Sleep apnea predicts cardiovascular death in patients with Marfan syndrome A cohort study

Sleep apnea predicts cardiovascular death in patients with Marfan syndrome A cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Sleep apnea predicts cardiovascular death in patients with Marfan syndrome A cohort study Nele Gessler, Peter Wohlmuth, Omar Anwar, Sebastian Debus, Christian Eickholt, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1706796/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Identification of possible risk factors is crucial to optimize predictive, preventive, and personalized medicine (PPPM) in Marfan syndrome (MFS). Despite a well known relationship between sleep apnea and MFS, the impact of sleep apnea on cardiovascular death and on aortic events remains unclear. Methods This is an investigator-initiated study with long-term follow-up data of 105 MFS patients. All participants were screened for sleep apnea regardless of symptoms. The primary endpoint was cardiovascular death and the secondary outcome was the occurrence of aortic events. Results Sleep apnea with an apnea-hypopnea-index (AHI) > 5/h was observed in 21.0% (22/105) with mild sleep apnea in 13% (14/105) and moderate to severe sleep apnea in 7.6% (8/105). After a median follow-up of 7.76 years [interquartile range: 6.84, 8.41], 10% (10/105) had died, with cardiovascular cause of death in 80% (8/10). After adjusting for age and body-mass-index (BMI), the AHI-score emerged as an independent risk factor for cardiovascular death (hazard ratio 1.712, 95%-confidence interval [1.061–2.761], p = 0.0276). The secondary outcome of aortic events occurred in 33% (35/105). There was no effect of the AHI-score on aortic events after adjusting for age and BMI (hazard ratio 0.965, 95%-confidence interval [0.617–1.509]), possibly due to a high number of patients with prior aortic surgery. Interpretation: Sleep apnea shows to be independently predictive of cardiovascular death in patients with Marfan syndrome. These findings highlight the necessity of early sleep apnea screening in MFS patients as an important adjunct to the PPPM management of the disease. Marfan syndrome Sleep apnea mortality PPPM 3PM Figures Figure 1 Figure 2 Figure 3 Introduction Marfan syndrome (MFS) is an inherited connective tissue disorder with a high risk for cardiovascular death due to aortic aneurysms and dissections ( 1 ). Before the development of preventive open-heart surgical procedures for prophylactic replacement of the aortic root, Marfan patients usually died at a mean age of 32 years ( 2 ). Predictive, preventive, and personalized medicine (PPPM) increased life expectancy to nearly normal because elective replacement of the proximal aorta is performed before aortic dissection or rupture develop ( 3 ). Care of Marfan patients is a personalized concept, which includes living conditions and family planning of the individual ( 4 , 5 ). To further optimize PPPM in MFS, it is crucial to identify possible risk factors for aortic events and cardiovascular death. The relationship between Marfan syndrome and sleep apnea is well known with a reported prevalence of obstructive sleep apnea between 31–42.5% in observational studies ( 6 – 8 ). An association between the occurrence of sleep apnea and aortic events was formally suggested ( 9 ) but not confirmed ( 6 , 7 ). Thus far, no long-term follow-up data are available regarding this topic. Besides the high risk for aortic events, MFS has several cardiovascular manifestations, including arrhythmias and myocardial involvement ( 10 ). Sleep apnea on the other hand is a well-known risk factor for several cardiovascular diseases, such as hypertension, arrhythmias, and congestive heart failure ( 11 ). Until now, the effect of sleep apnea on cardiovascular mortality has never been investigated in patients with MFS or other heritable thoracic aortic diseases (HTAD). The aim of this study was to evaluate the effect of sleep apnea on cardiovascular death and on aortic events in a large cohort of individuals with genetically confirmed MFS. Study Design And Methods Study design and population In this observational study, all adult patients presenting at the MFS outpatient clinic of a tertiary care center were offered screening for sleep apnea regardless of symptoms. These were patients with previously diagnosed MFS presenting for regular follow-up visits and patients with suspected MFS undergoing thorough clinical examination and genetic testing, all in accordance with current guidelines ( 12 , 13 ) or expert recommendations ( 14 ). If the diagnosis of MFS was not confirmed, patients were excluded from the study, as were patients already on continuous positive airway pressure therapy (CPAP-therapy). Only patients with genetically confirmed diagnosis of MFS (Gene with causative mutation: FBN 1 ) were analysed. Therapy and management of the MFS were carried out according to current guidelines ( 12 – 14 ) and according to the decision of the treating physician throughout the complete length of the observational period. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Hamburg research ethics committee approved our protocol. All patients provided written informed consent. The study was investigator-initiated and without external funding. The statistical analyses and interpretation of the data was approved by all authors. The data underlying this article will be shared dependant on a reasonable request to the corresponding author. We used portable 8-channel monitoring devices for ambulatory and unattended respiratory polygraphy, which was performed at baseline. During sleep, the devices recorded nasal flow with a pressure transducer system, oxygen saturation and pulse rate by finger oximetry, body position through a magnetic sensor, snoring sounds, and thoracic and abdominal movements through belts with pneumatic cushions for pressure measurement. All patients used the device for a single, full night at home. In addition to the electronic evaluation, all polygraphy measurements were analysed manually by a trained investigator and under the supervision of a specialist for sleep medicine. The diagnosis of sleep apnea was made in accordance with current guidelines ( 15 , 16 ). Sleep apnea was defined as an apnea-hypopnea-index (AHI) > 5/h. We defined an episode of apnea as the cessation of airflow lasting ≥ 10 seconds and hypopnea as a decrease in airflow of ≥ 50% lasting ≥ 10 seconds, associated with a decrease in oxygen saturation of ≥ 4% ( 17 ). Daytime sleepiness was assessed via Epworth Sleepiness Scale (ESS), defining daytime sleepiness with an ESS score > 10. Patients with an AHI > 5/h were referred to full polysomnography for further diagnosis and evaluation of treatment. We performed echocardiography for left ventricular ejection fraction (LVEF) ( 13 ) and maximum aortic diameters at the level of the aortic sinuses ( 19 ). Magnetic resonance angiography was used for diameters of the ascending and descending aortas at established levels. We did not consider diameters at aortic sites with an aortic prosthesis. Prior results of 68 patients with Marfan syndrome have been published previously in a cross-sectional study ( 6 ). The study was then continued with the inclusion of further patients. Medical and/or surgical treatment as well as regular follow-up was performed as recommended by guidelines. Twelve years after inclusion of the first patient (median follow-up [IQR] of 7.76 [6.84, 8.41] years), we retrospectively analyzed the patients’ electronic medical records for adverse events. Endpoints The primary endpoint was cardiovascular death and the secondary outcome was the occurrence of any aortic event. Aortic events were defined as Stanford type A-dissection, Stanford type B-dissection, aortic rupture, or the need for surgery or intervention for progressive dilatation of aortic aneurysm, performed according to the recommendations of the current guidelines. These are class Ic recommendations in patients who have aortic root aneurysm, with maximal aortic diameter ≥ 50 mm, or class IIa recommendations in patients with maximal ascending aortic diameters ≥ 45 mm + risk factors (family history of aortic dissection and/or aortic size increase > 3 mm/year, severe aortic or mitral regurgitation, or desire for pregnancy) ( 20 ). Acute aortic events were defined as Stanford Type A-dissection, Stanford Type B-dissection, and aortic rupture. Further data of interest were the diameter of the ascending and descending aorta, daytime sleepiness and laboratory values. Statistical analysis The primary aim of this analysis was the impact of sleep apnea (baseline AHI) on cardio-vascular mortality and aortic events of MFS patients. Demographic data, echo, laboratory data, the medical history, sleep apnea data and Epworth