The Impact of Celiprolol in Vascular Ehlers–Danlos Syndrome: A Systematic Review of Current Evidence
Abstract
:1. Introduction
2. Methods
2.1. Data Search Strategy
2.2. Eligibility Criteria
2.3. Data Extraction and Quality Assessment
2.4. Quality Assessment
2.5. Statistical Analysis
3. Results
3.1. Study Selection and Quality Assessment
3.2. Baseline Characteristics
3.3. vEDS Type and Clinical Manifestation
3.4. Treatment Characteristics and Adverse Effects
3.5. The Impact of Celiprolol Treatments
3.5.1. Clinical Parameters
3.5.2. Vascular Events
3.5.3. Mortality
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACMG | American College of Medical Genetics |
AD | Autosomal Dominant |
AGTR1 | Angiotensin II Receptor Type 1 |
BMI | Body Mass Index |
BP | Blood Pressure |
CI | Confidence Interval |
COL1A1 | Collagen Type 1 Alpha 1 Chain Gene |
COL3A1 | Collagen Type III Alpha 1 Chain Gene |
DBP | Diastolic Blood Pressure |
EDS | Ehlers–Danlos Syndrome |
hEDS | Hypermobile Ehlers–Danlos Syndrome |
NOS | Newcastle–Ottawa Scale |
OR | Odds Ratio |
PRISMA | Preferred Reporting Items for Systematic Reviews and Meta-analysis |
SBP | Systolic Blood Pressure |
TGF-Beta | Transforming Growth Factor Beta |
vEDS | Vascular Ehlers–Danlos Syndrome |
References
- Malfait, F.; Francomano, C.; Byers, P.; Belmont, J.; Berglund, B.; Black, J.; Bloom, L.; Bowen, J.M.; Brady, A.F.; Burrows, N.P.; et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am. J. Med. Genet. Part C Semin. Med. Genet. 2017, 175, 8–26. [Google Scholar] [CrossRef] [PubMed]
- Caliogna, L.; Guerrieri, V.; Annunziata, S.; Bina, V.; Brancato, A.M.; Castelli, A.; Jannelli, E.; Ivone, A.; Grassi, F.A.; Mosconi, M.; et al. Biomarkers for Ehlers-Danlos Syndromes: There Is a Role? Int. J. Mol. Sci. 2021, 22, 10149. [Google Scholar] [CrossRef]
- Malfait, F.; Castori, M.; Francomano, C.A.; Giunta, C.; Kosho, T.; Byers, P.H. The Ehlers–Danlos syndromes. Nat. Rev. Dis. Primer 2020, 6, 64. [Google Scholar] [CrossRef] [PubMed]
- Busch, A.; Hoffjan, S.; Bergmann, F.; Hartung, B.; Jung, H.; Hanel, D.; Tzschach, A.; Kadar, J.; von Kodolitsch, Y.; Germer, C.T.; et al. Vascular type Ehlers-Danlos syndrome is associated with platelet dysfunction and low vitamin D serum concentration. Orphanet J. Rare Dis. 2016, 11, 111. [Google Scholar] [CrossRef]
- Olubajo, F.; Kaliaperumal, C.; Choudhari, K.A. Vascular Ehlers-Danlos Syndrome: Literature review and surgical management of intracranial vascular complications. Clin. Neurol. Neurosurg. 2020, 193, 105775. [Google Scholar] [CrossRef] [PubMed]
- Baderkhan, H.; Wanhainen, A.; Stenborg, A.; Stattin, E.L.; Björck, M. Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome. Eur. J. Vasc. Endovasc. Surg. 2021, 61, 326–331. [Google Scholar] [CrossRef]
- Ong, K.T.; Perdu, J.; De Backer, J.; Bozec, E.; Collignon, P.; Emmerich, J.; Fauret, A.L.; Fiessinger, J.N.; Germain, D.P.; Georgesco, G.; et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: A prospective randomised, open, blinded-endpoints trial. Lancet 2010, 376, 1476–1484. [Google Scholar] [CrossRef]
- Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef]
- Wells, G.A.; Shea, B.; O’Connell, D.; Peterson, J.; Welch, V.; Losos, M.; Tugwell, P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. In Proceedings of the 3rd Symposium on Systematic Reviews: Beyond the Basics, Oxford, UK, 3–5 July 2000. [Google Scholar]
- Buso, G.; Paini, A.; Agabiti-Rosei, C.; De Ciuceis, C.; Bertacchini, F.; Stassaldi, D.; Salvetti, M.; Ritelli, M.; Venturini, M.; Colombi, M.; et al. Despite celiprolol therapy, patients with vascular Ehlers-Danlos syndrome remain at risk of vascular events: A 12-year experience in an Italian referral center. Vasc. Med. 2024, 29, 265–273. [Google Scholar] [CrossRef]
- Frank, M.; Adham, S.; Seigle, S.; Legrand, A.; Mirault, T.; Henneton, P.; Albuisson, J.; Denarié, N.; Mazzella, J.M.; Mousseaux, E.; et al. Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study. J. Am. Coll. Cardiol. 2019, 73, 1948–1957. [Google Scholar] [CrossRef]
- Hoang, P.; Laurent, S.; Franck, M.; Jeunemaitre, X.; Boutouyrie, P. P1.10 Longitudinal Changes in Geometric and Functional Arterial Properties in Vascular Ehlers-Danlos Syndrome with Celiprolol. Artery Res. 2014, 8, 131. [Google Scholar] [CrossRef]
- Shalhub, S.; Black, J.H., III; Cecchi, A.C.; Xu, Z.; Griswold, B.F.; Safi, H.J.; Milewicz, D.M.; McDonnell, N.B. Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes. J. Vasc. Surg. 2014, 60, 160–169. [Google Scholar] [CrossRef]
- Brooke, B.S. Celiprolol therapy for vascular Ehlers-Danlos syndrome. Lancet 2010, 376, 1443–1444. [Google Scholar] [CrossRef] [PubMed]
- Matta, A.; Levai, L.; Elbaz, M.; Nader, V.; Parada, F.C.; Carrié, D.; Roncalli, J. Spontaneous Coronary Artery Dissection: A Review of Epidemiology, Pathophysiology and Principles of Management. Curr. Probl. Cardiol. 2023, 48, 101682. [Google Scholar] [CrossRef] [PubMed]
- Bergqvist, D.; Björck, M.; Wanhainen, A. Treatment of vascular Ehlers-Danlos syndrome: A systematic review. Ann. Surg. 2013, 258, 257–261. [Google Scholar] [CrossRef]
- Sellers, S.L.; Milad, N.; Chan, R.; Mielnik, M.; Jermilova, U.; Huang, P.L.; de Crom, R.; Hirota, J.A.; Hogg, J.C.; Sandor, G.G.; et al. Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan: Role of Angiotensin II Receptor Type 1-Independent Activation of Endothelial Function. Am. J. Pathol. 2018, 188, 574–585. [Google Scholar] [CrossRef]
- Gao, L.; Chen, L.; Fan, L.; Gao, D.; Liang, Z.; Wang, R.; Lu, W. The effect of losartan on progressive aortic dilatation in patients with Marfan’s syndrome: A meta-analysis of prospective randomized clinical trials. Int. J. Cardiol. 2016, 217, 190–194. [Google Scholar] [CrossRef]
- Dubacher, N.; Münger, J.; Gorosabel, M.C.; Crabb, J.; Ksiazek, A.A.; Caspar, S.M.; Bakker, E.N.T.P.; van Bavel, E.; Ziegler, U.; Carrel, T.; et al. Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers-Danlos syndrome. Cardiovasc. Res. 2020, 116, 457–465. [Google Scholar] [CrossRef]
