Sudden Unexplained Death: History
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Subjects: Cardiac & Cardiovascular Systems
Contributor:
Simone Grassi

Sudden unexplained death (SUD) is a fatal event that encompasses several heart disorders which lead to abrupt and unpredicted death. Normally, the victim has no known history of heart disease. In adult population (16–64 years) the SUD rate is 11/100,000 per year, while, in the young population (<16 years of age), it is 7.5/100,000. Please note that sudden unexplained death is sometimes used as a synonym of sudden unexpected death but some authors use this term to specifically indicate sudden deaths in which both autopsy and toxicology testing are negative. 

  • cardiomyopathies
  • sudden cardiac death
  • forensic autopsy
  • post-mortem genetic testing
  • virtopsy

1. Introduction

According to the evidence of the last 15 years, most of the SUD cases (at least the 5–20% of them) are of cardiac origin [1]. It is well known that Sudden Cardiac Death (SCD) is one of the most common causes of death in developed countries, with a yearly incidence of 30–200/100,000. In young population, SCD is a rare event, having an incidence of approximately 2–5/100,000 patients per year [2]. Coronary artery disease and acquired cardiomyopathies are the most frequent causes of SCD in the adults, while in those younger than 35 years the main cause of SCD is represented by non-ischemic diseases [3][4]. Cardiomyopathies are the main cause of SCD in those younger than 35 years, while up to 40% of young cases of SCD are caused by pathogenic alterations in the genes that code for ion channels or proteins associated with their proper functioning [5][6]. Currently, nearly the 20% of total deaths in young population remain without a conclusive explanation after a complete autopsy [7][8][9][10]. Inherited arrhythmogenic syndromes—channelopathies—account for most of the autopsy-negative cases (if acute intoxications are excluded). On the other hand, cardiomyopathies are generally thought to have distinctive macroscopic and microscopic features. However, in the forensic field cardiomyopathies are often extremely challenging, mainly because of two factors: (i) the phenotypes of cardiomyopathies gradually develop, and some of cases of SCD occur in young victims, with only mild microscopic and/or macroscopic signs of disease; (ii) when the diagnosis has not been made before the death, at the autopsy it is often difficult to distinguish a cardiomyopathy from another pathological (or from a physiological) condition.

2. Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies

Inherited cardiomyopathies (Table 1) are relatively common and SCD is often the first manifestation of disease. When a correct diagnosis has not been made before the death, identifying a cardiomyopathy at the autopsy is extremely important for forensic and public health issues. From a public health point of view, diagnosing inherited cardiomyopathies is essential to identify other carriers of the pathogenic variants within the family and promptly adopt preventive measures. Indeed, it is very common that in the family of the victim a post-mortem diagnosis of cardiomyopathy allows new diagnoses—that would not have been otherwise made (since, as said, cardiomyopathies are generally autosomal dominant and have incomplete penetrance and variable expressivity). From a medico-legal point of view, the pathologist is often asked to determine whether the cause of the death was a condition that, for example, the cardiologist of the victim should have diagnosed. This issue is particularly relevant in countries, like Italy, where athletes have to regularly undergo cardiologic evaluation to exclude diseases, like cardiomyopathies, that contraindicate physical activity [11]. In these cases, especially when ECGs of uncertain significance were obtained and no radiological procedures were indicated, finding that the death was caused, for example, by a phenotype-positive cardiomyopathy is essential to prove the liability of the physician. Moreover, as said, it is important to distinguish inherited cardiomyopathies from myocarditis and infective cardiomyopathies. This issue is of great medico-legal relevance because, in case of death of an inpatient, if a hospital-acquired infection is suspected, it is important to assess whether the cause of the death was a primary cardiomyopathy or a myocarditis/secondary cardiomyopathy. Currently, this problem is particularly relevant, since in about one third of the critically ill COVID-19 patients a cardiomyopathy is found [12][13].

Table 1. The main features of inherited HCM, Arrhythmogenic Cardiomyopathy (ACM) and Dilated Cardiomyopathy (DCM).

  HCM ACM DCM
Prevalence 1/500 [14] 1/2000 [15] 1/2500 [16]
Typical macroscopic features Abnormal wall thickness (≥15 mm) of the LV that cannot be explained by abnormal loading conditions [17] Fibrofatty replacement of the myocardium of the right ventricle and/or the left ventricle [18] LV or biventricular dilatation that cannot be explained by abnormal loading conditions or coronary artery disease [19]
Typical histopathological features Myocytes hypertrophy, disarray, thickened intramural arterioles with luminal narrowing, myocardial fibrosis [20][21] Fibrofatty replacement of the ventricular myocardium with a subepicardial-mid-mural or transmural distribution [18] Replacement fibrosis, interstitial fibrosis, atrophied and/or hypertrophied cardiomyocytes, nuclear pleomorphism [22]
Differential diagnosis (examples) Athlete’s heart, hypertensive cardiomyopathy, glycogen/lysosomal storage diseases, amyloid/sarcoid cardiomyopathy [23] Adipositas cordis, Uhl’s anomaly, PRKAG2 cardiac syndrome, myocarditis, HCM [18] Acquired DCMs, ischemic cardiomyopathy, hypertensive heart disease, athlete’s heart, left ventricular noncompaction [24][22]
Main SCD risk factors LV wall thickness ≥ 30 mm, anamnestic factors (personal history of cardiac arrest, sustained ventricular arrhythmias, syncope), familiarity for SCD, ejection fraction < 50%, nonsustained ventricular tachycardia (NSVT), LV apical aneurysm, extensive late gadolinium enhancement, mutations of troponin T gene [20][23] Number of premature ventricular complexes and of anterior and inferior leads with T-wave inversion at 24-h Holter monitoring, younger age, male sex [25] Mutations of LMNA gene, personal history of syncopes or nonsustained ventricular tachycardia, delayed enhancement identification, frequent premature ventricular contractions, familiarity for SCD [26]
Genetics More than 50 genes coding for sarcomeric proteins (e.g., MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL3) and non-sarcomeric proteins (e.g., CSRP3, FHL1, PLN) [27] More than 15 genes coding for desmosomal proteins (e.g., PKP2, DSP, DSG2, DSC2) and non-desmosomal proteins (e.g., TMEM43, PLN) [18] More than 60 genes coding for proteins with different functions, such as ion channels, transcription factors, sarcomeric/desmosomal/nuclear proteins (e.g., TTN, LMNA, MYH7, TNNT2, MYBPC3, RBM20, MYPN, SCN5A, BAG3, PLN) [19]
Diagnostic rate of post-mortem genetic testing Nearly 80% [5][14] Nearly 50% [5][14] Nearly 30–40% [5][14][28]
Indicated technique for virtopsy MR (technically difficult) [29] MR [29] CT, MR [29]

3. Conclusions

Autopsies of forensic cases of inherited cardiomyopathies are extremely challenging when the phenotypes of these diseases are mild or difficult to be distinguished from physiological or other pathological conditions. In these cases, if accurate microscopic analysis is not diriment, virtopsy and (in particular) post-mortem genetic testing can be of great help. The results of molecular autopsies should always be interpreted by a team composed by (at least) a forensic pathologist and a forensic geneticist and, if uncertain, should be always communicated stressing that the significance of a variant can be dynamic.

This entry is adapted from the peer-reviewed paper 10.3390/ijms22084124

References

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