title: Heart Failure, Left Ventricular Remodeling, and Circulating Nitric Oxide Metabolites.
abstract: Stable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOMlevels 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.
  
  
  
  We compared serum NOMamong 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 NOMlevels 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 NOMbetween 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). NOMdid not correlate with LV mass, or LV diffuse fibrosis.
  
  
  
  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.
authors.affiliation: Corporal Michael J. Crescenz VAMC, Philadelphia, PA University of Pennsylvania School of Medicine, Philadelphia, PA Hospital of the University of Pennsylvania, Philadelphia, PA Julio.chirinos@uphs.upenn.edu.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Chirinos
authors.affiliation: Corporal Michael J. Crescenz VAMC, Philadelphia, PA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Akers
authors.affiliation: Rowan University School of Osteopathic Medicine, Stratford, NJ.
authors.forename: Lien
authors.initials: L
authors.lastname: Trieu
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, PA Children's Hospital of Philadelphia Research Institute, Philadelphia, PA.
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, PA Children's Hospital of Philadelphia Research Institute, Philadelphia, PA.
authors.forename: Paschalis-Thomas
authors.initials: PT
authors.lastname: Doulias
authors.affiliation: Corporal Michael J. Crescenz VAMC, Philadelphia, PA Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Ali
authors.initials: A
authors.lastname: Tariq
authors.affiliation: Corporal Michael J. Crescenz VAMC, Philadelphia, PA Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Izzah
authors.initials: I
authors.lastname: Vasim
authors.affiliation: Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Maheswara R
authors.initials: MR
authors.lastname: Koppula
authors.affiliation: Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Amer Ahmed
authors.initials: AA
authors.lastname: Syed
authors.affiliation: Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Haideliza
authors.initials: H
authors.lastname: Soto-Calderon
authors.affiliation: Corporal Michael J. Crescenz VAMC, Philadelphia, PA University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: Corporal Michael J. Crescenz VAMC, Philadelphia, PA University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.affiliation: Corporal Michael J. Crescenz VAMC, Philadelphia, PA University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: Corporal Michael J. Crescenz VAMC, Philadelphia, PA University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Payman
authors.initials: P
authors.lastname: Zamani
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005355:Fibrosis; D006321:Heart / Q000000981:diagnostic imaging; D006333:Heart Failure / Q000097:blood* / Q000503:physiopathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000097:blood* / Q000000981:diagnostic imaging / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000097:blood* / Q000378:metabolism; D009929:Organ Size; D011446:Prospective Studies; D013318:Stroke Volume; D014481:United States; D014493:United States Department of Veterans Affairs; D020257:Ventricular Remodeling
chemical_list: D009569:Nitric Oxide
keywords: diastolic heart failure; heart failure; hypertrophy/remodeling; myocardial fibrosis; myocardial structure