Abstract
Objectives
Studies indicate that other cardiovascular problems than aortic disease are a burden for patients with Marfan syndrome (MFS). The aim of the study was to assess the extent of this issue.
Methods
A registry-based population study of patients with a Ghent II verified MFS diagnosis. Each patient was matched with up to 100 controls on age and sex. From the Danish healthcare system, we identified 407 MFS patients (from 1977 to 2014) and their cardiovascular events and compared them with those in 40,700 controls. Total follow-up time was 16,439 person years.
Results
Mitral valve disease was significantly more common in MFS [HR: 58.9 (CI 38.1–91.1)] and happened earlier and more often in women than men with MFS [age at first registration: 22 vs. 38 years, HR: 2.1 (CI 1.0–4.4)]. Heart failure/cardiomyopathy was also more common in MFS [HR: 8.7 (CI 5.7–13.4)] and men were more affected than women, and at younger age [39 vs. 64 years, HR: 0.18 (CI 0.06–0.55)].
In all cases, atrioventricular block [HR: 4.9 (1.5–15.6)] was related to heart surgery. Supraventricular [HR: 9.7 (CI 7.5–12.7)] and ventricular tachycardia [HR: 7.7 (CI 4.2–14.3)] also occurred more often than in the control group. The risk of sudden cardiac death was increased [HR: 8.3 (CI 3.8–18.0)] but the etiology was unclear due to lack of autopsies.
Conclusion
Non-aortic cardiovascular disease in patients with MFS is exceptionally prevalent and the range of diseases varies between women and men. Physicians caring for MFS patients must be aware of this large spectrum of cardiovascular diseases.
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Availability of data and materials and code availability
The information used in the analyses combine Danish administrative registers (as described in the paper). The data use is subject to the European Union’s General Data Protection Regulation (GDPR). The data are physically stored on computers at Statistics Denmark and the data may not be transferred to computers outside Statistics Denmark. Researchers interested in obtaining access to the register data employed in this paper are required to submit a written application to gain approval from Statistics Denmark. The application must include a detailed description of the proposed project, its purpose, as well as a description of the required datasets, variables, and analysis population. Applications can be submitted by researchers who are affiliated with Danish institutions accepted by Statistics Denmark, or by researchers outside of Denmark who collaborate with researchers affiliated with these institutions.
References
Dietz HC, Cutting GR, Pyeritz RE et al (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337–339. https://doi.org/10.1038/352337a0
Thomson J, Singh M, Eckersley A, Cain SA, Sherratt MJ, Baldock C (2019) Fibrillin microfibrils and elastic fibre proteins: functional interactions and extracellular regulation of growth factors. Semin Cell Dev Biol 89:109–117. https://doi.org/10.1016/j.semcdb.2018.07.016
Loeys BL, Dietz HC, Braverman AC et al (2010) The revised Ghent nosology for the Marfan syndrome. J Med Genet 47:476–485. https://doi.org/10.1136/jmg.2009.072785
Groth KA, Stochholm K, Hove H et al (2017) Aortic events in a nationwide Marfan syndrome cohort. Clin Res Cardiol 106(2):105–112. https://doi.org/10.1007/s00392-016-1028-3
Groth KA, Stochholm K, Hove H, Andersen NH, Gravholt CH (2018) Causes of mortality in the Marfan syndrome (from a Nationwide Register Study). Am J Cardiol 122(7):1231–1235. https://doi.org/10.1016/j.amjcard.2018.06.034
von Kodolitsch Y, Demolder A, Girdauskas E et al (2019) Features of Marfan syndrome not listed in the Ghent nosology—the dark side of the disease. Expert Rev Cardiovasc Ther 17:883–915. https://doi.org/10.1080/14779072.2019.1704625
Rybczynski M, Mir TS, Sheikhzadeh S et al (2010) Frequency and age-related course of mitral valve dysfunction in the Marfan syndrome. Am J Cardiol 106:1048–1053. https://doi.org/10.1016/j.amjcard.2010.05.038
Winther S, Williams LK, Keir M et al (2019) Cardiovascular magnetic resonance provides evidence of abnormal myocardial strain and primary cardiomyopathy in Marfan syndrome. J Comput Assist Tomogr 43:410–415. https://doi.org/10.1097/RCT.0000000000000863
Isekame Y, Gati S, Aragon-Martin JA, Bastiaenen R, Kondapally Seshasai SR, Child A (2016) Cardiovascular management of adults with Marfan syndrome. Eur Cardiol 11:102–110. https://doi.org/10.15420/ecr/2016:19:2
