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.

Validating a Curvature‐Based Marker of Cervical Carotid Tortuosity for Risk Assessment in Heritable Aortopathies

“…Stephens et al developed a height‐adjusted vertebral tortuosity index and found an association between height‐adjusted vertebral tortuosity index and the occurrence of a cardiovascular event before 30 years of age (area under the curve=0.71). 10 In multivariate analysis, they found that older age was the only factor associated with increased cardiovascular event rate, whereas height‐adjusted vertebral tortuosity index was not; however, height‐adjusted vertebral tortuosity index was associated with events among those with high‐risk variants <40 years of age, suggesting effect modification by genotype and age. 10 It also suggests that the effect of height is only significant in patients <40 years of age.…”

“… 10 In multivariate analysis, they found that older age was the only factor associated with increased cardiovascular event rate, whereas height‐adjusted vertebral tortuosity index was not; however, height‐adjusted vertebral tortuosity index was associated with events among those with high‐risk variants <40 years of age, suggesting effect modification by genotype and age. 10 It also suggests that the effect of height is only significant in patients <40 years of age. These inconsistent findings may, in part, be related to the use of TI as a measure of arterial tortuosity.…”

“…Specifically, there are 2 limitations due to confounding factors: age and time. Prior studies assessing arterial tortuosity as a marker for adverse outcomes have circumvented the first potential confounding factor by limiting their data to ages <50 years, 8 , 10 based on evidence that arterial tortuosity has less discrimination in older subjects due to the natural development of tortuosity with aging. Morris et al found an association between increased vertebral tortuosity index and the end point of cardiac surgery before 10 years of age in patients with heritable connective tissue disorders, 8 mostly Marfan syndrome and LDS.…”

“…Studies have demonstrated an association between vertebral or carotid arterial tortuosity and adverse aortic events in patients with heritable connective tissue disorders, including LDS, Marfan syndrome, and vascular Ehlers‐Danlos syndrome. 8 , 9 , 10 Increased tortuosity in these cases correlated with a higher likelihood of aortic dissection, rupture, and the need for surgical intervention at an earlier age. 8 , 9 , 10 However, the interpretation of these findings is limited by their use of tortuosity measurements obtained from surveillance imaging after the occurrence of associated risks like aortic dissection and early surgical intervention.…”

“… 8 , 9 , 10 Increased tortuosity in these cases correlated with a higher likelihood of aortic dissection, rupture, and the need for surgical intervention at an earlier age. 8 , 9 , 10 However, the interpretation of these findings is limited by their use of tortuosity measurements obtained from surveillance imaging after the occurrence of associated risks like aortic dissection and early surgical intervention. Consequently, a significant gap in using arterial tortuosity as a marker of disease severity lies in the absence of a temporal relation between the measured outcomes, hindering the establishment of a clear cause‐and‐effect relationship.…”