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-(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 ± 0.7 vs. 8.4 ± 0.5 mmol/L), lower PDH flux (0.005 ± 0.001 vs. 0.017 ± 0.002 s(-1)), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E'] 12.2 ± 0.8 vs. 20 ± 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 ± 0.002 s(-1)), reversed diastolic dysfunction (E/E' 14 ± 1), and normalized blood glucose levels (7.5 ± 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.

Figure 1

Biochemical characterization of the type II diabetic model - (a) fasting blood glucose concentration (mM), (b) fasting plasma insulin concentration (pmol) and (c) epididymal fat pad weight normalised to body weight. *p≤0.05

Figure 2

Protein expression of the three cardiac isoforms of pyruvate dehydrogenase kinase (PDK), along with uncoupling protein 3 (UCP3) and medium chain acyl-CoA dehydrogenase (MCAD) – (a) cardiac PDK4 expression, (b) cardiac PDK1 expression, (c) cardiac PDK2 expression, (d) cardiac UCP3 expression and (e) cardiac MCAD expression. *p≤0.05

Figure 3

An example in vivo spectral time-course taken from a control Wistar rat heart showing the injection and subsequent decay of the hyperpolarized [1-¹³C]pyruvate due to the recovery back to thermal equilibrium and exchange with [1-¹³C]lactate, [1-¹³C]alanine and ¹³C bicarbonate.

Figure 4

Assessment of in vivo cardiac carbohydrate metabolism using hyperpolarized [1-¹³C]pyruvate magnetic resonance spectroscopy – (a) cardiac PDH flux, (b) cardiac ¹³C-label transfer to lactate and (c) cardiac ¹³C-label transfer to alanine. *p≤0.05.

Figure 5

Assessment of cardiac systolic and diastolic function using echocardiography – (a) left ventricular ejection fraction, (b) maximal early diastolic peak velocity : late peak velocity (E/A) and (c) pre-load independent E/E’. *p≤0.05.