Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe −/− mice treated with colchicine had 50% reduction in aortic oil Red O + plaque area compared to saline control (p = .001) and lower oil Red O + staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36 + staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of

Background: We recently reported the first risk allele for SCAD, a variant (rs9349379-A) in the PHACTR1/EDN1 genetic locus (Adlam et al J Amer Coll Cardiol 73:58-66, 2019). Purpose: We sought to determine the clinical characteristics and initial genetic data for 11 families, in which more than one member has had an episode of SCAD. Methods: Participants were recruited via social media. Informed consent was obtained for whole genome sequencing and collection of clinical information. SCAD was confirmed by review of coronary angiograms and clinical data collected by phone interview and review of specialist letters. Results: Of 235 participants recruited to date, 23 cases showed familial clustering involving sister-sister pairs in six families, three first-degree cousins in one family (picture), two first-degree cousins in two families, a mother-son pair, and a family with concordant monozygotic twins, that is both twins having had SCAD. In an additional family, SCAD is discordant in monozygotic twins. A comparison of symptoms, age at SCAD, clinical syndrome, cardiovascular risk factors, SCAD risk factors, environmental triggers, SCAD location, acute management, left ventricular function and recurrent SCAD events in these families versus isolated cases, will be presented. Three sister-sister pairs have undergone whole genome sequencing and these data sets are undergoing segregation analysis to identify rare variants that are present exclusively in affected family members. Conclusions: To our knowledge, this is the largest assembly of SCAD cases with familial clustering reported to date. It provides strong evidence supporting an underlying genetic basis for SCAD, which most likely is a multi-genic disorder that also involves important gene-environment interactions.

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