Biology Reference
In-Depth Information
5 Cardiac Muscle Pathogenesis in Duchenne
Muscular Dystrophy
Like skeletal muscle, cardiac muscle is also severely affected by the loss of
dystrophin with cardiomyopathy beginning early in DMD patients. Left ventricle
(LV) dysfunction is readily detectable in patients in their teens. By 18 years of age,
clinically relevant symptoms of cardiomyopathy are evident in 90% of patients
(Chenard et al.
1993
; de Kermadec et al.
1994
; Finsterer and St
ollberger
2003
).
Substantial improvements in noninvasive respiratory support have extended patient
longevity, but are accompanied by increased incidence of severe cardiac dysfunc-
tion (Eagle et al.
2007
). This has necessarily led to an upturn in the management of
cardiac dysfunction that now predominates in the late stages of DMD.
In contrast to skeletal muscle, the impact of dystrophin-deficiency on cardiac
function in humans has received much less attention. Over time, a DMD-asso-
ciated dilated cardiomyopathy (DCM) can develops as a consequence of the
absence of dystrophin from the heart (Finsterer and St
€
ollberger
2003
). Similar
to skeletal muscle, the absence of dystrophin in the cardiomyocyte enhances
membrane permeability leading to Ca
2+
overload. Pathologically, high intracellu-
lar Ca
2+
concentrations result in excessive protease activity and impair mitochon-
drial oxidative phosphorylation, causing widespread cardiomyocyte necrosis.
Cardiomyocyte death results in inflammation and extensive fibrosis, particularly
of the LV wall, reducing ventricular compliance and diastolic function (Moriuchi
et al.
1993
; Frankel and Rosser
1976
). Atrial and ventricular chamber walls
stretch and thin out due to cardiomyocyte death, leading to chamber dilation.
As a result, both systolic and diastolic function of the dystrophin-deficient heart is
impaired. Eventually, DCM develops into congestive heart failure. DCM may be
associated with arrhythmias and other electrical impulse conduction defects that
also contribute to cardiac dysfunction (Finsterer and St
€
ollberger
2003
;Thrush
et al.
2009
). Sinus tachycardia (abnormally fast heart rate) is a prevalent arrhyth-
mia in DMD. Short PR intervals, tall R waves, and prominent Q waves are also
common impulse conduction abnormalities (Finsterer and St
€
ollberger
2003
;
€
Thrush et al.
2009
).
In the clinic, ACE inhibitors and
b
-adrenergic blockade provide the mainstay
of therapeutic intervention in DMD (Finsterer and St
ollberger
2003
). While these
interventions are often effective for enhancing systolic function in DMD hearts,
diastolic dysfunction is left largely unaddressed. This is an important point relevant
to the potential utility of PDE5A inhibitors in treating DMD-associated DCM since
sildenafil, currently used to treat erectile dysfunction and pulmonary hypertension,
will be tested in large clinical study for efficacy in treating diastolic dysfunction in
heart failure (ClinicalTrials.gov Identifier: NCT00781508). Despite current inter-
ventions, DMD deaths from cardiac failure are on the rise and according to some
estimates, death from congestive heart failure and/or arrhythmias can account for
20-50% of deaths in DMD (Finsterer and Stollberger
2003
; Ishikawa et al.
1999
).
€
