Abstract 12109: Cardiac LDLR Drives Chimeric SARS-CoV-2-Induced Myocarditis in K18 Hace2tg Mice

Introduction: Cardiovascular disease patients with COVID-19 present prolonged hospitalization and increased mortality. Cardiovascular complications including myocarditis have been reported in association with COVID-19. We recently reported that levels of cardiac low-density lipoprotein receptor (LDLR) are elevated in patients with heart failure. We hypothesized that LDLR may play a role in COVID-19-induced myocarditis. Methods: K18 h ACE2 tg mice were inoculated with SARS-CoV-2 Washington (WA-1) native strain, replication-competent chimeric (ch) SARS-CoV-2, or PBS and lung viral load and histopathology were compared (N=4). We interrogated the LDLR in 4-month-old K18 h ACE2 tg mice via intravenous injection of AAV9-cTnT-hLDLR (gain of function), AAV9-cTnT-hIDOL (Induced Degrader of LDLR, loss of function), or AAV9-cTnT-Luciferase (control). After 4 weeks, mice were inoculated intratracheally with chSARS-CoV-2. Five days after inoculation, mice were sacrificed, and blood and tissues collected for histopathological analysis and RNA/protein studies to evaluate myocarditis. Myocarditis was established by histological analysis according to the Dallas criteria. Results: Both native SARS-CoV-2 and chSARS-CoV-2 had ~60% infectivity as measured by qPCR and immunostaining. Over-expression (OE) of cardiomyocyte-specific hLDLR together with chSARS-CoV-2 induced myocarditis with prominent cardiomyocyte degeneration, necrosis, and immune cell infiltration: T cells (59 cells/mm 2 ;p<0.05) and Macrophages (109 cells/mm 2 ;p=0.0002) compared to the single control groups. In addition, hLDLR-OE increased heart expression of Osteopontin (12.6 vs 1.2%;p<0.05), pAKT(Ser473) (14.4 vs 3.5; p<0.05) and ICAM-1 (9.0 vs 3.3%; p<0.05). OE of cardiac-specific hIDOL mice infected with chSARS-CoV-2 reduced macrophage infiltration into the heart compared to hLDLR-OE myocarditis and control chSARS-CoV-2 groups (p<0.0001 and p<0.05), respectively. hIDOL-OE reduced cardiac ICAM-1 compared to myocarditis and control chSARS-CoV-2 groups (p<0.01 and p<0.05), respectively. Conclusions: Cardiac LDLR drives COVID-19-associated myocarditis in a new mouse model of SARS-CoV-2 infection.