Background
Family history (FHx) of cardiovascular disease (CVD) is a well-known risk factor for incident CVD, and considered a proxy of cardiovascular heritability. Indeed, large-scale genetic studies have identified tens of loci for CVD, underscoring its polygenic nature and confirming the heritable component. However, little is known about the influence of a positive FHx and the polygenic burden on atherosclerotic plaque composition nor secondary cardiovascular events. 

Materials and methods
A total of 1,788 carotid endarterectomy patients from the Athero-Express Biobank Study were included. FHx was defined as having parents or siblings who developed CVD before the age of 60 and determined by questionnaire. A weighted polygenic risk score for CVD was calculated based on a meta-analytic approach that combined large-scale genetic association data consisting of 1.7 million genetic variants (MetaGRS). Atherosclerotic plaques were immunohistochemically stained and analyzed for macrophages, smooth muscle cells, intraplaque hemorrhage (IPH), calcifications, lipid core size, intraplaque vessels, and collagen content. Composite secondary cardiovascular events during 3-years follow-up consisted of myocardial infarction, stroke, coronary interventions, peripheral interventions and cardiovascular death. We assessed the impact of FHx and PRS on plaque composition and secondary cardiovascular event-free survival through linear, logistic, and Cox-regression modelling. 

Results
Patients with positive FHx (n = 744, 42%) were characterized by a more severe cardiovascular risk profile at baseline. Positive FHx was associated with a higher risk of secondary cardiovascular events during 3-years of follow-up, adjusted hazard ratio (HR) 1.29, 95% CI 1.03-1.60, p = 0.024.  Patients with a high genetic risk (those in the top 20% of the MetaGRS distribution) had more secondary cardiovascular events during follow-up compared with those in the bottom 80% (adjusted HR 1.35, 95% CI 1.01-1.79, p= 0.041), even after correction for cardiovascular risk factors including FHx. MetaGRS was associated with more vulnerable plaque characteristics, including high macrophage content, adjusted odds ratio (OR) 1.49, 95% CI 1.12-1.99 (p = 0.006) and more fat content, adjusted OR 1.59, 1.11-2.29, (p= 0.013). 

Conclusion
In severely atherosclerotic patients, both positive FHx and higher polygenic burden of CVD were independently associated with increased risk of secondary cardiovascular events. In line with this, higher polygenic burden of CVD was correlated with more vulnerable plaques. Our study further underscores the proposition to include PRS as a complement to FHx in individual risk assessment, and advances the concept to use genetic data for selecting high risk study populations when exploring new therapeutic strategies of CVD prevention.

02 - FAMILY HISTORY AND POLYGENIC RISK OF CARDIOVASCULAR DISEASE ARE ASSOCIATED WITH A WORSE SECONDARY CARDIOVASCULAR OUTCOME IN PATIENTS UNDERGOING CAROTID ENDARTERECTOMY