Late diagnosis of Marfan syndrome is associated with unplanned aortic surgery and cardiovascular death

Background Marfan syndrome (MFS) guidelines recommend optimal pharmacological therapy (OPT) and replacement of the ascending aorta (RAA) at 5.0cm diameters to prevent acute type A aortic dissection (ATAAD) and death. The effect of early MFS diagnosis and initiation of therapy on outcomes is not known. Objective To evaluate the effect of age at MFS diagnosis and therapy initiation on delayed RAA and death. Methods This retrospective observational cohort study with long-term follow-up included consecutive patients with MFS, pathogenic FBN1 variant, and regular visits to a European Reference Network Center. We considered MFS diagnosis at age ≥21 years late, and OPT initiation at age <21 years early. Outcomes were delayed RAA with aneurysm diameter >5.0cm or ATAAD, and death from all causes. We used landmark design starting at age 21 years to determine associations with outcomes. Results The study group consisted of 288 patients (45.1% male), including 169 patients with late MFS diagnosis (58.7%) and 63 with early OPT (21.9%). During mean follow-up of 25±14.7 years, 78 patients had delayed RAA, with 42 operations for ATAAD and 36 for aneurysms ≥5.0cm. There were 33 deaths, including 11 deaths late after ATAAD. All deaths were cardiovascular. Late diagnosis, but not early OPT, showed univariate association with delayed RAA (P<0.001) and death (P=0.025). Multivariate Cox regression analysis confirmed late diagnosis as predictor of delayed RAA (hazard ratio (HR)=8.01; 95% confidence interval (95%CI) 2.52-25.45; P<0.001) and death (HR=4.68; 95%CI 1.17-18.80; P=0.029). Conclusions Late diagnosis of Marfan syndrome is associated with delayed surgery and death. ### Competing Interest Statement Jens Brickwedel receives honoraria from VASCUTEK Deutschland GMBH for consulting work. Till Joscha Demal was supported by the Clinician Scientist Programme of the German Center for Cardiovascular Research [DZHK; FKZ 81X3710109]. Eike Sebastian Debus provides consultancy services for Terumo Aortic. Paulus Kirchhof (PK) was partially supported by European Union AFFECT-AF (grant agreement 847770), and MAESTRIA (grant agreement 965286), British Heart Foundation (PG/20/22/35093; AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. PK received research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last three years. PK is listed as inventor on two issued patents held by University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Johannes Petersen receives honoraria from Medtronic and Edwards Lifescience for consulting work. Meike Rybczynski holds lectures for Novartis Pharma. All other authors did not declare a relationship with industry and other relevant entities-financial or otherwise. ### Funding Statement There was no financial support provided for this work Disclosures: Jens Brickwedel receives honoraria from VASCUTEK Deutschland GMBH for consulting work. Till Joscha Demal was supported by the Clinician Scientist Programme of the German Center for Cardiovascular Research [DZHK; FKZ 81X3710109]. Eike Sebastian Debus provides consultancy services for Terumo Aortic. Paulus Kirchhof (PK) was partially supported by European Union AFFECT-AF (grant agreement 847770), and MAESTRIA (grant agreement 965286), British Heart Foundation (PG/20/22/35093; AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. PK received research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last three years. PK is listed as inventor on two issued patents held by University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Johannes Petersen receives honoraria from Medtronic and Edwards Lifescience for consulting work. Meike Rybczynski holds lectures for Novartis Pharma. All other authors did not declare a relationship with industry and other relevant entities-financial or otherwise. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Ethics Committee of the Hamburg Medical Association in Hamburg, Germany, under registration number 2012-10518-BO-ff. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes There are no external datasets or supplementary materials online at other repositories that pertain to this manuscript