Forensic Pathological Study of 334 Cases of Sudden Cardiac Death in Genoa (Italy) District

Forensic pathological study of 334 cases of sudden cardiac death in Genoa (Italy) district. A seven-year report

Rosario Barranco1, Nicolò Vernazza1, Francesco Ventura1,*

______Abstract: Background. Sudden cardiac death (SCD) is one of the main causes of death worldwide. The analysis of such cases is a complex and delicate task, which is invariably carried out by the forensic pathologist. Methods. We conducted a retrospective analysis of cases of SCD identified among cases of sudden death on the basis of complete autopsy study at the Institute of Legal Medicine from 2011 to 2017. Objectives. Our aim was to analyze the epidemiological data and etiological distribution. This review is the first study to analyze the etiological distribution and epidemiological data of SCD in an area of north-western Italy from the perspective of forensic identification. Results. In the period considered, 334 cases of SCD were identified; the mean age of the subjects was 65.4 years, and males were clearly predominant (78.14%). In 91.62% of our overall series, the cause of SCD was coronary atherosclerotic disease (CAD), the highest occurrence of which was found in subjects aged over 60 years (98.02%). In over 85% cases of CAD, the left anterior descending artery (LAD) presented sclerotic degeneration and stenosis. A markedly lower percentage of CAD (28.58%; 4 cases) was found in subjects aged less than 40 years, in whom the leading cause of SCD was hypertrophic cardiomyopathy (35.72%; 5 cases). Conclusions. That the leading cause of SCD was CAD. In subjects aged less than 40 years, hypertrophic cardiomyopathy was the most frequent pathology. LAD was the coronary branch most often involved in CAD-related SCD. Key Words: autopsy, sudden cardiac death, necropsy, coronary atherosclerotic heart disease, epidemiology, pathology.

INTRODUCTION 60-70% of SCD [6], especially in subjects over 40 years of age, SCD in adolescents and young adults is often caused Sudden cardiac death (SCD) is unexpected by a congenital disease that has gone unrecognized, such natural death due to cardiac causes; it occurs within as cardiomyopathies or pathologies of the conduction a short period of time, generally within one hour after system [7-11]. In these latter cases, autopsy diagnosis is the onset of symptoms, in subjects without a history particularly important in order to implement strategies of potentially fatal heart disease [1]. In the case of that may prevent fatal events among the subject's relatives unwitnessed death, the definition of SCD requires that [12]. the subject be seen in a stable condition within the 24 According to a pathophysiological model, cardiac hours prior to death [2-3]. In general, cases in which arrest may occur as a result of a mechanical cause when pathology examination (macroscopic and histological) the action of the heart and cardio-circulatory system is and toxicological findings are negative are classified as impaired by mechanical factors (i.e. cardiac tamponade) “sudden arrhythmic death syndrome” [4-5]. or as a result of an electrical conduction disorder, as in the Although coronary disease is the cause of over case of arrhythmia (often ventricular fibrillation) [13-14].

1) University of Genova, Department of Legal and Forensic Medicine, Genova, Italy * Corresponding author: University of Genova, Department of Legal and Forensic Medicine, via De’ Toni 12, 16132, Genova, Italy, Tel.: + 39-010-3537838, Fax: +39-010-3537643, E-mail: [email protected]

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Although a great many books, guidelines and Italian, 81 from South America and 32 of African origin. articles have described how an autopsy should be carried out in the case of sudden death [6, 15-17], there is no Pathology of SCD uniform approach in all centers, even within the same The forensic-pathological diagnoses made on country [6]. the basis of thorough post-mortem examination of the A very complex task for the forensic pathologist 334 cases of SCD are reported in Figure 1. is to ascertain the cause and nature of sudden cardiac The most common pathology was coronary death [18-19]. A difficulty inherent in these cases is atherosclerotic heart disease (306 out of 334 cases; the lack of precision in the anamnesis and clinical and 91.62%) in which a mismatch occurred between symptomatic data prior to the 24 hours before death [20]. myocardial oxygen demand (proportional to myocardial The present review is a prospective-observational study effort) and the supply of oxygen (proportional to regarding autopsy and histological analyses of cases of coronary flow). Coronary atherosclerotic heart disease SCD recorded at the Institute of Legal Medicine from was identified as the occurrence of myocardial infarction 2011 to 2017. or critical narrowing. In some of this group, a myocardial infarction MATERIALS AND METHODS with rupture of the left ventricle and cardiac tamponade was observed (22 cases out of 306). Identifying cases Cardiomyopathy accounted for 8 cases (2.40%): In this review, we examined the records of 7 cases of hypertrophic cardiomyopathy and 1 case of diagnoses made on autopsy at the Institute of Legal Medicine in the period 2011-2017, in order to identify cases of sudden cardiac death. We did not consider cases of sudden unexpected infant death, which are analyzed at another regional center. In the period considered, we identified 334 cases of sudden cardiac death on a total of 1153 corpses that had undergone autopsy. In the cases identified, autopsy, including histopathological examination, had been carried out by scrupulously following the recommendations made by Basso et al. [21].

