DCA Drug Reactivates Heart Energy Metabolism to Counter Sepsis-Induced Cardiac Failure

Sepsis kills over 270,000 Americans annually and frequently triggers cardiomyopathy—impaired ventricular filling, reduced contractility, and diminished cardiac output—that dramatically worsens prognosis. Despite this, the molecular underpinnings of septic heart failure remain poorly characterized. This study investigated whether restoring mitochondrial glucose oxidation via PDH reactivation could improve cardiac performance during sepsis.

Researchers used the well-validated cecal ligation and puncture (CLP) murine model of polymicrobial sepsis. Adult male C57BL/6 mice underwent CLP or sham surgery and received either dichloroacetate (DCA, 25 mg/kg IP) or vehicle. Cardiac function was assessed by high-resolution micro-echocardiography including speckle-tracking strain analysis at 12 and 30 hours. PDH activity was measured via western blot of the phospho-Ser300 E1α subunit. Cardiac metabolites were quantified by LC-MS/MS, and spatial metabolomics was performed using MALDI FT-ICR imaging mass spectrometry.

CLP significantly increased phosphorylation of the PDH E1α subunit, indicating PDH inactivation in cardiac tissue. DCA administration reduced this phosphorylation back to baseline without altering total PDH protein levels, confirming enzyme reactivation. Echocardiographically, CLP mice exhibited reduced stroke volume by 12 hours—driven by decreased left ventricular end-diastolic volume—and further developed significant reductions in ejection fraction by 30 hours. DCA-treated CLP mice maintained stroke volume and preserved LVEDV, LVESV, and LVEF comparable to sham controls. Global longitudinal strain and longitudinal strain rate, impaired in all CLP mice at 12 hours, significantly recovered in DCA-treated animals by 30 hours, suggesting improved intrinsic myocardial contractility independent of loading conditions.

Metabolomics revealed that CLP trended toward elevating ketogenic amino acids (valine, leucine, isoleucine), succinate, and palmitoyl carnitine in cardiac tissue at 30 hours—markers of impaired TCA cycle flux and fatty acid oxidation. DCA administration trended toward normalization of these intermediates. MALDI imaging mass spectrometry spatially resolved TCA cycle metabolites including fumarate, malate, citrate/isocitrate, cis-aconitate, and succinate within cardiac tissue sections. Notably, itaconate—an immunometabolic mediator derived from aconitate and associated with macrophage inflammation—was significantly elevated in CLP hearts and substantially reduced by DCA treatment, suggesting a link between myocardial metabolic reprogramming and inflammatory signaling.

These findings establish for the first time that PDH suppression contributes mechanistically to septic cardiomyopathy, and that pharmacologic PDH reactivation with DCA improves both cardiac loading parameters and contractility in this preclinical model. The itaconate finding is particularly intriguing given its known role in innate immune metabolic switching. While the results are promising, validation in larger animal models, dose-optimization studies, and investigation of DCA's safety profile in this context are needed before clinical translation.