Prevention of Sudden cardiac death
Sudden cardiac death secondary to heart failure with reduced systolic
function is well-studied in the adult population, and decreased ejection
fraction (<35%) remains an indication for primary prevention
ICD placement, even in absence of documented ventricular
tachyarrhythmia25,26. ICD placement has been shown
quite definitively to reduce mortality in this adult
population27. In the pediatric dilated cardiomyopathy
population, the mechanism of death is more likely to be a heart failure
death rather than a sudden arrhythmic death. This incidence of sudden
death in the pediatric age group is far lower than what is found in the
adult cohorts. It is therefore far more difficult to predict sudden
cardiac death from decreased function alone, and far fewer primary
prevention ICDs are placed in the setting of decreased LV ejection
fraction without concurrent clinically significant arrhythmias. A study
of 85 patients with idiopathic dilated cardiomyopathy and mean ejection
fraction of 25% found just one sudden cardiac death, despite a 60%
mortality rate over the course of the study28. The
study, which excluded dystrophin-deficient cardiomyopathy, found no
statistically significant difference in survival among patients with
either atrial or ventricular arrhythmias, and the majority of deaths
were from heart failure or transplantation. The Pediatric Cardiomyopathy
Registry also sought to answer this question in a registry of over 3,500
infants, children and adolescents younger than 18 years
old29. Despite a high overall five year mortality
rate, the 5 year sudden cardiac death rate was estimated at 3% (of 280
overall deaths), far below the 14% two-year mortality rate reported in
adults without ICD implantation27. Left ventricular
dilation with posterior wall thinning and early onset of clinic disease
(<14.3 years) were significantly associated with risk of
sudden cardiac death. Antiarrhythmic medication usage was associated
with SCD, however detailed arrhythmias and holter data was not
available.
While arrhythmias are common in advanced Duchenne cardiomyopathy,
declining left ventricular systolic function remains the most powerful
cardiac predictor of mortality though it does not predict whether it
will be due to sudden arrhythmic death or a heart failure
death30. A study of 442 holters across 235 patients
found late gadolinium enhancement, left ventricular dilation and older
age were all associated with decreased cardiac function. Most
importantly, patients with severe decrease in systolic cardiac function
(LV EF<35%) were at higher risk for clinically significant
arrhythmias. While 3 study patients died over the four year timeframe,
none had cardiac death, or severe dysfunction23.
To help mitigate mortality secondary to systolic dysfunction in Duchenne
cardiomyopathy, pharmacotherapy has been generally adopted from adult
consensus statements, which are frequently
updated31,32. Inhibition of the renin-angiotensin
system inhibition, via angiotensin converting enzyme inhibition(ACEI) or
angiotensin receptor blockers (ARB) remains first line treatment, and
have been demonstrated to improve LV systolic function in DMD33. Studies in the past decade have identified benefit
from aldosterone inhibition with either spironolactone or
eplerenone34-36, though the use of these agents is too
new to demonstrate mortality benefit. Beta-adrenergic antagonists are a
mainstay of treatment in adult heart failure, and when used in children
with dilated cardiomyopathy may serve to decrease the burden of
ventricular arrhythmias as well.
Current treatment guidelines support ICD implantation in patients with
medically treated nonischemic cardiomyopathy (LVEF ≤ 35%) and mild
heart failure symptoms, with recommendation of Class
I37. The supportive data for this recommendation are
predominantly derived from the SCH-HeFT trial which enrolled patients
with a median age of 60 years and included those with ischemic
cardiovascular substrate38. It is unclear if these
results and documented benefit can be readily extrapolated to the much
younger muscular dystrophy population39. Additional
data from the Pediatric Cardiomyopathy Registry and other similar series
demonstrate very low rate of sudden arrhythmic death in the pediatric
population, contrasting their adult
couterparts28,29,40. Consequently, it remains unclear
at what age the incidence of sudden arrhythmic death increases and when
ICD implantation is most beneficial. Additional considerations for ICD
implantation in this population include the technical challenge
difficulties brought about by body habitus including severe
kyphoscoliosis, respiratory muscle weakness, and sedation-related
complications2. A multi-center study recently sought
to describe the use of ICDs in advanced Duchenne cardiomyopathy,
reviewing 436 males with DMD. Of these, 57 patients (13%) had severe
dysfunction, and just nine underwent ICD implantation. There were two
appropriate shocks and no inappropriate shocks in the study, and just
3/16 deaths in severe LV dysfunction group. Nine additional patients met
ICD implantation criteria but did not receive an ICD. Four of these
patients died (respiratory failure, multisystem organ failure and an
embolic stroke following VAD and of unknown etiology). The authors
concluded that DMD cardiomyopathy has similarities to both ischemic and
non-ischemic cardiomyopathy, and that for patients with symptoms on
GDMT, ICD implantation may be beneficial41. It is
important to note that many of these patients in this study were not on
guideline directed medical therapy. Surveys of patients with DMD and
caregivers do suggest interest in a discussion about potential benefits
of ICDs, should a life-prolonging benefit be
demonstrated42.