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

Abstract

Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete’s heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants.

Sudden Death without a Clear Cause after Comprehensive Investigation: An Example of Forensic Approach to Atypical/Uncertain Findings

“…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.…”

“…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.…”

Eosinophilic Infiltration of the Sino-Atrial Node in Sudden Cardiac Death Caused by Long QT Syndrome

“…Hence, according to current evidence, no certain significance can be given to the anomalies found at the CCS [ 50 ]. The other finding during the heart microscopic examination (fatty infiltration of the right ventricular wall) is of no pathologic significance, since the disposition of the adipose tissue follows the physiological pattern of the so-called “adipositas cordis” [ 51 ]. Indeed, the victim was obese, and fatty infiltration of the heart is a typical and generally benign feature in obese subjects.…”

Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples

“…This case was a 24-year-old female patient who suffered an SCD event and did not carry any other LP variation. It is not unusual for an SCD event to occur in early stages before a structural alteration is developed [ 11 ]. Thus, we strongly believe that our results should be taken into account when interpreting this variant in the future since it is plausible that TTN _c.301796_30179-5insG may be related to SCD.…”