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Abstract 164: β-adrenergic Stimulation Exacerbates Preclinical Arrhythmogenic Right Ventricular Cardiomyopathy Due To Desmoplakin Mutation
- Source :
- Circulation Research. 115
- Publication Year :
- 2014
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2014.
-
Abstract
- Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias and sudden cardiac death. We previously demonstrated that cardiac-specific overexpression of human mutant desmoplakin (DSPR2834H) leads to ARVC in mice at 6 months of age. However, the potential role and mechanism(s) of DSP in preclinical ARVC under cardiac stress remains unclear. Objectives: This study is aimed to elucidate the impact of DSP in the development of ARVC under adrenergic stimulation. Methods: Three-month-old non-transgenic (NTg), wild-type DSP (Tg-DSPWT) and Tg-DSPR2834H mice without obvious signs of ARVC, including right and left ventricular dysfunction, arrhythmias, were infused with either vehicle or isoproterenol (30mg/kg/d) for 2 weeks using mini-osmotic pumps. During isoproterenol infusion, electrocardiography (ECG) was monitored daily on conscious mice. Echocardiography and cardiac MRI were performed before and after 2-week of isoproterenol infusion. Myocardial tissues from both RV and LV were subjected to cellular, biochemical and histopathological analysis. Results: Isoproterenol resulted in cardiac hypertrophy to a similar degree amongst all genotypes; however, mortality occurred only in Tg-DSPR2834H mice. Vehicle-treated mice from all genotypes showed largely normal ECGs, whereas isoproterenol led to various types of arrhythmia in Tg-DSPR2834H mice including ventricular tachycardia and QT prolongation. Echocardiography analysis revealed LV dysfunction (decreased factional shortening) in isoproterenol-treated Tg-DSPR2834H mice compared to other treatment groups. Interstitial fibrosis and lipid infiltration was prominent in the Tg-DSPR2834H myocardium. MRI analysis is being performed to understand the RV and LV geometry and function. Conclusion: Our preliminary data confirms the essential role of desmoplakin in response to adrenergic stimulation. Studies investigating the electrophysiological, geometrical and cellular mechanisms of the pro-arrhythmic nature of DSPR2834H dysfunction are ongoing which may ultimately provide critical experimental data on prevention of asymptomatic preclinical ARVC in humans.
- Subjects :
- medicine.medical_specialty
biology
medicine.diagnostic_test
Physiology
Desmoplakin
business.industry
Cardiomyopathy
medicine.disease
Ventricular tachycardia
QT interval
Asymptomatic
Right ventricular cardiomyopathy
Sudden cardiac death
Internal medicine
cardiovascular system
medicine
Cardiology
biology.protein
medicine.symptom
Cardiology and Cardiovascular Medicine
business
Electrocardiography
Subjects
Details
- ISSN :
- 15244571 and 00097330
- Volume :
- 115
- Database :
- OpenAIRE
- Journal :
- Circulation Research
- Accession number :
- edsair.doi...........552cf587908446427d4f681913216b18