Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study

Abstract

Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 6 0.7 vs. 8.4 6 0.5 mmol/L), lower PDH flux (0.005 6 0.001 vs. 0.017 6 0.002 s -1 ), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E9] 12.2 6 0.8 vs. 20 6 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 6 0.002 s -1 ), reversed diastolic dysfunction (E/E9 14 6 1), and normalized blood glucose levels (7.5 6 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy.It is now firmly established that type 2 diabetes contributes to an increased risk for the development of heart failure (1). Although some of this risk can be attributed to increased coronary artery disease and hypertension, it is becoming clear that patients with type 2 diabetes are also at risk for the development of "diabetic cardiomyopathy" (2-5), which manifests across a spectrum from subclinical left ventricular (LV) diastolic dysfunction (i.e., transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E9]) to overt systolic failure (6). As the incidence of type 2 diabetes is rapidly increasing, understanding the pathophysiology behind diabetic cardiomyopathy and developing new treatment strategies is of increasing clinical importance.Cardiac metabolism and altered substrate use are now emerging as candidate mechanisms underpinning diabetic cardiomyopathy and, as such, are targets for novel treatments (7,8). The cardiac metabolic changes in type 2 diabetes are linked to an increase in circulating fatty acid levels that results from insulin insensitivity and a failure to suppress adipose tissue hormone-sensitive lipase (9). This increase in fatty acid availability, and consequently increased cardiac usage, is thought to result in a loss of efficiency between substrate use and ATP production in the diabetic heart (10). Chan...

Assessing the influence of isoflurane anesthesia on cardiac metabolism using hyperpolarized [1‐13C]pyruvate

“…Isoflurane is the most commonly used anesthetic nowadays . In a typical setting, the depth of anesthesia is adjusted on the basis of the heart rate (HR) and rate of breathing . Thus, the actual amount of narcotic agent consumed by the animal remains difficult to assess.…”

Hyperpolarized 13 C Metabolic MRI of the Human Heart

“…In addition to its scientific value as a powerful tool for investigating normal cardiac metabolism, 11 developments in preclinical models support the potential clinical value of 13 C MRI in evaluating pathologies of the human heart, including myocardial viability after acute ischemia/reperfusion injury, 12 early- and late-onset metabolic changes in the failing heart, 13 and diabetic cardiomyopathy. 14 …”

Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance

“…) and diastolic function in the diabetic heart (Le Page et al . ), where PDC flux is impaired. In our study, chronic treatment of the hypoxic heart with DCA resulted in evidence of increased flux through the PDC reaction, with a doubling of cardiac acetylcarnitine content.…”

“…Furthermore, the impact of chronic PDC activation on cardiac adaptation to hypoxia is also unresolved. However, the impaired PDC activity seen in the diabetic heart (Seymour & Chatham, 1997) can be normalised with chronic DCA treatment (Le Page et al 2015), and improves diastolic function. Therefore, assuming cardiac PDC activity is suppressed with chronic hypoxia, prolonged stimulation of the PDC may be beneficial.…”