Gene Expression and Ultrastructural Evidence for Metabolic Derangement in the Primary Mitral Regurgitation Heart

Abstract

Chronic neurohormonal activation and hemodynamic load cause derangement in myocardial substrate utilization. We test the hypothesis that the primary mitral regurgitation heart (PMR) heart shows altered metabolic gene profile and cardiac ultrastructure consistent with decreased fatty acid and glucose metabolism despite LVEF > 60%. Metabolic gene expression in right atrial (RA), left atrial (LA), and left ventricular (LV) biopsies from donor hearts (n = 10) and from patients with moderate to severe PMR (n = 11) at surgery showed decreased mRNA glucose transporter type 4 (GLUT-4), GLUT-1 and insulin receptor substrate 2 and increased mRNA hexokinase 2, O-linked N-acetylglucosamine transferase and O-GlcNAcase, rate-limiting steps in the hexosamine biosynthetic pathway. Pericardial fluid levels of Neuropeptide Y were 4-fold higher than simultaneous plasma indicative of increased sympathetic drive. Quantitative TEM shows glycogen accumulation, glycophagy, increased lipid droplets, and mitochondrial cristae lysis. These findings are associated with increased mRNA for glycogen synthase kinase 3β, decreased carnitine palmitoyl transferase 2, and fatty acid synthase in PMR vs. normals. Cardiac magnetic resonance/positron emission tomography for 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake showed decreased LV [18F]FDG uptake and increased plasma HbA1c, free fatty acids, mtDAMPs in a separate cohort of stable moderate PMR patients with LVEF > 60% (n = 8) vs. normal controls (n = 8). The PMR heart has a global ultrastructural and metabolic gene expression pattern of decreased glucose uptake along with increased glycogen and lipid droplets. Further studies must determine whether this presentation is an adaptation or maladaptation in the PMR heart in the clinical evaluation of PMR.