:988-995
Zamani, Payman; French, Benjamin; Brandimarto, Jeffrey A et al. (2016) Effect of Heart Failure With Preserved Ejection Fraction on Nitric Oxide Metabolites. Am J Cardiol 118:1855-1860

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