- Gorosabel, M.C.; Dubacher, N.; Meienberg, J.; Matyas, G. Vascular Ehlers-Danlos syndrome: Can the beneficial effect of celiprolol be extrapolated to bisoprolol? Eur. Heart J. Cardiovasc. Pharmacother. 2020, 6, 199–200. [Google Scholar] [CrossRef]
- Oderich, G.S.; Panneton, J.M.; Bower, T.C.; Lindor, N.M.; Cherry, K.J.; Noel, A.A.; Kalra, M.; Sullivan, T.; Gloviczki, P. The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: A 30-year experience. J. Vasc. Surg. 2005, 42, 98–106. [Google Scholar] [CrossRef]
- Jeunemaitre, X.; Mousseaux, E.; Frank, M.; Adham, S.; Pitocco, F.; Billon, C.; Yakhlef, M.B.; El Hachmi, M.; Bura-Rivière, A.; Lapébie, F.X.; et al. Efficacy of Irbesartan in Celiprolol-Treated Patients With Vascular Ehlers-Danlos Syndrome. Circulation 2025, 151, 686–695. [Google Scholar] [CrossRef] [PubMed]
- Eguchi, K.; Hoshide, S.; Kario, K. Effects of Celiprolol and Bisoprolol on Blood Pressure, Vascular Stiffness, and Baroreflex Sensitivity. Am. J. Hypertens. 2015, 28, 858–867. [Google Scholar] [CrossRef] [PubMed]
- Abdelkrim, M.A.; Martignat, L.; Gogny, M.; Desfontis, J.C.; Noireaud, J.; Mallem, M.Y. Celiprolol induces β3-adrenoceptors-dependent relaxation in isolated porcine coronary arteries. Can. J. Physiol. Pharmacol. 2013, 91, 791–796. [Google Scholar] [CrossRef] [PubMed]
- Caruso, F.S.; Berger, B.M.; Darragh, A.; Weng, T.; Vukovich, R. Effect of celiprolol, a new beta 1-alpha 2 blocker, on the cardiovascular response to exercise. J. Clin. Pharmacol. 1986, 26, 32–38. [Google Scholar] [CrossRef]
- Nawarskas, J.J.; Cheng-Lai, A.; Frishman, W.H. Celiprolol: A Unique Selective Adrenoceptor Modulator. Cardiol. Rev. 2017, 25, 247–255. [Google Scholar] [CrossRef]
- Dietz, H.C. TGF-beta in the pathogenesis and prevention of disease: A matter of aneurysmic proportions. J. Clin. Investig. 2010, 120, 403–407. [Google Scholar] [CrossRef]
- Wang, Y.; Ait-Oufella, H.; Herbin, O.; Bonnin, P.; Ramkhelawon, B.; Taleb, S.; Huang, J.; Offenstadt, G.; Combadière, C.; Rénia, L.; et al. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J. Clin. Investig. 2010, 120, 422–432. [Google Scholar] [CrossRef]
- Wanhainen, A.; Van Herzeele, I.; Bastos Goncalves, F.; Bellmunt Montoya, S.; Berard, X.; Boyle, J.R.; D’Oria, M.; Prendes, C.F.; Karkos, C.D.; Kazimierczak, A.; et al. European Society for Vascular Surgery (ESVS) 2024 Clinical Practice Guidelines on the Management of Abdominal Aorto-Iliac Artery Aneurysms. Eur. J. Vasc. Endovasc. Surg. 2024, 67, 192–331. [Google Scholar] [CrossRef]
- Czerny, M.; Grabenwöger, M.; Berger, T.; Aboyans, V.; Della Corte, A.; Chen, E.P.; Desai, N.D.; Dumfarth, J.; Elefteriades, J.A.; Etz, C.D.; et al. EACTS/STS Guidelines for diagnosing and treating acute and chronic syndromes of the aortic organ. Eur. J. Cardio-Thorac. Surg. 2024, 65, ezad426. [Google Scholar] [CrossRef]
Study | Country | Study Design | Follow-up Duration | Sample Size | Celiprolol Dose and Titration | Max Dose Reached (%) | Vascular Events (%) | Mortality | Side Effects (%) | Key Findings |
