2.1. Cardiovascular System

The first cause of SD worldwide is cardiovascular diseases, accounting for approximately 90% of such cases [9]. These data are referred to developed countries such as the USA, Japan, and various European countries. When the cardiovascular system is involved, SCD is used. The definitions of SCD are not the same across the scientific community [12]. The incidence of SCD increases with age, varying from about 1 per 1000 per year in subjects of 35–40 years, 2 per 1000 per year by 60 years, and 200 per 1000 per year in the elderly [13,14]. The use of post-mortem imaging is very important in the classification of SCD. Based on these criteria, they may be divided into coronary and non-coronary causes:

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  coronary artery diseases (CAD) represent the majority of cardiovascular deaths, even if the data about the percentage are various, ranging from 56.87% [15] to 80% [9]. The percentage of CAD deaths is closely related to age: indeed, it was highest in subjects over 40 years old. CAD may be further divided into atherosclerotic and non-atherosclerotic types. In this subdivision, the atherosclerotic type accounts for most cases, while non-atherosclerotic coronary artery diseases are included in congenital abnormalities, embolism, arteritis, dissecting aneurysms, and external compression or ostial obstruction;
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  non-coronary cardiovascular diseases are strictly related to congenital anomalies, valvular heart diseases such as rheumatic heart disease and syphilis, hypertensive heart disease, myocarditis, ruptured aortic aneurysm (acute aortic dissection), and cardiomyopathy [16]. In a simplistic classification, SD due to cardiac genetic alterations could be subdivided into two main groups, channelopathies, and cardiomyopathies [17,18].

The so-called SCDs in the majority of cases are due to coronary artery disease. The post-mortem findings both at the gross examination and at the histological investigations frequently support this kind of diagnosis, describing a clinical picture of severe coronary artery atherosclerosis. They may be associated with coronary artery thrombosis, recent myocardial infarction, and myocardial fibrosis subsequent to different events such as infarction. Nevertheless, these findings are variable and relatively infrequent: for these reasons, they may not be considered decisive to validate the diagnosis [19].

The autopsy finding of critical coronary stenosis (defined as one or more of the major extramural coronary arteries with more than 75% narrowing of the luminal cross-section) is sufficient to invoke a diagnosis of SCD, and this is consistently detected in 90% or more of these patients. Death is believed to be due to rhythm disorders, i.e., dysrhythmias, in most of these cases. In the adult, it is estimated that 10 to 25% of SCD could be related to cardiac channelopathies [20].

Several risk factors for SCD have been reported [21], with age and sex representing two important factors: indeed, the risk of SD is greater in males and obviously increases with age. The death rate improves significantly in middle-old age, especially from age 45 to 64 years [22]. Another important factor is the presence of previous coronary artery disease [23]. Patients with known coronary artery disease had a fourfold greater incidence of SD. Nevertheless, about 55% of those dying suddenly had manifested no prior evidence of coronary artery disease. Another important heart disease closely related to SCD is left ventricular hypertrophy: as previously described, patients with ECG evidence of left ventricular hypertrophy had a 5-fold increased incidence of SD.

In this scenario, hypertension and blood cholesterol may be considered two important indirect risk factors in the insurgence of SCD events. Notably, men with systolic blood pressures >160 mm Hg have an incidence of SD three times greater than those who have systolic pressures <140 mm Hg; moreover, elevated cholesterol levels are generally regarded as a risk factor, even if, to date, no stepwise trend proportional to serum cholesterol has been noted [24]. Obviously, overweight and obese status is related to SCD. It has been described that the risk of this tragic event increases progressively with increased weight, arriving at more than doubled for those weighing 120% or more than their ideal weight [25]. Other important indirect factors that could be considered are cigarette smoking and alcohol/drug abuse. In particular, smokers had a 3-fold greater incidence of SD than non-smokers; moreover, the abuser (meaning smokers of >1 pack per day) had higher rates than did smokers of <1 pack per day [26].