Sleepiness scores (AHI, ODI, ESS) were documented in all individuals. Death, cardio-vascular death, occurrence and type of aortic events were examined during follow up. Continuous data were summarized as means ± standard deviations (SD) or as medians [25th and 75th percentiles] as appropriate. Categorical data were presented as % (N). Freedom from aortic events and cardio-vascular survival were estimated and graphically displayed using the Kaplan-Meier method. Survival estimates were stratified by the presence of sleep apnea and shown with 95% confidence intervals. Effects of sleep apnea on cardio-vascular mortality and acute aortic events were examined using Cox proportional hazards models. The Cox models were adjusted for age and body mass index (BMI) using restricted cubic spline functions with three knots. Results were presented with hazard ratios and 95% confidence intervals. Median follow up as well as first and third quartiles were estimated using the reverse Kaplan-Meier method. All p-values were two-sided and a p-value < 0.05 was considered significant. All calculations were performed with the statistical analysis software R (R Core Team, 2021). Results Between February 2007 and December 2017, 205 patients were screened for sleep apnea. We excluded 32 patients, in whom the diagnosis of heritable thoracic aortic disease (HTAD) was not confirmed, as well as 17 patients with Loeys-Dietz syndrome, 25 patients with other syndromic aortic diseases, and 26 patients with other non-syndromic aortic diseases (Fig. 1 ). Finally, the study group consisted of 105 patients with Marfan syndrome (mean age 40 ± 13 years, 54% women). Table 1 shows the baseline characteristics of the total study cohort, including age, preexisting interventions or surgery, baseline aortic diameter and laboratory values. Table 1 Baseline data (n = 105) Characteristic N Marfan syndrome N = 105 Age (years) 105 40 ± 13 Women 105 57 (54%) Body mass index (kg/m²) 105 23.5 ± 4.9 Baseline measurements proBNP 103 110 [57–253] LV-EF (%) 105 56 ± 10 LVEDD (mm) 58 55 ± 10 Ascending aorta diameter (mm) (only in patients without prior aortic root surgery) 62 37 ± 7 Ascending aorta diameter prior surgery (mm) (only in patients with prior aortic root surgery) 30 53 ± 8 Descending aorta diameter (mm) 98 26 ± 10 Pre-existing aortic events Prior Aortic surgery 105 45 (43%) Prior Aortic root surgery 105 44 (42%) Prior Aortic event 105 No event 59 (56%) A-Dissection 17 (16%) B-Dissection 5 (4.8%) Elective intervention for progressive dilatation 23 (22%) Abdominal aortic aneurysm 1 (1%) Note: For continuous variables, data are presented as the means and standard deviations. b (a-c) represent the median b with [lower quartile a and the upper quartile c] for continuous variables. For categorical variables, results are expressed as frequencies and percentages. N is the number of non-missing values. The mean BMI (SD) was 23.5 (± 4.9), and baseline brain natriuretic peptide (BNP) [interquartile range, IQR] was 110 [57, 253] pg/ml. Of all patients, 43% (45/105) had prior aortic surgery and preceding aortic dissection type A was present in 16% (17/105) at baseline (Table 1 ). The results of sleep apnea screening are shown in Table 2 . Sleep apnea with an AHI > 5/h was diagnosed in 21.0% (22/105) of patients. Mild sleep apnea was observed in 13% (14/105) of all patients and moderate to severe sleep apnea in 7.6% (8/105). CPAP-therapy was initiated in 7 patients (7%). Table 2 Sleep apnea data (n = 105) Characteristic N Marfan syndrome N = 105 ESS Score 105 6.9 ± 3.8 AHI 105 5 ± 8 ODI 105 5 ± 8 Sleep apnea category 105 No sleep apnea (AHI ≤ 5) 83 (79%) Mild (AHI 6–15) 14 (13%) Mod/Severe (AHI > 15) 8 (7.6%) CPAP therapy indicated 105 7 (6.7%) Predominantly central sleep apnea in patients with sleep apnea (> 50% of episodes + AHI > 5) 104 44 (42%) Note: For continuous variables, data are presented as means and standard deviations. For categorical variables, results are expressed as frequencies and percentages. N is the number of non-missing values. Predominately central sleep apnea was present in 32% (7/22) of patients with sleep apnea. Endpoints The median follow-up [IQR] was 7.76 [6.84, 8.41] years. 5/105 (4.8%) patients were lost to follow-up. Death from any cause was observed in 9.5% (10/105) of all MFS patients. A cardiovascular cause was present in 80% (8/10) of the deceased. Further details of the causes of deaths are shown in Table 3 . Aortic events occurred in 35/105 patients (33%) during follow-up (Table 3 ). Table 3 Outcome data – Death and aortic events (n = 105) Characteristic N Marfan syndrome N = 105 Death (all cause) 105 10 (9.5%) Cause of death 10 Non cardiovascular 2 (20%) Cardiovascular 8 (80%) Cause of death (in detail) 10 Cardiovascular cause Aortic dissection 2 (20%) Aortic rupture 2 (20%) Progression of heart failure 1 (10%) Sudden cardiac death, arrhythmia 1 (10%) Mesenteric ischemia after a) enlargement of dissecting aneurysm of desc. aorta b) extensive surgery of aneurysm of desc. aorta 2 (20%) Non cardiovascular cause: Sepsis 2 (20%) Aortic diameter Ascending aorta diameter (mm) at follow up 80 35.0 ± 6.2 Descending aorta diameter (mm) at follow up 89 28 ± 13 Aortic event (any) 105 35 (33%) Type : 100 A-dissection 4 (4%) B-dissection 3 (3%) Elective intervention for progressive dilatation (aortic dilatation or false lumen expansion) 29 (29%) Location and type : Proximal aortic event 100 24 (24%) Distal aortic event 100 16 (16%) Note: For categorical variables, results are expressed as frequencies and percentages. N is the number of non-missing values. Figure 2 shows the primary outcome of cardiovascular death in relation to sleep apnea. Patients with sleep apnea showed a significantly lower survival rate with regards to cardiovascular death, compared to patients without sleep apnea (p = 0.0309). After adjusting for age and BMI, the AHI-score shows to be an independent risk factor for cardiovascular death with a HR [95% CI] of 1.712 [1.061–2.761], referring to an eight-unit increase in AHI-score (p = 0.0276). That means, in case of an increase of AHI from 5 to 15/h, there is an 22% increase in risk for cardiovascular death. Regarding the secondary outcome of aortic events, there was no significant effect of AHI-score after adjusting for age and BMI (HR [95% CI]: 0.965 [0.617–1.509]), referring to an eight-unit increase in AHI-score. Similar effects were observed for the AHI-score on acute aortic events (HR [95% CI]: 1.247 [0.508–3.058]). Figure 3 shows that patients with sleep apnea had a lower “aortic event”-free survival compared to patients without sleep apnea, but without significant difference between the groups (p = 0.215). The results for acute aortic events were similar and without a significant impact (p = 0.216). Additionally, the occurrence of sleep apnea or the AHI-score had no significant impact on the proximal or distal aortic growth rate (p = 0.619 and p = 0.122 respectively). An analysis of the secondary endpoint aortic events in the subgroup of patients with (45/105) and without (60/105) prior aortic surgery, showed a weak effect of the AHI-score in patients without prior surgery (HR [95% CI]: 1.339 [0.878–2.044]) without reaching significance (p = 0.175). There was no effect in patients with prior aortic surgery (HR [95% CI]: 0.799 [0.373–1.714], p = 0.565). Discussion Main findings We present an observational study of 105 Marfan patients with a median 7.76-year follow up period from baseline. It is the first study focusing on the primary endpoint cardiovascular death in relation to sleep apnea in this rare disease. Our results demonstrate that sleep apnea is associated with an increased risk for cardiovascular death, independent of the patients’ BMI or age. There was no effect on the secondary endpoints 1) aortic events in general, 2) acute aortic events, or 3) the proximal or distal aortic growth rate, probably due to the high number of patients with prior aortic surgery. Sleep apnea and mortality Our study establishes an association of sleep apnea with cardiovascular mortality in Marfan syndrome. There may be several explanation for this finding. First, sleep apnea in general, leads to an increased risk of cardiovascular disease, including difficult-to-control blood pressure, coronary artery disease, congestive heart failure, arrhythmias and stroke ( 11 ). It is known that patients with sleep apnea have a higher prevalence of atrial and ventricular arrhythmia compared to the general population ( 21 ). Additionally, an increased risk of cardiovascular mortality was reported in patients with severe sleep apnea ( 22 ). The negative effects of sleep apnea on the cardiovascular system in MFS are probably similar to non-Marfan patients, and a reasonable explanation for the increased risk for