H-01142-2002-R1 OXIDATIVE CAPACITY IN FAILING HEARTS

Although high energy phosphate (HEP) metabolism is abnormal in failing hearts (CHF), it is unclear whether oxidative capacity is impaired. This study used the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) to determine whether reserve oxidative capacity exists during the high workload produced by catecholamine infusion in hypertrophied and failing hearts. Left ventricular hypertrophy (LVH) was produced by ascending aortic banding in 21 swine; 9 animals developed CHF. Basal myocardial PCr/ATP measured with 31P-NMRS was decreased in both LVH and CHF hearts (corresponding to an increase in free [ADP]), while ATP was decreased in hearts with CHF. Infusion of dobutamine and dopamine (each 20 Pg/kg/min iv) caused an approximate doubling of MVO2 in all groups and decreased PCr/ATP in the normal and LVH groups. During continuing catecholamine infusion, DNP (2-8 mg/kg iv) caused further increases of MVO2 in normal and LVH hearts with no change in PCr/ATP. In contrast, DNP caused no increase in MVO2 in the failing hearts; the associated decrease of PCr/ATP suggests that DNP decreased the mitochondrial proton gradient, thereby causing ADP to increase to maintain adequate ATP synthesis. Key words: heart failure, LVH, mitochondria, high energy phosphates, nuclear magnetic resonance