phase with left ventricular dysfunction appears lower with the two
most commonly describedPRKAG2mutations (Arg302Gln and
Asn488Ile), with transplantation reported in one case at age
42 years [12, 24, 65].5.4 Sudden Death A recent summary of published cases estimated sudden death to
affect ~9% of mutation carriers, with a mean age of death at
33.4 years [17]. A more recent case series (n¼34) reported sudden
death in as many as 32% of individuals, with a mean age of 44 years
[67]. Given the high rate of permanent pacemaker implantation
(reported as ~43% [17]), frequently in the age range of
30–40 years, it is likely that timely pacemaker implantation prevents
sudden death in many mutation carriers. The majority of cases in
this age group are thought to reflect the occurrence of pre-excited
atrial fibrillation triggering ventricular fibrillation or perhaps even
primary ventricular fibrillation (the latter more likely in the setting
of severe cardiac hypertrophy or progression to a dilated hypoki-
netic ventricular phenotype), rather than high-grade AV conduc-
tion block [27].
While runs of non-sustained ventricular tachycardia have been
identified using Holter ambulatory ECG monitoring in a small
proportion ofPRKAG2 mutation carriers (largely with severe
LVH) [24], there are no data regarding aborted episodes of SCD
in patients withPRKAG2mutations who have received an implant-
able cardioverter defibrillator (ICD), although analysis of such
events could yield mechanistic insights. In our own experience,
manyPRKAG2mutation carriers who have received an ICD were
initially misdiagnosed with (classical) familial HCM and received it
for primary prevention purposes. One of our three patients with an
ICD has experienced inappropriate therapies that were triggered by
atrial fibrillation and a consequent fast ventricular rate beyond the
programmed rate cutoff for device therapy. In a series of patients
carrying the Arg302Gln mutation who underwent electrophysio-
logical study, none had inducible sustained ventricular tachycardia
on programmed ventricular stimulation [27], an observation mir-
rored during study of TGR302Qmice [33]. These findings may
reflect the relatively lower degree of myocardial fibrosis encoun-
tered inPRKAG2cardiomyopathy compared to familial HCM
(Fig. 10)—indeed, a recent cardiovascular magnetic resonance
study identified late gadolinium enhancement, a marker of focal
fibrosis, in only two of six mutation carriers analyzed, both of
whom displayed severe LVH (Fig.12)[ 76]. The molecular sub-
strate for this is unclear, but recent findings from human iPS cell-
derived cardiomyocyte models bearing the Asn488Ile mutation
suggest that this may involve attenuated TGFβsignalling [40].
5.5 Ventricular
Hypertrophy
Together, LVH and ventricular pre-excitation represent the most
common clinical features in patients withPRKAG2mutations,
with a frequency of LVH of 78% (n¼41) in one large patient606 Arash Yavari et al.