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 (TG(N488I)) or wild-type (TG(WT)) 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, approximately 50% of TG(N488I) mice displayed sinus bradycardia and features suggestive of pre-excitation, not seen in TG(WT) mice. The electrophysiologic studies revealed a distinct atrioventricular (AV) connection apart from the AV node, using programmed stimulation. In TG(N488I) mice with pre-excitation, procainamide blocked bypass tract conduction, whereas adenosine infusion caused AV block in TG(WT) 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 TG(N488I) pups had ECG features of pre-excitation, increasing to seven of eight pups by week 4. By nine weeks, one TG(N488I) mouse with WPW syndrome lost this phenotype, whereas TG(WT) 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 TG(WT) 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.
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Authors | Vickas V Patel, Michael Arad, Ivan P G Moskowitz, Colin T Maguire, Dorothy Branco, J G Seidman, Christine E Seidman, Charles I Berul |
Journal | Journal of the American College of Cardiology
(J Am Coll Cardiol)
Vol. 42
Issue 5
Pg. 942-51
(Sep 03 2003)
ISSN: 0735-1097 [Print] United States |
PMID | 12957447
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Arrhythmia Agents
- Multienzyme Complexes
- Protein Serine-Threonine Kinases
- AMP-Activated Protein Kinases
- Adenosine
- Procainamide
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Topics |
- AMP-Activated Protein Kinases
- Adenosine
- Age Factors
- Animals
- Anti-Arrhythmia Agents
- Biopsy
- Cardiomegaly
(complications, genetics, pathology)
- Disease Models, Animal
- Disease Progression
- Electrocardiography
- Electrophysiologic Techniques, Cardiac
(methods)
- Electrophysiology
- Genotype
- Heart Conduction System
- Mice
- Mice, Transgenic
- Multienzyme Complexes
(genetics)
- Mutation, Missense
(genetics)
- Phenotype
- Pre-Excitation Syndromes
(diagnosis, genetics)
- Procainamide
- Protein Serine-Threonine Kinases
(genetics)
- Single-Blind Method
- Ventricular Dysfunction
(diagnosis, genetics)
- Wolff-Parkinson-White Syndrome
(complications, genetics, pathology)
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