Abstract MP47: IFNγ-Mediated Associations Between Chronic Stress Related-Neural Activity And PCSK9: Data From The Washington, D.C. Cardiovascular Health And Needs Assessment

Abstract

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in dyslipidemia and is linked to cardiovascular disease risk. To our knowledge, the potential link between psychosocial stressors, PCSK9 levels, and related dyslipidemia has not been evaluated. Hypothesis: IFNγ mediates the association between amygdalar activity (AmygA) and PCSK9. Methods: Participants from the D.C. Cardiovascular Health and Needs Assessment (DC-CHNA), a community-engaged cohort study, were recruited to the NIH Clinical Center and underwent phenotyping, including 18 FDG PET/CT to assess AmygA as a marker of chronic stress-related neural activity. Cytokines, PCSK9, and lipoprotein (a) (Lp(a)) were measured using ELISA-based techniques. Regression modeling identified associations between AmygA and PCSK9 and between PCSK9 and Lp(a) while adjusting for atherosclerotic cardiovascular disease (ASCVD) 10-year risk score and body mass index (BMI). Mediation analysis was used to evaluate IFNγ, TNFα, and IL-6 as potential mediators. Results: The DC-CHNA consisted of 60 African American participants (mean age 61±11 years, 93% female) at risk for ASCVD. AmygA associated with PCSK9 and IFNγ after adjusting for ASCVD and BMI; additionally, IFNγ associated with PCSK9 ( Figure ). Mediation analysis indicated that IFNγ mediated 45.8% of the AmygA and PCSK9 relationship. TNFα and IL-6 did not mediate the relationship. Lastly, PCSK9 associated with Lp(a) independent of ASCVD risk factors (β=0.34, p=0.013). Conclusions: The role of psychosocial stressors in PCSK9 related-dyslipidemia is not well known. Thus, we show that AmygA, a measure of chronic stress, associated with PCSK9 in an IFNγ-mediated fashion. PCSK9 then associated with Lp(a) which is notable as Lp(a) is thought to be largely genetically determined and highly atherogenic. Future research should further this hypothesis-generating study by prospectively investigating the impact of psychosocial stressors on PCSK9 and dyslipidemia in larger, diverse populations.