Heart failure with reduced ejection fraction (HFrEF) affects roughly 3 million in the U.S. and is a mortal and morbid disease. HFrEF impairs a patient's ability to exercise and perform activities of daily living. Although weak cardiac pumping ability clearly contributes to chronic disability associated with HFrEF, abnormal skeletal muscle in patients with HFrEF is also a key debilitating factor. Skeletal muscle is therefore a vital target for treatment of HFrEF. Inorganic nitrate enhances aerobic exercise capacity and muscle power in preliminary studies of patients with HFrEF. The overarching aim of our study (and the follow-up randomized clinical trial [RCT]) is to determine whether inorganic nitrate offers a new, safe and effective treatment for ameliorating the disability due to HFrEF.
The Specific Aims of this study are 1) to determine the best dose of inorganic nitrate for patients with HFrEF; 2) to determine the best primary endpoint (aerobic capacity or muscle power) and the number of patients that will be needed for the RCT; and 3) to set up the infrastructure and manuals needed for standardized performance of the RCT protocols across multiple medical centers.
For Aim 1, the effects of 10mmol and 20mmol of KNO3 vs. placebo on hemodynamics, and blood levels of nitrate and nitrite and breath NO will be measured and any side effects noted.
In Aim 2, a small, phase II clinical trial of 2 wk of KNO3 treatment (dose determined by Aim 1) in a randomized, placebo-controlled, non-crossover design study will be performed. The endpoints of this aim will be aerobic capacity (peak oxygen consumption ? VO2peak), measured during treadmill exercise using a metabolic cart and peak quadriceps muscle power measured using a Biodex machine.
In Aim 3, all of the infrastructure needed for the RCT will be constructed. A RedCAP? database for data entry, storage, and export from all RCT sites will be created. All Cores (Data Coordinating Center, Imaging Analysis Core, Laboratory Core, Exercise Analysis Core, Pharmacy Core) for the RCT will be established and Manuals of Operation will be written. The potential impact of finding a new, safe and effective treatment that helps millions of patients beat the disability of HFrEF is enormous.

Public Health Relevance

The overarching goal of this study is to test whether a new therapy ? inorganic nitrate ? can improve exercise capacity in patients debilitated by heart failure. To set up a randomized clinical trail (RCT) of inorganic nitrate, we will determine the optimal dosing and then perform a small study to determine the number of patients needed. We will also develop the manuals and infrastructure necessary for the RCT. If inorganic nitrate is found safe and effective for improving aerobic exercise capacity, muscle power, and speed of muscle contraction, it would offer a completely new therapy for millions of people suffering from heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Planning Grant (R34)
Project #
5R34HL138253-03
Application #
9754867
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Desvigne-Nickens, Patrice
Project Start
2017-08-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Mulkareddy, Vinaya; Racette, Susan B; Coggan, Andrew R et al. (2018) Dietary nitrate's effects on exercise performance in heart failure with reduced ejection fraction (HFrEF). Biochim Biophys Acta Mol Basis Dis :
Coggan, Andrew R; Peterson, Linda R (2018) Dietary Nitrate Enhances the Contractile Properties of Human Skeletal Muscle. Exerc Sport Sci Rev 46:254-261
Sletten, A C; Peterson, L R; Schaffer, J E (2018) Manifestations and mechanisms of myocardial lipotoxicity in obesity. J Intern Med 284:478-491