Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction

Abstract

Aims To assess the hemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We assessed carotid and aortic pressure-flow relations non-invasively before and after the administration of 0.4 mg of sublingual-nitroglycerin (NTG; n=26), and in a separate sub-study, in response to 12.9 mmol of inorganic nitrate (n=16). NTG did not consistently reduce wave reflections arriving at the proximal aorta (change in real part of reflection coefficient, 1st harmonic:-0.09; P=0.01; 2nd harmonic:-0.045, P=0.16; 3rd harmonic:+0.087; P=0.05), but produced profound vasodilation in the carotid territory, with a significant reduction in systolic blood pressure (133.6 vs 120.5 mmHg; P=0.011) and a marked reduction in carotid bed vascular resistance (19580 vs. 13078 dynes·s/cm5; P=0.001) and carotid characteristic impedance (3440 vs. 1923 dynes·s/cm5; P=0.002). Inorganic nitrate, in contrast, consistently reduced wave reflections across the first 3 harmonics (change in real part of reflection coefficient, 1st harmonic: -0.12; P=0.03; 2nd harmonic:-0.11, P=0.01; 3rd harmonic:-0.087; P=0.09) and did not reduce blood pressure, carotid bed vascular resistance or carotid characteristic impedance (P=NS). Conclusions NTG produces marked vasodilation in the carotid circulation, with a pronounced reduction in blood pressure and inconsistent effects on central wave reflections. Inorganic nitrate, in contrast, produces consistent reductions in wave reflections, and unlike NTG, it does so without significant hypotension or cerebrovascular dilatation. These hemodynamic differences may underlie the different effects on exercise capacity and side effect profile of inorganic vs. organic nitrate in HFpEF.

The role of ventricular–arterial coupling in cardiac disease and heart failure: assessment, clinical implications and therapeutic interventions. A consensus document of the European Society of Cardiology Working Group on Aorta & Peripheral Vascular Diseases, European Association of Cardiovascular Imaging, and Heart Failure Association

“…However, these results may also indicate that the use of inhaled sodium nitrite with its short half‐life in not an effective treatment in this clinical setting. In contrast to inorganic nitrite, orally administered inorganic nitrate has a longer half‐life (∼5–8 h) and does not seem to commonly induce hypotension with single or continued administration …”

Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): Clinical and Therapeutic Considerations

“…In contrast to inorganic nitrate, organic nitrates in HFpEF (1) induce a less consistent reduction in wave reflection, (2) can markedly reduce mean arterial pressure at rest, (3) lack the selective vasodilatory effect during exercise in exercising muscle, (4) exert prominent cerebrovascular vasodilatory effects, which accounts for the high incidence of headaches (and may also expose the already susceptible cerebrovascular microvasculature to excessive pressure and flow pulsatility), (5) induce tolerance or pseudo-tolerance, and (6) increase oxidative stress [102, 106, 107]. In a recent multi-center trial, isosorbide mononitrate reduced outpatient activity in a dose-dependent manner in this population [108].…”

Design of the SILICOFCM study: Effect of sacubitril/valsartan vs lifestyle intervention on functional capacity in patients with hypertrophic cardiomyopathy

“…Lifestyle intervention has been shown to improve exercise tolerance in HCM but at the same time limited effect on cardiac structure and function was reported . Recent studies have demonstrated that dietary supplementation with inorganic nitrate improves exercise capacity and hemodynamic function in patients with heart failure preserved ejection fraction . The potential physiological effect of a combined physical activity and dietary nitrate on HCM phenotype has not been previously investigated and is subject to evaluation in the present SILICOFCM study.…”

“…Recently, several reports demonstrated that dietary supplementation with NO 3− —that is particularly abundant in beetroot juice—increases exercise capacity in patients suffering from heart failure with preserved ejection fraction . Ingested NO 3− is converted to nitrite (NO 2− ) by anaerobic bacteria in the oral cavity that is subsequently reduced to nitric oxide (NO) by metalloproteins (eg, deoxyhemoglobin or deoxymyoglobin) .…”

“…Physical activity intervention is associated with a significant increase in exercise tolerance, but appears to have limited effect on measures of cardiac morphology or function in patients with HCM . Dietary supplementation with inorganic nitrate (ie, concentrated nitrate‐rich beetroot juice) improves exercise capacity, vasodilatation and cardiac output reserves while reduces arterial wave reflections, which are linked to a left ventricular diastolic dysfunction and remodeling . Combined physical activity and dietary nitrate intervention has not previously been evaluated in HCM.…”