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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.
摘要：
背景动脉弯曲与Marfan和Loeys-Dietz综合征的不良事件相关，但在血管Ehlers-Danlos综合征中仍未得到充分研究。方法和结果在年龄<50岁时诊断为致病性COL3A1变异的受试者包括来自2个机构和GenTAC注册(遗传触发的胸主动脉动脉瘤和心血管疾病国家注册)。使用磁共振或计算机断层扫描血管造影计算高度调整的椎动脉弯曲指数（VTI-h）。VTI-h与（1）心血管事件（动脉夹层/破裂，动脉瘤需要介入,stroke),或（2）使用受试者操作曲线分析（使用30岁的结果）和混合效应泊松回归对发病率比率进行评估，评估年龄<50岁时的中空器官塌陷/破裂。在65名受试者中（54%为男性），VTI-h中位数为12(四分位数间距，8-16).46％的变体是错误的，剪接位点在31%,和无效/基因缺失的14%。32名受试者（49％）有59个事件，包括28个解剖，5动脉破裂，4个需要干预的动脉瘤，4笔画,11个中空器官破裂，和7个气胸。受试者操作曲线分析建议在VTI-h≥15.5时对心血管事件进行最佳区分(灵敏度为70%，特异性76%)，与非心血管事件无关联(曲线下面积，0.49[95%CI，0.22-0.78]）。通过多变量分析，年龄较大与心血管事件发生率增加相关，而VTI-h≥15.5则不相关(发生率比，1.79[95%CI，0.76-4.24]，P=0.185）。然而,VTI-h≥15.5与高风险变异<40年的患者中的事件相关(发生率比，4.14[95%CI，1.13-15.10]，P=0.032),提示基因型和年龄的影响修饰。结论血管迂曲增加与血管Ehlers-Danlos综合征患者心血管事件发生率升高相关。当结合基因型和年龄进行评估时，椎体弯曲指数可能是预后的有用生物标志物。
