Metabolic adaptation and remodelling in myocardial cells following low oxygen stress, in order to attain an increase in metabolic efficiency, often involves reversion to a fetal metabolic phenotype in the adult heart.  One major metabolic pathway regulator is pyruvate dehydrogenase (PDH) which acts as the gateway between the glycolytic and Krebs cycle and is crucial to NADH delivery to mitochondrial respiratory protein Complex I.  Despite extensive studies of PDH activity in disease, PDH function and regulation in the failing human heart is not well studied. 

Methods  Left ventricular samples from human non-failing (n=20) and end-stage failing (n=20) adult human hearts were assayed for PDH enzyme activity and expression of  PDH component protein subunits, as well as its regulating kinase, pyruvate dehydrogenase kinase 4 (PDK4), using enzymatic, ELISA and western blotting methods.  To elucidate PDH regulation, human cultured ventricular cardiomyocytes (Promocell) were grown in myocyte growth medium (MGM) and induced to hypertrophy by a further 24 hr incubation with 0.1 µM angiotensin II (Ang II). Cells were then treated for 30 minutes prior to measurements with PDK inhibitors (0.2mM dichloroacetate (DCA), or 5 mM pyruvate), or PDK activators (0.6 mM NADH plus 50 µM Acetyl CoA).  Following treatments, cells were measured for PDK4 expression using the PDK4 ELISA assay on cell extracts (Abcam).

Results & Conclusions The increased glycolytic metabolism characteristic of failing human hearts involves greater PDH activity and augmented protein subunit expression (p<0.001 compared to non-failing hearts), as well as a decrease in PDK4 expression, thus allowing greater activation of PDH activity.

Acute treatment of cardiomyocytes with PDK activators/inhibitors modulates PDK4 expression.  Previous studies have demonstrated that PDK4 knock-out mice possess greater resistance to ischemia-reperfusion injury.  PDK regulation thus provides crucial intrinsic adaptive capacity to switch to more efficient recruitment and utilisation of energy.