cardiovascular death in Marfan patients with sleep apnea. In a cross-sectional study, Muiño-Mosquera et al. confirmed that Marfan patients with sleep apnea tend to have higher systolic blood pressures, larger distal aortic diameters and a higher prevalence of ventricular arrhythmias ( 7 ). These differences were, however, not significant after adjusting for confounders ( 7 ). Second, MFS is not only an aortic disease, but has several manifestations with possible risks for cardiovascular death, including ventricular arrhythmias and myocardial involvement ( 10 ). Due to great achievements in medical and surgical diagnostics and therapy (including PPPM strategy), death from other cardiovascular causes, excluding aortic events, have become more visible and treatable in the last years ( 23 ). Our results are in line with these findings, showing 20% deaths of cardiovascular causes beside aortic events. In our study, we observed high rates of mild sleep apnea, which may indicate an early state of sleep apnea in this rather young population. Yet, we were able to show that sleep apnea is a significant risk factor for cardiovascular death. Even in case of an increase of AHI from 5 to 15/h, there is an 22% increase in risk for cardiovascular death. This novel finding demonstrates the relevance of sleep apnea screening in this group of patients as an important adjunct to the management of Marfan syndrome. Based on these results, further studies are needed to evaluate different therapy options for sleep apnea in this group of patients, preferably as multicenter trials. Sleep apnea and aortic events The results of our study did not show a significant effect of sleep apnea or the AHI-score on aortic events or the proximal or distal aortic growth rate in patients with Marfan syndrome. Interestingly, further analyses of the subgroups of patients with and without prior aortic surgery showed, that there was a weak effect of the AHI-score on aortic events in patients without prior surgery. Due to the low number of patients in the subgroup, we did not reach the level of significance. In contrast to this subgroup, there was absolutely no effect in patients with prior aortic surgery. Therefore, we believe that the high number of patients with prior aortic surgery (42%) might have influenced the aortic event rate during follow-up and therefore be one explanation for the non-significant effect of the AHI-score on the secondary outcome. Limited data is published regarding this important topic. Sowho et al. showed that a high risk for sleep apnea (detected by a composite survey score) was associated with aortic enlargement and a threefold increased risk of having prior aortic root replacement in patients with Marfan syndrome ( 24 ). Kohler et al. compared Marfan patients with and without sleep apnea and observed a significantly shorter aortic event free survival in sleep apnea patients ( 9 ). They showed an association between the AHI-score and aortic events independent of the patients’ BMI. However, this association was no longer significant after adjusting for further covariates like age, gender, baseline aortic diameter, systolic blood pressure and antihypertensive medication ( 9 ). Regarding the general population beside Marfan syndrome, several studies indicate that sleep apnea alone elevates the risk for aortic dissection, aortic dilatation and aortic rupture ( 25 – 27 ), whereas others did not confirm these findings ( 28 ). It was also observed that the duration of an oxygen saturation < 90% influenced the sizes of the ascending aorta and the main pulmonary artery, showing greater dimensions in patients with sleep apnea ( 29 ). Summing up, whether sleep apnea leads to an increased risk for aortic events in MFS remains unclear and needs further investigation in larger cohorts, preferably in patients without prior aortic surgery or intervention. Predictive, preventive, and personalized medicine The PPPM proposes, implements, and supports the need of paradigm shift from reactive medical services to predictive, preventive, and personalized medicine concepts of health ( 30 ). Care of patients with Marfan syndrome has been roughly in line with this concept for years, as it aims to prevent patients from life threatening complications. Additional to guideline recommendations for preventive surgery, treatment of patients is a personalized concept, which includes living conditions and family planning of the individual. Due to the autosomal dominant heredity, PPPM is not limited to the individual patient but includes the whole family ( 30 ). Our results demonstrate sleep apnea to be predictive for cardiovascular death. Therefore, early sleep apnea screening may serve as an additional predictive diagnostic measure in a complex and multifactorial setting of this inherited connective tissue disease. Further studies are needed to evaluate treatment of sleep apnea with regard to secondary and tertiary prevention of cardiovascular complication in this rare disease. Limitations Few aspects may weaken reproducibility in other populations. First, our study was observational with varying observation times across individuals. Second, besides age and BMI, other confounders may exist. Third, sleep apnea screening was offered to all patients, regardless of symptoms. Nevertheless, several patients did not participate, which may have excluded an important proportion of patients leading to selection bias of the study cohort. Additionally, the power of the comparisons was low due to the small number of patients and the low number of events. The effects on the secondary endpoints might have been clearer in a larger group of patients. However, the effect of sleep apnea on the primary endpoint cardiovascular mortality was seen clearly. Interpretation and outlook Sleep apnea shows to be independently predictive of cardiovascular death in patients with Marfan syndrome. Even with only mild sleep apnea the impact on mortality is significant. Therefore, early screening of sleep apnea may be an important adjunct to the PPPM management of Marfan syndrome. Take-Home Points Research Question: To examine the effect of sleep apnea on cardiovascular death and on aortic events in patients with Marfan syndrome. Results: Sleep apnea shows to be independently predictive of cardiovascular death in patients with Marfan syndrome. Interpretation: These findings highlight the necessity of early sleep apnea screening in MFS patients as an important adjunct to the PPPM management of the disease. Abbreviations AHI: Apnea-hypopnea-index BMI: Body-mass-index CPAP: Continuous positive airway pressure therapy (CPAP-therapy) ESS: Epworth Sleepiness Scale HR: Hazard ratio HTAD: Heritable thoracic aortic diseases IQR: Interquartile range LVEF: Left ventricular ejection fraction MFS: Marfan syndrome ODI: Oxygen desaturation index PPPM: Predictive, preventive, and personalized medicine SD: Standard deviations Declarations Acknowledgments The authors thank the patients for their participation in the study. We also send many thanks to all investigators, study coordinators and members of the study team. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests NG reports grants from Boston Scientific, grants from Medtronic and support from Bayer Vital outside the submitted work. SD reports institutional grants from COOK Medical and honoraria from Bayer Vital, outside the submitted work. CE reports grants and/or personal fees from Abbott, Biosense Webbster, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo and Medtronic outside the submitted work. SH reports grants from Meril Life, Boston Scientific and Spectranetics, outside the submitted work. ET reports honoraria from Abiomed and travel compensation from Bayer Vital, Edwards and Amgen outside the submitted work. SW reports grants and personal fees from Abbott, Boston Scientific and Medtronic, and personal feels from Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Bayer Vital, Acutus, and Daiichi Sankyo, outside the submitted work. All other authors have nothing to disclose. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Nele Gessler, Ekaterina Adam, Meike Rybczynski, Peter Wohlmuth and Yskert von Kodolitsch. The first draft of the manuscript was written by Nele Gessler and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Hamburg research ethics committee approved our protocol (17 Oct 2008, PV3031). All patients provided written informed consent. Consent to participate All patients provided written informed consent. 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Eur Heart J. 2021 Oct 14; doi: 10.1093/eurheartj/ehab724.2454 . Patel N, Donahue C, Shenoy A, Patel A, El-Sherif N. Obstructive sleep apnea and arrhythmia: A systemic review. Int J Cardiol. 