Natural history of arterial morbidity in vascular ehlers-danlos syndrome

Abstract Background Vascular Ehlers-Danlos syndrome (vascular EDS) is a rare inherited connective tissue disorder, responsible of exceptional organ fragility. The disease is caused by pathogenic COL3A1 variants with a dominant negative effect, except for variants leading to haploinsufficiency. The course of the disease is characterized by the occurrence of recurrent spontaneous arterial accidents (dissections, aneurysm formation, spontaneous ruptures), typically of medium size arteries. Purpose To describe the natural history of arterial accidents in a molecularly characterized population of patients with vascular EDS, that benefited from repeated standardized vascular monitoring in a tertiary referral centre. Methods All patients from the French natural reference centre for vascular EDS were included in a retrospective cohort study. Standardized monitoring of arterial beds was performed at molecular diagnosis (baseline) and every 15 months thereafter in clinically silent patients, by CT-angiogram or MRA, and by vascular Doppler Ultrasound. In case of symptomatic arterial accidents, diagnostic imaging was also reviewed for arterial defects. Arterial lesions were sorted by date of diagnosis and staged by anatomical location and by type of defect. Results Between January 2000 and March 2017, n=144 patients (n=91 index, Sex Ratio 0.68) were diagnosed with vascular EDS at a mean age of 34.0 [25.0; 41.0] years, and regularly followed-up in our centre for a median 5.80 [3.45; 8.80] years. Types of COLA3A1 variants were glycine substitutions (68%), splice-site (31.8%) and those leading to haplosufficiency (8.3%). During follow-up a median 1.57 [0.9; 3.0] arterial accidents per 5 years occurred and n=17 (11.8%) patients died. At first referral, a majority of patients (68.8%) had already presented a disease-related event, predominantly arterial ones, totalling 232 arterial defects (dissections, 72%; aneurysms, 11.2%; ruptures, 9%; carotid cavernous fistula, 4.3% and arteriovenous fistula, 0.9%). Vascular assessment at baseline identified another 255 arterial defects in the same patients that had not been reported previously. At each further vascular monitoring, one third (36%) of patients presented with new arterial defects, a majority of which (66%) were clinically silent. Moreover, 15% of patients at each vascular assessment had evolved on previously diagnosed arterial lesions (healing or aggravation). Notably, neither symptomatic arterial event nor silent evolutivity occurred in haploinsufficient patients. Conclusion This study gives an extensive insight into distribution, nature and timeline of arterial defects in patients with vascular EDS in a large patient cohort. Besides known and expected arterial morbidity and mortality, a consistent proportion of clinically silent patients developed new arterial lesions, suggesting that progression of arterial pathology in vascular EDS is not limited to symptomatic arterial events.