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.
Highlights
The diabetic heart has a decreased ability to metabolize glucose
Meldonium improves in vivo glucose utilization in the diabetic heart, contributing to improved cardiac recovery post-ischemia
This study aimed to investigate the effects of Meldonium on in vivo cardiac metabolism and function in control and diabetic rodent hearts, using hyperpolarized magnetic resonance spectroscopy (MRS) and CINE magnetic resonance imaging (MRI), respectively
Summary
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. 60–70% of ATP production comes from fatty acids (FAs), and the remaining 30–40% comes from glucose and lactate In diseases such as diabetes, this balance is shifted even further in favour of fatty acid oxidation[8,9]. Drugs that target this metabolic imbalance in the diabetic heart are of great therapeutic interest One such drug is the anti-ischemic agent Meldonium (trimethylhydrazinium propionate), which is sold under the brand name Mildronate. The anti-ischemic actions of Meldonium are thought to originate from a switch in the balance of fuel utilization in the heart towards more oxygenefficient glucose metabolism. These effects arise from the impact of Meldonium on the synthesis and transport of the amino acid derivative, L-carnitine
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