2017 Feb;1;228:967–70. doi: 10.1016/j.ijcard.2016.11.137 . Demolder A, von Kodolitsch Y, Muiño-Mosquera L, De Backer J. Myocardial Function, Heart Failure and Arrhythmia in Marfan Syndrome: A Systematic Literature Review. Diagnostics (Basel). 2020 Sep 25;10(10):751. doi: 10.3390/diagnostics10100751 . PMID: 32992882; PMCID: PMC7599866. Sowho M, MacCarrick G, Dietz H, Jun J, Schwartz AR, Neptune ER. Association of sleep apnoea risk and aortic enlargement in Marfan syndrome. BMJ Open Respir Res. 2021 Nov;8(1):e000942. doi: 10.1136/bmjresp-2021-000942 . Zhou X, Liu F, Zhang W, Wang G, Guo D, Fu W, Wang L. Obstructive sleep apnea and risk of aortic dissection: A meta-analysis of observational studies. Vascular. 2018 Oct;26(5):515–523. doi: 10.1177/1708538118766102. Epub 2018 Mar 22. PMID: 29566589. Zhang X, Zhang T, Zhang X, Zhang C, Chen J, Han F, Guo W. Obstructive sleep apnea syndrome: a risk factor for Stanford's type B aortic dissection. Ann Vasc Surg. 2014 Nov;28(8):1901–8. doi: 10.1016/j.avsg.2014.07.014 . Epub 2014 Aug 7. PMID: 25108088. Gaisl T, Baumgartner P, Rejmer P, Osswald M, Roeder M, Thiel S, Stämpfli SF, Clarenbach CF, Tanner FC, Kohler M. Prevalence of Obstructive Sleep Apnea in Patients with Thoracic Aortic Aneurysm: A Prospective, Parallel Cohort Study. Respiration. 2020;99(1):19–27. doi: 10.1159/000502892. Epub 2019 Sep 25. PMID: 31553996. Teng HI, Huang CC, Chiang CH, Huang PH, Chung CM, Lin SJ, Chen JW, Leu HB, Chan WL, Lee CY. Sleep apnea and risk of aortic dissection: A nonrandomized, pair-matched cohort study. J Chin Med Assoc. 2016 Aug;79(8):422–7. doi: 10.1016/j.jcma.2015.10.014 . Epub 2016 May 10. PMID: 27174510. Castellana R, Aringhieri G, Gargani L, Maestri M, Schirru A, Bonanni E, Faraguna U. Effects of obstructive sleep apnea on the thoracic aorta and the main pulmonary artery: assessment by CT. J Clin Sleep Med. 2021 Jan 1;17(1):3–11. doi: 10.5664/jcsm.8770 . PMID: 32876043; PMCID: PMC7849640. Golubnitschaja O, Baban B, Boniolo G, Wang W, Bubnov R, Kapalla M, et al. Medicine in the early twenty-first century: paradigm and anticipation-EPMA position paper 2016. EPMA J. 2016;7(1):23. Supplementary Files SupplementaryfilesGessleretal.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 17 Jun, 2022 Reviewers invited by journal 17 Jun, 2022 Editor assigned by journal 15 Jun, 2022 First submitted to journal 13 Jun, 2022 Editorial decision: Major revisions 05 Jun, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1706796","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":114307153,"identity":"751dbf11-bd79-4e02-93e2-bba74cec7f03","order_by":0,"name":"Nele Gessler","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYPACCwYG9gYGxoYCBgY2IrVIMDDwHABqMSBJi0QCRAtBYM7AfvHhjz8ScuYzHz/+OMPAJo+Pvf0Bw4+KbTi1WDbwFBvztkkYy9xOM5PcYJBWzMZzxoCx58xtnFoMDvCkSTM2SCTOkE4wY3xgcDixTSKHgZmxDa+W9J9Ah9XPkDz++eMDg/9ALekPCGhhP8bAwyaRICHBYwB02AGglgQD/FoO8zBLA/1iOIMnp0xyhkEy2C8H8frlePvDjz/+2MhLsB/f/LGnwi5Pvr394YMfFbi1MDDzoMZFAog4gFs9CLA/wNQyCkbBKBgFowAZAAA1qVLpXFrDjwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-5626-7749","institution":"Asklepios Hospital Saint Georg: Asklepios Klinik Sankt Georg","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Nele","middleName":"","lastName":"Gessler","suffix":""},{"id":114307154,"identity":"62ff1359-ac1a-46ac-968e-47c2830c60b6","order_by":1,"name":"Peter Wohlmuth","email":"","orcid":"","institution":"Asklepios Hospital Saint Georg: Asklepios Klinik Sankt 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Asklepios Klinikum Harburg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gunther","middleName":"","lastName":"Wiest","suffix":""},{"id":114307166,"identity":"5f21ef00-f23f-4981-860c-2c99c31a9504","order_by":13,"name":"Stephan Willems","email":"","orcid":"","institution":"Asklepios Hospital Saint Georg: Asklepios Klinik Sankt Georg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stephan","middleName":"","lastName":"Willems","suffix":""},{"id":114307167,"identity":"60fe6107-694f-4cc2-b4ce-f520c0e14655","order_by":14,"name":"Ekaterina Adam","email":"","orcid":"","institution":"Universitatsklinikum Hamburg-Eppendorf Universitares Herz- und Gefasszentrum","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ekaterina","middleName":"","lastName":"Adam","suffix":""},{"id":114307168,"identity":"4adb18aa-9ca2-4559-865a-20f09a3982fa","order_by":15,"name":"Yskert Von Kodolitsch","email":"","orcid":"","institution":"Universitatsklinikum Hamburg-Eppendorf Universitares Herz- und Gefasszentrum","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yskert","middleName":"","lastName":"Von Kodolitsch","suffix":""}],"badges":[],"createdAt":"2022-05-30 07:40:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1706796/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1706796/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":23006867,"identity":"9e5abda4-1e3c-4549-92b8-e09bb1593280","added_by":"auto","created_at":"2022-06-23 16:01:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45171,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-1706796/v1/9d9b05984d113578b1712b3f.png"},{"id":23006869,"identity":"6ef491e7-2347-4ffa-bf44-c78f02f2a339","added_by":"auto","created_at":"2022-06-23 16:01:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":174138,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for the primary outcome: A) For MFS patients without sleep apnea (No OSA) at baseline (AHI≤5); B) For MFS patients with sleep apnea (OSA) at baseline (AHI\u0026gt;5).\u003c/p\u003e\u003cp\u003eThe first primary outcome was a death from cardiovascular causes.\u0026nbsp;\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-1706796/v1/1f4715189a31a8dbddf309d2.png"},{"id":23006868,"identity":"49ae6092-e256-4ff7-8555-567d81ac4007","added_by":"auto","created_at":"2022-06-23 16:01:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":185419,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for first secondary outcome: A) For MFS patients without sleep apnea (No OSA) at baseline (AHI≤5); B) For MFS patients with sleep apnea (OSA) at baseline (AHI\u0026gt;5).\u003c/p\u003e\u003cp\u003eThe first secondary outcome was the occurrence of any aortic events.\u0026nbsp;\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-1706796/v1/984e70937f5e374c4b32930c.png"},{"id":23006873,"identity":"3358e195-295c-4849-807f-a02a40eb4b1b","added_by":"auto","created_at":"2022-06-23 16:01:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":628902,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1706796/v1/fa6b928b-5686-4fbb-be01-b6331932a670.pdf"},{"id":23006870,"identity":"a4cdc414-5941-43a1-8a43-6599ce4fd651","added_by":"auto","created_at":"2022-06-23 16:01:35","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":18045,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryfilesGessleretal.docx","url":"https://assets-eu.researchsquare.com/files/rs-1706796/v1/77eaba19af2a1cc3470fd6c4.docx"}],"financialInterests":"","formattedTitle":"Sleep apnea predicts cardiovascular death in patients with Marfan syndrome \nA cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMarfan syndrome (MFS) is an inherited connective tissue disorder with a high risk for cardiovascular death due to aortic aneurysms and dissections (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Before the development of preventive open-heart surgical procedures for prophylactic replacement of the aortic root, Marfan patients usually died at a mean age of 32 years (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Predictive, preventive, and personalized medicine (PPPM) increased life expectancy to nearly normal because elective replacement of the proximal aorta is performed before aortic dissection or rupture develop (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Care of Marfan patients is a personalized concept, which includes living conditions and family planning of the individual (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). To further optimize PPPM in MFS, it is crucial to identify possible risk factors for aortic events and cardiovascular death.\u003c/p\u003e \u003cp\u003eThe relationship between Marfan syndrome and sleep apnea is well known with a reported prevalence of obstructive sleep apnea between 31\u0026ndash;42.5% in observational studies (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAn association between the occurrence of sleep apnea and aortic events was formally suggested (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) but not confirmed (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Thus far, no long-term follow-up data are available regarding this topic. Besides the high risk for aortic events, MFS has several cardiovascular manifestations, including arrhythmias and myocardial involvement (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Sleep apnea on the other hand is a well-known risk factor for several cardiovascular diseases, such as hypertension, arrhythmias, and congestive heart failure (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUntil now, the effect of sleep apnea on cardiovascular mortality has never been investigated in patients with MFS or other heritable thoracic aortic diseases (HTAD).