Myocardial energy starvation and ketone metabolism in patients with type 2 diabetes

Patients with type 2 diabetes(T2D) are ‘cardiac energy-deficient’ and this deficiency contributes to their excess heart failure(HF) risk.

The key mechanisms for cardiac energy deficiency are reduced myocardial blood flow, loss of metabolic flexibility over the choice of energy fuels and mitochondrial dysfunction.

The contribution of these changes to the development of HF has not been systematically studied.Recent studies have highlighted the potential role of ketone bodies as a significant fuel source, and suggested an association between mild ketosis and improved clinical outcome in T2D. Two work packages will be performed.

Work-package1 aims to: - Elucidate the mechanisms of the energy-starved state of the heart in diabetes; - Determine how alterations of cardiac energy metabolism differ between prediabetes, T2D, and concomitant T2D and HF; - Determine if ketones induce a differential response in mitochondrial respiration and whether this differential response varies along the continuum of diabetic heart disease.

Data will be acquired from patients undergoing aortic valve surgery for comprehensive assessments including: cardiovascular magnetic resonance imaging and spectroscopy; coronary sinus sampling studies; high resolution respirometry and liquid chromatography-triple quadrupole-mass spectrometry metabolomics from heart samples.

Work-package 2 will explore the impact of ketone infusion on cardiac energy generation and contractile function in T2D patients.