Abstract
Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36 months read in the core laboratory of 608 trial subjects, aged 6 months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz) > 3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year > 90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R2 = 0.01) or by change in AoR diameter (AoRd)/year > 90th percentile with higher sinotubular junction z-score and non-white race (R2 = 0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R2 = 0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34 cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364.
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Acknowledgements
Pediatric Heart Network Investigators: In addition to the authors, the following investigators participated in the Pediatric Heart Network Marfan Trial. National Heart, Lung, and Blood Institute: Gail Pearson, Mario Stylianou, Victoria Pemberton. Network Chair: Lynn Mahony, University of Texas Southwestern Medical Center. Data Coordinating Center: New England Research Institutes, Lynn Sleeper* (PI), Sharon Tennstedt* (PI), Steven Colan, Gloria Klein*, Lin Guey*, Lisa Wruck*, Thomas Travison*, Shan Chen*, Eric Gerstenberger*, Tanya Olesker*, David F. Teitel*. Core Clinical Site Investigators: Boston Children’s Hospital, Boston, MA: Jane Newburger (PI), Ronald V. Lacro (Study Co-chair), Martha King, Carolyn Dunbar-Masterson, Jill Handisides, Andrea Posa*, Quincy Nang*, Cara Hass; Children’s Hospital of New York, NY: Daphne Hsu (PI)*, Wyman Lai (PI)*, William Hellenbrand*, Beth Printz*, Mary J. Roman, Richard Devereux, Rosalind Korsin, Greysi Sherwood*; Children’s Hospital of Philadelphia, PA: Victoria Vetter (PI), Stephen Paridon, Marie Gleason, Reed Pyeritz; Nicole Mirarchi*, Sandra DiLullo*, Agbenu Ejembi, Ruth Morgan*, Tonia Morrison; Cincinnati Children’s Medical Center, OH: D. Woodrow Benson* (PI), William Border*, James Cnota, Haleh Heydarian, Jeanne James*, Michelle Hamstra, Kathryn Hogan*, Lois Bogenschutz*; Duke University, NC: Page A. W. Anderson (PI) - deceased, Jennifer S. Li (PI), Stephanie Burns Wechsler, Amanda Cook*, Charles Sang, Wesley Covitz*, Mingfen Xu, Lori Jo Sutton, Kari Crawford*, Summer Roberts*, Deborah Palmer; Medical University of South Carolina: J. Philip Saul* (PI), Andrew Atz, Geoffrey Forbus, Teresa Atz, Patricia Infinger, Aparna Choudhury*; Primary Children’s Hospital and the University of Utah, Salt Lake City, UT: LuAnn Minich (PI), Richard Williams, Angela Yetman*, Marian Shearrow, Michelle Robinson*, June Porter*; Hospital for Sick Children, Toronto, Canada: Brian McCrindle (PI), Timothy J. Bradley*, Jennifer Russell, Jack Colman, Elizabeth Radojewski*, Svetlana Khaikin*, Nancy Slater*; Johns Hopkins University School of Medicine, MD: Harry C. Dietz (Study Co-chair), William J. Ravekes, Mary Rykiel, Elisabeth Sparks, Gretchen Oswald, Jennifer Leadroot*. Auxiliary Site Investigators: Washington University School of Medicine, St. Louis, MO: Charles Canter (PI), Angela Sharkey*, Alan Braverman, Cheryl Rainey; Texas Children’s Hospital Houston, TX: John L. Jefferies*, Timothy Slesnick*, Aimee Liou (PI), Hugo Martinez*, Andres Menesses*, Tunu Tenende*; Stanford University Medical Center, Stanford, CA: David Liang (PI), Elisabeth Merkel; Ghent University Hospital, Ghent, Belgium: Bart Loeys*, Julie De Backer (PI), Jan Maarten Cobben, Thierry Sluysmans, Anne De Paepe, Sylvia De Nobele; Mount Sinai Hospital, New York, NY: Bruce Gelb (PI), Shubhika Srivastava, Tejani Mendiz-Ramdeen*, Constance Weismann, Emily Lawrence, Stephanie Chin, Helen Ko, Jen Le Yau; Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA: Steven Webber* (PI), Stacey Drant (PI), Jane Luce, Kevin Stiegler*; Vanderbilt University, Nashville, TN: Larry Markham (PI), Cheryl Kinnard*, Cheri Stewart, Sue Sommers, Carol Madison; Ann & Robert H. Lurie Children’s Hospital, Chicago, IL: Luciana Young* (PI), Megan Domenico*, Kathryn Waitzman*, Carla Lozano*; Children’s Hospital and Clinics of Minnesota, St. Paul, MN: Mary Ella Pierpont (PI), Charles Baker, Erin Zielinski*, Heidi Vander Velden, Alison Overman; Seattle Children’s Hospital, Seattle, WA: Mark Lewin (PI), Aaron Olson, Amy Payne; Cedars-Sinai Medical Center, Los Angeles, CA: David Rimoin (PI)—deceased, Mitchel Pariani*, Robert Siegel (PI), Asim Rafique*; Rady Children’s Hospital, UCSD, San Diego, CA: Paul Grossfeld, Arlene Smith, Terri McLees-Palinkas*. Echocardiography Core Laboratory: Boston Children’s Hospital: Steven D. Colan (Director), Elif Seda Selamet Tierney*, Jami Levine, Shari Trevey, Marga Rivera. Protocol Review Committee: Michael Artman, Chair; Erle Austin, H. Scott Baldwin, Daniel Bernstein, Timothy Feltes, Julie Johnson, Thomas Klitzner, Jeffrey Krischer, G. Paul Matherne, Kenneth G. Zahka. Data and Safety Monitoring Board: John Kugler, Chair; David J. Driscoll, Mark Galantowicz, Sally A. Hunsberger, Thomas J. Knight, Holly Taylor.
* no longer at the institution listed.
Funding
Supported by U01 grants from the NHLBI (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, and HL085057) and the Food and Drug Administration Office of Orphan Products Development and by the Marfan Foundation.
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The authors do not have any conflict of interest. The views expressed in this article are those of the authors and do not represent the official views of the National Heart, Lung, and Blood Institute (NHLBI) or the National Institutes of Health.
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A complete list of investigators who participated in the Pediatric Heart Network Marfan Trial is provided in the Acknowledgement section.
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Hoskoppal, A., Menon, S., Trachtenberg, F. et al. Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome. Pediatr Cardiol 39, 1453–1461 (2018). https://doi.org/10.1007/s00246-018-1916-6
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DOI: https://doi.org/10.1007/s00246-018-1916-6