Aydin A, Adsay BA, Sheikhzadeh S et al (2013) Observational cohort study of ventricular arrhythmia in adults with Marfan syndrome caused by FBN1 mutations. PLoS ONE 8:1–10. https://doi.org/10.1371/journal.pone.0081281
Yetman AT, Bornemeier RA, McCrindle BW (2003) Long-term outcome in patients with Marfan syndrome: is aortic dissection the only cause of sudden death? J Am Coll Cardiol 41:329–332. https://doi.org/10.1016/s0735-1097(02)02699-2
Schaeffer BN, Rybczynski M, Sheikhzadeh S et al (2015) Heart rate turbulence and deceleration capacity for risk prediction of serious arrhythmic events in Marfan syndrome. Clin Res Cardiol 104:1054–1063. https://doi.org/10.1007/s00392-015-0873-9
Erbel R, Aboyans V, Boileau C et al (2014) 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The task force for the diagnosis and treatment of aortic diseases of the european society of cardiology (ESC). Eur Heart J 35:2873–2926. https://doi.org/10.1093/eurheartj/ehu281
Schmidt M, Schmidt SAJ, Sandegaard JL, Ehrenstein V, Pedersen L, Sørensen HT (2015) The danish national patient registry: a review of content, data quality, and research potential. Clin Epidemiol 7:449–490. https://doi.org/10.2147/CLEP.S91125
Johannesdottir SA, Horváth-Puhó E, Ehrenstein V, Schmidt M, Pedersen L, Sørensen HT (2012) Existing data sources for clinical epidemiology: the danish national database of reimbursed prescriptions. Clin Epidemiol 4:303–313. https://doi.org/10.2147/CLEP.S37587
Sundbøll J, Adelborg K, Munch T et al (2016) Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study. BMJ Open 6:e012832. https://doi.org/10.1136/bmjopen-2016-012832
Groth KA, Hove H, Kyhl K et al (2015) Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet J Rare Dis 10:153. https://doi.org/10.1186/s13023-015-0369-8
Eggebrecht H, Schmermund A, von Birgelen C et al (2015) Resistant hypertension in patients with chronic aortic dissection. J Hum Hypertens 19:227–231. https://doi.org/10.1038/sj.jhh.1001800
Sato C, Wakabayashi K, Suzuki H (2014) Natural course of isolated spontaneous coronary artery dissection in Marfan syndrome. Int J Cardiol 177:20–22. https://doi.org/10.1016/j.ijcard.2014.09.061
Kunkala MR, Schaff HV, Li Z et al (2013) Mitral valve disease in patients with Marfan syndrome undergoing aortic root replacement. Circulation 128:S243-247. https://doi.org/10.1161/CIRCULATIONAHA.112.000113
Cañadas V, Vilacosta I, Bruna I, Fuster V (2010) Marfan syndrome. Part 1: pathophysiology and diagnosis. Nat Rev Cardiol 7:256–265. https://doi.org/10.1038/nrcardio.2010.30
Judge DP, Biery NJ, Keene DR et al (2014) Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 114:172–181. https://doi.org/10.1172/JCI20641
Wei H, Hu JH, Angelov SN et al (2017) Aortopathy in a mouse model of Marfan syndrome is not mediated by altered transforming growth factor beta signaling. J Am Heart Assoc 24(6):e004968. https://doi.org/10.1161/JAHA.116.004968
Habashi JP, Judge DP, Holm TM et al (2006) Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312:117–121. https://doi.org/10.1126/science.1124287
Mueller GC, Stark V, Steiner K et al (2013) Impact of age and gender on cardiac pathology in children and adolescents with Marfan syndrome. Pediatr Cardiol 34:991–998. https://doi.org/10.1007/s00246-012-0593-0
Glesby MJ, Pyeritz RE (1989) Association of mitral valve prolapse and systemic abnormalities of connective tissue. A phenotypic continuum. JAMA 262:523–528
Rippe M, De Backer J, Kutsche K et al (2016) Mitral valve prolapse syndrome and MASS phenotype: stability of aortic dilatation but progression of mitral valve prolapse. Int J Cardiol Heart Vasc 10:39–46. https://doi.org/10.1016/j.ijcha.2016.01.002
Pedersen MW, Groth KA, Mortensen KH, Brodersen J, Gravholt CH, Andersen NH (2019) Clinical and pathophysiological aspects of bicuspid aortic valve disease. Cardiol Young 29:1–10. https://doi.org/10.1017/S1047951118001658
Milleron O, Ropers J, Arnoult F et al (2019) Clinical significance of aortic root modification associated with bicuspid aortic valve in Marfan syndrome. Circ Cardiovasc Imaging 12:e008129. https://doi.org/10.1161/CIRCIMAGING.118.008129
Grande-Allen KJ, Cochran RP, Reinhall PG, Kunzelman KS (2001) Mechanisms of aortic valve incompetence: finite-element modeling of Marfan syndrome. J Thorac Cardiovasc Surg 122:946–954. https://doi.org/10.1067/mtc.2001.116314
Debl K, Djavidani B, Buchner S et al (2009) Dilatation of the ascending aorta in bicuspid aortic valve disease: a magnetic resonance imaging study. Clin Res Cardiol 98:114–120. https://doi.org/10.1007/s00392-008-0731-0
