Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency frequently present cardiomyopathy and heartbeat disorders. However, the underlying factors, which may be of cardiac or extra cardiac origins, remain to be elucidated. In this study, we tested for metabolic and functional alterations in the heart from 3- and 7-mo-old VLCAD null mice and their littermate counterparts, using validated experimental paradigms, namely, 1) ex vivo perfusion in working mode, with concomitant evaluation of myocardial contractility and metabolic fluxes using (13)C-labeled substrates under various conditions; as well as 2) in vivo targeted lipidomics, gene expression analysis as well as electrocardiogram monitoring by telemetry in mice fed various diets. Unexpectedly, when perfused ex vivo, working VLCAD null mouse hearts maintained values similar to those of the controls for functional parameters and for the contribution of exogenous palmitate to β-oxidation (energy production), even at high palmitate concentration (1 mM) and increased energy demand (with 1 μM epinephrine) or after fasting. However, in vivo, these hearts displayed a prolonged rate-corrected QT (QTc) interval under all conditions examined, as well as the following lipid alterations: 1) age- and condition-dependent accumulation of triglycerides, and 2) 20% lower docosahexaenoic acid (an omega-3 polyunsaturated fatty acid) in membrane phospholipids. The latter was independent of liver but affected by feeding a diet enriched in saturated fat (exacerbated) or fish oil (attenuated). Our finding of a longer QTc interval in VLCAD null mice appears to be most relevant given that such condition increases the risk of sudden cardiac death.

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Patients with fatty acid oxidation (FAO) defects develop a cardiomyopathy, yet the underlying mechanism is unclear. Using our established working mouse heart model and 13C‐methodology, we have compared the metabolic phenotype of hearts from VLCAD deficient (VLCAD−/−) mice, which is the most common FAO disorder in human, and their control VLCAD+/+ counterparts. The expression of selected metabolic genes was also assessed using qPCR. Unexpectedly, 3 month‐old fed or fasted, or 7 month‐old fed VLCAD−/− mouse hearts displayed values for exogenous long chain FAO that were similar to controls, suggesting a compensatory mechanism, although the partitioning of these FA between oxidation and triglycerides was altered in these hearts. Gene expression profiling data revealed little or no difference in the transcript levels for other long chain FAO enzymes (Acadl and Acad9) in 3 or 7 month‐old VLCAD−/− hearts, but that of hormone sensitive lipase (Hsl) was significantly decreased (p<0.001) at 7 months following fasting. Finally, VLCAD−/− hearts showed additional lipid alterations, namely a 30% (p<0.001) decline in docosahexaenoic acid levels in cardiac phospholipids at 3 and 7 months. Collectively, our data highlight unexpected age‐dependent metabolic alterations in VLCAD deficient mouse hearts, which may contribute to cardiomyopathy development. (Supported by NIH & CIHR)