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Optical Mapping Approaches on Muscleblind-like Compound Knockout Mice for Understanding Mechanistic Insights into Ventricular Arrhythmias in Myotonic Dystrophy

Kuang-Yung LeeChung-Chuan ChouPo-Cheng ChangYi-Chia WeiCarol Seah

College of Medicine, Chang Gung University and Chang Gung Memorial Hospital Taiwan

摘要:Cardiac sudden deaths due to lethal arrhythmias are common in myotonic dystrophy(dystrophia myotonica [DM])patients.DM is an autosomal dominant disease presenting multisystemic features.It is caused by microsatellite(C(C)TG)n expansion in the untranslated region of the DMPK gene(DM type Ⅰ,DM1)or CNBP gene(DM type Ⅱ,DM2).The extended double stranded RNA hairpins form "RNA foci" in the nuclei and colocalize with Muscleblind-like(MBNL)proteins.The sequestration and loss of function of the developmentally critical MBNL causes RNA misregulation and accounts for DM phenotypes.We proved the hypothesis by creating Mbnl knockout(KO)mouse models and recapitulated DM symptoms including cardiac conduction block and unexpected sudden death.In this experiment,we performed in vivo electrophysiological studies and optical mapping on Mbnl compound KO mice(Mbnl1-/-);Mbnl2+/-),which exhibit severe myotonia and splicing alteration,to investigate the mechanisms of ventricular tachyarrhythmias in DM.These mutant mice were more vulnerable to anesthesia and programmed electrical pacing and experienced sudden apnea and cardiac arrest during premedication of general anesthesia.Most of the remaining mutants had atrial tachycardia and/or atrioventricular block,but none in WT mice.The mutant mice also showed more frequent pacing-induced ventricular tachyarrhythmias than WT mice.Optical mapping revealed prolonged action potential duration,slower conduction velocity,and steeper conduction velocity restitution curves in the mutants than WT mice.Spatially discordant alternans was more easily inducible in the mutants than WT mice.However,no changes of calcium dynamics were observed in the mutants.These findings indicate MBNL loss of function is deleterious to DM hearts and infer the possibility that altered dynamic nature of INa may be involved in DM ventricular arrhythmogenesis.
会议名称:

BIT’s 9th Annual International Congress of Cardiology-2017

会议时间:

2017-11-15

会议地点:

Singapore

  • 专辑:

    医药卫生科技

  • 专题:

    心血管系统疾病

  • 分类号:

    R541.7

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