---|---|---|---|---|---|---|---|---|---|---|
Baderkhan et al., 2021 [6] | Sweden | Prospective Cohort | 22 months (range 1–98) | 40 | Started at 100 mg BID; uptitrated every 3–6 months to 400 mg/day | 65% | 12.5% (5/40) including fatal ruptures | 4 deaths from vascular rupture | 35% (dizziness, fatigue, headache, etc.) | Pulse/BP reduced; 5 patients stopped due to AEs |
Buso et al., 2023 [10] | Italy | Prospective Cohort | 72 ± 41 months | 26 | Up to 400 mg/day; most patients received 400 mg, 1 at 200 mg | 61.50% | 70% (14/20); 12 vascular events | 3 deaths (hepatic, splenic artery rupture) | 3.85% (fatigue) | Some events occurred at full dose; mortality noted |
Frank et al., 2019 [11] | France | Retrospective Cohort | 5.3 years (median) | 104 | 100 mg daily; titrated by 100 mg/month to 400 mg/day | 62.50% | 26% (27/104) | Improved survival in 400 mg group | 3.5% (fatigue) | Hospitalizations and mortality improved at 400 mg |
Hoang et al., 2019 [12] | France | Cohort (Abstract) | 5 years | 43 | Not reported | N/A | Not reported | Not reported | Not reported | BP ↑ but changes may reflect aging, not drug effect |
Ong et al., 2010 [7] | France and Belgium | RCT (Blinded-Endpoint) | 47 ± 5 months | 25 (celiprolol) | 100 mg increased every 6 months up to 400 mg BID | 88% | 20% (5/25); control 50% (14/28) | 1 death in celiprolol group, 3 in control | 12% (mild/moderate fatigue) | RCT: celiprolol reduced vascular events by 64% |
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Saputra, P.B.T.; Widiarti, W.; Siahaan, P.P.; Putra, R.M.; Putranto, J.N.E.; Budiarto, R.M.; Luthfah, N.; Multazam, C.E.C.Z.; D’Oria, M.; Alkaff, F.F. The Impact of Celiprolol in Vascular Ehlers–Danlos Syndrome: A Systematic Review of Current Evidence. Med. Sci. 2025, 13, 74. https://doi.org/10.3390/medsci13020074
Saputra PBT, Widiarti W, Siahaan PP, Putra RM, Putranto JNE, Budiarto RM, Luthfah N, Multazam CECZ, D’Oria M, Alkaff FF. The Impact of Celiprolol in Vascular Ehlers–Danlos Syndrome: A Systematic Review of Current Evidence. Medical Sciences. 2025; 13(2):74. https://doi.org/10.3390/medsci13020074
Chicago/Turabian StyleSaputra, Pandit Bagus Tri, Wynne Widiarti, Paulus Parholong Siahaan, Rendra Mahardhika Putra, Johanes Nugroho Eko Putranto, Raden Mohammad Budiarto, Nadya Luthfah, Chaq El Chaq Zamzam Multazam, Mario D’Oria, and Firas Farisi Alkaff. 2025. "The Impact of Celiprolol in Vascular Ehlers–Danlos Syndrome: A Systematic Review of Current Evidence" Medical Sciences 13, no. 2: 74. https://doi.org/10.3390/medsci13020074
APA StyleSaputra, P. B. T., Widiarti, W., Siahaan, P. P., Putra, R. M., Putranto, J. N. E., Budiarto, R. M., Luthfah, N., Multazam, C. E. C. Z., D’Oria, M., & Alkaff, F. F. (2025). The Impact of Celiprolol in Vascular Ehlers–Danlos Syndrome: A Systematic Review of Current Evidence. Medical Sciences, 13(2), 74. https://doi.org/10.3390/medsci13020074