The impact of Marfan syndrome on long-term outcomes in acute type A aortic dissection after extensive arch surgery

Introduction

Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin-1 gene (1,2). The condition becomes particularly critical when patients develop acute type A aortic dissection (ATAAD), a life-threatening condition that significantly increases morbidity and mortality risks. Despite some research on long-term outcomes of surgical treatment for ATAAD in MFS patients, the overall impact of MFS on ATAAD prognosis remains unclear, largely due to the lack of comparative studies with non-MFS patients. Furthermore, the increasing adoption of total arch replacement with frozen elephant trunk (TAR with FET) for ATAAD treatment necessitates a thorough evaluation of its long-term outcomes (3,4). To address these knowledge gaps, our center conducted a long-term follow-up study to investigate the impact of MFS on outcomes in ATAAD patients who underwent TAR with FET. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0366/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study protocol was reviewed and approved by the Ethics Committee of Fuwai Hospital (No. 2023-2084). Given the retrospective design, the requirement for written informed consent was waived.

Study population and data collection

The cohort comprised patients who underwent TAR with FET for ATAAD at Fuwai Hospital between 2010 and 2018. Patients were categorized into MFS and non-MFS groups (Figure 1). The diagnosis of MFS was established based on the Ghent or revised Ghent criteria (5,6). A thorough analysis of the institutional medical records was performed to compile a comprehensive dataset. This included patients’ preoperative clinical profiles, intraoperative surgical variables, and postoperative clinical trajectories and endpoints. As previous described (4), TAR with FET was performed in patients meeting any of the following criteria: (I) the primary tear located in the arch or descending aorta, with the dissection extending retrogradely to the ascending aorta or the proximal aortic arch; (II) aneurysm formation in the arch or its distal end with a size ≥4.0 cm; (III) severe brachiocephalic artery pathology, including dissection, stenosis, occlusion, or aneurysm formation; (IV) concomitant MFS.

Figure 1 Patient selection flow chart. A total of 1,086 patients with acute type A aortic dissection underwent total arch replacement with frozen elephant trunk and were divided into two groups based on the presence of Marfan syndrome. FET, frozen elephant trunk; TAR, total arch replacement.

Long-term outcomes were obtained through outpatient visits and telephonic interviews for patients unable to attend in-person consultations. Follow-up terminated in December 2023. Aortic computed tomography angiography was conducted at 3, 6, and 12 months post-discharge, followed by annual reviews. Reintervention on the residual distal aorta was indicated when any of the following criteria were met: maximum aortic diameter exceeding 50 mm, rapid aortic expansion (≥10 mm per year on serial imaging), or morphological warning signs including new or enlarging periaortic hematoma, saccular aneurysm formation, or radiographic signs suggestive of impending rupture.

Surgical techniques

All patients underwent median sternotomy and cardiopulmonary bypass (CPB). The details of TAR with FET technique have been previously described (4). The surgical procedures are detailed in Appendix 1.

Endpoints and definitions

The primary endpoints included operative mortality, long-term survival, reoperation rate, and self-care ability. Operative mortality was defined according to the Society of Thoracic Surgeons criteria as death occurring within 30 days after surgery or during the same hospitalization (7). Reoperation was characterized as any subsequent major surgical intervention involving the aorta, aortic valve, or atrioventricular valves. For surviving patients, self-care ability was assessed using the activities of daily living (ADL) scale (8). This scale was stratified into four distinct levels: complete loss of self-care ability (Level 1); partial self-care requiring assistance (Level 2); complete self-care but inability to perform general physical work (Level 3); capable of performing general physical work (Level 4). The Type, Entry location, and Malperfusion status (TEM) classification system was used to define and categorize aortic dissection and malperfusion (9).

Statistical analysis

The statistical analysis is detailed in Appendix 1.

