Dyssynchronous heart failure: mitochondrial distribution and functions mirror regional workload and energy demand in a large-animal model of ventricular desynchronization

Aims In dyssynchronous heart failure (DHF), left bundle branch block (LBBB) causes inhomogeneous left ventricular (LV) workload and systolic dysfunction. We aimed to investigate underlying metabolic remodelling in an ovine model. Methods and results Eleven sheep with dual-chamber-pacemakers for LBBB-like activation (DHF) were studied at baseline and after eight weeks. Six untreated sheep served as controls (CTRL). Regional workload was evaluated using invasive hemodynamics and echocardiography. 18F-fluorodeoxyglucose-tracer positron-emission-tomography/computed tomography visualized regional glucose-uptake. Magnetic resonance imaging assessed fibrosis (late gadolinium enhancement, LGE). Septal and lateral wall tissue was analysed with histology, confocal microscopy, ultra-high-performance liquid chromatography-high resolution mass-spectrometry (UHPLC-HRMS). Dyssynchrony induced low septal and high lateral asymmetry in workload and glucose-uptake. After 8 weeks, DHF animals exhibited LV dilation and LVEF decline (31.1 ± 5.1% vs. 59.4 ± 3.5% at baseline, P < .05). Septal thinning and lateral hypertrophy rebalanced workload and glucose-uptake. No fibrosis was seen on LGE or histology. DHF-animals showed enrichment of mitochondria at the intercalated discs (EMID-sign)—highest in the lateral wall (DHF septal 7.0 ± 4.8% vs. lateral 48.4 ± 12.3%, P < .05). Mitochondrial redox balance in DHF shifted towards a more oxidized state without evidence of oxidative stress. Metabolomics revealed no differences between septal and lateral walls but severe energy depletion of tricarboxylic acid cycle substrates and phosphocreatine in DHF (fold change DHF/CTRL 0.01, P < .01). Conclusion Experimental DHF is characterized by non-fibrotic, dilated LV without signs of oxidative stress. Workload increase in the lateral wall leads to hypertrophy and EMID, homogenizing metabolic profiles between wall segments. However, the ventricle enters energy starvation and systolic dysfunction.