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EXPERIMENTAL STUDY

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

Vickas V. Patel, MD, PhD^*, Michael Arad, MD, Ivan P. G. Moskowitz, MD, PhD, Colin T. Maguire, BS, Dorothy Branco, BS, J. G. Seidman, PhD, Christine E. Seidman, MD, FACC^|| and Charles I. Berul, MD, FACC^,*

^* Molecular Cardiology Research Center and Section of Cardiac Electrophysiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts, USA
Department of Pathology and Cardiac Registry, Children's Hospital, Boston, Massachusetts, USA
Department of Cardiology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
^|| Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA

Manuscript received December 26, 2002; revised manuscript received May 8, 2003, accepted May 21, 2003.

^* Reprint requests and correspondence: Dr. Charles I. Berul, Department of Cardiology, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
charles.berul{at}cardio.chboston.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 (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, 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.

Abbreviations and Acronyms   AMP = adenosine monophosphate   AV = atrioventricular   CCh = carbamyl choline   EPS = electrophysiologic study   ERP = effective refractory period   HBE = His-bundle electrogram   MHC = myosin heavy chain   SVT = supraventricular tachycardia   VA = ventriculo-atrial   WPW = Wolff-Parkinson-White

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