Results

Baseline characteristics

A total of 1,086 patients diagnosed with ATAAD underwent TAR with FET procedure, including 104 MFS patients (9.6%) and 982 non-MFS patients (90.4%). Baseline characteristics are summarized in Table 1. The mean age of the entire cohort was 46.61 (10.13) years. MFS patients were significantly younger, had lower body mass index and lower prevalence of hypertension compared to non-MFS patients (all P<0.001). MFS patients showed significantly higher rates of family history of aortic disease and prior cardiovascular surgery (both P<0.001). Preoperatively, moderate to severe aortic insufficiency was significantly more common in MFS patients (P<0.001). Regarding TEM classification, MFS patients more frequently had ascending aorta entry (TEM-E1: 76.9% vs. 56.6%), while non-MFS patients more commonly presented with aortic arch entry (TEM-E2: 31.8% vs. 15.4%) (both P<0.001). Malperfusion patterns showed coronary involvement (TEM-M1) in 20.0%, supra-aortic involvement (TEM-M2) in 64.5%, and visceral/spinal/iliac arteries involvement (TEM-M3) in 45.1% of patients, with TEM-M3 type more symptomatic in non-MFS patients (P=0.01).

Operative conditions

The operative conditions are summarized in Table 2. MFS patients were significantly more likely to undergo root replacement surgery compared to non-MFS patients [79 (76.0%) vs. 223 (22.7%), P<0.001]. However, as illustrated in Figure S1, the proportion of root-sparing procedures in MFS patients showed an increasing trend over time. A total of 46 (4.2%) patients received aorta-femoral artery bypass surgery, with a relatively higher proportion observed in MFS patients [9 (8.7%) vs. 37 (3.8%), P=0.03]. Furthermore, MFS patients experienced significantly longer hypothermic circulatory arrest (HCA) time [21.54 (5.98) vs. 19.34 (7.16) minutes, P=0.003] with lower core temperature [22.83 (2.75) vs. 23.70 (3.56) ℃, P=0.02] compared to non-MFS patients.

Operative outcomes

Postoperative details are summarized in Table 3. The overall operative mortality rate was 7.4% (80/1,086) and was comparable between the non-MFS and MFS groups [76 (7.7%) vs. 4 (3.8%), P=0.17]. No significant differences were observed between groups for major complications, including re-exploration for bleeding, stroke, paraplegia, and low cardiac output syndrome (all P>0.05). MFS patients demonstrated significantly shorter postoperative recovery times, with reduced duration of mechanical ventilation [14.75 (11.00, 21.00) vs. 20.00 (14.00, 45.00) hours, P<0.001] and shorter intensive care unit stay [46.00 (21.75, 81.00) vs. 72.00 (41.00, 120.00) hours, P<0.001]. Additionally, MFS patients had a lower incidence of continuous renal replacement therapy (3.8% vs. 10.8%, P=0.03).

Long-term outcomes

The follow-up was complete for all patients, with a median duration of 6.08 (4.20, 8.22) years. During this period, a total of 89 late deaths occurred, including 9 in the MFS group. The causes of late deaths, detailed in Table S1, did not differ significantly between the MFS and non-MFS groups. Overall survival rates at 5 and 10 years were 87.3% and 80.6%, respectively (Figure 2A). The 5- and 10-year survival rates for the MFS group were 90.1% and 84.5%, respectively, slightly higher than the non-MFS group’s 87.0% and 80.2%. However, long-term survival analysis revealed no statistically significant difference between the MFS and non-MFS groups (P=0.22), as illustrated in Figure 2B.

Figure 2 Survival and functional outcomes analyses. (A) Long-term survival curve for all patients. (B) Kaplan-Meier analysis for long-term survival comparison between Marfan and non-Marfan syndrome groups. (C) Competing risk analysis for reoperation and death stratified by Marfan syndrome status. (D) Competing risk analysis for incomplete self-care and death stratified by Marfan syndrome status.

The overall reoperation rate at 5 and 10 years was 6.2% and 15.4%, respectively. However, MFS patients exhibited a significantly higher reoperation rate compared to non-MFS patients (P<0.001), with 5-year reoperation rates of 19.2% vs. 4.7% and 10-year reoperation rates of 31.8% vs. 13.4%, as shown in Figure 2C. Of the 69 reoperations performed, 25 occurred in the MFS group. Notably, 72.0% (18/25) of these reoperations in MFS patients were for thoracoabdominal aorta replacement, as detailed in Table S2. Radiographic follow-up demonstrated that complete false lumen thrombosis at the distal end of the stent graft was significantly less frequent in MFS patients compared to non-Marfan patients (61.5% vs. 85.3%, P<0.001), providing objective evidence that persistent false lumen patency underlies the predominance of thoracoabdominal reinterventions in this population. Regarding quality of life, over 90% of surviving patients in both groups maintained complete self-care ability and could engage in general physical work (Figure S2). The rate of incomplete self-care did not differ significantly between the MFS and non-MFS groups (P=0.62), as depicted in Figure 2D.

