Effects of inorganic nitrate supplementation on cardiovascular function and exercise tolerance in heart failure

Abstract

Heart failure (HF) results in a myriad of central and peripheral abnormalities that impair the ability to sustain skeletal muscle contractions and, therefore, limit tolerance to exercise. Chief among these abnormalities is the lowered maximal oxygen uptake, which is brought about by reduced cardiac output and exacerbated by O2 delivery-utilization mismatch within the active skeletal muscle. Impaired nitric oxide (NO) bioavailability is considered to play a vital role in the vascular dysfunction of both reduced and preserved ejection fraction HF (HFrEF and HFpEF, respectively), leading to the pursuit of therapies aimed at restoring NO levels in these patient populations. Considering the complementary role of the nitrate-nitrite-NO pathway in the regulation of enzymatic NO signaling, this review explores the potential utility of inorganic nitrate interventions to increase NO bioavailability in the HFrEF and HFpEF patient population. Although many preclinical investigations have suggested that enhanced reduction of nitrite to NO in low Po2 and pH environments may make a nitrate-based therapy especially efficacious in patients with HF, inconsistent results have been found thus far in clinical settings. This brief review provides a summary of the effectiveness (or lack thereof) of inorganic nitrate interventions on exercise tolerance in patients with HFrEF and HFpEF. Focus is also given to practical considerations and current gaps in the literature to facilitate the development of effective nitrate-based interventions to improve exercise tolerance in patients with HF.

Keywords: beetroot juice; fatigue; nitric oxide; nitrite; skeletal muscle.

Conflict of interest statement

E.W. is a co-applicant on patents related to the therapeutic use of inorganic nitrate and nitrite.

Figures

Figure 1.

Top: schematic of the two parallel pathways for NO formation: the NOS-dependent and nitrate-nitrite-NO pathways. Middle: impact of inorganic nitrate and nitrite supplementation on many of the dysfunctional cardiorespiratory and skeletal muscle elements found in patients with HFpEF and HFrEF. Bottom: impact of inorganic nitrate and nitrite supplementation on exercise efficiency and tolerance in patients with HFpEF and HFrEF. See text for additional information. a-Vo2 difference, arteriovenous O2 content difference; NO, nitric oxide; NO3−, nitrate; NO2−, nitrite; NOS, nitric oxide synthase; PCWP, pulmonary capillary wedge pressure; V̇o2peak, peak oxygen uptake; WRmax, maximal power output.

Figure 2.

Effect of dietary inorganic nitrate supplementation (with beetroot juice) on mean resting systolic blood pressure from HFpEF and HFrEF studies published previously. See Table 1 and text for additional information. The following HFpEF studies were not included: Zamani et al. (31), no available resting systolic blood pressure data; Shaltout et al. (44), no within-subject data comparison (i.e., control vs. inorganic nitrate) preexercise training; and Borlaug et al. (45), protocol used inhaled (nebulized) nitrite. The following HFrEF study was not included: Coggan et al. (50), no available resting systolic blood pressure data. Standard deviation/error bars omitted for clarity. *P < 0.05 vs. control.