Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiac hypertrophy and Wolff-Parkinson-White syndrome.
OBJECTIVE
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.
Patel
Vickas V
VV
Molecular Cardiology Research Center and Section of Cardiac Electrophysiology, University of Pennsylvania, Philadelphia, PA, USA.
Arad
Michael
M
Moskowitz
Ivan P G
IP
Maguire
Colin T
CT
Branco
Dorothy
D
Seidman
J G
JG
Seidman
Christine E
CE
Berul
Charles I
CI
D055372:AMP-Activated Protein Kinases; D000241:Adenosine; D000367:Age Factors; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001706:Biopsy; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods; D004594:Electrophysiology; D005838:Genotype; D006329:Heart Conduction System; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D011226:Pre-Excitation Syndromes / Q000175:diagnosis* / Q000235:genetics*; D011342:Procainamide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016037:Single-Blind Method; D018754:Ventricular Dysfunction / Q000175:diagnosis* / Q000235:genetics*; D014927:Wolff-Parkinson-White Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology
D000889:Anti-Arrhythmia Agents; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000241:Adenosine; D011342:Procainamide