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dysfunction (Spurney et al.
2008
). Thus, collectively, these data indicate pro-
nounced left ventricular dysfunction in
mdx
hearts.
As observed in humans, contractile dysfunction is often accompanied by
arrhythmias and abnormal electrical impulse conduction. Electrocardiographic
studies reveal that
mdx
and DMD hearts exhibit similar aberrant impulse interval
characteristics including deep Q waves, a decreased S:R wave ratio, polyphasic
R waves, shortened PR interval and QTc intervals and cardiac arrhythmias, such as
premature ventricular contractions (Chu et al.
2002
; Wehling-Henricks et al.
2005
;
Bostick et al.
2009
). In summary, dystrophin-deficiency negatively affects cardio-
myocyte survival and function in
mdx
mice. Furthermore,
mdx
hearts recapitulate
key features of cardiomyopathy in DMD hearts including cardiomyocyte necrosis,
susceptibility to mechanical stress, diastolic dysfunction, systolic dysfunction, and
impulse propagation defects.
6 Vascular Dysfunction Contributes to the Pathogenesis
of DMD
While research in DMD has primarily focused on dystrophin function in skeletal
muscle and, to a lesser extent, cardiac muscle, smooth muscle dysfunction may also
play a role in the dystrophic phenotype. Both dystrophin and nNOS
m
are expressed
in VSMCs (Ward et al.
2005
; Ito et al.
2006
; Fig.
1
). Indeed, abnormalities in
smooth muscle in
mdx
mice appear to contribute to the dystrophic phenotype, for
example, by impairing blood supply during exercise (Ito et al.
2006
). This is
particularly relevant to the therapeutic utility of PDE5 inhibitors in dystrophy
because PDE5A is highly expressed in VSMCs in the vascular beds of the circula-
tory system; thus, any consideration of the effects of systemic PDE5A inhibition on
mdx
pathology must also consider any potential impact on VSMC function (Wallis
et al.
1999
). Furthermore, vascular dysfunction has long been suspected to contrib-
ute to the dystrophic pathology of DMD (Mendell et al.
1971
).
Evidence of vascular dysfunction, specifically small clusters of necrotic fibers,
was first observed in skeletal muscle biopsies from DMD patients over 40 years
ago. This muscle pathology could be recapitulated by vascular obstruction, suggest-
ing that muscle necrosis could result from defects in a shared blood vessel. This
reasoning formed the basis for the vascular hypothesis proposed by Engel and
coworkers that stated that skeletal muscle microcirculation dysfunction could
account for the pathogenesis of DMD (Mendell et al.
1971
). This hypothesis was
largely abandoned when no structural abnormalities of the vasculature were found
(Jerusalem et al.
1974
). However, the vascular theory was revisited when Victor
and coworkers demonstrated that
a
-adrenergic receptor-mediated sympathetic
vasoconstriction was unopposed in the exercising hind limbs of
mdx
and KN1
(nNOS knockout 1) mice and contracting forearms of DMD patients (Thomas
et al.
1998
; Sander et al.
2000
). Thus, during exercise, dystrophin-deficient muscles
