Energy Metabolism in the Failing Right Ventricle: Limitations of Oxygen Delivery and the Creatine Kinase System.
Pulmonary arterial hypertension (PAH) results in hypertrophic remodeling of the right ventricle (RV) to overcome increased pulmonary pressure. This increases the O2 consumption of the myocardium, and without a concomitant increase in energy generation, a mismatch with demand may occur. Eventually, RV function can no longer be sustained, and RV failure occurs. Beta-adrenergic blockers (BB) are thought to improve survival in left heart failure, in part by reducing energy expenditure and hypertrophy, however they are not currently a therapy for PAH. The monocrotaline (MCT) rat model of PAH was used to investigate the consequence of RV failure on myocardial oxygenation and mitochondrial function. A second group of MCT rats was treated daily with the beta-1 blocker metoprolol (MCT + BB). Histology confirmed reduced capillary density and increased capillary supply area without indications of capillary rarefaction in MCT rats. A computer model of O2 flux was applied to the experimentally recorded capillary locations and predicted a reduction in mean tissue PO2 in MCT rats. The fraction of hypoxic tissue (defined as PO2 < 0.5 mmHg) was reduced following beta-1 blocker (BB) treatment. The functionality of the creatine kinase (CK) energy shuttle was measured in permeabilized RV myocytes by sequential ADP titrations in the presence and absence of creatine. Creatine significantly decreased the KmADP in cells from saline-injected control (CON) rats, but not MCT rats. The difference in KmADP with or without creatine was not different in MCT + BB cells compared to CON or MCT cells. Improved myocardial energetics could contribute to improved survival of PAH with chronic BB treatment.
['Fowler|Ewan D|ED|0000-0001-5580-2156', 'Hauton|David|D|', 'Boyle|John|J|', 'Egginton|Stuart|S|0000-0002-3084-9692', 'Steele|Derek S|DS|', 'White|Ed|E|']
D000319:Adrenergic beta-Antagonists D000818:Animals D003402:Creatine Kinase D004195:Disease Models, Animal D004734:Energy Metabolism D004789:Enzyme Activation D006333:Heart Failure D006976:Hypertension, Pulmonary D000860:Hypoxia D008297:Male D008928:Mitochondria D016686:Monocrotaline D032342:Muscle Cells D010100:Oxygen D051381:Rats D018497:Ventricular Dysfunction, Right
creatine kinase pulmonary artery hypertension heart failure monocrotaline beta blocker myocardial hypoxia right ventricle failure