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

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.

Keywords: Afterload; Heart failure with preserved ejection fraction; Inorganic nitrate; Mitochondria; Therapy; Wave reflections.

Figure 1

NO generation via nitric oxide synthase (NOS) or through the nitrate/nitrite/NO pathway. NOS requires molecular oxygen for conversion of L-arginine to NO and citrulline. In the settings of hypoxia, NOS-mediated NO generation is very inefficient. On the other hand, the activation of nitrate/nitrite to NO occurs to a greater extent in the setting of ischemia and acidosis,^, and operates largely through NOS-independent mechanisms and is chiefly driven by deoxyhemoglobin.^, This is ideal for HFpEF because is generates NO “when” and “where” it is needed. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Drug Discovery. Lundberg, Weitzberg, Gladwin, 2008.

Figure 2

Systemic peripheral mechanisms by which inorganic nitrate enhanced aerobic capacity in HFpEF