During a 5-year period, 159 SD were identified in individuals aged 1 to 40 years-old, corresponding to an annual incidence of 2,4 (95%CI 1,5 − 3,6) per 100.000 people-years. SD victims had a mean age of 32 ± 7 years-old, the majority being of male gender (72,3%, n = 115). There were 112 (70,4%) cases of SD of cardiac origin. The remaining causes were respiratory (16,4%, n = 26), neurologic (7,5%, n = 12), digestive (3,1%, n = 5), hematologic (1,2%, n = 2), genito-urinary (0,6%, n = 1) and endocrinologic/metabolic (0,6%, n = 1) (Fig. 2). Non-cardiac causes of sudden death are detailed in Table 1.
Table 1
– Non-cardiac causes of sudden death
Non-cardiac causes of sudden death
|
N = 47, n (%)
|
Respiratory
Lower respiratory tract infections
Acute bronchopneumonia
Acute lobar pneumonia
Acute purulent bronchitis
Upper respiratory tract infections
Acute laryngitis
Acute severe amygdalitis with prominent lymphoid follicular hyperplasia
Acute alveolar hemorrhage
Acute diffuse alveolar disease
Acute pulmonary edema
in the context of Still’s Disease
in the context of Sickle Cell Anemia crisis
|
26 (55,3)
7 (14,9)
7 (14,9)
2 (4,2)
1 (2,1)
1 (2,1)
3 (6,4)
3 (6,4)
1 (2,1)
1 (2,1)
|
Neurologic
Hemorrhagic stroke
Generalized tonic-clonic seizure
Subarachnoid hemorrhage
Acute meningitis
Brain ventriculitis and acute cervical medullary hemorrhage
|
12 (25,5)
4 (8,5)
4 (8,5)
2 (4,2)
1 (2,1)
1 (2,1)
|
Digestive
Acute peritonitis
Secondary to gastric ulcer perforation
Secondary to intestinal perforation
Gastric hemorrhage
Granulomatous necrotizing hepatitis
|
5 (10,6)
2 (4,2)
1 (2,1)
1 (2,1)
1 (2,1)
|
Hematologic
Intravascular disseminated coagulation secondary to severe sepsis to Streptococcus suis
Lymphoproliferative disease
|
2 (4,2)
1 (2,1)
1 (2,1)
|
Genito-urinary
Ulcerated infected uterine cervix carcinoma
|
1 (2,1)
1 (2,1)
|
Endocrinological/Metabolic
Severe hypoglycemia in the context of insulin-treated DM
|
1 (2,1)
1 (2,1)
|
DM – Diabetes Mellitus
Histopathological diagnosis in sudden cardiac death victims
Histopathological diagnoses obtained in SCD victims are depicted in Table 2, with a descending order of frequency. The most frequent cardiac diagnosis was atherosclerotic coronary artery disease (CAD) (n = 37, 33,0%), which included cases of documented type 1 AMI (AHA type VI lesion) (n = 16, 43,2%), presumed type 2 AMI (AHA type IV or V lesions) with an estimated luminal narrowing from 50 to 75% (n = 6, 16,2%) or more than 75% (n = 13, 35,1%), one case in which coronary arteries were not sent for anatomopathological analysis but histological myocardial infarction was detected, and another in which no histology was requested although macroscopic examination detected myocardial wall infarction and rupture with associated hemopericardium. A minority of victims with atherosclerotic CAD had histological evidence of myocardial infarction (n = 12, 32,4%), three of which corresponded to presumed type 2 AMI. AMI as a final cause of SCD could then be confirmed in 21 (18,8%) individuals who had evidence of myocardial ischemic lesions and/or type 1 AMI. There was no evidence of myocardial fibrosis or scar in the remaining cases of suspected type 2 AMI.