In this context, an infrequent but always tragic event occurs when SD happens in an apparently healthy young adult from spontaneous causes. Although the causes of SD in young subjects are scarce, the most prevalent cause of death is related to cardiovascular disease, with primary arrhythmogenic disorders, atherosclerotic events, cardiomyopathies, and myocarditis as the main contributors. Indeed, in a recent article by Vos et al. [27], cardiovascular diseases and genetic arrhythmias accounted for about 50% of their SD cases. Indeed, based on international data, it is estimated that up to one-third of infantile and juvenile SCD may be explained by cardiac channelopathies [28,29,30,31]. The most frequent channelopathies include the long QT syndrome (LQTS), short QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) [32,33,34]. Moreover, in the case of SCD in young people, it could be possible to detect pathogenic mutations in genes encoding structural proteins. These mutations could determine several diseases such as hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy (AC) [35]. The majority of these cardiomyopathies may be diagnosed at autopsy, considering that usually, anatomo-morphological changes in cardiac tissue are detected, especially in young adults [36]. Indeed, as recently described, a primary myocardial fibrosis at autopsy is strictly related to variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy; when autopsy does not show these findings, primary myocardial fibrosis may represent an alternative phenotypic expression of structural disease-associated genetic variants, or that risk-associated fibrosis was expressing before the primary disease [37]. Contrariwise, when this tragic event occurs in an infant, a structurally normal heart is usually reported in the post-mortem documentation [38].

One of the most difficult problems for forensic pathologists is the diagnose of SD in subjects with acute cardiac processes that progress rapidly, with non-specific symptoms, leading to death without evident morphological alterations. In these cases, innovative approaches are frequently proposed. For example, post-mortem magnetic resonance imaging could be one of the most promising tools to identify cardiac pathological alterations, highlighting evidence otherwise not visible with routine autopsy [39]. In the same way, the use of biochemical markers in cadaver fluids is frequently investigated as complementary indicators to help to reach valid conclusions about the cause of death. Although the ideal sampling site is debatable, several studies propose either pericardial fluid or peripheral veins as the location for the biological sample. A recent article suggests that cardiac troponin I (cTnI) values in pericardial fluid and the troponin ratio (pericardial fluid/serum ratio) may be helpful in SCD [40]. Finally, immunohistochemical investigation combined with western blot analysis is used to detect morphological changes in myocardial specimens of fatal SD, quantifying the effects of cardiac expression of inflammatory mediators (CD15, IL-1β, IL-6, TNF-α, IL-15, IL-8, MCP-1, ICAM-1, CD18, tryptase) and structural and functional cardiac proteins (troponin I and troponin C) [41].

When SD occurs in a young subject, it may occur during sports activities. In large post-mortem investigations studies of athlete populations in the United States, hypertrophic cardiomyopathy was the most common cardiovascular cause of SD [42]. The second most frequent cardiovascular cause of SD in the subjects practicing sports activities is congenital coronary-artery anomalies: in these cases, the artery originates from the wrong aortic sinus (more commonly, the left main coronary artery originates from Valsalva’s right sinus) [43]. Other causes of death are congenital cardiac malformations, such as congenital valvular disease, aortic stenosis, myxomatous mitral valve degeneration (typically associated with Marfan’s syndrome), as well as other causes such as myocarditis and coronary atherosclerotic disease [44,45,46].

A molecular autopsy should be considered fundamental in the case of SD in young people, seeking to always incorporate genetic testing into the post-mortem examination. Moreover, it has been proposed that community-based data aggregation and sharing should be mandatory, leading to an improved classification of genetic variants [47,48].

2.2. Respiratory System

The most important cause of death in the case of nc-SD involving the respiratory system is acute pulmonary embolism (APE). The symptoms of APE are various with a complex clinical picture. Indeed, APE is characterized by numerous clinical manifestations with a complex interaction between different organs. In this scenario, it is very difficult to make an immediate diagnosis [49].

