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Prolonged QT interval and lipid alterations beyond β-oxidation in very long-chain acyl-CoA dehydrogenase null mouse
Roselle Gélinas1, Julie Thompson-Legault, Bertrand Bouchard
1Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada.
Insights
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency causes cardiac issues. VLCAD-deficient mice showed prolonged QTc intervals, indicating arrhythmia risk, despite normal ex vivo heart function.
Area of Science:
- Cardiology
- Metabolic Disorders
- Molecular Biology
Background:
- Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is linked to cardiomyopathy and arrhythmias.
- The exact causes of cardiac dysfunction in VLCAD deficiency are not fully understood.
Purpose of the Study:
- To investigate cardiac metabolic and functional changes in VLCAD-deficient mice.
- To elucidate the underlying factors contributing to cardiac abnormalities in VLCAD deficiency.
Main Methods:
- Ex vivo working heart perfusion with (13)C-labeled substrates to assess contractility and metabolism.
- In vivo telemetry for electrocardiogram monitoring.
- Targeted lipidomics and gene expression analysis in mice on various diets.
Main Results:
- VLCAD null mouse hearts maintained ex vivo function and energy production from palmitate.
- In vivo, VLCAD null mice exhibited prolonged QTc intervals, indicating arrhythmias.
- Accumulation of triglycerides and reduced docosahexaenoic acid in phospholipids were observed.
Conclusions:
- Cardiac dysfunction in VLCAD deficiency may stem from in vivo factors, not solely impaired ex vivo function.
- Prolonged QTc intervals in VLCAD deficiency highlight an increased risk of sudden cardiac death.
- Dietary fat composition influences lipid alterations in VLCAD deficiency.
Abstract:
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.