\u003c/p\u003e \u003cp\u003eThe aim of this study was to evaluate the effect of sleep apnea on cardiovascular death and on aortic events in a large cohort of individuals with genetically confirmed MFS.\u003c/p\u003e"},{"header":"Study Design And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eIn this observational study, all adult patients presenting at the MFS outpatient clinic of a tertiary care center were offered screening for sleep apnea regardless of symptoms. These were patients with previously diagnosed MFS presenting for regular follow-up visits and patients with suspected MFS undergoing thorough clinical examination and genetic testing, all in accordance with current guidelines (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) or expert recommendations (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). If the diagnosis of MFS was not confirmed, patients were excluded from the study, as were patients already on continuous positive airway pressure therapy (CPAP-therapy). Only patients with genetically confirmed diagnosis of MFS (Gene with causative mutation: \u003cem\u003eFBN 1\u003c/em\u003e) were analysed. Therapy and management of the MFS were carried out according to current guidelines (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and according to the decision of the treating physician throughout the complete length of the observational period.\u003c/p\u003e \u003cp\u003e All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Hamburg research ethics committee approved our protocol. All patients provided written informed consent. The study was investigator-initiated and without external funding. The statistical analyses and interpretation of the data was approved by all authors. The data underlying this article will be shared dependant on a reasonable request to the corresponding author.\u003c/p\u003e \u003cp\u003eWe used portable 8-channel monitoring devices for ambulatory and unattended respiratory polygraphy, which was performed at baseline. During sleep, the devices recorded nasal flow with a pressure transducer system, oxygen saturation and pulse rate by finger oximetry, body position through a magnetic sensor, snoring sounds, and thoracic and abdominal movements through belts with pneumatic cushions for pressure measurement. All patients used the device for a single, full night at home. In addition to the electronic evaluation, all polygraphy measurements were analysed manually by a trained investigator and under the supervision of a specialist for sleep medicine. The diagnosis of sleep apnea was made in accordance with current guidelines (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Sleep apnea was defined as an apnea-hypopnea-index (AHI)\u0026thinsp;\u0026gt;\u0026thinsp;5/h. We defined an episode of apnea as the cessation of airflow lasting\u0026thinsp;\u0026ge;\u0026thinsp;10 seconds and hypopnea as a decrease in airflow of \u0026ge;\u0026thinsp;50% lasting\u0026thinsp;\u0026ge;\u0026thinsp;10 seconds, associated with a decrease in oxygen saturation of \u0026ge;\u0026thinsp;4% (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDaytime sleepiness was assessed via Epworth Sleepiness Scale (ESS), defining daytime sleepiness with an ESS score\u0026thinsp;\u0026gt;\u0026thinsp;10. Patients with an AHI\u0026thinsp;\u0026gt;\u0026thinsp;5/h were referred to full polysomnography for further diagnosis and evaluation of treatment.\u003c/p\u003e \u003cp\u003eWe performed echocardiography for left ventricular ejection fraction (LVEF) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) and maximum aortic diameters at the level of the aortic sinuses (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Magnetic resonance angiography was used for diameters of the ascending and descending aortas at established levels. We did not consider diameters at aortic sites with an aortic prosthesis.\u003c/p\u003e \u003cp\u003ePrior results of 68 patients with Marfan syndrome have been published previously in a cross-sectional study (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The study was then continued with the inclusion of further patients. Medical and/or surgical treatment as well as regular follow-up was performed as recommended by guidelines. Twelve years after inclusion of the first patient (median follow-up [IQR] of 7.76 [6.84, 8.41] years), we retrospectively analyzed the patients\u0026rsquo; electronic medical records for adverse events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint was cardiovascular death and the secondary outcome was the occurrence of any aortic event. Aortic events were defined as Stanford type A-dissection, Stanford type B-dissection, aortic rupture, or the need for surgery or intervention for progressive dilatation of aortic aneurysm, performed according to the recommendations of the current guidelines. These are class Ic recommendations in patients who have aortic root aneurysm, with maximal aortic diameter\u0026thinsp;\u0026ge;\u0026thinsp;50 mm, or class IIa recommendations in patients with maximal ascending aortic diameters\u0026thinsp;\u0026ge;\u0026thinsp;45 mm\u0026thinsp;+\u0026thinsp;risk factors (family history of aortic dissection and/or aortic size increase\u0026thinsp;\u0026gt;\u0026thinsp;3 mm/year, severe aortic or mitral regurgitation, or desire for pregnancy) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAcute aortic events were defined as Stanford Type A-dissection, Stanford Type B-dissection, and aortic rupture.\u003c/p\u003e \u003cp\u003eFurther data of interest were the diameter of the ascending and descending aorta, daytime sleepiness and laboratory values.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe primary aim of this analysis was the impact of sleep apnea (baseline AHI) on cardio-vascular mortality and aortic events of MFS patients. Demographic data, echo, laboratory data, the medical history, sleep apnea data and Epworth Sleepiness scores (AHI, ODI, ESS) were documented in all individuals. Death, cardio-vascular death, occurrence and type of aortic events were examined during follow up.\u003c/p\u003e \u003cp\u003eContinuous data were summarized as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (SD) or as medians [25th and 75th percentiles] as appropriate. Categorical data were presented as % (N). Freedom from aortic events and cardio-vascular survival were estimated and graphically displayed using the Kaplan-Meier method. Survival estimates were stratified by the presence of sleep apnea and shown with 95% confidence intervals.\u003c/p\u003e \u003cp\u003eEffects of sleep apnea on cardio-vascular mortality and acute aortic events were examined using Cox proportional hazards models. The Cox models were adjusted for age and body mass index (BMI) using restricted cubic spline functions with three knots. Results were presented with hazard ratios and 95% confidence intervals.\u003c/p\u003e \u003cp\u003eMedian follow up as well as first and third quartiles were estimated using the reverse Kaplan-Meier method.\u003c/p\u003e \u003cp\u003eAll p-values were two-sided and a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. All calculations were performed with the statistical analysis software R (R Core Team, 2021).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBetween February 2007 and December 2017, 205 patients were screened for sleep apnea. We excluded 32 patients, in whom the diagnosis of heritable thoracic aortic disease (HTAD) was not confirmed, as well as 17 patients with Loeys-Dietz syndrome, 25 patients with other syndromic aortic diseases, and 26 patients with other non-syndromic aortic diseases (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eFinally, the study group consisted of 105 patients with Marfan syndrome (mean age 40\u0026thinsp;\u0026plusmn;\u0026thinsp;13 years, 54% women). Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the baseline characteristics of the total study cohort, including age, preexisting interventions or surgery, baseline aortic diameter and laboratory values.