fibrillation and atrial flutter have been described from the age of
2 years (but with no LVH even up to age of 41 years) in association
with the Arg531Gly variant [30], while the Arg531Gln mutation
results in a rapidly fatal syndrome presenting in prenatal or neonatal
life with massive cardiomegaly, bradycardia in utero, ventricular
pre-excitation, and profound non-lysosomal glycogen
accumulation [26].3 PRKAG2Disease Mechanisms: Insights from Murine Models
To elucidate the pathophysiological mechanisms underlying the
cardiac phenotype associated withPRKAG2mutations, a number
of murine disease models have been developed. With the exception
of a recently described gene targeted model [31], these share a
similar design, namely, cardiac-restricted overexpression of human
mutant or WTPRKAG2cDNA under the control of a powerful,
cardiac-specific promoter (α-myosin heavy chain,α-MHC) result-
ing in primarily fetal atria and postnatal ventricular expression
[32–35]. These overexpressing transgenic (TG) models near uni-
formly recapitulate the more severe end of the human disease
spectrum, including severe LVH (Fig.2), ventricular pre-excita-
tion, profound cardiac glycogen accumulation, ventricular dysfunc-
tion, and early mortality (Table2).3.1 Basis
of PRKAG2-Associated
Ventricular
Pre-excitation
Surface ECG recordings of all four TG mouse models overexpres-
sing mutantPRKAG2have identified mice with apparent ventricu-
lar pre-excitation (i.e., short PR interval and widening of the QRS
complex) (Fig.3). Multiple patterns of ventricular activation have
been described in the same mice [32], suggesting multiple acces-
sory connections, as have been observed in the human disease
[36]. Importantly, cardiac-restricted overexpression of WT
PRKAG2appears insufficient to induce ventricular pre-excitation
[37]. Consistent with the temporal expression profile of the trans-
gene promoter, surface ECG recordings are normal at birth, with
subsequent evidence of ventricular pre-excitation emerging in the
majority of TG mice overexpressing mutantPRKAG2by 4 weeks,
i.e., postnatal manifestation [37]; loss of pre-excitation in adult TG
mice, confirmed by electrophysiological study (EPS), has also been
documented. In addition to pre-excitation, older mice up to
15 months of age display spontaneous supraventricular tachycardia
and sinus bradycardia and pauses [37].
In the case of the TGN488Iand TGR302Qmodels, the presence
of functional accessory pathways has been confirmed using detailed
in vivo EPS combined with pharmacological challenge. These have
revealed procainamide-sensitive, adenosine-resistant functioning
accessory pathways permitting atrioventricular (AV) conduction
outside the AV node-His pathway [33, 37]. Moreover, in the case588 Arash Yavari et al.