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

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 TGN488I 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 TGN488I 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.