Table 2
– Anatomopathological diagnosis in sudden cardiac death victims
Main anatomopathological diagnosis
|
N = 112, n (%)
|
Mean age ± SD (years-old)
|
Gender predominance
|
Atherosclerotic coronary artery disease
Type VI complicated lesion (AHA classification) *
|
37 (33,0)
16 (14,3)
|
34 ± 4 (p < 0,047)
|
Male (83,8%; p = 0,032)
|
LVH**
Evolution towards dilation
Associated with fibrosis
With extensive area of myocardial scar
Associated myxomatous mitral valve disease
|
17 (15,2)
8 (7,1)
4 (3,6)
2 (1,8)
1 (0,9)
|
33 ± 8
|
NS
|
Hypertrophic CM***
|
3 (2,7)
|
19 ± 9,5 (p = 0,001)
|
NS
|
Acute pulmonary embolism
With documented deep venous thrombosis
|
14 (12,5)
9 (8,0)
|
33 ± 6
|
Women (78,6%; p < 0,001)
|
Dilated LV
Probable etiology:
Post-partum
Ethanolic
Ischemic
Post-myocarditis
|
10 (8,9)
2 (1,8)
2 (1,8)
1 (0,9)
1 (0,9)
|
31 ± 8
|
NS
|
Valvular Heart disease
Myxomatous mitral valve disease
Severe aortic stenosis
Degenerative mitral valve disease
|
7 (6,2)
4 (3,6)
2 (1,8)
1 (0,9)
|
36 ± 4
|
NS
|
Acute myocarditis
|
5 (4,5)
|
20 ± 11 (p = 0,002)
|
NS
|
Acute pulmonary edema/acute heart failure
|
5 (4,5)
|
34 ± 5
|
NS
|
Ascending aorta dissection and pericardial tamponade
|
5 (4,5)
|
30 ± 8
|
NS
|
Congenital Heart Disease
Corrected
|
5 (4,5)
3 (2,7)
|
33 ± 4
|
NS
|
Left ventricular fibrosis
Mild and multifocal fibrosis
Fibrosis with myocardial scar
|
2 (1,8)
1 (0,9)
1 (0,9)
|
38 ± 4
|
NS
|
Arrhythmogenic Right Ventricle CM
|
1 (0,9)
|
30
|
NS
|
Acute left main coronary artery dissection
|
1 (0,9)
|
24
|
NS
|
Legend: *Corresponds to clinical type 1 myocardial infarction, ** Not meeting criteria for Hypertrophic CM, ***Two cases with anatomopathological and genetic data, one case with a previously known diagnosis and whose heart was not sent for anatomopathological analysis. |
AHA = American Heart Association; CM = Cardiomyopathy, NS = non-significant |
In the toxicological analysis, there were two individuals with the final diagnosis of type 1 AMI and one with presumed type 2 AMI who had positive non-toxic cannabinoids plasma levels and none had positive cocaine levels or other drugs.
There were three cases of HCM, including one victim with 30 years-old who had a previously known diagnosis and whose heart was not sent for anatomopathological analysis, and another two children, with genetic evaluation and autopsy macro and microscopic typical pattern (supplementary material 1).
Left ventricular (LV) dilation and associated fibrosis was present in two cases, one of which was a victim who had previous coronary artery bypass grafting (CABG). No significant bypass stenosis at gross and histological examination was observed in that patient and a final diagnosis of ischemic cardiomyopathy with an anterior myocardial scar, complicated with acute pulmonary edema was made (supplementary material 1). A presumptive etiology was suggested for five other cases of LV dilation: two SD occurred three- and four-months following delivery, probably in the context of an arrhythmia secondary to post-partum cardiomyopathy in 37- and 17-years-old females, respectively. The older victim also had an history of alcohol abuse and significant liver disease (case 74 from supplementary material 2). Two other cases also had a history of alcohol abuse and possibly corresponded to ethanolic cardiomyopathy (cases 75 and 81); the fifth case corresponded to a male aged 18, without previous relevant medical history, where, despite the absence of myocardial fibrosis or histological evidence of myocarditis on the dilated ventricle, additional features on histopathological examination raised the hypothesis of subacute myocarditis due to a viral infection or auto-immune disease (case 72).
