The reversibility of ventricular pre-excitation and other mani-
festations ofPRKAG2disease has been investigated in a series of
elegant experiments using a tetracycline-controlled binary
α-MHC-driven system of Asn488Ile transgene expression in mice.
Early transgene suppression (using oral doxycycline administration)
from prenatal up to 8 weeks of adult life (TGOFF(E-8 weeks)) was
sufficient to prevent ventricular pre-excitation—even with
subsequent expression of the mutant transgene for 12 weeks—
and associated with a histologically intact annulus fibrosus
[16]. In contrast, Asn488Ile transgene suppression commencing
after 4 weeks (TGOFF(4–16 weeks)) reduced the frequency of overt
pre-excitation from ~50% to 11%, while mutant transgene suppres-
sion beyond 8 weeks of life (TGOFF(8–20 weeks)) was found to have
no effect on the development or persistence of pre-excitation
[16]. Early transgene suppression (TGOFF(E-8 weeks)) was also asso-
ciated with a reduction in myocardial glycogen level and delayed,
but did not prevent, LVH and LV chamber dilatation or reduced
ventricular systolic function [16]. However, TGOFF(8–20 weeks)mice
had similar rates of sinoatrial and AV block to mice (TGON) which
had not undergone any mutant transgene suppression, indicating
that early suppression of mutantPRKAG2transgene expression,
and associated glycogen reduction, could prevent pre-excitation
but did not favorably impact upon cardiac conduction system dis-
ease or prevent eventual adverse ventricular remodelling and heart
failure.
While the murine studies suggest accumulation of a critical
mass of glycogen to be a prerequisite for development of ventricular
pre-excitation, this does not exclude other potential AMPK-
mediated, glycogen-independent contributors to accessory path-
way formation, such as abnormal AV canal development [39],
particularly in the setting of a relatively hypomorphic annulus
fibrosus. Recent findings of reduced TGFβsignalling in human
induced pluripotent stem cell (iPSC)-derived cardiomyocytes
expressing aPRKAG2mutation have suggested a molecular sub-
strate for this [40].3.2 The Role
of Glycogen
and Glycogen-
Independent Disease
Mechanisms
Multiple lines of evidence highlight glycogen excess as an impor-
tant contributor to the pathogenesis ofPRKAG2cardiomyopathy:
prominent cardiac glycogen accumulation in human PRKAG2
mutation carriers and murine transgenic models [13, 32]; cardiac
phenotypic overlap with inherited disorders of glycogen metabo-
lism (e.g., infantile Pompe disease), including the presence of ven-
tricular pre-excitation; amelioration of the disease phenotype in
parallel with change in myocardial glycogen content in experimen-
tal models [16]; the well-established role of AMPK in regulating
cellular glucose uptake and glycogen metabolism [41–43], with
evidence of enhanced glucose uptake and reduced glycolytic flux
in isolated TGN488Ihearts [44]; and the observation of increasedPRKAG2 syndrome 593