Effect of MFS on early and long-term outcomes

Univariable logistic regression analysis revealed that MFS was not significantly associated with operative mortality [odds ratio 0.477, 95% confidence interval (CI): 0.143–1.179; P=0.16]. This analysis identified 20 other variables with potential effects (P<0.05) on operative mortality (Table S3). As detailed in Table S4, the impact of MFS on operative mortality remained insignificant across all three multivariable regression models.

Table 4 summarizes the association of MFS with long-term outcomes. Similar to operative mortality, MFS showed no significant effect on long-term mortality in either unadjusted [hazard ratio (HR) 0.705, 95% CI: 0.400–1.242; P=0.23] or multivariable models. Univariable Cox regression identified 25 pre- and intra-operative variables associated with long-term mortality (Table S5). In Model 3 (Table S6), several independent risk factors for long-term mortality were identified.

Notably, MFS consistently showed a significant association with the requirement for reoperation across all models (Table 4) (unadjusted: HR 3.863, 95% CI: 2.425–6.155, P<0.001; Model 1: HR 2.744, 95% CI: 1.643–4.582, P<0.001; Model 2: HR 2.122, 95% CI: 1.220–3.692, P=0.008; Model 3: HR 2.060, 95% CI: 1.183–3.586, P=0.01). Univariable competing risk Cox regression analysis identified six variables potentially affecting reoperation requirement (Table S7), which were incorporated into the final models. As shown in Table S8, in addition to MFS, a history of thoracic endovascular aortic repair (Model 3: HR 5.824, 95% CI: 2.331–14.549, P<0.001) and longer HCA time (Model 3: HR 1.041, 95% CI: 1.009–1.074, P=0.01) were also associated with an increased risk of reoperation. Conversely, older age appeared to be a protective factor against reoperation (Model 3: HR 0.967, 95% CI: 0.946–0.988, P=0.002).

Discussion

In this study, we report the long-term outcomes of surgical repair for ATAAD in patients with MFS compared to contemporaneous non-MFS patients. While early results are satisfactory, our findings particularly emphasize the importance of long-term postoperative monitoring for MFS patients to prevent potentially catastrophic events. To our knowledge, this study represents the largest and most comprehensive analysis to date, contributing valuable insights to the existing research field and potentially informing future treatment strategies for this high-risk patient population.

Contemporary surgical outcomes in MFS

Although MFS patients present with multiple symptoms affecting the eyes, skeletal system, and cardiovascular system, aortic dissection and rupture remain the primary causes of death in MFS patients (10). Over the past 40 years, with advancements in aortic surgical techniques, the lifespan of MFS patients has increased from the third or fourth decade to the eighth decade (11,12). However, clinical outcomes in patients with concurrent ATAAD remain a focal point of concern. Despite the more aggressive pathological nature of MFS, studies from the International Registry of Acute Aortic Dissection data show no statistical difference in hospital mortality between patients with and without MFS (13). Research from The German Registry for Acute Aortic Dissection Type A also indicates that surgical outcomes in MFS patients are comparable to those in the general registry population. However, due to the lack of concurrent non-MFS control groups in previous studies which mostly focused on long-term outcomes exclusively in MFS patients, the true impact of MFS remains uncertain (14). In our study cohort, MFS patients achieved a satisfactory mortality rate of 3.8%, and MFS did not influence operative mortality, as verified by multivariable logistic regression analyses with multiple models.

Root management strategy in MFS

David and colleagues (15) suggest that the aortic valve-sparing technique can reduce the risk of anticoagulation-related complications associated with mechanical prosthetic valves and valve degradation associated with biological prostheses. Similarly, in the context of ATAAD, the majority of non-MFS patients in our cohort successfully retained their valves, with root replacement performed in less than one-quarter of cases. Dell’Aquila and colleagues (16) argue that the benefits of root preservation in ATAAD treatment do not apply to MFS patients. Considering the reduced aortic valve leaflet toughness and strength in MFS patients and their relatively younger age, our cohort showed a higher proportion of root replacement in MFS compared to non-MFS patients. Encouragingly, these tailored root management strategies—favoring preservation in non-MFS patients while advocating more aggressive replacement in MFS patients—yielded equally satisfactory clinical outcomes across both populations. Notably, the increasing use of root-sparing procedures in MFS patients over time (Figure S1) likely reflects refinement of valve-preserving techniques and more stringent patient selection, primarily among those with structurally competent valves and mild or no aortic valve regurgitation. This temporal trend does not conflict with our strategy, as complete root replacement remains our preferred approach in MFS patients presenting with moderate or greater aortic valve regurgitation. Based on these findings, we advocate that timely identification of AR severity and individualized root management strategy—complete replacement for moderate or greater AR, and selective preservation for those with favorable valve anatomy—can provide predictable and favorable long-term outcomes for ATAAD patients with MFS.