Fatal pulmonary embolism (PE) represents the common cause of SD related to the respiratory system, usually resulting from a complication of deep venous thrombosis (DVT). Typical symptom and signs of PE is angina with pleuritic chest pain as a consequence of pleural involvement due to pulmonary infarction [50,51]. In fulminant PE, up to 90% of cardiac arrests occur within 1 to 2 h after the onset of symptoms [52]. The mortality rate related to PE is high and it is due to the principal causes: pulmonary mainstream obstruction and liberation of vasoconstrictive mediators from the thrombi [53]. For example, pulmonary thromboembolism has been identified as one of the common clinical pictures of COVID-19, justifying SD in several subjects who died from SARS-CoV-2 infection [54,55,56]. Other clinical pictures of APE are: symptoms similar to acute respiratory distress syndrome (ARDS) [57]; fever syndrome with or without pseudopneumonia [58]; acute right heart failure/shock/hypotension (often with epigastric pain) [59]; left heart failure (with pulmonary congestion) [60]; chest pain similar to pleuritic syndrome with or without hemoptysis (with or without effusion) [61]; similar to acute coronary syndrome (ACS) (with or without chest pain) [62]; syncope [63]; complete atrioventricular (AV) block with idioventricular rhythm [49]; persistent or paroxysmal atrial fibrillation (AF), atrial flutter, atrial tachycardia [64]; paroxysmal supraventricular tachycardia (PSVT) [49]; DVT and silent PE [65]; platypnea-orthodeoxia [66]; abdominal pain without acute abdomen [64]; and delirium [67].

Other causes of SD strictly related to the respiratory system are:

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  Massive hemoptysis. The common causes of massive hemoptysis could be generated by tuberculosis, bronchiectasis, lung abscesses, and mycetomas [68]; another important cause of massive hemoptysis is lung cancer that could generate this symptoms in about 20% of patients [69]. Moreover, cystic fibrosis is reported to be another cause of massive hemoptysis [70].
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  Severe pneumonia. This cause is considered one of the natural causes of nc-SD [71]. It could be generated both by viral and bacterial agents, generating different diseases involving myocardial ischemia, a maladaptive response to hypoxia, sepsis-related cardiomyopathy, or other phenomena [72,73]. It is interesting to note that the recent pandemic infection of SARS-CoV-2 could generate severe pneumonia with subsequent cardiac arrest [74].
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  Asthma. In a recent study performed in Denmark in young people with uncontrolled asthma, Gullach et al. [75] described that in their cohort, the predominant cause of death was SCD followed by a fatal asthma attack. This clarified the concept that asthma could be considered as a trigger for underlying unknown heart diseases [76].
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  Anaphylaxis. Refers to the event cascade that may follow exposure to a particular antigen and causing an acute multi-organ response, with cardiac, coronary/systemic arterial, and dermatological involvement [77]. Cardiovascular symptoms can be the sole manifestation of food allergies, especially in cases where the tragic event occurs during exercise [78]; in similar cases, death may mimic SCD and only a complete autopsy with a full histological and immunohistochemical investigation may disclose the exact cause of death.
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  Airway obstruction. Another important cause of nc-SD is hypoxia secondary to pulmonary processes, including small and large airway obstruction (bronchospasm, aspiration, foreign body, edema). Treating the cause of hypoxia/hypoxemia must be done quickly because this is one of the potentially reversible causes of cardiac arrest [79]. Proper oxygenation and ventilation are key to restoring adequate amounts of oxygen into the system and negating lethal cardiac rhythm [80]. It is important to note that accidental aspiration of an element into the airways is a widespread clinical scenario among children under 3 years old, and it represents the leading cause of infantile death [81].

2.3. Central Nervous System

Among the nc-SDs, an important category is the imbalance of the autonomic nervous system control of the cardiovascular system. For these reasons, several neurological conditions, such as stroke, epileptic attacks and brain trauma, drugs, and catecholamine toxicity, may be related to SD [82].

Stroke represents the first cause of SD in this category; it is possible to distinguish three kinds of stroke:

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  Intracerebral hemorrhage (ICH) secondary to hypertension or other causes. ICH represents about 10% of strokes. Hypertension is the most important risk factor in order to determine the risk for ICH: for example, Roberts et al. described two cases who died from non-traumatic ICH [83]. Moreover, in a recent study, Verdecchia et al. remarked its value as an independent prognostic marker for SD in the long-term [84].
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  Brain infarction secondary to atherosclerosis or embolism. Moreover, a strong positive relationship exists between decreased heart rate variability (HRV) and SD [85]. Brain infarction is implicated in causing diminished HRV and is strictly associated with symptomatic carotid disease [86].
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  Subarachnoid hemorrhage (SAH), secondary to ruptured berry aneurysm or other causes. It represents about 5% of stroke, and smoking, high blood pressure, increasing age, and possibly female sex are independent risk factors for SAH [87].

