Increasing carbohydrate oxidation improves contractile reserves and prevents hypertrophy in porcine right heart failure
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- Aarhus University Hospital Skejby
- Research Unit for Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Comparative Medicine Lab, Aarhus University Hospital, Skejby, Denmark.
- Nuffield Department of Clinical Medicine
- Institute of Clinical Sciences
- Institute of Microbiology and Infection, College of Medical and Dental Science, University of Birmingham, Birmingham, UK.
In heart failure, myocardial overload causes vast metabolic changes that impair cardiac energy production and contribute to deterioration of contractile function. However, metabolic therapy is not used in heart failure care. We aimed to investigate the interplay between cardiac function and myocardial carbohydrate metabolism in a large animal heart failure model. Using magnetic resonance spectroscopy with hyperpolarized pyruvate and magnetic resonance imaging at rest and during pharmacological stress, we investigated the in-vivo cardiac pyruvate metabolism and contractility in a porcine model of chronic pulmonary insufficiency causing right ventricular volume overload. To assess if increasing the carbohydrate metabolic reserve improves the contractile reserve, a group of animals were fed dichloroacetate, an activator of pyruvate oxidation. Volume overload caused heart failure with decreased pyruvate dehydrogenase flux and poor ejection fraction reserve. The animals treated with dichloroacetate had a larger contractile response to dobutamine stress than non-treated animals. Further, dichloroacetate prevented myocardial hypertrophy. The in-vivo metabolic data were validated by mitochondrial respirometry, enzyme activity assays and gene expression analyses. Our results show that pyruvate dehydrogenase kinase inhibition improves the contractile reserve and decreases hypertrophy by augmenting carbohydrate metabolism in porcine heart failure. The approach is promising for metabolic heart failure therapy.
|Publication status||Published - 18 May 2020|