Cardiovascular causes of sudden unexpected death in children and adolescents (0–17 years)

Background Little is known about the causes of unexpected death in minors (0–17 years). In young adults an important cause is cardiovascular disease, with primary arrhythmogenic disorders, atherosclerotic events, cardiomyopathies and myocarditis as main contributors. The aim of this autopsy study was to determine the contribution of cardiovascular disease to unexpected death in minors. Methods and results In the Netherlands, systematic investigation of all cases of unexplained death in minors was compulsory in a nationwide governmental project during a 15-month period. Autopsies were performed according to a standardised protocol (autopsy rate 85%). A cardiovascular cause of death was found in 13/56 cases (23%). In the group <1 year, the main cardiovascular causes were various congenital defects (n = 3) and myocarditis (n = 2). In the 1–9 year group, no cardiovascular causes were found. In the 10–14 year group, hypertrophic cardiomyopathy (n = 1) and ruptured ascending aortic aneurysm (n = 1) were among the observed cardiovascular causes. In 14/56 (25%) cases autopsy revealed no structural abnormalities that could explain the sudden death, mostly in the group <1 year. Conclusion This national cohort with a high autopsy rate reveals a high incidence (23%) of cardiovascular diseases as the pathological substrate of sudden unexpected death in children. Another high percentage of minors (25%) showed no structural abnormalities, with the possibility of a genetic arrhythmia. These findings underline the importance of systematic autopsy in sudden death in minors, with implications for cardiogenetic screening of relatives. Electronic supplementary material The online version of this article (10.1007/s12471-018-1152-y) contains supplementary material, which is available to authorized users.


Cardiovascular autopsy
Examination of the heart and great arteries included recording of heart weight, developmental abnormalities, measurement of the atrial and ventricular dimensions, myocardial thickness, structure and insertion of cardiac valves and aortic root including coronary ostia. Macroenzyme (LDH) staining of one entire biventricular myocardial slice was perfomed for detection of acute cardiomyocyte damage. Sections for histologic examinations were taken from both ventricles (in most cases a complete biventricular heart slice) and atrioventricular nodal area/interventricular septum and stained with haematoxylin and eosin (H&E).
If a myocarditis was suspected on routine H&E stained slides, additional CD3 and CD68 immunohistochemical stains were performed to detect T-lymphocytes and macrophages respectively. In cases of presence of focal infiltrates with only discrete myocardial damage, the case was categorized as borderline myocarditis. [1] Diffuse inflammatory infiltration with substantial myocardial damage was categorized as fulminant myocarditis. 3

Cardiovascular findings of uncertain significance
In 13/56 autopsied cases (23%) a cardiovascular cause of death was found. Additionally, we found cardiovascular abnormalities of which the association with the death was uncertain. [2] These cardiovascular abnormalities of uncertain significance were present in 14 cases (25%).
In one of these cases another cardiovascular disease was found to be the main cause of death.
In 4 cases no other cause of death was found and the cases were classified as 'no structural abnormalities'. In total, cardiovascular abnormalities (cardiovascular causes of death and cardiovascular findings of uncertain significance) were found in 26/56 cases. (46%) Findings of uncertain significance included: small atrium septum defect (n=2), abberant right subclavian artery/arteria lusoria (right subclavian artery originating from the descending aorta and running behind the esophagus to the right (n=2)), pulmonary venolobar (Scimitar) syndrome which was already diagnosed before death (n=1), abnormal outlet of the coronary sinus in the left atrium (n=1), a high take off of the left coronary artery with a collateral artery connecting the right coronary artery to the left without histological signs of acute ischemia (n=1), and borderline/focal myocarditis (n=8).

Borderline myocarditis
In 2/56 (4%) cases a fulminant myocarditis was found to be the cause of death. In one of these cases a parvovirus was detected in the myocardium. In another 8/56 cases (14%), age range 1 to 14 years, one or more clustered myocardial infiltrates of T-lymphocytes and macrophages, with focal indication of cardiomyocyt damage, were present (online supplemental figure I).
These were diagnosed as borderline lymphocytic myocarditis according to the Dallas criteria. [1] Histologic examination of the remaining organs showed similar infiltrates in 4 larynx, trachea, lungs, tonsils, liver and/or brain in 7 of 8 cases. A cause of death, unrelated to the focal myocarditis, was found in 5 of these cases (intussusception with pulmonary edema, gangrenous purpura, brain herniation due to dysfunction of a ventricular-peritoneal shunt, and pneumonia (2x)). The other three children died of unknown causes, since borderline myocarditis is considered to be an uncertain cause of death. [2] 5

Borderline myocarditis
We found limited focal lymphocytic myocarditis in 8/56 cases (14%), which, according to the recent guidelines of autopsy in sudden cardiac death, should be interpreted as at most an uncertain cause of death. [2] Our results, with an evident cause of death other than the borderline myocarditis in 5/8 cases, confirm this statement. Since we also found mild lymphohistiocytic infiltrates in the liver, lungs and/or brain in most of these cases (7 out of 8), this focal myocarditis most likely represents a generalized viral infection, as suggested by