Pyruvate Dehydrogenase Complex Stimulation with Dichloroacetate May Improve Septic Cardiac Dysfunction

Abstract

Background: Cardiomyopathy is a common complication of sepsis that contributes to increased morbidity and mortality. However, the molecular mechanisms underlying septic cardiomyopathy are poorly understood. Dichloroacetate (DCA) improves mitochondrial respiration and survival in a mouse model of sepsis by inhibiting pyruvate dehydrogenase kinase which inactivates pyruvate dehydrogenase (PDH) through phosphorylation of its subunits. In this study, we explore the role of DCA in septic cardiac dysfunction using a murine sepsis model.

Methods: Cecal ligation and puncture (CLP) was performed in mice to investigate molecular and echocardiographic response to sepsis. DCA was administered to test the effects of PDH activation on cardiac performance during early and late sepsis and myocardial metabolic substrate production. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry was used to reveal spatial alterations in metabolism.

Results: CLP significantly increased phosphorylation of the PDH E1α subunit (PDH inactivation), and DCA treatment reduced PDH E1α phosphorylation (PDH activation) to baseline without affecting total PDH E1α levels. Administration of DCA at the time of CLP improved cardiac preload and stroke volume without affecting cardiac contractility at 12 h after CLP. However, there was a significant increase in cardiac contractility at 30 h after DCA administration independent of cardiac loading conditions. This improved cardiac function after DCA administration was associated with a trend toward decreased production of metabolic intermediates such as ketogenic amino acids, succinate, and palmitoyl carnitine. Imaging mass spectrometry revealed an increase in itaconate expression upon CLP that was mitigated by DCA administration.

Conculsions: Our findings revealed that sepsis decreased PDH activity in cardiac tissue. Rebalancing PDH activity with DCA improved cardiac performance after CLP. While imaging mass spectrometry identified changes in itaconate concentration and enabled detection of tricarboxylic acid cycle metabolites, further investigation is necessary to determine whether DCA is an effective therapeutic agent for septic cardiomyopathy.

Keywords: Cardiomyopathy; infection; inflammation; metabolism; shock.