Sudden Cardiac Death Caused by a Fatal Association of Hypertrophic Cardiomyopathy (MYH7, p.Arg719Trp), Heterozygous Familial Hypercholesterolemia (LDLR, p.Gly343Lys) and SARS-CoV-2 B.1.1.7 Infection

Abstract

Hypertrophic cardiomyopathy (HCM) and heterozygous familial hypercholesterolemia (HeFH), two of the most common genetic cardiovascular disorders, can lead to sudden cardiac death. These conditions could be complicated by concomitant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as in the case herein described. A young amateur soccer player died in late October 2020 after a fatal arrhythmia and the autopsy revealed the presence of HCM with diffuse non-obstructive coronary disease. The molecular autopsy revealed a compound condition with a first mutation in the MYH7 gene (p.Arg719Trp) and a second mutation in the LDLR gene (p.Gly343Cys): both have already been described as associated with HCM and HeFH, respectively. In addition, molecular analyses showed the presence of SARS-CoV-2 lineage B.1.1.7 (UK variant with high titer in the myocardium. Co-segregation analysis within the family (n = 19) showed that heterozygous LDLR mutation was maternally inherited, while the heterozygous MYH7 genetic lesion was de novo. All family member carriers of the LDLR mutation (n = 13) had systematic higher LDL plasma concentrations and positive records of cardiac and vascular ischemic events at young age. Considering that HCM mutations are in themselves involved in the predisposition to malignant arrhythmogenicity and HeFH could cause higher risk of cardiac complications in SARS-CoV-2 infection, this case could represent an example of a potential SARS-CoV-2 infection role in triggering or unmasking inherited cardiovascular disease, whose combination might represent the cause of fatal arrhythmia at such a young age. Additionally, it can provide clues in dating the presence of the SARS-CoV-2 lineage B.1.1.7 in Northern Italy in the early phases of the second pandemic wave.

Keywords: LDLR; MYH7; SARS-CoV-2; familial hypercholesterolemia; fatal arrhythmia; hypertrophic cardiomyopathy; lineage B.1.1.7.

Figure 1

(A) Two chambers view of the proband’s heart. The increased thickness of the left lateral ventricle wall (2.0 cm) and the inter ventricular septum (1.8 cm) is evidenced by black dotted lines. (B) Hematoxylin-eosin staining of the myocardium shows cardiomyocytes disarray which is often seen in hypertrophic cardiomyopathy (HCM). (C) Epicardium exhibits a focus with lymphocytic infiltrate (dark purple dots; red arrow) indicative of lymphocytic myocarditis.

Figure 2

(A) Real time PCR (RT-PCR) shows the positivity of the proband for all the three SARS-CoV-2 genes (threshold cycle values below 25). RFU = relative fluorescent units. (B) Electropherograms show the identification of a heterozygous genetic variant in the MYH7 (p.Arg719Trp) gene and a missense heterozygous mutation in the LDLR (p.Gly343Cys) gene in the proband.

Figure 3

Pedigree of the family with heterozygous familial hypercholesterolemia (HeFH) (n = 19). Squares indicate males and circles represent females, while slashed symbols mean deceased members. The proband (III:1) is marked by a red arrow. +/− indicates the presence of LDLR (p.Gly343Cys) mutation.