Other than stroke causes include:

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  Bacterial meningitis: despite advances in clinical care, it remains a severe disease with a high risk of complications that may lead to SD [88];
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  Epilepsy: it is named sudden unexpected death in epilepsy (SUDEP), referring to the sudden and unexpected death of an epileptic patient with no other health issues during normal activity. The exact cause of SUDEP has not been established yet; however, it is assumed to be caused by multiple organ failure [89];
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  Brain tumor: even if it represents a rare event, an undiagnosed primary brain tumor may be considered a risk factor for SD. For example, Riezzo et al. described three cases of SD due to glioblastoma [90].

2.4. Abdominal Causes

The abdominal region could be involved in the generation of SD. Indeed, even if these causes are a less common cause of SD when compared to other conditions, they are equally important [91,92]. Particularly, the prevalent cause of death involving the abdominal region is massive bleeding into the peritoneal cavity or gastrointestinal tract: it could be linked to different diseases such as duodenal ulcer, gastric ulcer, ulcerative colitis or diverticulitis, malignancy, ruptured ectopic pregnancy, and ruptured viscus for the presence of bowels (e.g., ovarian cysts) [93,94,95].

Moreover, nc-SD involving the abdominal region could be generated by other diseases such as acute liver failure [96] or acute pancreatitis [97].

2.5. Endocrine System

Even if rare, endocrine diseases should be closely related to nc-SD. Notably, when other causes are excluded, this tragic event may be related to different pathological statuses such as adrenal insufficiency (although infrequent, it may occur in individuals treated for other critical conditions where impairment of corticoadrenal function often happen) [98,99], diabetic coma [100], severe hypothyroidism (myxedema) [101], parathyroid crisis [102,103], thymoma [104], etc.

2.6. Iatrogenic

The cases of nc-SD could be related to iatrogenic causes. In particular, even if it is frequently under-evaluated, it could be generated by problems related to prescription drugs [105]. Other causes may be related to the sudden withdrawal of steroids or other drugs. SD represents a complication of other tragic events related to medical errors, such as anesthesia or mismatched blood transfusion [106].

2.7. Miscellaneous

The so-defined miscellaneous category includes drug abuse: it could be related both to the assumption of controlled or uncontrolled substances [107]. In the first case, it is related to the assumption of legal drugs but with errors in the assumption (principally in older people) or voluntary wrong assumption (self-poisoning or for doping purposes), i.e., the use/abuse of anabolic-androgenic steroids (AAS). To date, AASs are frequently used not only to treat both hormonal diseases and other pathologies characterized by muscle loss, but by young people (athletes or individuals) to improve both physical appearance and performance [108,109]. AAS use/abuse is strictly related to the improved risk for SD [110,111].

In the other case, it is related to the assumption of drugs for “recreational” purposes [112]. For example, cocaine in its various forms could be closely related to fatal cardiac arrhythmia, microvascular injury, and acute myocardial ischemia due to coronary vasospasm are the most important causes of cocaine-related SDs. The cardiotoxicity of cocaine is not limited to massive doses of the drug, and underlying heart disease is not a prerequisite for cocaine-related cardiac deaths. Moreover, cocaine is associated with many health complications, including gastrointestinal ischemia/infarction and hemorrhage. For this reason, its assumption may generate SD [113]. Other recreational drugs such as heroin [114], marijuana [115], potent synthetic cannabinoids [116], as well as psychotropic drugs consumed by young people [117] may be related to SDs. Moreover, the proportion of users of recreational drugs was unexpectedly high, even more prevalent than other cardiovascular risk factors. Toxic effects could play an important role as triggers of SD, particularly in young people.

Other miscellaneous nc-SDs could be generated by anaphylaxis or bacteremic shocks, shock from dread, fright or emotion (vagal inhibition), sickle cell crisis, alcoholism, etc. [118,119].

The authors thank the Scientific Bureau of the University of Catania for language support.