Abstract 4346455: The ICAM1 p.K56M HFpEF Risk Variant and Measures of Adiposity

Introduction: Intercellular adhesion molecule (ICAM)-1 has been implicated in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). The ICAM1 p.K56M variant (rs5491) alters ICAM-1 binding function and is present in ~35% of Black individuals, but is rare in other race/ethnicity groups. Although ICAM1 p.K56M (rs5491) is associated with increased risk of HFpEF, granular pathways connecting rs5491 to HFpEF remain unclear. The presence of adiposity, and specifically pericardial fat, has also been strongly associated with increased risk of HFpEF. Hypothesis: As ICAM1 p.K56M and adiposity are both separately associated with HFpEF, we hypothesized that the rs5491 variant is associated with measures of adiposity. Methods: Among the Black individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) we assessed associations between rs5491 and baseline adiposity measures (body mass index [BMI], waist circumference, pericardial fat volume, and hepatic fat). Pericardial fat volume and hepatic attenuation were quantified by computed tomography (CT) at baseline examination. As higher hepatic fat is indicated by lower hepatic attenuation, the inverse of hepatic attenuation was used for models evaluating hepatic fat. Results: Among 1,590 individuals (mean age 62±10 years, 54% female, mean BMI 30±6 kg/m2), 594 (37%) had one or more copy of rs5491, median pericardial fat volume was 61.2 (IQR: 42.3-86.5) cm3 and median hepatic attenuation was 64.1 (IQR: 57.8-69.9) Hounsfield units (HU). There were weak to modest but statistically significant correlations between pericardial fat and other adiposity measures (Figure 1A). Each additional rs5491 allele was significantly associated with higher pericardial fat volume after covariate adjustment, which included adjustment for BMI (Figure 1B). There were no significant associations of rs5491 with hepatic fat, BMI, or waist circumference. Conclusions: In an older cohort of Black individuals, the ICAM1 p.K56M HFpEF risk variant (rs5491) was significantly associated with higher pericardial fat volume, but not with other measures of adiposity. These findings suggest that pericardial adiposity may be a pathway by which rs5491 promotes HFpEF risk.