Long-term benefits of TAR with FET in MFS

Previous studies have primarily focused on MFS root management, and while some research suggests that performing aortic arch replacement simultaneously with root replacement appears beneficial for ATAAD (17,18), TAR remained limited in clinical practice, with FET procedures being even more scarcely reported (14,19). Our center has established TAR with FET as the standard surgical approach for arch involving ATAAD (4). The results demonstrated favorable long-term survival rates and quality of life across the entire cohort. Notably, MFS patients who underwent TAR with FET showed comparable outcomes to non-MFS patients in terms of both early mortality and long-term survival. Multiple Cox models demonstrated that MFS does not impact long-term survival, which can be attributed to the thorough arch repair and downstream aortic remodeling achieved by TAR with FET (20), and the presence of FET that facilitates safer secondary operations by providing a suitable clamping zone.

Disease progression and reoperation challenges

The cardiovascular manifestations of MFS are inherently multifaceted and progressive. Beyond initial surgery, patients may require subsequent operations over time. A 28-year follow-up study of 73 MFS cases showed that 25% of patients with previous aortic dissection required secondary aortic surgery (17). A 15-year follow-up study including 88 MFS patients demonstrated that ATAAD history was the primary determining factor for subsequent surgery on initially untreated aortic segments (10). The distal aorta remains a critical vulnerability in MFS patients (21). While our study demonstrated comparable long-term survival and quality of life between MFS and non-MFS patients, the reoperation rate in the MFS cohort warrants attention, reaching 31.8% at 10 years. The risk of reoperation among MFS patients was twofold higher compared to their non-MFS counterparts. Analysis revealed two major factors contributing to the higher reoperation rate in MFS patients. First, while TAR with FET provides thorough arch reconstruction, its capacity for aortic remodeling appears limited in certain downstream segments with persistent patent false lumen, despite its role in mitigating or delaying aortic expansion. These untreated regions may eventually progress to thoracoabdominal aortic aneurysms necessitating life-saving secondary interventions. Second, the inherent tissue fragility in MFS patients presents ongoing challenges; even after meticulous root replacement, patients remain at risk for root anastomotic leakage or pseudoaneurysm formation due to chronic hemodynamic stress. This complexity adds to the treatment burden and poses significant challenges in postoperative management. Current literature predominantly focuses on early outcomes, with long-term studies compromised by inadequate follow-up rates or incomplete data collection (22). While patient education regarding follow-up compliance represents a crucial first step, the broader challenge lies in establishing standardized protocols for lifestyle modifications, optimizing medical therapy, and implementing early detection strategies to enhance long-term outcomes.

Limitations

This retrospective study has several limitations. MFS diagnosis was based on Ghent criteria without genetic testing, leaving the number of patients with pathogenic mutations unknown; furthermore, family history of aortic disease may be underreported due to incomplete documentation inherent to retrospective medical record review. Additionally, all eligible patients underwent TAR with FET, preventing comparison with proximal surgery approaches. Finally, the target core temperature for HCA evolved from deep (18 ℃) to moderate hypothermia (25 ℃) over the study period, representing a potential era effect that may not be fully eliminated despite statistical adjustment.

