Bioenergetic protection of failing atrial and ventricular myocardium by vasopeptidase inhibitor omapatrilat.
Deficient bioenergetic signaling contributes to myocardial dysfunction and electrical instability in both atrial and ventricular cardiac chambers. Yet, approaches capable to prevent metabolic distress are only partially established. Here, in a canine model of tachycardia-induced congestive heart failure, we compared atrial and ventricular bioenergetics and tested the efficacy of metabolic rescue with the vasopeptidase inhibitor omapatrilat. Despite intrinsic differences in energy metabolism, failing atria and ventricles demonstrated profound bioenergetic deficiency with reduced ATP and creatine phosphate levels and compromised adenylate kinase and creatine kinase catalysis. Depressed phosphotransfer enzyme activities correlated with reduced tissue ATP levels, whereas creatine phosphate inversely related with atrial and ventricular load. Chronic treatment with omapatrilat maintained myocardial ATP, the high-energy currency, and protected adenylate and creatine kinase phosphotransfer capacity. Omapatrilat-induced bioenergetic protection was associated with maintained atrial and ventricular structural integrity, albeit without full recovery of the creatine phosphate pool. Thus therapy with omapatrilat demonstrates the benefit in protecting phosphotransfer enzyme activities and in preventing impairment of atrial and ventricular bioenergetics in heart failure.
Cha
Yong-Mei
YM
Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Dzeja
Petras P
PP
Redfield
Margaret M
MM
Shen
Win K
WK
Terzic
Andre
A
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004285:Dogs; D004734:Energy Metabolism / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology*; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D011480:Protease Inhibitors / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D013841:Thiazepines / Q000008:administration & dosage*; D018754:Ventricular Dysfunction / Q000503:physiopathology / Q000517:prevention & control
D002316:Cardiotonic Agents; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat