Phenotype‐driven molecular autopsy for sudden cardiac death

A phenotype‐driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1–40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty‐five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.     

Drugs and sudden cardiac death

The last 10–15 years have seen the emergence of increasing numbers of “designer” recreational drugs taken for their mood elevating and euphoric effects. They are unlicensed, untested and there is often only scant information on toxic levels. They are associated with sudden death, most likely through cardiac arrhythmias but have a number of other complications including acute kidney injury, rhabdomyolysis, cerebral oedema and serotonin syndrome which may also ultimately lead to death. This article covers the major classes of these drugs that may be encountered and considers some of the pharmacology and pathophysiological effects.     

Cardiogenic shock and sudden cardiac death

The study of 148 cases of sudden cardiac death revealed in 25 (17%) of them morphological signs of cardiogenic shock characterized by severe microcirculatory disorders: uneven blood-filling of the vessels of the microcirculatory bed and increasing number of nonfunctioning capillaries in the myocardium and hypothalamus; signs of juxtamedullar shunting in the kidneys and the development of sludge phenomenon in different parts of their microcirculatory bed combined with high activity of renin in the plasma. The signs of cardiogenic shock in the group of observations of sudden cardiac death were noted predominantly in the presence of myocardial infarction, large foci of ischemia in the heart or multiple scattered foci of cardiomyocyte damage. Cardiogenic shock was found to occur in sharp reduction of the density of adrenergic nerve structures in the myocardium.     

Arterial hypertension and sudden cardiac death

Prevalence and severity of arterial hypertension in 345 sudden cardiac death (SCD) cases have been assessed basing on post-mortem morphologic examination of the kidneys involving special staining and quantitation of renal arteriolar lesion. Incidence rate for arterial hypertension was determined both for the whole group of cases and subgroups recognized by a variant of myocardial damage, i.e. alcoholic cardiomyopathy, recent myocardial infarction, thrombosis, microfocal or postinfarction cardiosclerosis. SCD was found to be closely associated with arterial hypertension, evidenced by common parenchymal affections similar to chronic pyelonephritis, or rare diabetic glomerulosclerosis. The occurrence and severity of arterial hypertension varied for different subgroups, being a more frequent finding in microfocal versus postinfarction cardiosclerosis and thrombosis (52.6, 31.6 and 28.2%, respectively), and minimal in alcoholic cardiomyopathy. Comparison of arterial hypertension severity and chronic pyelonephritis incidence for the two most numerous groups demonstrated the gravest condition in postinfarction cardiosclerosis than in microfocal one. The potential role of arterial hypertension in the mechanism of cardiac sudden death is discussed.     

Churg-Strauss syndrome and sudden cardiac death.

Churg-Strauss syndrome is a rare disorder characterized by necrotizing vasculitis, granulomas with eosinophilic necrosis, and tissue infiltration by eosinophils. Sudden cardiac death is rarely described in Churg-Strauss syndrome. In this article, we describe a case of Churg-Strauss syndrome with multiorgan involvement manifested as sudden cardiac death. To the best of our knowledge, this form of presentation has not been reported. A 49-year-old woman was found dead in her room. No premonitory complaints had been noted during the days preceding her death. Past medical history did not reveal any relevant illness. At autopsy, multiorganic Churg-Strauss syndrome with prominent cardiac involvement was found. Therefore, this syndrome in the active vasculitic phase may be asymptomatic and may involve predominantly the heart. This variant of the syndrome may be fulminant and present as sudden cardiac death. This form can only be elucidated by autopsy study.     

The investigation of sudden cardiac death

Pathologists are faced with an increasing complexity in the cardiac diseases that cause sudden natural death in the absence of coronary artery disease. A significant proportion of such natural sudden deaths are due to familial heart muscle disease (cardiomyopathy). The phenotypic characteristics of both hypertrophic cardiomyopathy and arrythmogenic right ventricular dysplasia are wider than previously thought and the hearts may be very close to normal on naked eye examination. Detailed histology of the myocardium is needed to identify such cases. Up to 200 sudden deaths a year in England occur in young, apparently fit individuals in whom toxicology and detailed examination of the heart for structural abnormalities is negative. Genetic defects in ion channels (long QT interval) are now known to be one cause of this phenomenon. In investigating a case of sudden death without cause, a study of the family -- if they wish it -- may be helpful in arriving at a cause.     

Lethal immunoglobulins: Autoantibodies and sudden cardiac death

Sudden cardiac death (SCD) is an unexpected death due to cardiac causes that occurs in a short time period (generally within 1?h of symptom onset) in a person with known or unknown cardiac disease. Patients with cardiomyopathies, myocarditis, ischemic heart disease and cardiac channelopathies are at risk of SCD. However, a certain percentage of autopsy-negative cases of SCD in the young (<35?years) remain unexplained even after a post-mortem genetic testing. Autoantibodies against cardiac proteins may be potentially involved in the pathogenesis of different heart diseases and in the occurrence of unexplained SCD. In this review we analyze clinical and animal studies that elucidate the prevalence of these autoantibodies in patients with different cardiac diseases and their pathophysiological relevance. We propose a classification of the autoantibodies associated with heart diseases and focus on their molecular and cellular effects. Anti-beta adrenergic receptor antibodies and anti-muscarinic acetylcholine receptor antibodies affect myocardial electrophysiological properties and were reported to be the independent predictors of SCD in patients with different heart diseases. Autoimmune mechanism is proposed for cardiac-related adverse reactions following human papillomavirus (HPV) vaccination. The pentapeptid sharing between HPV's antigens, adrenergic receptors and muscarinic acetylcholine receptors supports this assumption. The dysregulating effects of the autoantibodies against calcium and potassium ion channels can be the basis for autoimmune phenocopies of genetic cardiac channelopathies, which are also associated with SCD.     