Inclusion and exclusion criteria We considered only those cases in which death occurred within an hour of the onset of symptoms due to cardiovascular pathologies [22]. In cases of unwitnessed death, we included only those cases in which the deceased person's relatives had reported that he/she had apparently been in good health and free from symptoms within 24 hours of the fatal event. Obviously, deaths due to non- cardiac causes, such as accidents, drug and alcohol abuse, poisoning, epilepsy or acute pulmonary embolism were excluded from the analysis.

RESULTS

Demographics Of the 334 subjects, 261 (78.14%) were male and 73 (21.86%) were female. The youngest subject was 21 years of age; the mean age of the subjects was 65.4 years, and the median age was 65 years. A small percentage of subjects (4.19%) were under 40 years of age: 12 men and 2 women. The 40-60-year age-range comprised 168 subjects (50.30% of the total): 35 women and 133 men. A considerable number of subjects (152; 45.51%) were over 60 years of age: 36 women and 116 men. As to the ethnicity of the subjects, 221 cases were Figure 1. The etiological distributions of sudden cardiac death in the different age groups.

11 Barranco R. et al. Forensic pathological study of 334 cases of sudden cardiac death in Genoa (Italy) district

Table 1. Forensic pathological diagnoses of 334 SCD cases <40 year-old age 40-60 year-old age >60 year-old age Etiological distributions Total distributions group group groups, Coronary atherosclerotic 4 cases (28.58%) 153 cases (91.07%) 149 cases (98.02%) 306 cases (91.62%) heart disease Hypertrophic 5 cases (35.72%) 2 cases (1.19%) - 7 cases (2.09%) cardiomyopathy Arrhythmogenic right 1 case (7.14%) - - 1 case (0.30%) ventricular dysplasia Myocarditis - 4 cases (2.38%) - 4 cases (1.19%) Valvular heart disease - 2 cases (1.19%) - 2 cases (0.60%) Pericarditis - 1 case (0.60%) 1 case (0.66%) 2 cases (0.60%) Takotsubo syndrome - - 2 cases (1.32%) 2 cases (0.60%) Sudden unexplained death 4 cases (28.58%) 6 cases (3.57%) - 10 cases (3%) arrhythmogenic right ventricular dysplasia. In these cases valve disease and rupture of the tendinous cords were the diagnosis was made according to the pathological recorded. In 6 cases, the cause of death remained unclear diagnostic criteria and findings [23-27]. (sudden unexplained death), as only nonspecific findings In 2 cases (postmenopausal women), autopsy and emerged. histology findings revealed widespread contraction band The third group (over 60 years) comprised 152 necrosis formed by hypercontracted, deeply eosinophilic subjects. All but 3 had coronary atherosclerotic heart myocardial cells. Moreover, there were a thinning of the disease. In 15 subjects, rupture of the left ventricle and myocardial cells, interstitial edema and fibrosis, mostly at cardiac tamponade were observed. In 1 case, death was the cardiac apex. No obstructive coronary artery lesions caused by left ventricular insufficiency secondary to were present. In both cases, the women suffered from exudative pericarditis. In 2 cases, a Takotsubo syndrome Takotsubo cardiomyopathy. Thus, given the absence of was found (thanks also to anamnestic data and previous other cardiac pathologies, the most likely hypothesis cardiological examinations). was deemed cathecholamine toxicity due to Takotsubo cardiomyopathy, based on reports in the literature from Pathology of coronary atherosclerotic disease authoritative references [28-31]. In the cases reviewed, 91.62% (306/334) of We observed 6 cases of inflammatory/infective sudden cardiac deaths were related to a coronary pathology: 4 of myocarditis (1.19%) (according to the atherosclerotic disease (CAD). The oldest age-group diagnostic findings from the literature [23-24]) and 2 (> 60 years) displayed the highest percentage of CAD of pericarditis (0,60%). Only in 2 cases was mitral valve (98.02%). disease and rupture of the tendinous cords discovered. Pathological findings attributable to myocardial However, in 10 cases (3%), despite thorough post- ischemia (considering both healed myocardial mortem and histological examination according to Basso infarction and early-acute infarction) were detected et al. [21], only nonspecific findings emerged, and the (macroscopically and histologically). cause of death could not be precisely ascertained. In all these cases of CAD, the degree and The cases that we reviewed were subdivided distribution of the coronary stenoses were studied. In 7 into three age-groups: under 40 years, between 40 and cases (2,29%), the obstruction (of at least one coronary) 60 years, and over 60 years. In 41 cases (12.27%) it was was less than 25%; in 18.95% (58 cases) the stenosis was established that death had occurred during sport or other of 25-50% (grade-II lesions); in 28,10% (86 cases) it was physical activity (including strenuous work). of 51-75% (grade-III - significant stenosis), and in 50.66% The first group (under 40 years) comprised 14 (155 cases) a grade-IV stenosis (>76%) was found. subjects. Of these, 4 presented coronary atherosclerotic With regard to the distribution of stenosis in the heart disease, 5 hypertrophic cardiomyopathy, 1 three main coronary branches, our study revealed that arrhythmogenic right ventricular dysplasia; in 4 cases, the the left anterior descending artery (LAD) was involved cause of death remained unknown (sudden unexplained in 85.3% of cases; in 60.8%, the circumflex branch of death) despite the exclusion of extracardiac causes. the left coronary was involved, and in 52.2% the right The second group (40-60 years) accounted for coronary. Moreover, a high percentage of cardiomegaly 168 subjects. In 153 cases, a disease of the coronary was recorded; in only 4.57% (14 cases) of cases was the arteries was identified as the cause of death. In this weight of the heart within physiological limits (270-360 g subgroup, 7 subjects presented cardiac rupture and in men and 200-280 g in women [32]). In two cases, the cardiac tamponade. In addition, 2 cases of non- heart weighed over 1 kg (maximum value of 1135 g in a obstructive hypertrophic cardiomyopathy, 4 cases of 52-year-old man). myocarditis, 1 case of pericarditis and 2 cases of mitral

