At the autopsy, the only relevant macroscopic finding was the myocardial bridging of left anterior descending coronary artery in the context of a normal heart. In general terms, MB is a congenital coronary anomaly (mean length: 14.64 ± 9.03 mm, mean thickness: 1.23 ± 1.32 mm) that usually affects (as in our case) the middle tract of left anterior descending coronary artery and is often found for the first time only at autopsy [30,31,32]. According to many authors, when it is particularly thick (2 mm is generally indicated as cut-off), it may cause myocardial ischemia, but it is controversial if it can be considered a possible cause of SCD [32,33]. Myocardial bridging has been also reported in men with no family history of sudden cardiac death in which the first clinical manifestations of BrS were acute chest pain and syncope [34,35]. A causal relationship between this coronary anomaly and BrS has never been proved, but Riezebos et al. hypothesized that “interaction between the provoked ischemia and the specific repolarization abnormalities that are caused by the Brugada syndrome could provide an electrophysiological substrate that may increase individual susceptibility to life-threatening ventricular tachyarrhythmias” [35].

Microscopic examination of the atria and ventricles found some interesting and complex features. Starting from the left ventricle, fibrosis and disarray in the myocardial area above the MB were described. These features have already been associated to MB in young cases of SD [32,36]. In particular, considering the young age, the presence of fibrosis and disarray without ventricular hypertrophy in regions far from the septum (as in our case) is compatible with an early phenotype of HCM (but it has also been reported as a sign of MB-related myocardial ischemia) [32,36,37]. It should be considered that the abnormal (>500 g) weight of the heart is also suggestive of HCM.

In our case, there also was a sign suggestive of arrhythmogenic cardiomyopathy (ACM): the fatty infiltration of the right ventricle. However, this feature was only found in the antero-lateral region of the right ventricle, a localization that is typical of physiological conditions [38]. Moreover, the fatty infiltration was clearly separated by the myocardium, and there were no signs of necrosis/atrophy of the myocytes (that are typical of ACM), no fibrous or fibro-fatty infiltration of the myocardium (common among young cases of ACM) and no inflammatory infiltrates (that can be present, for example, in ACM hot phases, i.e., the phases of acute myocarditis that can suddenly complicate the disease) [37,39]. Finally, NGS found no variant pathogenic for ACM. All these data suggest a physiological condition. However, this finding is atypical, because fatty infiltration of the myocardium generally affects elderly or obese patients, and our case was young and non-obese (albeit overweight). Hence, since the absence of signs of cardiomyopathy, a clear pathogenic significance cannot be given to the findings. However, it should be considered that some authors reported that fatty infiltration could cause arrhythmias because it represents a structural barrier to the heart electrical impulse and causes oxidative stress. In particular, previous cases of sudden death in patients with fat of the free wall of the right ventricle have been reported [40].

Another interesting microscopic feature was the fibrosis of the sino-atrial node area. In sudden death cases, it is important that an expert pathologist carefully examines the conduction system, as recommended, among others, by Ottaviani and Buja and by The Royal College of Pathologists [12,13]. Indeed, this analysis can help to find the cause of the death but is complicated, for example, by the interindividual anatomical variability [12]. The feature we found in our case is considered physiological (to at least some extent) since fibrosis has been described as a “modulator of structural and functional integrity” of sino-atrial node [41]. In our case, the found amount of fibrosis in the sino-atrial node area is relatively unusual for the young age of the victim (fibrosis is generally more extended in older patients) [41]. However, despite the crucial function of this pacemaker and the presence of important structures, such as Nav1.5 channels-in the periphery of its area, according to current evidence, no pathological significance of this feature can be assessed [41,42].

In conclusion, the autopsy revealed a long and thick MB located in a very proximal tract of the coronary artery and surrounded by signs suggestive of HCM/MB-caused ischemic damage. Moreover, fatty infiltration of the right ventricle and significant fibrosis of the sino-atrial node area were found. These features are relatively common in the general population but are atypical in a young and healthy patient.

In our case, the victim was reportedly a habitual cannabis consumer, and the friend who witnessed his death told the police that he had smoked cannabis few tens of minutes before his death. Toxicologic testing was positive for cannabis use. However, THC concentration in peripheral blood was low. Marijuana use has been associated with a wide spectrum of cardiac adverse effects and, in particular, with arrhythmias (e.g., atrial fibrillation/flutter, atrioventricular block/asystole, sick sinus syndrome and ventricular tachycardia) [11]. However, in our case, the low level of blood THC and the absence of urine do not allow to make inference on the time of the assumption.

Currently, postmortem genetic testing is not mandatory, but in the cases of suddenly died young persons it can often give a substantial contribution to find the cause of the death [32,43,44,45,46]. In general terms, the diagnostic yield of molecular autopsy performed through Next-Generation Sequencing mainly depends on the chosen approach (target sequencing vs. whole exome sequencing vs. whole genome sequencing), on the specific arrhythmogenic syndrome (it varies from 15–30% for Short QT syndrome to 80–85% for Long QT syndrome) and on the presence of other cases of disease in the family (it is generally higher in familial rather than in sporadic cases) [32,44]. In Brugada syndrome, the diagnostic yield is 30–35% [32,44].

In our case, we identified two rare missense variants in the index case, affecting TTN and SLMAP. Both of them can be considered variants rather than polymorphisms since they are associated to a very low frequency in the general population. Since the sequencing was not genome-wide, the presence of variants in genes not included in the panel could not be excluded.

TTN gene codifies for a very large protein called titin, that an important role in skeletal muscles and myocardium contractile functions. Mutations in this gene have been related to familial dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or familial HCM. However, the variant we found had previously been described and was classified as likely benign. Anyway, since TTN gene has been associated with HCM before, and in our case, some signs of HCM were found, and experimental studies should be undertaken to certainly assess the significance of this variant (although two in silico tools suggest it is likely benign).

The variant c.599C > T of the SLMAP gene is a very interesting finding because sarcolemmal membrane-associated protein gene has previously been associated with Brugada syndrome [47,48]. As said, the significance of this variant is still unknown, but all the three in silico tools predictors consulted suggest its pathogenicity.

Hence, we analyzed scientific literature on this theme to verify if cannabis smoking and Brugada syndrome can have combined pro-arrhythmogenic effects.