Aortic Dimensions and Clinical Outcome in Patients With SMAD3 Mutations
2018; Wolters Kluwer; Volume: 11; Issue: 11 Linguagem: Inglês
10.1161/circgen.118.002329
ISSN2574-8300
AutoresAllard T. van den Hoven, Lidia R. Bons, Sara J. Baart, Adriaan Moelker, Ingrid M.B.H. van de Laar, Annemien E. van den Bosch, Jos A. Bekkers, Hence J.M. Verhagen, Denise van der Linde, Jolien W. Roos‐Hesselink,
Tópico(s)Congenital Heart Disease Studies
ResumoHomeCirculation: Genomic and Precision MedicineVol. 11, No. 11Aortic Dimensions and Clinical Outcome in Patients With SMAD3 Mutations Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBAortic Dimensions and Clinical Outcome in Patients With SMAD3 Mutations A.T. van den Hoven, MD, Lidia R. Bons, MD, Sara J. Baart, MSc, Adriaan Moelker, MD, PhD, Ingrid M.B.H. van de Laar, MD, PhD, Annemien E. van den Bosch, MD, PhD, Jos A. Bekkers, MD, PhD, Hence J.M. Verhagen, MD, PhD, Denise van der Linde, MD, PhD and Jolien W. Roos-Hesselink, MD, PhD A.T. van den HovenA.T. van den Hoven Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (A.T.v.d.H., L.R.B., A.E.v.d.B., D.v.d.L., J.W.R.-H.) , Lidia R. BonsLidia R. Bons Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (A.T.v.d.H., L.R.B., A.E.v.d.B., D.v.d.L., J.W.R.-H.) , Sara J. BaartSara J. Baart Department of Clinical Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (S.J.B.) , Adriaan MoelkerAdriaan Moelker Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands (A.M.) , Ingrid M.B.H. van de LaarIngrid M.B.H. van de Laar Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands (I.M.B.H.v.d.L.) , Annemien E. van den BoschAnnemien E. van den Bosch Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (A.T.v.d.H., L.R.B., A.E.v.d.B., D.v.d.L., J.W.R.-H.) , Jos A. BekkersJos A. Bekkers Department of Cardio-Thoracic Surgery, Erasmus Medical Center, Rotterdam, The Netherlands (J.A.B.) , Hence J.M. VerhagenHence J.M. Verhagen Department of Vascular Surgery, Erasmus Medical Center, Rotterdam, The Netherlands (H.J.M.V.) , Denise van der LindeDenise van der Linde Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (A.T.v.d.H., L.R.B., A.E.v.d.B., D.v.d.L., J.W.R.-H.) and Jolien W. Roos-HesselinkJolien W. Roos-Hesselink Jolien W. Roos-Hesselink, MD, PhD, Department of Cardiology, Erasmus University Medical Center, Room RG-435, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Email E-mail Address: [email protected] Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (A.T.v.d.H., L.R.B., A.E.v.d.B., D.v.d.L., J.W.R.-H.) Originally published2 Nov 2018https://doi.org/10.1161/CIRCGEN.118.002329Circulation: Genomic and Precision Medicine. 2018;11:e002329Pathogenic SMAD3 mutations are a known cause of early aortic dilatation and dissection. In combination with osteoarthritis at young age this is encapsulated in the aneurysms-osteoarthritis syndrome.1 Aneurysms-osteoarthritis syndrome has many similarities with Loeys-Dietz syndrome and is recognized by some as part of Loeys-Dietz syndrome.2 It is currently unknown how the rate of aortic dilatation in SMAD3 patients compares to other syndromic causes of aortic dilatation.We have followed SMAD3 mutation carriers in our center per in-house protocol since December 2011. This protocol includes yearly ECG-gated contrast-enhanced thoraco-abdominal computed tomography angiography. In 10 patients earlier scans were available (2003 to 2011), which were included only when aortic diameters could be reliably measured according to protocol standards. Aortic dimensions were repeatedly measured perpendicular to the vessel at 8 standardized levels using double-oblique multiplanar reconstruction by an experienced cardiovascular radiologist, blinded to clinical data and to previous measurements. To account for correlations between multiple measurements within each patient, average time trends were estimated using linear mixed models. Cubic splines were used to model nonlinear growth curves. Patient-specific intercepts and slopes allowed for individual deviations from the average growth. As described in our in-house protocol patients with an aortic diameter of 42 mm or above are considered in the interdisciplinary heart team for intervention. The study protocol was approved by the medical ethics committee of our center.Baseline characteristics are shown in Figure (A). When looking at the average increase per year (Figure [B]), significant growth was seen at 3 levels: the sino-tubular junction, the ascending aorta, and the level of the diaphragm. The average growth was largest at the sino-tubular junction with 0.4 mm/y (95% CI, 0.12–0.62; P=0.005), followed by the ascending aorta and diaphragm with 0.2 mm/y (95% CI, 0.04–0.38, P=0.018 and 95% CI, 0.10–0.27; P T, SMAD3 ex 9. Data are shown as mean±SD, median (25%–75%), or n (%). B, aortic growth: average of all aortic measurements per level of the aorta, shaded gray areas indicate the 95% CI for the estimate. ST indicates sino-tubular.The mean rate of increase in aorta diameter in the normal population is 0.07 and 0.09 mm per year of life in women and men, respectively.3 The natural course of this process is influenced by many factors such as age, sex, and blood pressure. In the past