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DISCUSSION percentage is higher than the values reported in previous studies: 80% [1] and 41.6% [22]. It is also higher than the Although sudden cardiac death (SCD) is one of percentage reported by Wang (50.3%) [37]. It is, however, the leading causes of death in Europe, Canada and the in line with the study by Moore et al. [43], in which United States, its exact incidence has not been precisely atherosclerotic coronary disease was the cause of 93.5% defined [33]. The European Society of Cardiology has of cases of SCD. reported an incidence of between 36 and 128 deaths In our case-series, the high percentage of cases of per 100,000 persons per year. Among adolescents and CAD surely reflects the high mean age of our subjects, the adults aged less than 30 years, the overall risk of SCD is highest value (98.02%) being found in those aged over 1/100,000 [6; 34-36]. In general, in Italy most autopsies 60 years. By contrast, CAD was observed in 28.58% of on victims of SCD are carried out in the forensic centers subjects younger than 40 years of age, and in 91.07% of of Legal Medicine. those aged between 40 and 60 years. These findings once This review is the first study to analyze the again demonstrate that older age is a major risk factor for etiological distribution and epidemiological data of SCD coronary atherosclerosis, as reported by several previous in a part of north-western Italy from the perspective of studies [22, 44], with a steeply rising trend after the age of forensic identification. 40 years. The mean age of the subjects in the present study In the present study, the left anterior descending was 65.4 years. This is much higher than the mean age of artery (LAD) was affected by atherosclerosis in 85% 43.8 years reported by Wang et al. [37] in a study of 553 of cases; involvement of the right coronary and the cases of SCD and that of 38.2 years reported by Wu et al. circumflex branch of the left coronary was less frequently [22] in 1656 cases. This marked difference can be ascribed observed. These findings show that the LAD is much to several factors, the main one being that, according to more susceptible to atherosclerotic damage than the the Italian National Institute of Statistics (ISTAT), the other coronary branches. Moreover, it should be population of the Liguria Region has the highest mean underlined that, in the vast majority of cases, the coronary age in the country and the highest percentage of over-60s: hypoperfusion caused an overload of work, ventricular more than 28% of the total [38]. dysfunction, and a markedly higher percentage of cardiac It is well known that men have a higher incidence hypertrophy than in previous studies [18]. of SCD than women [18; 39-40]. In our study, males The percentage of SCD that occurred during were 3.57 times more numerous than females. This ratio, physical effort (12.27%) was relatively high (considering however, is markedly lower than the male/female ratio of the total of the cases). In over 68% (28 cases) the subjects 10/1 reported in other studies [18]. The higher incidence were aged between 40 and 60 years. During physical of SCD in men is undoubtedly influenced by lifestyle effort, the myocardial demand for oxygen increases, differences related to the pressure of work, especially while the blood flow in the coronary arteries is relatively among middle-aged men. Moreover, before the age of scant. This may cause myocardial ischemia or arrhythmia, menopause, women are protected against cardiovascular leading to SCD. In the group of subjects under 40 years of diseases by female hormones. Accordingly, we observed a age, hypertrophic cardiomyopathy was the most frequent peak in the male/female ratio in subjects under 40 years cause of SCD (35.72%). of age, followed by those aged between 40 and 60 years. Surprisingly, in comparison with other Among the over-60s, the ratio declined (the percentage observational studies [22], cases of myocarditis were of women increased). The age-related increase in SCD extremely rare in our series, accounting for only 1.19% of among women is presumably the result of postmenopausal all cases of SCD. Unexpectedly, no case of this pathology hormonal modifications and the consequent rise in was found in subjects aged less than 40 years. cardiovascular risk. In our series, the relatively low incidence of In the adult population, the leading cause of infective/inflammatory diseases (considering that the sudden death is undoubtedly coronary heart disease. The incidence of myocarditis in other studies [22] was 11.9%) highest prevalence of such cases is observed in subjects and of other cardiomyopathies, as well as the absence with a history of previous myocardial infarction, in of cases of coronary development anomalies, may whom the risk of SCD is extremely high between 6 and have been due to an efficient strategy of screening and 18 months after the event [2]. A study found that sudden diagnosis that reduced the occurrence of SCD through death due to coronary disease was 6 times more common the implementation of adequate therapy. among subjects aged 60-69 years than in the general Sudden unexplained death (SUD) accounted for population [41], and a similarly high incidence of SCD 3% of the SCDs across all age-groups. Specifically, in 4 was seen among subjects aged 55-66 years in the series subjects aged less than 40 years (28.58%) and in 6 subjects examined by Penttilä [18;42] . aged 40-60 years (3,57%), the cause of SCD could not be In 91.62% of the subjects in our series, the precisely established, as only aspecific findings emerged. cause of SCD was atherosclerotic coronary disease. This This percentage is markedly lower than the values

