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The Nitrate-Nitrite-NO Pathway and Its Implications for Heart Failure and Preserved Ejection Fraction

  • Pharmacologic Therapy (W H W Tang, Section Editor)
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Abstract

The pathogenesis of exercise intolerance in patients with heart failure and preserved ejection fraction (HFpEF) is likely multifactorial. In addition to cardiac abnormalities (diastolic dysfunction, abnormal contractile reserve, chronotropic incompetence), several peripheral abnormalities are likely to be involved. These include abnormal pulsatile hemodynamics, abnormal arterial vasodilatory responses to exercise, and abnormal peripheral O2 delivery, extraction, and utilization. The nitrate-nitrite-NO pathway is emerging as a potential target to modify key physiologic abnormalities, including late systolic left ventricular (LV) load from arterial wave reflections (which has deleterious short- and long-term consequences for the LV), arterial vasodilatory reserve, muscle O2 delivery, and skeletal muscle mitochondrial function. In a recently completed randomized trial, the administration of a single dose of exogenous inorganic nitrate has been shown to exert various salutary arterial hemodynamic effects, ultimately leading to enhanced aerobic capacity in patients with HFpEF. These effects have the potential for both immediate improvements in exercise tolerance and for long-term “disease-modifying” effects. In this review, we provide an overview of key mechanistic contributors to exercise intolerance in HFpEF, and of the potential therapeutic role of drugs that target the nitrate-nitrite-NO pathway.

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Authors and Affiliations

  1. University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Julio A. Chirinos & Payman Zamani

  2. Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Julio A. Chirinos & Payman Zamani

  3. Ghent University, Ghent, Belgium

    Julio A. Chirinos

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  1. Julio A. Chirinos
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Correspondence to Julio A. Chirinos.

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Conflict of Interest

Julio A. Chirinos has received personal fees from Brystol Myers Squibb, OPKO Healthcare, Fukuda Denshi, Microsoft and Merck, grants from National Institutes of Health, American College of Radiology Network, Fukuda Denshi, Microsoft, Brystol Myers Squibb, and non-financial support from Atcor Medical outside the submitted work. In addition, Dr. Chirinos is named as inventor in a pending University of Pennsylvania patent application for the use of inorganic nitrates/nitrites for the treatment of HFpEF.

Payman Zamani declares that he has no conflict of interest.

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Chirinos, J.A., Zamani, P. The Nitrate-Nitrite-NO Pathway and Its Implications for Heart Failure and Preserved Ejection Fraction. Curr Heart Fail Rep 13, 47–59 (2016). https://doi.org/10.1007/s11897-016-0277-9

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