decade, much attention has been paid to genetic aortopathies. In Marfan syndrome, for example, the aorta dilates fastest at the level of the sinus of Valsalva with a rate of ≈0.49±0.5 mm per year.4 In comparison to Loeys-Dietz syndrome, where the aorta can grow at rates of up to 10 mm/y, dilatation in our cohort may seem relatively mild.5 However, in earlier studies mortality was high, and although no deaths occurred during our follow-up, it should be noted that this could be explained by the intensive management and preventive surgery at relatively mild dilatation of the aorta.The current results differ from a previous report from our group, especially in growth rate and location of fastest growth, which can be explained by longer follow-up duration, inclusion of milder cases discovered by family screening, and by using different analysis methods. Still, we can appreciate that SMAD3 mutation carriers show aortic dilatation at a rate similar to other genetic aortopathies, dilatation occurs predominantly at the sino-tubular junction and ascending aorta, but also in all other parts of the aorta and large arteries. With this study we provide evidence that SMAD3 mutations cause an aggressive form of aortic dilatation, warranting vigilant follow-up. The fastest growth rate (0.4 mm/y) was observed at the level of the sino-tubular junction. In 64% (18 of 28) of the patients in this study, a potentially fatal arterial pathology was discovered. However, for the management of SMAD3 patients this implies that the current protocol adequately addresses the clinical problem in these patients as no patients died from aortic rupture or suffered from aortic dissection during follow-up. Additionally, this study provides an important measure of reference to other known causes of genetic aortopathies. More research is needed to determine predictors for fast growth and possible medical therapies in SMAD3 patients hopefully resulting in a better understanding and improved outcome.AcknowledgmentsThe study was approved by the medical ethical committee of the Erasmus medical center.Sources of FundingThis study was funded by a grant of the Dutch Heart Foundation (The Hague, The Netherlands, grant number: 2013T093). The Dutch Heart Foundation had no influence on study design; in the collection, analysis and interpretation of data; in the writing of the report; or the decision to submit the article for publication. Additionally, this work was supported by funding from the Dutch Heart Foundation (2014T007) and Erasmus University Rotterdam Fellowship to Dr van de Laar.DisclosuresNone.FootnotesJolien W. Roos-Hesselink, MD, PhD, Department of Cardiology, Erasmus University Medical Center, Room RG-435, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Email j.[email protected]nlReferences1. van der Linde D, et al. Progression rate and early surgical experience in the new aggressive aneurysms-osteoarthritis syndrome.Ann Thorac Surg. 2013; 95:563–569. doi: 10.1016/j.athoracsur.2012.07.009CrossrefMedlineGoogle Scholar2. Schepers D, et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.Hum Mutat. 2018; 39:621–634. doi: 10.1002/humu.23407CrossrefMedlineGoogle Scholar3. Vriz O, et al. Normal values of aortic root dimensions in healthy adults.Am J Cardiol. 2014; 114:921–927. doi: 10.1016/j.amjcard.2014.06.028CrossrefMedlineGoogle Scholar4. Detaint D, et al. Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy.Heart. 2014; 100:126–134. doi: 10.1136/heartjnl-2013-304920CrossrefMedlineGoogle Scholar5. Loeys BL, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor.N Engl J Med. 2006; 355:788–798. doi: 10.1056/NEJMoa055695CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Gouda P, Kay R, Habib M, Aziz A, Aziza E and Welsh R (2022) Clinical features and complications of Loeys-Dietz syndrome: A systematic review, International Journal of Cardiology, 10.1016/j.ijcard.2022.05.065, 362, (158-167), Online publication date: 1-Sep-2022. Dekker S, Thijssen C, Linde D, vd Laar I, Saris J, van Es A, Doormaal P, van Bronswijk P, van Kooten F and Roos-Hesselink J (2022) Neurovascular abnormalities in patients with Loeys-Dietz syndrome type III, European Journal of Medical Genetics, 10.1016/j.ejmg.2022.104424, 65:2, (104424), Online publication date: 1-Feb-2022. van Dorst D, de Wagenaar N, van der Pluijm I, Roos-Hesselink J, Essers J and Danser A (2020) Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment, Cardiovascular Drugs and Therapy, 10.1007/s10557-020-07116-4, 35:6, (1233-1252), Online publication date: 1-Dec-2021. Gong J, Zhou D, Jiang L, Qiu P, Milewicz D, Chen Y and Yang B (2020) In Vitro Lineage-Specific Differentiation of Vascular Smooth Muscle Cells in Response to SMAD3 Deficiency, Arteriosclerosis, Thrombosis, and Vascular Biology, 40:7, (1651-1663), Online publication date: 1-Jul-2020. November 2018Vol 11, Issue 11 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002329PMID: 30571188 Originally publishedNovember 2, 2018 Keywordsaneurysmcomputed tomography angiographyLoeys-Dietz syndromeaortic diseasesosteoarthritisPDF download Advertisement SubjectsAneurysmComputerized Tomography (CT)Genetics
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