13 Barranco R. et al. Forensic pathological study of 334 cases of sudden cardiac death in Genoa (Italy) district recorded in another series; indeed, Wu et al. reported victim's relatives. SUD in 15.2% of their overall series and in 24.9% of Limitations. It should be pointed out that routinely subjects aged less than 35 years. Moreover, another study genetic analysis were not carried out on cadaveric reported a 29% rate of SUD in subjects aged 1-35 years samples. However, if a hereditary cardiovascular disease [45]. is suspected, the victim's relatives were always informed In sum, in cases of SCD, thorough diagnostic and advised to undergo cardiological diagnostic research must always be carried out in order to ascertain examinations and specific genetic tests. the cause of death and to exclude possible genetic or Our retrospective study of 334 cases of hereditary diseases. In this regard, it is important to SCD showed that the leading cause of SCD was implement a proper strategy of prevention in order CAD. However, in subjects aged less than 40 years, to reduce the risk of SCD among the victim's relatives. hypertrophic cardiomyopathy was the most frequent Indeed, if a hereditary congenital pathology is suspected, pathology. Moreover, our study revealed that the LAD the subject's relatives must be informed and prompted to was the coronary branch most often involved in CAD- undergo preliminary cardiological examinations, such as related SCD, and that senescence-related atherosclerosis ECG and echocardiography. is the main risk for CAD. In our study, the incidence of Unfortunately, however, especially in children, SUD was lower than that reported in other retrospective phenotypical expression is low, and it is not always studies. possible to detect functional anomalies by means of In SCD cases, the role of the Forensic Pathologist diagnostic techniques. Moreover, such pathologies are is especially challenging, often entailing a comprehensive often asymptomatic. For this reason, genetic screening multidisciplinary approach. The autopsy and heart should also be recommended, as this is the earliest means sample analyses must follow specified and up-to-date of identifying genetic carriers of asymptomatic heart guidelines [21,46] making sure to obtain everything diseases. The value of this approach is obvious, given that, required an accurate analysis. Furthermore, after gross in most cases, SCD is the first and only manifestation of examination, it is advisable to preserve the entire organ heart disease. Moreover, the risk of cardiac arrest is clearly under formalin and, in case of diagnostic doubts or higher when specific mutations are present. Thus, in cases failure to make a diagnosis, transfer the fixed heart of SCD, the role of the forensic pathologist is clearly of the (and accompanying data) to a tertiary referral center utmost importance, not only at the autopsy table but also specializing in cardiopathology for a second opinion. in dealing with the victim's relatives. In conclusion, an accurate pathological diagnosis Conflict of interest. The authors declare that of the heart disease leading to SCD yields extremely there is no conflict of interest. important information for both the community and the

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