Conclusions

In patients with ATAAD undergoing TAR with FET, MFS does not affect operative mortality and long-term survival. However, compared to non-MFS patients, MFS patients have a higher risk of reoperation, necessitating vigilant follow-up and timely re-examination at specialized centers.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0366/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0366/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0366/prf

Funding: This study was supported by the Beijing Natural Science Foundation (No. L251021).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0366/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study protocol was reviewed and approved by the Ethics Committee of Fuwai Hospital (No. 2023-2084). Given the retrospective design, the requirement for written informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337-9. [Crossref] [PubMed]
2. Judge DP, Dietz HC. Marfan’s syndrome. Lancet 2005;366:1965-76. [Crossref] [PubMed]
3. Sun L, Qi R, Zhu J, et al. Total arch replacement combined with stented elephant trunk implantation: a new "standard" therapy for type a dissection involving repair of the aortic arch? Circulation 2011;123:971-8. [Crossref] [PubMed]
4. Zhang K, Qiu J, Wu J, et al. Long-term outcomes in total arch replacement combined with frozen elephant trunk for acute type A aortic dissection. J Thorac Cardiovasc Surg 2025;170:994-1005.e9. [Crossref] [PubMed]
5. De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417-26. [Crossref] [PubMed]
6. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-85. [Crossref] [PubMed]
7. Maximus S, Milliken JC, Danielsen B, et al. Defining operative mortality: Impact on outcome reporting. J Thorac Cardiovasc Surg 2016;151:1101-7. [Crossref] [PubMed]
8. Zhang K, Zhou C, Gao S, et al. The optimal degree of core temperature for hypothermic circulatory arrest in complex aortic arch surgery: results from 1310 patients. Eur J Cardiothorac Surg 2024;66:ezae311. [Crossref] [PubMed]
9. Authors/Task Force Members. EACTS/STS Guidelines for Diagnosing and Treating Acute and Chronic Syndromes of the Aortic Organ. Ann Thorac Surg 2024;118:5-115.
10. Schoenhoff FS, Jungi S, Czerny M, et al. Acute aortic dissection determines the fate of initially untreated aortic segments in Marfan syndrome. Circulation 2013;127:1569-75. [Crossref] [PubMed]
11. Silverman DI, Burton KJ, Gray J, et al. Life expectancy in the Marfan syndrome. Am J Cardiol 1995;75:157-60. [Crossref] [PubMed]
12. Goldfinger JZ, Preiss LR, Devereux RB, et al. Marfan Syndrome and Quality of Life in the GenTAC Registry. J Am Coll Cardiol 2017;69:2821-30. [Crossref] [PubMed]
13. de Beaufort HWL, Trimarchi S, Korach A, et al. Aortic dissection in patients with Marfan syndrome based on the IRAD data. Ann Cardiothorac Surg 2017;6:633-41. [Crossref] [PubMed]
14. Farag M, Büsch C, Rylski B, et al. Early outcomes of patients with Marfan syndrome and acute aortic type A dissection. J Thorac Cardiovasc Surg 2023;166:25-34.e8. [Crossref] [PubMed]
15. David TE, Armstrong S, Maganti M, et al. Long-term results of aortic valve-sparing operations in patients with Marfan syndrome. J Thorac Cardiovasc Surg 2009;138:859-64; discussion 863-4. [Crossref] [PubMed]
16. Dell'Aquila AM, Concistrè G, Gallo A, et al. Fate of the preserved aortic root after treatment of acute type A aortic dissection: 23-year follow-up. J Thorac Cardiovasc Surg 2013;146:1456-60. [Crossref] [PubMed]
17. Puluca N, Burri M, Cleuziou J, et al. Consecutive operative procedures in patients with Marfan syndrome up to 28 years after initial aortic root surgery. Eur J Cardiothorac Surg 2018;54:504-9. [Crossref] [PubMed]
18. Botta L, Russo V, La Palombara C, et al. Stent graft repair of descending aortic dissection in patients with Marfan syndrome: an effective alternative to open reoperation? J Thorac Cardiovasc Surg 2009;138:1108-14. [Crossref] [PubMed]
19. Shrestha M, Martens A, Kaufeld T, et al. Single-centre experience with the frozen elephant trunk technique in 251 patients over 15 years. Eur J Cardiothorac Surg 2017;52:858-66. [Crossref] [PubMed]
20. Chen Y, Ma WG, Zhi AH, et al. Fate of distal aorta after frozen elephant trunk and total arch replacement for type A aortic dissection in Marfan syndrome. J Thorac Cardiovasc Surg 2019;157:835-49. [Crossref] [PubMed]
21. den Hartog AW, Franken R, Zwinderman AH, et al. The risk for type B aortic dissection in Marfan syndrome. J Am Coll Cardiol 2015;65:246-54. [Crossref] [PubMed]
22. Carrel T, Sundt TM 3rd, von Kodolitsch Y, et al. Acute aortic dissection. Lancet 2023;401:773-88. [Crossref] [PubMed]