If double is the trouble, the triple is undoable: a fatal association of Hypertrophic Cardiomyopathy (MYH7 pArg719Trp), Heterozygous Familial Hypercholesterolemia (LDLR pGlu343Lys) and SARS CoV-2 infection

Introduction: Hypertrophic Cardiomyopathy (HCM;MIM #192600) and Heterozygous Familial Hypercholesterolemia (HeFH;MIM #144010) are the most common genetic cardiovascular disorders. Although the phenotypical spectrum can be extremely different, both HCM and HeFH can lead to severe heart failure and sudden cardiac death. As the SARS-CoV-2 pandemic spread medical oriented pathologists felt the need to a closer cooperation with cardiologists and pneumologists. In this report, we describe a successful interdisciplinary workout between pathologists, cardiologists, clinical pathologists and geneticists in a case of a young man who suddenly died after a fatal arrythmia and resulted positive for SARS-CoV-2 virus with high titer in myocardium. Methods and Results: The proband is 32-year-old man who suddenly died during physical exercise. The emergency electrocardiogram (ECG) documented a fatal sustained ventricular arrythmia. Autopsy findings showed increased thickness of interventricular septum (IVS;18mm) and left posterior wall (LPW;20 mm). Non-obstructive diffuse coronary artery disease (CAD) was also observed. Furthermore, the presence of multifocal cardiac myocytes injury with lymphocytic myocarditis prompted the search of cardiotropic viruses. Real-Time PCR (RT-PCR) identified a high concentration of SARS-CoV-2 (Ct=13 for Orf1ab, Rdrp and N genes). Molecular autopsy identified two genetic variants classified as pathogenic in the MYH7 (p.Arg719Trp) and LDLR (p.Glu343Lys) genes. Co-segregation analysis within the family (N=22) showed that LDLR mutation was maternally inherited, while MYH7 genetic lesion was de novo. The LDLR mutation carriers (N=12) had LDL plasma concentrations above the 95th percentile (>130 mg/dL) and positive records of cardiac (N=5) and vascular (N=7) ischemic events at young age. Conclusion: Our findings support the idea that the electrical remodeling associated with a genetic substrate and a concomitant presence of diffuse CAD and SARS-CoV-2-induced myocarditis can trigger a fatal arrhythmia. Despite the outcome, the continued investigation throughout the use molecular autopsy led to the identification of the underlying arrhythmic mechanism. This finding is of paramount importance for the first-degree relatives in which the identification of the pathogenic substrate, that renders them vulnerable to an increased risk for life-threatening cardiac events, including sudden death, might prompt for clinical and tailored treatments.