Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiac hypertrophy and Wolff-Parkinson-White syndrome

Vickas V. Patel, Michael Arad, Ivan P.G. Moskowitz, Colin T. Maguire, Dorothy Branco, J. G. Seidman, Christine E. Seidman, Charles I. Berul*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

OBJECTIVES: We sought to characterize an animal model of the Wolff-Parkinson-White (WPW) syndrome to help elucidate the mechanisms of accessory pathway formation. BACKGROUND: Patients with mutations in PRKAG2 manifest cardiac hypertrophy and ventricular pre-excitation; however, the mechanisms underlying the development and conduction of accessory pathways remain unknown. METHODS: We created transgenic mice overexpressing either the Asn488Ile mutant (TGN488I) or wild-type (TGWT) human PRKAG2 complementary deoxyribonucleic acid under a cardiac-specific promoter. Both groups of transgenic mice underwent intracardiac electrophysiologic, electrocardiographic (ECG), and histologic analyses. RESULTS: On the ECG, ∼50% of TGN488I mice displayed sinus bradycardia and features suggestive of pre-excitation, not seen in TGWT mice. The electrophysiologic studies revealed a distinct atrioventricular (AV) connection apart from the AV node, using programmed stimulation. In TGN488I mice with pre-excitation, procainamide blocked bypass tract conduction, whereas adenosine infusion caused AV block in TGWT mice but not TG N488I mice with pre-excitation. Serial ECGs in 16 mice pups revealed no differences at birth. After one week, two of eight TGN488I pups had ECG features of pre-excitation, increasing to seven of eight pups by week 4. By nine weeks, one TGN488I mouse with WPW syndrome lost this phenotype, whereas TGWT pups never developed pre-excitation. Histologic investigation revealed postnatal development of myocardial connections through the annulus fibrosum of the AV valves in young TG N488I but not TGWT mice. CONCLUSIONS: Transgenic mice overexpressing the Asn488Ile PRKAG2 mutation recapitulate an electrophysiologic phenotype similar to humans with this mutation. This includes procainamide-sensitive, adenosine-resistant accessory pathways induced in postnatal life that may rarely disappear later in life.

Original languageEnglish
Pages (from-to)942-951
Number of pages10
JournalJournal of the American College of Cardiology
Volume42
Issue number5
DOIs
StatePublished - 3 Sep 2003
Externally publishedYes

Funding

FundersFunder number
Children's Hospital Research Foundation
Howard Hughes Medical Institute

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