title: Assessment of metabolic phenotypes in patients with non-ischemic dilated cardiomyopathy undergoing cardiac resynchronization therapy.
abstract: Studies of myocardial metabolism have reported that contractile performance at a given myocardial oxygen consumption (MVO2) can be lower when the heart is oxidizing fatty acids rather than glucose or lactate. The objective of this study is to assess the prognostic value of myocardial metabolic phenotypes in identifying non-responders among non-ischemic dilated cardiomyopathy (NIDCM) patients undergoing cardiac resynchronization therapy (CRT). Arterial and coronary sinus plasma concentrations of oxygen, glucose, lactate, pyruvate, free fatty acids (FFA), and 22 amino acids were obtained from 19 male and 2 female patients (mean age 56 ± 16) with NIDCM undergoing CRT. Metabolite fluxes/MVO2 and extraction fractions were calculated. Flux balance analysis (FBA) was performed with MetaFluxNet 1.8 on a metabolic network of the cardiac mitochondria (189 reactions, 230 metabolites) reconstructed from mitochondrial proteomic data (615 proteins) from human heart tissue. Non-responders based on left ventricular ejection fraction (LVEF) demonstrated a greater mean FFA extraction fraction (35% ± 17%) than responders [18 ± 10%, p = 0.0098, area under the estimated ROC curve (AUC) was 0.8238, S.E. 0.1115]. Calculated adenosine triphosphate (ATP)/MVO2 using FBA correlated with change in New York Heart Association (NYHA) class (rho = 0.63, p = 0.0298; AUC = 0.8381, S.E. 0.1316). Non-responders based on both LVEF and NYHA demonstrated a greater mean FFA uptake/MVO2 (0.115 ± 0.112) than responders (0.034 ± 0.030, p = 0.0171; AUC = 0.8593, S.E. 0.0965). Myocardial FFA flux and calculated maximal ATP synthesis flux using FBA may be helpful as biomarkers in identifying non-responders among NIDCM patients undergoing CRT.
authors.affiliation: Division of Nuclear Medicine, University of California-San Diego, UCSD Medical Center-Hillcrest, 200 West Arbor Drive, San Diego, CA 92103-8758, USA. sobrzut@ucsd.edu
authors.forename: Sebastian
authors.initials: S
authors.lastname: Obrzut
authors.forename: Jay
authors.initials: J
authors.lastname: Tiongson
authors.forename: Neema
authors.initials: N
authors.lastname: Jamshidi
authors.forename: Huy Minh
authors.initials: HM
authors.lastname: Phan
authors.forename: Carl
authors.initials: C
authors.lastname: Hoh
authors.forename: Ulrika
authors.initials: U
authors.lastname: Birgersdotter-Green
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D058406:Cardiac Resynchronization Therapy; D002311:Cardiomyopathy, Dilated / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption; D010641:Phenotype; D011446:Prospective Studies; D040901:Proteomics; D019289:Pyruvic Acid / Q000097:blood; D013318:Stroke Volume; D013997:Time Factors; D017211:Treatment Failure; D016277:Ventricular Function, Left
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D010100:Oxygen