Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers‐Danlos Syndrome

Abstract

Background Arterial tortuosity is associated with adverse events in Marfan and Loeys‐Dietz syndromes but remains understudied in Vascular Ehlers‐Danlos syndrome. Methods and Results Subjects with a pathogenic COL3A1 variant diagnosed at age <50 years were included from 2 institutions and the GenTAC Registry (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions). Height‐adjusted vertebral artery tortuosity index (VTI‐h) using magnetic resonance or computed tomography angiography was calculated. Associations between VTI‐h and outcomes of (1) cardiovascular events (arterial dissection/rupture, aneurysm requiring intervention, stroke), or (2) hollow organ collapse/rupture at age <50 years were evaluated using receiver operator curve analysis (using outcome by age 30 years) and mixed‐effects Poisson regression for incidence rate ratios. Of 65 subjects (54% male), median VTI‐h was 12 (interquartile range, 8–16). Variants were missense in 46%, splice site in 31%, and null/gene deletion in 14%. Thirty‐two subjects (49%) had 59 events, including 28 dissections, 5 arterial ruptures, 4 aneurysms requiring intervention, 4 strokes, 11 hollow organ ruptures, and 7 pneumothoraces. Receiver operator curve analysis suggested optimal discrimination at VTI‐h ≥15.5 for cardiovascular events (sensitivity 70%, specificity 76%) and no association with noncardiovascular events (area under the curve, 0.49 [95% CI, 0.22–0.78]). By multivariable analysis, older age was associated with increased cardiovascular event rate while VTI‐h ≥15.5 was not (incidence rate ratios, 1.79 [95% CI, 0.76–4.24], P =0.185). However, VTI‐h ≥15.5 was associated with events among those with high‐risk variants <40 years (incidence rate ratios, 4.14 [95% CI, 1.13–15.10], P =0.032), suggesting effect modification by genotype and age. Conclusions Increased arterial tortuosity is associated with a higher incidence rate of cardiovascular events in Vascular Ehlers‐Danlos syndrome. Vertebral tortuosity index may be a useful biomarker for prognosis when evaluated in conjunction with genotype and age.