P5539Genetic heterogeneity of spontaneous coronary artery dissection (SCAD)

Introduction SCAD is a rare coronary event that may cause acute coronary syndromes (ACS). SCAD predominantly occurs in apparently healthy, young to middle aged women (up to 95% of cases). The known causes include: heritable connective tissue diseases, fibromuscular dysplasia, arteritis, contraceptives, cocaine abuse and chest trauma. A variable proportion of patients manifests progression to longer segments of the same vessel or recurrence of dissection in other coronary arteries. SCAD can be the first manifestation of a previously unrecognised systemic disease. Methods In 2010 we started collecting consecutive SCAD, as first clinical manifestation, in patients addressed to our attention for investigation of genetic or non genetic causes, after successful management of the acute phase and exclusion of systemic inflammatory and autoimmune diseases. All patients underwent genetic visit and counselling, collection of clinical reports and imaging records, clinical cardiologic evaluation with pan-angio CT scan, biochemical testing including coagulation-related tests, and and genetic testing of genes causing connective tissue diseases. Parallel clinical family screening and genetic testing were systematically performed. Results The series is constituted of 35 patients (28F and 7M) (age at onset, mean ± SD, 44±7.6 years) with ACS-SCAD (20 STEMI and 15 NSTEMI) and 9 second dissections in a different coronary artery. Two sisters had ACS-SCAD caused by dissection of the same coronary artery. We identified pathologic mutations (n=19/35, 54%) in COL3A1 (n=3), FBN1 (n=1), FBN1+TGFBR1 (n=1), TGFBR1 (n=2), TGFBR2 (n=1), MYLK (n=1), SMAD3 (n=1), COL5A1 (n=1 homozygous), COL5A2 (n=1), MYH11 (n=1), TGFB2 (n=1), ABCC6 (1 homozygous), ELN (2 homozygous sisters and 1 heterozygous unrelated patient), NOTCH1 (n=1). In 8 (23%) patients we identified VUS classified as C3 because previously unreported and predicted as uncertain on the basis of in silico analyses. In the remaining 8 patients we only identified C2 variants. A second SCAD (14 days to 78 months after the first event) occurred in 9 patients (9/35, 25%) (COL3A1 (n=2), FBN1 (n=1), FBN1+TGFBR1 (n=1), MYLK (n=1), COL5A2 (n=1), NOTCH1 (n=1) COL5A2 (n=1) and 1 with a C2 variant in COL3A1. Two patients with thrombocytosis were carriers of the somatic JAK2 V617F mutation. Extra-coronary arterial dilations/aneurysms occurred in 13 families; in the follow-up 2 patients demonstrate dissection in non-coronary arteries. Conclusions Our series, with the potential bias of a referral centre for inherited cardiovascular disease, demonstrated that SCAD is the possible first manifestation of a genetic disorder and that neither disease gene or mutation predicts the risk of a second coronary event. SCAD is a potentially fatal coronary event associated with ACS, warning for familial disease and unpredictable risk of recurrence.