Heart Failure, Left Ventricular Remodeling, and Circulating Nitric Oxide Metabolites

Abstract

BackgroundStable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOM levels integrate the influence of NO‐synthase‐derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NOM. Furthermore, nitrate and nitrite, the most abundant NOM, can be reduced to NO via the nitrate‐nitrite‐NO pathway.Methods and ResultsWe compared serum NOM among subjects without heart failure (n=126), subjects with heart failure and preserved ejection fraction (HFpEF; n=43), and subjects with heart failure and reduced ejection fraction (HFrEF; n=32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NOM levels were measured after reduction to NO via reaction with vanadium (III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower unadjusted levels of NOM (8.0 μmol/L; 95% CI 6.2–10.4 μmol/L; ANOVA P=0.013) than subjects without HF (12.0 μmol/L; 95% CI 10.4–13.9 μmol/L) or those with HFrEF (13.5 μmol/L; 95% CI 9.7–18.9 μmol/L). There were no significant differences in NOM between subjects with HFrEF and subjects without HF. In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure, and glomerular filtration rate, HFpEF remained a predictor of lower NOM (β=−0.43; P=0.013). NOM did not correlate with LV mass, or LV diffuse fibrosis.Conclusions HFpEF, but not HFrEF, is associated with reduced plasma NOM, suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.

Poor Glycemic Control Is Associated With Increased Extracellular Volume Fraction in Diabetes

“…While determining myocardial regions of interest in MOLLI images, we avoided areas that were immediately adjacent to the blood-endocardium interface in order to avoid potential partial volume effects. The myocardium-blood partition coefficient (l) was computed as the slope of the blood 1/T1 change to the myocardial 1/T1 change, as computed with linear regression using all available measurements, as previously described (10). Hematocrit was measured from venous blood the day of the MRI scan.…”

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

“…Interestingly, two separate studies have recently demonstrated that patients with HFpEF exhibit a reduced circulating NO metabolite pool [104, 105] (composed largely of nitrate and to a lesser extent nitrite), which may limit the intrinsic activity of this pathway. As reviewed in detail elsewhere [100, 102], exogenous inorganic nitrate supplementation represents a promising therapeutic approach in HFpEF.…”

Non-invasive intraventricular pressure differences estimated with cardiac MRI in subjects without heart failure and with heart failure with reduced and preserved ejection fraction

“…HFpEF was defined as the presence of all of the following: (1) New York Heart Association (NYHA) Class II–IV symptoms consistent with HF; (2) LV ejection fraction >50%; (3) Mitral inflow early diastolic (E wave) to annular tissue velocity (e’) ratio >14,10 or at least two of the following: (a) an average mitral E/e’ ratio >8; (b) treatment with a loop diuretic for control of HF symptoms; (c) left atrial volume index >34 mL/m 2 of body surface area; (d) NT-pro B-type natriuretic peptide level >200 pg/mL; (e) LV mass index >149 g/m 2 in men and 122 g/m 2 in women (measured by cardiac MRI) 11. No-HF subjects had an LVEF >50%, no significant valvular disease, and no symptoms and signs consistent with HF 12…”