Abstract 9981: Systolic Heart Failure is Associated with Decreased Mitochondrial Respiration in Biopsies From Human Left Ventricle
Heart failure (HF) with left ventricular systolic dysfunction (LVSD) is associated with a shift in substrate utilization (metabolic remodeling) and reduced ATP and phosphocreatine (PCr) content. We hypothesized that these changes could be caused by reduced mitochondrial oxidative phosphorylation (OXPHOS) and reduced mitochondrial creatine kinase (miCK) capacity. Myocardial biopsies were obtained from left ventricle of patients undergoing cardiac valve- and left ventricular assist device (LVAD), surgery. The patients were stratified in two groups according to left ventricular ejection fraction (LVEF): Controls (LVEF= 55±2%, n=14) and LVSD (LVEF= 17±3%, n=12). Mitochondrial respiration was measured in permeabilized muscle fibers during successive additions of Krebs cycle substrates. In a separate experiment we assessed the oxidation of octanoyl-L-carnitine, a medium chain fatty-acid (MCFA). The kinetics of miCK was determined from APD titrations in the presence or absence of creatine, revealing the in situ enzyme capacity (Vmax) and sensitivity (C50). Octanoyl-L-carnitine elicited 41 % lower respiration in LVSD than in controls (10±2 vs. 17±2 ρmol sec-1 mg-1, respectively, figure 1, P<0.05), whereas the sensitivity (C50) for octanoyl-L-carnitine was the same in both groups. Maximal respiratory capacity with dual electron input through complex I and II (malate, glutamate, succinate) was lower in the LVSD group compared with controls (76±8 vs. 104 ±7 pmol sec-1 mg-1, respectively, P<0.05). Addition of creatine increased ADP sensitivity significantly in both groups (62 % vs 42 % reduction C50 respectively, P<0.05), but revealed no significant differences in Vmax. The novel finding of this study is that human LVSD is associated with a markedly diminished OXPHOS capacity, particularly in the oxidation of MCFA. This offers a candidate mechanism for decreased reliance on fatty-acid utilization in HF and for decreased myocardial ATP and PCr content.
- © 2011 by American Heart Association, Inc.