Patel Vickas V, Arad Michael, Moskowitz Ivan P G, Maguire Colin T, Branco Dorothy, Seidman J G, Seidman Christine E, Berul Charles I
Molecular Cardiology Research Center and Section of Cardiac Electrophysiology, University of Pennsylvania, Philadelphia, PA, USA.
J Am Coll Cardiol. 2003 Sep 3;42(5):942-51. doi: 10.1016/s0735-1097(03)00850-7.
We sought to characterize an animal model of the Wolff-Parkinson-White (WPW) syndrome to help elucidate the mechanisms of accessory pathway formation.
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.
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.
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.
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.
我们试图对 Wolff-Parkinson-White（WPW）综合征的动物模型进行特征描述，以帮助阐明旁路形成的机制。
PRKAG2 基因突变的患者表现出心脏肥大和心室预激；然而，旁路发育和传导的潜在机制仍不清楚。
我们在心脏特异性启动子的控制下，创建了过表达 Asn488Ile 突变体（TG(N488I)）或野生型（TG(WT)）人 PRKAG2 互补脱氧核糖核酸的转基因小鼠。两组转基因小鼠均接受了心内电生理、心电图（ECG）和组织学分析。
在心电图上，约 50%的 TG(N488I)小鼠表现出窦性心动过缓和提示预激的特征，而 TG(WT)小鼠未出现这些特征。电生理研究显示，通过程控刺激，在房室结之外存在一条独特的房室（AV）连接。在有预激的 TG(N488I)小鼠中，普鲁卡因胺可阻断旁路传导，而腺苷输注在 TG(WT)小鼠中可导致房室传导阻滞，但在有预激的 TG(N488I)小鼠中则不会。对 16 只幼鼠进行的连续心电图检查显示，出生时无差异。一周后，8 只 TG(N488I)幼鼠中有 2 只具有预激的心电图特征，到第 4 周时增加到 8 只幼鼠中的 7 只。到 9 周时，一只患有 WPW 综合征的 TG(N488I)小鼠失去了这种表型，而 TG(WT)幼鼠从未出现预激。组织学研究显示，在年轻的 TG(N488I)小鼠而非 TG(WT)小鼠中，通过房室瓣纤维环有心肌连接的出生后发育。
过表达 Asn488Ile PRKAG2 突变的转基因小鼠重现了与该突变人类相似的电生理表型。这包括出生后诱导产生的对普鲁卡因胺敏感、对腺苷耐药的旁路，这种旁路在生命后期可能很少消失。
