Hyperpolarized magnetic resonance shows that the anti‐ischemic drug meldonium leads to increased flux through pyruvate dehydrogenase in vivo resulting in improved post‐ischemic function in the diabetic heart. (17th January 2021)

• Record Type: Journal Article
• Authors: Savic, Dragana; Ball, Vicky; Holzner, Lorenz; Hauton, David; Timm, Kerstin N.; Curtis, M. Kate; Heather, Lisa C.; Tyler, Damian J.
• Is Part Of: NMR in biomedicine. Volume 34:Number 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-01-17
• Subjects: cardiac function -- diabetes -- hyperpolarized MRI -- langendorff perfusion -- meldonium -- metabolism -- pyruvate dehydrogenase flux -- streptozotocin; Nuclear magnetic resonance -- Periodicals; Magnetic Resonance Spectroscopy -- Periodicals; 574
• DOI: 10.1002/nbm.4471
• Languages: English
• ISSNs: 0952-3480

Abstract

Abstract : The diabetic heart has a decreased ability to metabolize glucose. The anti‐ischemic drug meldonium may provide a route to counteract this by reducing l ‐carnitine levels, resulting in improved cardiac glucose utilization. Therefore, the aim of this study was to use the novel technique of hyperpolarized magnetic resonance to investigate the in vivo effects of treatment with meldonium on cardiac metabolism and function in control and diabetic rats. Thirty‐six male Wistar rats were injected either with vehicle, or with streptozotocin (55 mg/kg) to induce a model of type 1 diabetes. Daily treatment with either saline or meldonium (100 mg/kg/day) was undertaken for three weeks. in vivo cardiac function and metabolism were assessed with CINE MRI and hyperpolarized magnetic resonance respectively. Isolated perfused hearts were challenged with low‐flow ischemia/reperfusion to assess the impact of meldonium on post‐ischemic recovery. Meldonium had no significant effect on blood glucose concentrations or on baseline cardiac function. However, hyperpolarized magnetic resonance revealed that meldonium treatment elevated pyruvate dehydrogenase flux by 3.1‐fold and 1.2‐fold in diabetic and control animals, respectively, suggesting an increase in cardiac glucose oxidation. Hyperpolarized magnetic resonance further demonstrated that meldonium reduced the normalized acetylcarnitine signal by 2.1‐fold in both diabetic and control animals. The increase in pyruvate dehydrogenase flux in vivo was accompanied by an improvement in post‐ischemic function ex vivo, as meldonium elevated the rate pressure product by 1.3‐fold and 1.5‐fold in the control and diabetic animals, respectively. In conclusion, meldonium improves in vivo pyruvate dehydrogenase flux in the diabetic heart, contributing to improved cardiac recovery after ischemia. Abstract : Glucose metabolism is decreased in the diabetic heart. Meldonium may provide a route to counteract this by reducing L‐carnitine levels and decreasing the uptake of fatty acids into the mitochondria, resulting in improved cardiac glucose utilization. Hyperpolarized magnetic resonance has revealed that meldonium treatment elevated pyruvate dehydrogenase flux in the diabetic heart, indicating an increase in cardiac glucose oxidation. In‐vivo glucose oxidation elevation was accompanied by an improvement in ex‐vivo post‐ischemic function, where meldonium elevated rate pressure following global ischemia.