Energy metabolism in the failing right ventricle: Limitations of oxygen delivery and the creatine kinase system

Ewan D. Fowler*, David Hauton, John Boyle, Stuart Egginton, Derek S. Steele, Ed White

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

2 Citations (Scopus)
145 Downloads (Pure)

Abstract

Pulmonary arterial hypertension (PAH) results in hypertrophic remodeling of the right ventricle (RV) to overcome increased pulmonary pressure. This increases the O 2 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 O 2 flux was applied to the experimentally recorded capillary locations and predicted a reduction in mean tissue P O2 in MCT rats. The fraction of hypoxic tissue (defined as P O2 < 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 K mADP in cells from saline-injected control (CON) rats, but not MCT rats. The difference in K mADP 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.

Original languageEnglish
Article number1805
JournalInternational Journal of Molecular Sciences
Volume20
Issue number8
DOIs
Publication statusPublished - 12 Apr 2019

Keywords

  • Beta blocker
  • Creatine kinase
  • Heart failure
  • Monocrotaline
  • Myocardial hypoxia
  • Pulmonary artery hypertension
  • Right ventricle failure

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