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Optical Mapping Approaches on Muscleblind-Like Compound Knockout Mice for Understanding Mechanistic Insights Into
Chung-Chuan Chou1,2, Po-Cheng Chang1,2, Yi-Chia Wei3
1Department of Cardiology, Chang Gung Memorial Hospital, Linkou, Taiwan.
Background:
Cardiac arrhythmias are common causes of death in patients with myotonic dystrophy (dystrophia myotonica [DM]). Evidence shows that atrial tachyarrhythmia is an independent risk factor for sudden death; however, the relationship is unclear.
Methods And Results:
Control wild-type (Mbnl1 ) and DM mutant (Mbnl1 ) mice were generated by crossing double heterozygous knockout (Mbnl1 ) mice. In vivo electrophysiological study and optical mapping technique were performed to investigate mechanisms of ventricular tachyarrhythmias. Transmission electron microscopy scanning was performed for myocardium ultrastructural analysis. DM mutant mice were more vulnerable to anesthesia medications and program electrical pacing: 2 of 12 mice had sudden apnea and cardiac arrest during premedication of general anesthesia; 9 of the remaining 10 had atrial tachycardia and/or atrioventricular block, but none of the wild-type mice had spontaneous arrhythmias; and 9 of 10 mice had pacing-induced ventricular tachyarrhythmias, but only 1 of 14 of the wild-type mice. Optical mapping studies revealed prolonged action potential duration, slower conduction velocity, and steeper conduction velocity restitution curves in the DM mutant mice than in the wild-type group. Spatially discordant alternans was more easily inducible in DM mutant than wild-type mice. Transmission electron microscopy showed disarranged myofibrils with enlarged vacuole-occupying mitochondria in the DM mutant group.
Conclusions:
This DM mutant mouse model presented with clinical myofibril ultrastructural abnormality and cardiac arrhythmias, including atrial tachyarrhythmias, atrioventricular block, and ventricular tachyarrhythmias. Optical mapping studies revealed prolonged action potential duration and slow conduction velocity in the DM mice, leading to vulnerability of spatially discordant alternans and ventricular arrhythmia induction to pacing.
Insights
Mice with myotonic dystrophy (DM) exhibit cardiac arrhythmias and myofibril abnormalities. This model reveals prolonged action potential duration and slow conduction, increasing vulnerability to ventricular arrhythmias.
Area of Science:
- Cardiovascular Research
- Genetics
- Molecular Biology
Background:
- Cardiac arrhythmias are a significant cause of mortality in myotonic dystrophy (DM) patients.
- Atrial tachyarrhythmia is a known risk factor for sudden death in DM, but underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the mechanisms of cardiac arrhythmias in a novel DM mouse model.
- To characterize the electrophysiological and ultrastructural abnormalities associated with DM.
Main Methods:
- Generation of DM mutant (Mbnl1) and control wild-type (Mbnl1) mice.
- In vivo electrophysiological studies and optical mapping.
- Transmission electron microscopy for myocardium ultrastructural analysis.
Main Results:
- DM mutant mice showed increased vulnerability to anesthesia and pacing, with higher incidence of atrial and ventricular arrhythmias.
- Optical mapping revealed prolonged action potential duration, slower conduction velocity, and increased susceptibility to spatially discordant alternans in DM mice.
- Electron microscopy identified disarranged myofibrils and enlarged mitochondria in DM mutant myocardium.
Conclusions:
- The DM mouse model recapitulates cardiac arrhythmias and myofibril abnormalities seen in human DM.
- Prolonged action potential duration and slow conduction velocity contribute to arrhythmia vulnerability in DM.
- This model provides insights into the pathophysiology of cardiac dysfunction in myotonic dystrophy.