The pathological investigation of sudden cardiac death

Sudden cardiac death is one of the leading causes of death in many different countries. Epidemiologists have refined criteria progressively for the definition of sudden death, while cardiologists have investigated relevant risk factors, especially in patients with cardiac failure and with inherited diseases of cardiac muscle. In contrast, pathologists are responsible for determining the precise cause of sudden death, but there is considerable variation in the way in which they approach this increasingly complex task. In this article, the methods that should be used in routine practice are described. The ideal autopsy involves careful scrutiny of the clinical records, a full macroscopic and microscopic examination, further laboratory tests and the formulation of a final diagnosis. In addition to a full written report, a synoptic proforma summary is desirable. If a uniform method of investigation is adopted, it will lead to improvements in standards of practice, allow meaningful comparisons between different communities and regions, and, most importantly, permit future trends in the patterns of disease that cause sudden death to be monitored.     

Molecular genetic basis of sudden cardiac death

In this review, the up-to-date understanding of the molecular basis of disorders causing sudden death will be described. Two arrhythmic disorders causing sudden death have recently been well described at the molecular level, the long QT syndromes (LQTS) and Brugada syndrome, and in this article we will review the current scientific knowledge of each disease. A third disorder, hypertrophic cardiomyopathy (HCM), a myocardial disorder causing sudden death, has also been well studied. Finally, a disorder in which both myocardial abnormalities and rhythm abnormalities coexist, arrhythmogenic right ventricular dysplasia (ARVD) will also be described. The role of the pathologist in these studies will be highlighted.     

The pathological investigation of sudden cardiac death

Globally sudden cardiac death is one of the leading causes of death. Epidemiologists in many different countries have studied the changing incidence of sudden cardiac death, while cardiologists and geneticists have investigated relevant risk factors and potential preventative treatments, especially in patients with inherited diseases of cardiac muscle. For their part, pathologists are responsible for determining the precise cause of sudden death, but there is considerable variation in the way in which they approach this increasingly complex task. In this review, the methods that should be used in routine practice are described. The ideal autopsy involves careful scrutiny of the clinical records, a full macroscopic and microscopic examination, further laboratory tests and the formulation of a final diagnosis. The written report should conclude with a clear and concise clinico-pathological summary stating, in particular, whether family members should be referred for screening. If a uniform method of investigation is adopted, it will lead to improvements in standards of practice, allow meaningful comparisons between different communities and regions, and, importantly, permit future trends in the patterns of disease that cause sudden death to be monitored.     

Isolated cardiac amyloidosis associated with sudden death

An unusual case of localized cardiac amyloidosis was associated with sudden death in the absence of prior symptoms of heart disease. Autopsy studies showed amyloid deposition in the ventricular myocardium and conduction system; there were no deposits in other viscera, and evidence of a plasma cell dyscrasia was lacking. Thus, it appears that isolated involvement of the heart by amyloidosis may cause death, even in patients who do not have a history of congestive heart failure or arrhythmia.     

Genetics of sudden cardiac death in the young

Sudden cardiac death (SCD) has an enormous impact on those who are left behind, evoking strong feelings of anxiety and incomprehension because such a dramatic event was not anticipated. Moreover, over the last decade a prominent genetic contribution to the pathogenesis of SCD has been unveiled. As many inherited cardiac diseases show an autosomal dominant pattern of inheritance, the risk of carrying the same inherited predisposition is a real concern for the relatives. In this article, we discuss the major causes of primary electrical disorders, cardiomyopathies and thoracic aortic dissection and address issues in genotype–phenotype correlation, personalized management and cardiogenetic counselling.     

Guidelines for autopsy investigation of sudden cardiac death

Although sudden cardiac death is one of the most important mode of death in Western Countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed, and the accurate diagnosis of the causes of sudden cardiac death is now of particular importance. Pathologists are responsible for determining the precise cause of sudden death but there is considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology developed guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate assessment of sudden cardiac death, including not only a protocol for heart examination and histological sampling, but also for toxicology and molecular investigation. Our recommendations apply to university medical centres, regional and district hospitals and all types of forensic medicine institutes. If a uniform method of investigation is adopted throughout the European Union, this will lead to improvements in standards of practice, allow meaningful comparisons between different communities and regions and, most importantly, permit future trends in the patterns of disease causing sudden death to be monitored.     

Guidelines for autopsy investigation of sudden cardiac death

Although sudden cardiac death is one of the most important mode of death in Western Countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed, and the accurate diagnosis of the causes of sudden cardiac death is now of particular importance. Pathologists are responsible for determining the precise cause of sudden death but there is considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology developed guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate assessment of sudden cardiac death, including not only a protocol for heart examination and histological sampling, but also for toxicology and molecular investigation. Our recommendations apply to university medical centres, regional and district hospitals and all types of forensic medicine institutes. If a uniform method of investigation is adopted throughout the European Union, this will lead to improvements in standards of practice, allow meaningful comparisons between different communities and regions and, most importantly, permit future trends in the patterns of disease causing sudden death to be monitored. *http://anpat.unipd.it/aecvp/