Mitral annular disjunction and arrhythmias in Marfan syndrome.

Marfan syndrome (MFS) is an inherited multisystem connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene. Although not prototypical features, ventricular arrhythmias (VAs) and sudden cardiac death are increasingly being reported in patients with MFS.1Muiño-Mosquera L. De Wilde H. Devos D. et al.Myocardial disease and ventricular arrhythmia in Marfan syndrome: a prospective study.Orphanet J Rare Dis. 2020; 15: 300Crossref PubMed Scopus (13) Google Scholar Recently, mitral annular disjunction (MAD) has been associated with VAs and sudden cardiac death.2Basso C. Perazzolo Marra M. Rizzo S. et al.Arrhythmic mitral valve prolapse and sudden cardiac death.Circulation. 2015; 132: 556-566Crossref PubMed Scopus (354) Google Scholar MAD has also been found to be highly prevalent in patients with MFS.3Demolder A. Timmermans F. Duytschaever M. Muiño-Mosquera L. De Backer J. Association of mitral annular disjunction with cardiovascular outcomes among patients with Marfan syndrome.JAMA Cardiol. 2021; 6: 1177-1186Crossref PubMed Scopus (11) Google Scholar However, the clinical significance of MAD in patients with MFS remains unclear. In this study, we sought to describe the clinical and echocardiographic characteristics of MAD in patients with MFS. This retrospective cohort study included consecutive patients with genotype-confirmed MFS who were seen at our institution from 1992 to 2020. Demographic, clinical, and imaging data were collected from the electronic medical records, and the latest studies were used for analysis. The primary outcomes of the study were the development of aortic, mitral, or arrhythmic events. Aortic events were defined as the development of aortic dissection, prophylactic aortic surgery due to aortic aneurysms, or aortic valve replacement or repair. Mitral events were defined as mitral valve replacement or repair. Arrhythmic events were defined as the development of atrial arrhythmias or VAs. MAD was defined as a separation of 3 mm or more between the left atrial wall–mitral valve leaflet junction and the base of the left ventricular (LV) wall. MAD was measured during end-systole in the parasternal long-axis view from the left atrial wall–mitral valve leaflet junction to the base of the LV posterolateral wall. The study was approved by the Mayo Clinic Institutional Review Board. Continuous variables were expressed as mean ± SD or median with interquartile range (IQR) for data with normal or skewed distribution, respectively. Continuous variables were compared using the 2-tailed Student t test or the Mann-Whitney U test and categorical variables using the χ2 or Fisher exact test, as appropriate. Kaplan-Meier analysis was performed to evaluate the age difference at aortic, mitral, and arrhythmic events in patients with and without MAD. All P values were 2-sided with a level of significance less than .05. Statistical analysis was performed using SPSS version 2.5 (SPSS, Inc, Chicago, IL). A total of 204 patients were included in the study. One hundred seven patients (52%) were male. The median age at the time of analysis was 39 years (IQR 26–53 years). The mean LV ejection fraction on transthoracic echocardiography was 57.3% ± 8.2%. Ninety-six patients (47%) had mitral valve prolapse (MVP), and 55 patients (27%) had bileaflet MVP. MAD was present in 61 patients (30%) with a mean distance of 6.5 ± 2.3 mm. At the time of analysis, patients with MAD were younger than those without MAD (29 [IQR 21–41] vs 45 [IQR 29–56]; P < .05) and had a higher prevalence of MVP (72% vs 36%; P < .05). Other baseline characteristics were similar between the 2 groups (Table 1). Eight patients with MAD (13%) had cardiac magnetic resonance imaging, with late gadolinium enhancement noted in 1 patient in the posterior mitral valve leaflet.Table 1Baseline characteristics and descriptive analysis of arrhythmic events stratified by the presence of MADCharacteristicTotal (N = 204)Patients without MAD (n = 143)Patients with MAD (n = 61)PAge at the time of MFS diagnosis (years)18 (12–39)22 (12–42)16 (12–28)<.05Age at the time of analysis (years)39 (26–53)45 (29–56)29 (21–41)<.05Male sex107 (52)79 (55)28 (46).22Medications β-Blocker113 (55)85 (59)28 (46).14 Antiarrhythmic drug16 (8)12 (8)4 (7).75Prior cardiac surgery26 (13)17 (12)9 (15).57ECG IVCD34 (17)27 (19)7 (11).23 LBBB3 (1)3 (2)1 (2).86 RBBB20 (10)16 (11)4 (7).35 QTc interval (ms)442.4 ± 63.3439.9 ± 58.6431.1 ± 73.9.59TTE LVEF (%)57.3 ± 8.257.0 ±8.358.3 ± 7.7.14 MVP96 (47)52 (36)44 (72)<.05 Bileaflet MVP55 (27)23 (16)32 (52)<.05 Mitral regurgitation181 (89)126 (88)55 (90).33 Aortic regurgitation116 (57)88 (62)28 (46).08Atrial arrhythmias36 (18)23 (16)13 (21).37 Paroxysmal AF25169 Persistent AF440 Permanent AF633 Atrial flutter532 Atrial tachycardia202Ventricular arrhythmias12 (6)9 (6)3 (5).70 Ventricular ectopy431 Nonsustained ventricular tachycardia752 Ventricular tachycardia110Values are presented as mean ± SD, median (interquartile range), or n (%).AF = atrial fibrillation; ECG = electrocardiogram; IVCD = intraventricular conduction delay; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; MAD = mitral annular disjunction; MFS = Marfan syndrome; MVP = mitral valve prolapse; QTc = corrected QT; RBBB = right bundle branch block; TTE = transthoracic echocardiography. Open table in a new tab Values are presented as mean ± SD, median (interquartile range), or n (%). AF = atrial fibrillation; ECG = electrocardiogram; IVCD = intraventricular conduction delay; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; MAD = mitral annular disjunction; MFS = Marfan syndrome; MVP = mitral valve prolapse; QTc = corrected QT; RBBB = right bundle branch block; TTE = transthoracic echocardiography. Aortic, mitral, and arrhythmic event rates were 46% (94 of 204), 10% (21 of 204), and 18% (36 of 204), respectively. There was no statistically significant difference in aortic or mitral event rate or age at event between patients with and without MAD (hazard ratio [HR] 1.32; 95% confidence interval [CI] 0.81–2.14; log-rank, P = .26 for aortic events and HR 1.63; 95% CI 0.62–4.30; log-rank, P = .32 for mitral events). Thirty-six patients (18%) had atrial arrhythmias; 6 of those (17%) underwent catheter ablation. The most common atrial arrhythmia was atrial fibrillation (Table 1). Twelve patients (6%) had VAs; 4 of those (33%) underwent catheter ablation. The most common VA was nonsustained ventricular tachycardia (Table 1). No statistically significant difference in arrhythmic event rates was noted between patients with and without MAD (P = .55). However, patients with MAD developed arrhythmic events at a younger age compared with those without MAD (40 years [IQR 33–52 years] vs 51 years [IQR 33–57 years]; HR 4.29; 95% CI 2.07–8.88; log-rank, P < .05). No correlation was found between MAD distance and age at arrhythmic event (r = −0.10; P = .73). Our study suggests that MAD is common in patients with MFS with a strong association with bileaflet MVP. Patients with MAD are at risk of developing arrhythmic events at a younger age and may require closer clinical follow-up. Screening for MAD could be of interest in patients with MFS since MAD was associated with a more severe phenotype developing arrhythmias at a younger age. The authors have no funding sources to disclose.