Among four individuals with myxomatous mitral valve disease, two had mitral valve prolapse, three had associated left ventricular hypertrophy (LVH) and one also had peri-valvular basal ventricular fibrosis.
Among the five cases (4,5%) of acute myocarditis identified, there was a 15-years-old boy with associated mild left ventricular dilation and fibrosis and a 23-years-old woman with simultaneous active peri-coronary inflammation, as well as small myocardial scars suggesting previous myocarditis episodes.
All victims with a final diagnosis of acute pulmonary edema/acute heart failure (n = 5, 4,5%) had no underlying cardiac structural abnormalities, and evidence of edema involving more than 50% of the lungs was present, frequently accompanied by generalized vascular congestion.
Among victims with ascending aorta dissection and pericardial tamponade (n = 5, 4,5%), a dissection arose in a pre-coarctation aneurysm, in which chronic peri-aortic inflammation was observed (case 99). Two other individuals had simultaneous non-significant CAD and one had significant 1-vessel CAD (50–75% stenosis).
Acute left main coronary artery dissection originating from medial tunica mucoid degeneration [extra-cellular mucoid matrix accumulation (MEMA)](18) of the ascending aorta was observed in one male subject. Further examination also revealed mitral valve myxomatous changes, suggesting a hereditary Marfan Syndrome (case 112).
Causes of sudden death by age strata
In order to analyze autopsy final causes of SD after histopathological diagnosis across age strata, we separated children and teenagers (≤ 18 years-old, n = 10, 6,3%), from early adulthood (19–34 years-old, n = 70, 44,0%) and from early middle-aged adults (35 to 40 years-old, n = 79, 49,7%) (Fig. 3).(12) There was a growing annual incidence of SD among age strata: 0,4 (95%CI 0,3 − 0,5), 2,5 (95%CI 1,6 − 3,7) and 6,3 (95%CI 4,8–8,1) per 100.000 people-years, respectively.
Among victims aged ≤ 18 years-old, the most common cause of SD was acute myocarditis (n = 2), HCM (n = 2) and dilated LV (n = 2), one of which corresponded to the case of subacute myocarditis with associated hepatitis and BALT hyperplasia, as discussed in the previous section. This younger group included a case of a 11-years-old girl who had LVH and fibrosis, including an extensive area of myocardial scar, also with associated BALT hyperplasia, probably secondary to previous myocarditis (case 44). Even though myocarditis may have been a direct or indirect cause of SD in 40,0% of these individuals (n = 4; cases 44, 72, 90, 91 from supplementary material 2), the prevalence of confirmed acute myocarditis was 21 times higher in children and teenagers (30,0%) than in middle-aged adults (2,0%) (OR 20,8; 95%CI 3,55–122,56, p = 0,001).
In adults, the most common diagnosis was atherosclerotic CAD, with a non-significant tendency to be more frequent in early middle-aged adults (27% vs 20%, OR 1,45; CI 0,69 − 3,04, p = 0,327) comparing to younger individuals. A similar tendency was observed in AMI as a final cause of SD, which was present in 16,5% (n = 13) of early middle-aged adults and 11,4% (n = 8) in early adulthood (p = 0,381). All expect 3 of these victims with AMI were 30 years-old or older. The subsequent three most common findings were LVH, lower respiratory tract infections and acute pulmonary embolism. There were no statistically significant differences when comparing diagnoses between early adulthood versus early middle-aged adults.
Clinical characteristics of sudden cardiac death victims
Addiction habits were reported in 31 (27,7%) cases and detected in 22 (71,0%) of those individuals, including 13 with alcohol abuse, eight with intravenous or non-intravenous drug abuse and/or five who smoked. There were 39 (34,8%) individuals who had prior medication, including 27 (69,2%) who were on psychotropics. In addition, there were eight (7,1%) victims who had anticonvulsant medication or a prior diagnosis of epilepsy. Among them, three diagnoses potentially associated with recurrent syncope were made: ARVC, severe aortic stenosis and possible SADS in a 27-years-old man with atherosclerotic CAD (AHA type III and IV lesions).
