Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiachypertrophy and Wolff-Parkinson-White …

VV Patel, M Arad, IPG Moskowitz, CT Maguire… - Journal of the American …, 2003 - jacc.org
VV Patel, M Arad, IPG Moskowitz, CT Maguire, D Branco, JG Seidman, CE Seidman…
Journal of the American College of Cardiology, 2003jacc.org
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 …
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 PRKAG2manifest 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 PRKAG2complementary 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 TGN488Imice displayed sinus bradycardia and features suggestive of pre-excitation, not seen in TGWTmice. The electrophysiologic studies revealed a distinct atrioventricular (AV) connection apart from the AV node, using programmed stimulation. In TGN488Imice with pre-excitation, procainamide blocked bypass tract conduction, whereas adenosine infusion caused AV block in TGWTmice but not TGN488Imice with pre-excitation. Serial ECGs in 16 mice pups revealed no differences at birth. After one week, two of eight TGN488Ipups had ECG features of pre-excitation, increasing to seven of eight pups by week 4. By nine weeks, one TGN488Imouse with WPW syndrome lost this phenotype, whereas TGWTpups never developed pre-excitation. Histologic investigation revealed postnatal development of myocardial connections through the annulus fibrosum of the AV valves in young TGN488Ibut not TGWTmice.
Conclusions
Transgenic mice overexpressing the Asn488Ile PRKAG2mutation 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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