Abstract 12016: Rare Variants in APOE Gene Are Associated With Disease-Onset and Outcomes of Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and may lead to tragic outcomes such as sudden cardiac death and heart failure. Previous studies have shown that HCM patients undergo significant lipid-related metabolic reprogramming. But whether lipid gene variants affect the diagnosis and prognosis of HCM patients remains unclear.

Methods and Results: Whole-exome sequencing was performed in 985 patients with HCM and 759 non-HCM controls to search for lipid gene variants. The APOE rare variants were more prevalent in patients with HCM than controls (odds ratio, 4.91, P < 0.001). Patients with APOE rare variants have higher left ventricular outflow tract gradient (LVOTG) (71.0 VS 38.0 mmHg, P = 0.035), higher triglycerides (1.59 VS 1.32 mmol/L, P = 0.051) and lower lipoprotein a (65.5 vs 113 mg/L, P = 0.076) in peripheral blood. APOE carriers also had elevated free fatty acids in 290 surgically resected myocardial tissue lipidomics data (P = 0.008). With a median follow-up time of 5.10 years, HCM patients with APOE rare variants were more likely to experience cardiovascular death (adjusted HR 4.8, P = 0.001) and all-cause death (adjusted HR 3.5, P = 0.008).

Conclusion: Our cohort data indicated that rare variants of APOE are associated with altered lipid metabolism in peripheral blood as well as myocardial tissue, increased LVOTG, and greater risk of HCM disease-onset as well as poor prognosis. We proposed that APOE might be associated with HCM and that its contribution to myocardial hypertrophy through lipotoxicity may be an emerging mechanism for HCM pathogenesis and progression.