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline data (n\u0026thinsp;=\u0026thinsp;105)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMarfan syndrome\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;105\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57 (54%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBody mass index (kg/m\u0026sup2;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline measurements\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eproBNP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110 [57\u0026ndash;253]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLV-EF (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLVEDD (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAscending aorta diameter (mm)\u003c/p\u003e\n \u003cp\u003e(only in patients without prior aortic root surgery)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAscending aorta diameter prior surgery (mm)\u003c/p\u003e\n \u003cp\u003e(only in patients with prior aortic root surgery)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDescending aorta diameter (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-existing aortic events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior Aortic surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior Aortic root surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrior Aortic event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA-Dissection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eB-Dissection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElective intervention for progressive dilatation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal aortic aneurysm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNote:\u0026nbsp;\u003c/strong\u003eFor continuous variables, data are presented as the means and standard deviations. b (a-c) represent the median b with [lower quartile a and the upper quartile c] for continuous variables. For categorical variables, results are expressed as frequencies and percentages.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eN is the number of non-missing values.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean BMI (SD) was 23.5 (\u0026plusmn;\u0026thinsp;4.9), and baseline brain natriuretic peptide (BNP) [interquartile range, IQR] was 110 [57, 253] pg/ml. Of all patients, 43% (45/105) had prior aortic surgery and preceding aortic dissection type A was present in 16% (17/105) at baseline (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe results of sleep apnea screening are shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Sleep apnea with an AHI\u0026thinsp;\u0026gt;\u0026thinsp;5/h was diagnosed in 21.0% (22/105) of patients. Mild sleep apnea was observed in 13% (14/105) of all patients and moderate to severe sleep apnea in 7.6% (8/105). CPAP-therapy was initiated in 7 patients (7%).\u003c/p\u003e\n\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSleep apnea data (n\u0026thinsp;=\u0026thinsp;105)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMarfan syndrome\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;105\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eESS Score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAHI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eODI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSleep apnea category\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo sleep apnea (AHI\u0026thinsp;\u0026le;\u0026thinsp;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 (79%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild (AHI 6\u0026ndash;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMod/Severe (AHI\u0026thinsp;\u0026gt;\u0026thinsp;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (7.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCPAP therapy indicated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePredominantly central sleep apnea in patients\u003c/p\u003e\n \u003cp\u003ewith sleep apnea (\u0026gt;\u0026thinsp;50% of episodes\u0026thinsp;+\u0026thinsp;AHI\u0026thinsp;\u0026gt;\u0026thinsp;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNote:\u0026nbsp;\u003c/strong\u003eFor continuous variables, data are presented as means and standard deviations. For categorical variables, results are expressed as frequencies and percentages.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eN is the number of non-missing values.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePredominately central sleep apnea was present in 32% (7/22) of patients with sleep apnea.\u003c/p\u003e\n\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003eEndpoints\u003c/h2\u003e\n \u003cp\u003eThe median follow-up [IQR] was 7.76 [6.84, 8.41] years. 5/105 (4.8%) patients were lost to follow-up.\u003c/p\u003e\n \u003cp\u003eDeath from any cause was observed in 9.5% (10/105) of all MFS patients. A cardiovascular cause was present in 80% (8/10) of the deceased. Further details of the causes of deaths are shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. Aortic events occurred in 35/105 patients (33%) during follow-up (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOutcome data \u0026ndash; Death and aortic events (n\u0026thinsp;=\u0026thinsp;105)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMarfan syndrome\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;105\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeath (all cause)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e10 (9.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCause of death\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon cardiovascular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiovascular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e8 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCause of death (in detail)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eCardiovascular cause\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic dissection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic rupture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProgression of heart failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSudden cardiac death, arrhythmia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMesenteric ischemia after\u003c/p\u003e\n \u003cp\u003ea) enlargement of dissecting aneurysm of desc. aorta\u003c/p\u003e\n \u003cp\u003eb) extensive surgery of aneurysm of desc. aorta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eNon cardiovascular cause: Sepsis\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAortic diameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAscending aorta diameter (mm) at follow up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDescending aorta diameter (mm) at follow up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAortic event (any)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eType\u003c/strong\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eA-dissection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eB-dissection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eElective intervention for progressive dilatation (aortic dilatation or false lumen expansion)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation and type\u003c/strong\u003e:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eProximal aortic event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDistal aortic event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNote:\u0026nbsp;\u003c/strong\u003eFor categorical variables, results are expressed as frequencies and percentages.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eN is the number of non-missing values.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows the primary outcome of cardiovascular death in relation to sleep apnea. Patients with sleep apnea showed a significantly lower survival rate with regards to cardiovascular death, compared to patients without sleep apnea (p\u0026thinsp;=\u0026thinsp;0.0309). After adjusting for age and BMI, the AHI-score shows to be an independent risk factor for cardiovascular death with a HR [95% CI] of 1.712 [1.061\u0026ndash;2.761], referring to an eight-unit increase in AHI-score (p\u0026thinsp;=\u0026thinsp;0.0276). That means, in case of an increase of AHI from 5 to 15/h, there is an 22% increase in risk for cardiovascular death.\u003c/p\u003e\n \u003cp\u003eRegarding the secondary outcome of aortic events, there was no significant effect of AHI-score after adjusting for age and BMI (HR [95% CI]: 0.965 [0.617\u0026ndash;1.509]), referring to an eight-unit increase in AHI-score. Similar effects were observed for the AHI-score on acute aortic events (HR [95% CI]: 1.247 [0.508\u0026ndash;3.058]). Figure \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e shows that patients with sleep apnea had a lower \u0026ldquo;aortic event\u0026rdquo;-free survival compared to patients without sleep apnea, but without significant difference between the groups (p\u0026thinsp;=\u0026thinsp;0.215). The results for acute aortic events were similar and without a significant impact (p\u0026thinsp;=\u0026thinsp;0.216).