Approximately 50% of patients with HF have a normal ejection fraction (HF with preserved ejection fraction, HFpEF). There are currently no effective pharmacologic interventions available for HFpEF. Given the enormous burden of HFpEF, finding effective therapies for this condition is a top priority. Exercise intolerance is the hallmrk of HFpEF and greatly impairs quality of life. Recent evidence links abnormalities in peripheral vasodilation to exercise intolerance in HFpEF. Inorganic circulating nitrite constitutes an important source of the potent vasodilator nitric oxide (NO), which operates preferentially in situations of hypoxia, as occurs in exercising muscle. Dietary nitrates also exert mitochondrial effects in skeletal muscle. In addition to these exercise-related effects, dietary nitrates exert peripheral effects that have the potential for chronic disease-modifying benefits in HFpEF, particularly a reduction in late systolic load, which appears to promote left ventricular remodelin and diastolic dysfunction. Our preliminary data from a double-blinded cross-over placebo-controlled trial demonstrates that a single dose of inorganic nitrate improves aerobic capacity, the peripheral vasodilator response to exercise, skeletal muscle mitochondrial oxidative function and left ventricular late systolic load. We propose a pilot randomized cross-over double-blind controlled trial to compare the effects of potassium nitrate (6 mEq orally three times daily) administered over 6 weeks on: (1) Clinical Endpoints: Exercise capacity (peak oxygen consumption [VO2], during a maximal exercise test) and quality of life (assessed with the Kansas City Cardiomyopathy Questionnaire). (2) Specific physiologic adaptations to exercise : a. Systemic vasodilator response to exercise (assessed via the change in systemic vascular resistance during maximal effort supine-bicycle exercise) b. Muscle tissue blood flow during exercise and muscle oxidative capacity: measured with arterial MRI spin labeling, phosphorus MRI spectroscopy and chemical exchange saturation transfer MRI techniques during a standardized plantar flexor exercise test. c. LV diastolic filling parameters (measured with echocardiography at rest and peak exercise) and myocardial strain (assessed with speckle-tracking echocardiography). (3) Late systolic LV load (assessed via time-resolved LV wall stress and aortic pressure-flow relations, using arterial tonometry and Doppler echocardiography). If our mechanistically-targeted intervention improves exercise capacity, exercise vascular and muscle reserve and arterial hemodynamics, it would establish a new, readily implementable therapeutic paradigm in HFpEF.

Public Health Relevance

Heart Failure with preserved ejection fraction (HFpEF) is a highly prevalent condition associated with high morbidity and mortality, for which no effective pharmacologic therapies are available. This randomized double-blinded cross-over trial will enroll 76 patients with HFpEF to test the hypothesis that potassium nitrate will improve exercise capacity, quality of life and key physiologic adaptations to exercise in HFpEF, including: vasodilatory reserve, the vasodilatory reserve in exercising muscle, LV systolic and diastolic function, muscle oxidative capacity and late systolic left ventricular afterload, which induces LV diastolic dysfunction and remodeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121510-01A1
Application #
8963158
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Shah, Monica R
Project Start
2015-09-11
Project End
2020-06-30
Budget Start
2015-09-11
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$638,264
Indirect Cost
$215,225
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Al-Badri, Ahmed; Hashmath, Zeba; Oldland, Garrett H et al. (2018) Poor Glycemic Control Is Associated With Increased Extracellular Volume Fraction in Diabetes. Diabetes Care 41:2019-2025
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Chirinos, Julio A; Sardana, Mayank; Syed, Amer Ahmed et al. (2018) Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension. J Am Soc Hypertens 12:681-689

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