Proteomics-informed computational modelling reveals impaired fatty acid metabolism and energetic deficiency in peripartum cardiomyopathy

Background Peripartum cardiomyopathy (PPCM) and dilated cardiomyopathy (DCM) exhibit overlapping clinical features and may share a common genetic architecture. While mitochondrial dysfunction and energy deficiency represent hallmark characteristics of DCM, the role of cardiac metabolic impairment in PPCM remains unknown. Purpose To compare cardiac bioenergetic phenotypes in PPCM and DCM through proteomics-based computational reconstruction of myocardial metabolism. Methods Left ventricular biopsies from patients with PPCM (n=6), DCM (n=6), and controls(n=18) underwent high-resolution mass spectrometry for quantitative proteomics. PPCM and DCM samples for obtained during heart transplantation for end-stage heart failure (LVEF <20%); unused donor hearts from individuals without cardiovascular comorbidities (LVEF 56±2%) served as controls. Patient-specific myocardial protein abundance profiles were integrated into a kinetic model capturing 296 biochemical reactions across all main energy delivering pathways. Personalised simulations were conducted to estimate maximal ATP production capacity, substrate flux distribution, and myocardial oxygen consumption under varying myocardial workload and substrate availability. Results There was a pronounced reduction in maximal ATP production capacity in PPCM compared with both DCM and control groups (P<0.001), while respiratory efficiency (ATP yield per mole of O2) remained preserved. Substrate flux analysis revealed a greater contribution of lactate to energy production at peak myocardial workload in PPCM compared with DCM and controls (16.5±2.2% vs. 11.3±5.2 vs. 10.3±7.5, respectively). Maximal myocardial fatty acid uptake capacity was reduced in PPCM (Figure 1A). Protein expression analysis showed a greater suppression of several key enzymes involved in fatty acid metabolism among patients with PPCM compared to DCM, providing a mechanistic link (Figure 1B). Conclusions Proteomics-informed metabolic modelling found severe and disease-specific energetic failure in PPCM, which was more pronounced than seen in DCM. These findings provide the first systems-level evidence that impaired fatty acid metabolism and energy deficiency may underpin PPCM, highlighting novel targets for metabolic intervention in maternal heart failure.