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.