Nicolo Dubacher1, Justyna Münger1, Maria C Gorosabel1, Jessica Crabb2, Agnieszka A Ksiazek3,4, Sylvan M Caspar1, Erik N T P Bakker5, Ed van Bavel5, Urs Ziegler6, Thierry Carrel7, Beat Steinmann8, Steffen Zeisberger3,9, Janine Meienberg1, Gabor Matyas1,7,10. 1. Center for Cardiovascular Genetics and Gene Diagnostics, Foundation for People with Rare Diseases, 8952, Schlieren-Zurich, Switzerland. 2. Institute of Mechanical Systems, Swiss Federal Institute of Technology Zurich, 8092, Zurich, Switzerland. 3. Institute for Regenerative Medicine, University of Zurich, 8091, Zurich, Switzerland. 4. Clinic for Small Animal Internal Medicine, University of Zurich, 8057, Zurich, Switzerland. 5. Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, 1000 GG, Amsterdam, The Netherlands. 6. Center for Microscopy and Image Analysis, University of Zurich, 8057, Zurich, Switzerland. 7. Department of Cardiovascular Surgery, University Hospital, 3010, Berne, Switzerland. 8. Division of Metabolism, University Children's Hospital, 8032, Zurich, Switzerland. 9. Wyss Zurich, University of Zurich, 8044 Zurich, Switzerland. 10. Zurich Center for Integrative Human Physiology, University of Zurich, 8057, Zurich, Switzerland.
Abstract
AIMS: Antihypertensive drugs are included in the medical therapy of vascular Ehlers-Danlos syndrome (vEDS). The β-blocker celiprolol has been suggested to prevent arterial damage in vEDS, but the underlying mechanism remains unclear. It is also unknown whether the widely used angiotensin II receptor type 1 antagonist losartan has a therapeutic effect in vEDS. Here, we evaluated the impact of celiprolol and losartan on the biomechanical integrity of the vEDS thoracic aorta. METHODS AND RESULTS: We established a new approach to measure the maximum tensile force at rupture of uniaxially stretched murine thoracic aortic rings. In a vEDS model, which we (re-)characterized here at molecular level, heterozygous mice showed a significant reduction in the rupture force compared to wild-type mice, reflecting the increased mortality due to aortic rupture. For the assessment of treatment effects, heterozygous mice at 4 weeks of age underwent a 4-week treatment with celiprolol, losartan, and, as a proof-of-concept drug, the matrix metalloproteinase inhibitor doxycycline. Compared to age- and sex-matched untreated heterozygous mice, treatment with doxycycline or celiprolol resulted in a significant increase of rupture force, whereas no significant change was detected upon losartan treatment. CONCLUSIONS: In a vEDS model, celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. As doxycycline is a broad-spectrum antibiotic with considerable side effects, celiprolol may be more suitable for a long-term therapy and thus rather indicated for the medication of patients with vEDS.
AIMS: Antihypertensive drugs are included in the medical therapy of vascular Ehlers-Danlos syndrome (vEDS). The β-blocker celiprolol has been suggested to prevent arterial damage in vEDS, but the underlying mechanism remains unclear. It is also unknown whether the widely used angiotensin II receptor type 1 antagonist losartan has a therapeutic effect in vEDS. Here, we evaluated the impact of celiprolol and losartan on the biomechanical integrity of the vEDS thoracic aorta. METHODS AND RESULTS: We established a new approach to measure the maximum tensile force at rupture of uniaxially stretched murine thoracic aortic rings. In a vEDS model, which we (re-)characterized here at molecular level, heterozygous mice showed a significant reduction in the rupture force compared to wild-type mice, reflecting the increased mortality due to aortic rupture. For the assessment of treatment effects, heterozygous mice at 4 weeks of age underwent a 4-week treatment with celiprolol, losartan, and, as a proof-of-concept drug, the matrix metalloproteinase inhibitor doxycycline. Compared to age- and sex-matched untreated heterozygous mice, treatment with doxycycline or celiprolol resulted in a significant increase of rupture force, whereas no significant change was detected upon losartan treatment. CONCLUSIONS: In a vEDS model, celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. As doxycycline is a broad-spectrum antibiotic with considerable side effects, celiprolol may be more suitable for a long-term therapy and thus rather indicated for the medication of patients with vEDS.
Authors: Caitlin J Bowen; Juan Francisco Calderón Giadrosic; Zachary Burger; Graham Rykiel; Elaine C Davis; Mark R Helmers; Kelly Benke; Elena Gallo MacFarlane; Harry C Dietz Journal: J Clin Invest Date: 2020-02-03 Impact factor: 14.808
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