TY - JOUR
T1 - Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome
AU - Stephens, Sara B.
AU - Shalhub, Sherene
AU - Dodd, Nicholas
AU - Li, Jesse
AU - Huang, Michael
AU - Oda, Seitaro
AU - Kancherla, Kalyan
AU - Doan, Tam T.
AU - Prakash, Siddharth K.
AU - Weigand, Justin D.
AU - Asch, Federico M.
AU - Beecroft, Taylor
AU - Cecchi, Alana
AU - Shittu, Teniola
AU - Preiss, Liliana
AU - Lemaire, Scott A.
AU - Devereux, Richard B.
AU - Pyeritz, Reed E.
AU - Holmes, Kathryn W.
AU - Roman, Mary J.
AU - Lacro, Ronald V.
AU - Shohet, Ralph V.
AU - Krishnamurthy, Rajesh
AU - Eagle, Kim
AU - Byers, Peter
AU - Milewicz, Dianna M.
AU - Morris, Shaine A.
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/10/3
Y1 - 2023/10/3
N2 - BACKGROUND: Arterial tortuosity is associated with adverse events in Marfan and Loeys-Dietz syndromes but remains under-studied 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.
AB - BACKGROUND: Arterial tortuosity is associated with adverse events in Marfan and Loeys-Dietz syndromes but remains under-studied 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.
KW - VEDS
KW - arterial rupture
KW - cardiovascular
KW - dissection
KW - genetics
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U2 - 10.1161/JAHA.123.029518
DO - 10.1161/JAHA.123.029518
M3 - Article
C2 - 37776192
AN - SCOPUS:85174080318
SN - 2047-9980
VL - 12
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 19
M1 - e029518
ER -