Keane MG, Wiegers SE, Plappert T, Pochettino A, Bavaria JE, Sutton MG (2000) Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions. Circulation. 102:35–39. https://doi.org/10.1161/01.cir.102.suppl3.iii-35
Zehr KJ, Matloobi A, Connolly HM, Orszulak TA, Puga FJ, Schaff HV (2005) Surgical management of the aortic root in patients with Marfan syndrome. J Heart Valve Dis. 14:121–128
Hetzer R, Siegel G, Delmo Walter EM (2016) Cardiomyopathy in Marfan syndrome. Eur J Cardiothorac Surg. 49:561–567. https://doi.org/10.1093/ejcts/ezv073
Meijboom LJ, Timmermans J, van Tintelen JP et al (2005) Evaluation of left ventricular dimensions and function in Marfan’s syndrome without significant valvular regurgitation. Am J Cardiol 95:795–797. https://doi.org/10.1016/j.amjcard.2004.11.042
Aalberts JJJ, van Tintelen JP, Meijboom LJ et al (2014) Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome. Gene 534:40–43. https://doi.org/10.1016/j.gene.2013.10.033
Cook JR, Carta L, Bénard L et al (2014) Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome. J Clin Invest 124:1329–1339. https://doi.org/10.1172/JCI71059
Campens L, Renard M, Trachet B et al (2015) Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans. Pediatr Res 78:256–263. https://doi.org/10.1038/pr.2015.110
Rouf R, MacFarlane EG, Takimoto E et al (2017) Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice. JCI Insight 2:e91588. https://doi.org/10.1172/jci.insight.91588
Gensicke NM, Cavanaugh NB, Andersen ND et al (2020) Accelerated Marfan syndrome model recapitulates established signaling pathways. J Thorac Cardiovasc Surg 159:1719–1726. https://doi.org/10.1016/j.jtcvs.2019.05.043
Christopher Y, Richmond JW (2018) Angiotensin, transforming growth factor β and aortic dilatation in Marfan syndrome: of mice and humans. Int J Cardiol Heart Vasc 12:71–80. https://doi.org/10.1016/j.ijcha.2018.02.009
Holm TM, Habashi JP, Doyle JJ et al (2011) Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332:358–361. https://doi.org/10.1126/science.1192149
Roman MJ, Devereux RB, Preiss LR et al (2017) Associations of age and sex with marfan phenotype: the national heart, lung, and blood institute gentac (genetically triggered thoracic aortic aneurysms and cardiovascular conditions) registry. Circ Cardiovasc Genet 10:e001647. https://doi.org/10.1161/CIRCGENETICS.116.001647
Kiotsekoglou A, Sutherland GR, Moggridge JC, Nassiri DK, Camm AJ, Child AH (2009) The unravelling of primary myocardial impairment in Marfan syndrome by modern echocardiography. Heart 95:1561–1566. https://doi.org/10.1136/hrt.2008.152934
Alpendurada F, Wong J, Kiotsekoglou A et al (2010) Evidence for Marfan cardiomyopathy. Eur J Heart Fail 12:1085–1091. https://doi.org/10.1093/eurjhf/hfq127
Schulz EG (2017) X-chromosome dosage as a modulator of pluripotency, signalling and differentiation? Philos Trans R Soc Lond B Biol Sci 5(372):20160366. https://doi.org/10.1098/rstb.2016.0366
Tashima Y, He H, Cui JZ et al (2020) Androgens accentuate TGF-β dependent Erk/Smad activation during thoracic aortic aneurysm formation in marfan syndrome male mice. J Am Heart Assoc 9:e015773. https://doi.org/10.1161/JAHA.119.015773
Borger MA, Mansour MC, Levine RA (2019) Atrial fibrillation and mitral valve prolapse: time to intervene? J Am Coll Cardiol 73:275–277. https://doi.org/10.1016/j.jacc.2018.11.018
Muiño-Mosquera L, De Wilde H, Devos D et al (2020) Myocardial disease and ventricular arrhythmia in Marfan syndrome: a prospective study. Orphanet J Rare Dis 15:300. https://doi.org/10.1186/s13023-020-01581-8
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All authors conceptualized and designed the study and supported the data collection. Analyses and calculations were done by Kirstine Stochholm. Niels Holmark Andersen drafted the initial manuscript. All authors reviewed and revised the manuscript.
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The study was approved by the Scientific Ethical Committee (31422) and the Danish Data Protection Agency (2011–41-6986).
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Andersen, N.H., Groth, K.A., Berglund, A. et al. Non-aortic cardiovascular disease in Marfan syndrome: a nationwide epidemiological study. Clin Res Cardiol 110, 1106–1115 (2021). https://doi.org/10.1007/s00392-021-01858-3
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DOI: https://doi.org/10.1007/s00392-021-01858-3