Genetically determined cardiomyopathies at autopsy: the pivotal role of the pathologist in establishing the diagnosis and guiding family screening

Abstract

Cardiomyopathies (CMP) comprise a heterogenous group of diseases affecting primarily the myocardium, either genetic and/or acquired in origin. While many classification systems have been proposed in the clinical setting, there is no internationally agreed pathological consensus concerning the diagnostic approach to inherited CMP at autopsy. A document on autopsy diagnosis of CMP is needed because the complexity of the pathologic backgrounds requires proper insight and expertise. In cases presenting with cardiac hypertrophy and/or dilatation/scarring with normal coronary arteries, a suspicion of inherited CMP must be considered, and a histological examination is essential. Establishing the actual cause of the disease may require a number of tissue-based and/or fluid-based investigations, be it histological, ultrastructural, or molecular. A history of illicit drug use must be looked for. Sudden death is frequently the first manifestation of disease in case of CMP, especially in the young. Also, during routine clinical or forensic autopsies, a suspicion of CMP may arise based on clinical data or pathological findings at autopsy. It is thus a challenge to make a diagnosis of a CMP at autopsy. The pathology report should provide the relevant data and a cardiac diagnosis which can help the family in furthering investigations, including genetic testing in case of genetic forms of CMP. With the explosion in molecular testing and the concept of the molecular autopsy, the pathologist should use strict criteria in the diagnosis of CMP, and helpful for clinical geneticists and cardiologists who advise the family as to the possibility of a genetic disease.

Autopsy of all young sudden death cases is important to increase survival in family members left behind

“…Both the clinical and genetic diagnoses and subsequent follow-up of family members of SCD cases with a suspected inherited basis are complex and require expertise in both genetic aspects of the disease as well as clinical cardiovascular investigation and management and care for the psychosocial well-being of the families. 22 , 48 , 56 , 117 , 123 , 124 In line with previous consensus statements and guidelines, we recommend the use of a multidisciplinary approach by pathologists, cardiologists, genetic counsellors, geneticists, specialized nurses, clinical psychologists, and patient support groups ( Figure 5 ). 46 , 47 , 56 , 117 In Denmark in 2006, specialized hospital-based units with a particular focus on inherited cardiac disease were implemented in recognition of the need for a dedicated and specialized effort with close cross-sectional collaboration.…”

“… 47 , 102 , 103 The Association for European Cardiovascular Pathology has also recently issued guidelines for diagnosis of genetic cardiomyopathies at autopsy. 48 Blood or spleen tissue should routinely be saved for potential toxicological and genetic testing if deemed necessary, and the examinations may also include biochemistry and microbiology in selected cases. 56 …”

Morphological and Genetic Aspects for Post-Mortem Diagnosis of Hypertrophic Cardiomyopathy: A Systematic Review

“…Thus, several cases are characterized by mutations in the genes encoding the structural components of the thick and thin filaments forming the cardiac muscle sarcomeres. The main genes encode for 11 sarcomeric proteins, showing >1400 mutations, affecting beta-myosin heavy chain, cardiac myosin binding protein C, cardiac troponin T, troponin I, alphatropomyosin, essential and regulatory myosin light chains, actin, alphamyosin heavy chain, titin, and muscle LIM protein [97,98]; frequently, the genetic test in the clinical setting reveals that most patients have mutations at the first three genes while the other genes represent a small fraction. The mutations are generally missense with a single amino acid substitution; then, small deletions or insertions are described [16,99].…”

Sudden death in young South European population: a cross-sectional study of postmortem cases

“…Similarly, nearly a third of cases (30,4%) had pathological findings of uncertain significance: LVH, LV dilation without evidence of myocardial scar (n = 15 and n = 9, respectively), myxomatous (n = 4) 26 or degenerative (n = 1) mitral valve disease, acute pulmonary edema or acute heart failure (n = 5) with coexisting LV interstitial fibrosis 15 , 27 . These pathological findings could not categorically be classified as culprit, yet they may represent innocent bystanders, and thus underlie possible cases of SADS.…”