\u003c/p\u003e\n \u003cp\u003eAdditionally, the occurrence of sleep apnea or the AHI-score had no significant impact on the proximal or distal aortic growth rate (p\u0026thinsp;=\u0026thinsp;0.619 and p\u0026thinsp;=\u0026thinsp;0.122 respectively).\u003c/p\u003e\n \u003cp\u003eAn analysis of the secondary endpoint aortic events in the subgroup of patients with (45/105) and without (60/105) prior aortic surgery, showed a weak effect of the AHI-score in patients without prior surgery (HR [95% CI]: 1.339 [0.878\u0026ndash;2.044]) without reaching significance (p\u0026thinsp;=\u0026thinsp;0.175). There was no effect in patients with prior aortic surgery (HR [95% CI]: 0.799 [0.373\u0026ndash;1.714], p\u0026thinsp;=\u0026thinsp;0.565).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eMain findings\u003c/h2\u003e \u003cp\u003eWe present an observational study of 105 Marfan patients with a median 7.76-year follow up period from baseline. It is the first study focusing on the primary endpoint cardiovascular death in relation to sleep apnea in this rare disease. Our results demonstrate that sleep apnea is associated with an increased risk for cardiovascular death, independent of the patients\u0026rsquo; BMI or age. There was no effect on the secondary endpoints 1) aortic events in general, 2) acute aortic events, or 3) the proximal or distal aortic growth rate, probably due to the high number of patients with prior aortic surgery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSleep apnea and mortality\u003c/h2\u003e \u003cp\u003eOur study establishes an association of sleep apnea with cardiovascular mortality in Marfan syndrome. There may be several explanation for this finding.\u003c/p\u003e \u003cp\u003eFirst, sleep apnea in general, leads to an increased risk of cardiovascular disease, including difficult-to-control blood pressure, coronary artery disease, congestive heart failure, arrhythmias and stroke (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). It is known that patients with sleep apnea have a higher prevalence of atrial and ventricular arrhythmia compared to the general population (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Additionally, an increased risk of cardiovascular mortality was reported in patients with severe sleep apnea (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The negative effects of sleep apnea on the cardiovascular system in MFS are probably similar to non-Marfan patients, and a reasonable explanation for the increased risk for cardiovascular death in Marfan patients with sleep apnea. In a cross-sectional study, Mui\u0026ntilde;o-Mosquera et al. confirmed that Marfan patients with sleep apnea tend to have higher systolic blood pressures, larger distal aortic diameters and a higher prevalence of ventricular arrhythmias (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). These differences were, however, not significant after adjusting for confounders (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSecond, MFS is not only an aortic disease, but has several manifestations with possible risks for cardiovascular death, including ventricular arrhythmias and myocardial involvement (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Due to great achievements in medical and surgical diagnostics and therapy (including PPPM strategy), death from other cardiovascular causes, excluding aortic events, have become more visible and treatable in the last years (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Our results are in line with these findings, showing 20% deaths of cardiovascular causes beside aortic events.\u003c/p\u003e \u003cp\u003eIn our study, we observed high rates of mild sleep apnea, which may indicate an early state of sleep apnea in this rather young population. Yet, we were able to show that sleep apnea is a significant risk factor for cardiovascular death. Even in case of an increase of AHI from 5 to 15/h, there is an 22% increase in risk for cardiovascular death. This novel finding demonstrates the relevance of sleep apnea screening in this group of patients as an important adjunct to the management of Marfan syndrome. Based on these results, further studies are needed to evaluate different therapy options for sleep apnea in this group of patients, preferably as multicenter trials.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSleep apnea and aortic events\u003c/h2\u003e \u003cp\u003eThe results of our study did not show a significant effect of sleep apnea or the AHI-score on aortic events or the proximal or distal aortic growth rate in patients with Marfan syndrome. Interestingly, further analyses of the subgroups of patients with and without prior aortic surgery showed, that there was a weak effect of the AHI-score on aortic events in patients without prior surgery. Due to the low number of patients in the subgroup, we did not reach the level of significance. In contrast to this subgroup, there was absolutely no effect in patients with prior aortic surgery. Therefore, we believe that the high number of patients with prior aortic surgery (42%) might have influenced the aortic event rate during follow-up and therefore be one explanation for the non-significant effect of the AHI-score on the secondary outcome.\u003c/p\u003e \u003cp\u003eLimited data is published regarding this important topic. Sowho et al. showed that a high risk for sleep apnea (detected by a composite survey score) was associated with aortic enlargement and a threefold increased risk of having prior aortic root replacement in patients with Marfan syndrome (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Kohler et al. compared Marfan patients with and without sleep apnea and observed a significantly shorter aortic event free survival in sleep apnea patients (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). They showed an association between the AHI-score and aortic events independent of the patients\u0026rsquo; BMI. However, this association was no longer significant after adjusting for further covariates like age, gender, baseline aortic diameter, systolic blood pressure and antihypertensive medication (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding the general population beside Marfan syndrome, several studies indicate that sleep apnea alone elevates the risk for aortic dissection, aortic dilatation and aortic rupture (\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), whereas others did not confirm these findings (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). It was also observed that the duration of an oxygen saturation\u0026thinsp;\u0026lt;\u0026thinsp;90% influenced the sizes of the ascending aorta and the main pulmonary artery, showing greater dimensions in patients with sleep apnea (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSumming up, whether sleep apnea leads to an increased risk for aortic events in MFS remains unclear and needs further investigation in larger cohorts, preferably in patients without prior aortic surgery or intervention.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePredictive, preventive, and personalized medicine\u003c/h2\u003e \u003cp\u003eThe PPPM proposes, implements, and supports the need of paradigm shift from reactive medical services to predictive, preventive, and personalized medicine concepts of health (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Care of patients with Marfan syndrome has been roughly in line with this concept for years, as it aims to prevent patients from life threatening complications. Additional to guideline recommendations for preventive surgery, treatment of patients is a personalized concept, which includes living conditions and family planning of the individual. Due to the autosomal dominant heredity, PPPM is not limited to the individual patient but includes the whole family (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur results demonstrate sleep apnea to be predictive for cardiovascular death. Therefore, early sleep apnea screening may serve as an additional predictive diagnostic measure in a complex and multifactorial setting of this inherited connective tissue disease. Further studies are needed to evaluate treatment of sleep apnea with regard to secondary and tertiary prevention of cardiovascular complication in this rare disease.\u003c/p\u003e \u003c/div\u003e\n\u003ch2\u003eLimitations\u003c/h2\u003e\n\u003cp\u003eFew aspects may weaken reproducibility in other populations. First, our study was observational with varying observation times across individuals. Second, besides age and BMI, other confounders may exist. Third, sleep apnea screening was offered to all patients, regardless of symptoms. Nevertheless, several patients did not participate, which may have excluded an important proportion of patients leading to selection bias of the study cohort. Additionally, the power of the comparisons was low due to the small number of patients and the low number of events. The effects on the secondary endpoints might have been clearer in a larger group of patients.