Assessment of Metabolic Phenotypes in Patients with Non-ischemic Dilated Cardiomyopathy Undergoing Cardiac Resynchronization Therapy

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

In vivo effect of the D-(-) isomer or natural form of 3-hydroxybutyrate on initial release of lactate dehydrogenase from the acutely ischaemic myocardium.

D-(-)-3-hydroxybutyrate, the isomer found in the circulation and in the urine of diabetic patients, generally is believed to be the physiologically important form of 3-hydroxybutyrate [10]. Little is known concerning the effects of an elevated plasma level of the D-(-) isomer of 3-hydroxybutyrate upon the acutely ischaemic heart. Using anaesthetized intact dogs with a balloon catheter inserted into the proximal part of the left anterior descending coronary artery (LAD), we have recently demonstrated that a 1 mM ketonaemia induced with the arginine salt of D-(-)-3-hydroxybutyric acid reduces the uptake of non-esterified fatty acids (NEFA) in the myocardial area distal to the inflated balloon [4]. The question arises as to whether the concomitant increase in ketone uptake in this area could be detrimental to the acutely ischaemic myocardium. Indeed, a previous study on isolated coronary ligated hearts from normal rats has shown that the rate of release of lactate dehydrogenase (LDH) during the first 90 min of ischaemia can be enhanced by replacing glucose (11 mM) in the perfusion fluid with either albumin-bound palmitate (0.9 mM) or sodium DL-3-hydroxybutyrate (10 mM) as the sole energy substrate [11]. This would suggest that the ketone might be as deleterious as its metabolic precursors for membrane integrity in the acutely ischaemic myocardium. In the present report, we examine the effect of arginine D-(-)-3-hydroxybutyrate on LDH release from ischaemic myocardium in our in vivo preparation. The dogs were treated with lidocaine in order to minimize the frequency and, hence, the adverse metabolic effects of ectopic beats.(ABSTRACT TRUNCATED AT 250 WORDS