Victims with prior cardiovascular history and risk factors, and their histopathological diagnosis are depicted in supplementary material 1. There were 16 (14,2%) who had at least one cardiovascular risk factor reported and seven (6,2%) had two or more. Among these, eight had autopsy histopathological diagnosis of atherosclerotic CAD, seven were diagnosed with LVH and one died from acute ascending aorta dissection. Furthermore, one victim aged 36 years-old had previous CABG surgery but no history of known risk factors. A 32-year-old man with non-toxic cannabinoid plasmatic levels and a previous diagnosis of Wolff-Parkinson-White Syndrome, had AHA type 4 and 5 lesions in the anterior descending artery causing a stenosis superior to 75% and a diagnosis of type 2 AMI was presumed. Finally, there were two individuals who had a previous history of unclassified arrhythmia and received the diagnosis of myxomatous mitral valve disease and of LVH, myocardial fibrosis and scar, respectively.
Circumstances of collapse/death in sudden cardiac death victims
Among individuals with a cardiac cause of SD, the place of collapse or of death was described in 55,4% (n = 62) of the autopsy reports. Of these, 56,4% of individuals died at home and 17,7% at the hospital or other health institution (Table 3). Regarding the circumstances of collapse, these were reported in 40 cases (35,7%), including 19 (47,5%) who were unknown in individuals as they were found death or after loss of consciousness and 15 (37,5%) who died at rest, including seven (17,5%) during sleep. Among victims who died during the night, there were two males and one female aged 31–40 years-old, all with LVH (cases 46, 48, 53), a 31-years-old female with mitral valve prolapse (case 82) and a 36 years-old man with atherosclerotic CAD (AHA type IV lesion, case 20), all without evidence of ischemic lesions, myocardial fibrosis or scar. Moreover, six (15,0%) SD occurred during or immediately after exertion: two individuals with a final diagnosis of type 1 AMI collapsed during physical effort at work (case 17) and after housework (case 27), respectively, one boy with HCM collapsed while running away from a dog (case 55), another with HCM died during the physical education class (case 57), one man with myxomatous mitral valve disease collapsed while playing football (case 84) and another man who collapsed immediately after playing football received the histopathological diagnosis of LVH and associated mild fibrosis, but no myocardial scar (case 38).
Table 3
Circumstances of collapse/death in sudden cardiac death victims
Reported circumstances of collapse/death
|
N = 112, n (%)
|
Place of collapse/death
Home
Hospital/other health institution
Work
Public place
Entertainment place
|
62 (55,4)
35 (56,4)
11 (17,7)
6 (9,7)
6 (9,7)
4 (6,4)
|
Circumstances of collapse
Unknown – found death/after loss of consciousness
At rest
During sleep
While in/immediately after exertion
|
40 (35,7)
19 (47,5)
15 (37,5)
7 (17,5)
6 (15,0)
|
Witness
Yes, of collapse
Yes, of the good health status 24h before the event
|
36 (32,1)
24 (66,7)
12 (33,3)
|
Symptoms 1h before death
Yes
Chest pain
Syncope/pre-syncope
Indisposition
Vomiting
Unknown
Palpitation
Dyspnea
No
Unknown in individuals who were found collapsed/death
|
51 (45,5)
19 (37,2)
6 (11,7)
4 (7,8)
3 (5,8)
2 (3,9)
2 (3,9)
1 (2,0)
1 (2,0)
6 (11,8)
26 (51,0)
|
Cardiopulmonary resuscitation
Yes
Pre-hospital
In-hospital
Unknown setting
No
|
55 (49,1)
42 (76,4)
24 (43,6)
7 (12,7)
11 (20,0)
13 (23,6)
|
Symptomatic status was considered unknown in 26 victims who were found dead or who died during sleep. Cardiopulmonary resuscitation (CPR) was performed in 42 (76,4%), the majority in pre-hospital setting including three cases who also received CPR from relatives and colleagues.