\u0026nbsp;However, the effect of sleep apnea on the primary endpoint cardiovascular mortality was seen clearly.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eInterpretation and outlook\u003c/h2\u003e\n\u003cp\u003eSleep apnea shows to be independently predictive of cardiovascular death in patients with Marfan syndrome. Even with\u0026nbsp;only mild sleep apnea the impact on mortality is significant.\u0026nbsp;Therefore, early screening of sleep apnea may be an important adjunct to the PPPM management of Marfan syndrome.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eTake-Home Points\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Question:\u0026nbsp;\u003c/strong\u003eTo examine the effect of sleep apnea on cardiovascular death and on aortic events in patients with Marfan syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u0026nbsp;\u003c/strong\u003eSleep apnea shows to be independently predictive of cardiovascular death in patients with Marfan syndrome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterpretation:\u0026nbsp;\u003c/strong\u003eThese findings highlight the necessity of early sleep apnea screening in MFS patients as an important adjunct to the PPPM management of the disease.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAHI: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Apnea-hypopnea-index\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBMI: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Body-mass-index\u003c/p\u003e\n\u003cp\u003eCPAP:\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Continuous positive airway pressure therapy (CPAP-therapy)\u003c/p\u003e\n\u003cp\u003eESS:\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Epworth Sleepiness Scale\u003c/p\u003e\n\u003cp\u003eHR:\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Hazard ratio\u003c/p\u003e\n\u003cp\u003eHTAD: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Heritable thoracic aortic diseases\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIQR:\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Interquartile range\u003c/p\u003e\n\u003cp\u003eLVEF:\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Left ventricular ejection fraction\u003c/p\u003e\n\u003cp\u003eMFS: \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Marfan syndrome\u003c/p\u003e\n\u003cp\u003eODI: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Oxygen desaturation index\u003c/p\u003e\n\u003cp\u003ePPPM:\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Predictive, preventive, and personalized medicine\u003c/p\u003e\n\u003cp\u003eSD: \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Standard deviations\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the patients for their participation in the study. We also send many thanks to all investigators, study coordinators and members of the study team.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNG reports grants from Boston Scientific, grants from Medtronic and support from Bayer Vital outside the submitted work.\u003c/p\u003e\n\u003cp\u003eSD reports institutional grants from COOK Medical and honoraria from Bayer Vital, outside the submitted work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCE reports grants and/or personal fees from Abbott, Biosense Webbster, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo and Medtronic outside the submitted work.\u003c/p\u003e\n\u003cp\u003eSH reports grants from Meril Life, Boston Scientific and Spectranetics, outside the submitted work.\u003c/p\u003e\n\u003cp\u003eET reports honoraria from Abiomed and travel compensation from Bayer Vital, Edwards and Amgen outside the submitted work.\u003c/p\u003e\n\u003cp\u003eSW reports grants and personal fees from Abbott, Boston Scientific and Medtronic, and personal feels from Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Bayer Vital, Acutus, and Daiichi Sankyo, outside the submitted work.\u003c/p\u003e\n\u003cp\u003eAll other authors have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Nele Gessler, Ekaterina Adam, Meike Rybczynski, Peter Wohlmuth and Yskert von Kodolitsch. The first draft of the manuscript was written by Nele Gessler and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Hamburg research ethics committee approved our protocol (17 Oct 2008, PV3031). All patients provided written informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003evon Kodolitsch Y, De Backer J, Sch\u0026uuml;ler H, Bannas P, Behzadi C, Bernhardt AM, Hillebrand M, Fuisting B, Sheikhzadeh S, Rybczynski M, K\u0026ouml;lbel T, P\u0026uuml;schel K, Blankenberg S, Robinson PN. Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome. 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EPMA J. 2016;7(1):23.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"epma-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"epmj","sideBox":"Learn more about [EPMA Journal](https://www.springer.com/journal/13167)","snPcode":"13167","submissionUrl":"https://submission.nature.com/new-submission/13167/3","title":"EPMA Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Marfan syndrome, Sleep apnea, mortality, PPPM, 3PM","lastPublishedDoi":"10.21203/rs.3.rs-1706796/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1706796/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIdentification of possible risk factors is crucial to optimize predictive, preventive, and personalized medicine (PPPM) in Marfan syndrome (MFS). Despite a well known relationship between sleep apnea and MFS, the impact of sleep apnea on cardiovascular death and on aortic events remains unclear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is an investigator-initiated study with long-term follow-up data of 105 MFS patients. All participants were screened for sleep apnea regardless of symptoms. The primary endpoint was cardiovascular death and the secondary outcome was the occurrence of aortic events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSleep apnea with an apnea-hypopnea-index (AHI)\u0026thinsp;\u0026gt;\u0026thinsp;5/h was observed in 21.0% (22/105) with mild sleep apnea in 13% (14/105) and moderate to severe sleep apnea in 7.6% (8/105). After a median follow-up of 7.76 years [interquartile range: 6.84, 8.41], 10% (10/105) had died, with cardiovascular cause of death in 80% (8/10). After adjusting for age and body-mass-index (BMI), the AHI-score emerged as an independent risk factor for cardiovascular death (hazard ratio 1.712, 95%-confidence interval [1.061\u0026ndash;2.761], p\u0026thinsp;=\u0026thinsp;0.0276). The secondary outcome of aortic events occurred in 33% (35/105). There was no effect of the AHI-score on aortic events after adjusting for age and BMI (hazard ratio 0.965, 95%-confidence interval [0.617\u0026ndash;1.509]), possibly due to a high number of patients with prior aortic surgery.\u003c/p\u003e\u003ch2\u003eInterpretation:\u003c/h2\u003e \u003cp\u003eSleep apnea shows to be independently predictive of cardiovascular death in patients with Marfan syndrome. These findings highlight the necessity of early sleep apnea screening in MFS patients as an important adjunct to the PPPM management of the disease.\u003c/p\u003e","manuscriptTitle":"Sleep apnea predicts cardiovascular death in patients with Marfan syndrome \nA cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-06-23 16:01:33","doi":"10.21203/rs.3.rs-1706796/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2022-06-17T09:53:01+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-06-17T09:30:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-06-16T01:14:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"EPMA Journal","date":"2022-06-13T12:16:33+00:00","index":"","fulltext":""},{"type":"decision","content":"Major revisions","date":"2022-06-05T13:59:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"epma-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"epmj","sideBox":"Learn more about [EPMA Journal](https://www.springer.com/journal/13167)","snPcode":"13167","submissionUrl":"https://submission.nature.com/new-submission/13167/3","title":"EPMA Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"896602a0-8e67-4124-8bca-dca4c1a673eb","owner":[],"postedDate":"June 23rd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-07-20T14:06:50+00:00","versionOfRecord":[],"versionCreatedAt":"2022-06-23 16:01:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1706796","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1706796","identity":"rs-1706796","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}