Evaluation of Mitral Annular Disjunction in Marfan Syndrome Using Cardiovascular Magnetic Resonance

Background: Data on the prevalence of mitral annular disjunction (MAD) in Marfan syndrome (MFS) based on cardiovascular magnetic resonance (CMR) is sparse. The purpose of this study was to assess prevalence, extent, and distribution of MAD in MFS using CMR and to examine its association with left heart parameters, aortic dimensions, and cardiovascular events.

Methods: This retrospective multicenter study included CMR studies of patients treated for MFS at four tertiary care medical centers with a (likely) pathogenic fibrillin-1 gene variant. Two radiologists (five and eight years of experience in CMR) evaluated datasets for MAD (at four points around the annulus, including measurement of extent) and mitral valve prolapse (MVP). Further assessment comprised volumetric and functional analysis of the left ventricle (LV), left atrial size, and aortic root diameters. Cardiovascular events included aortic (aortic surgery or aortic dissection), arrhythmic (sustained ventricular tachycardia or sudden cardiac death), and mitral events (mitral valve surgery, MVS).

Results: Among 91 patients (28.9±14.0 years, 47.3% female), 81.3% had MAD (extent: 6.1±2.6 mm). MAD was mostly found at the inferior insertion (72.5% of patients) and usually affected all sites (39.6% of patients). Left heart parameters and aortic dimensions did not differ between MAD and no MAD groups (P >0.05). MAD extent and localizations showed significant correlations with LV dilatation (e.g., inferior MAD: r=0.62 for end-diastolic volume index), decreased LV ejection fraction (e.g., anterolateral MAD: r=-0.46), and MVP (e.g., MAD distance: r=0.83), which was found in 44.6% of patients with MAD while only affecting 11.8% without MAD (P=0.017). Based on receiver operating characteristic analysis for the prediction of MVP prevalence, a threshold of 7.1 mm MAD extent was identified as the optimal cut-off value (sensitivity: 77.1 %, specificity: 89.3 %). Additionally, subgroup analysis applying different thresholds of MAD extent revealed a significantly larger displacement of MVP and LV volumes as well as higher aortic root z scores for a threshold of ≥ 8 mm. After a mean follow-up of 4.0±3.0 years, cardiovascular events [aortic: n=13 (14.3%), arrhythmic: n=2 (2.2%), and mitral: n=2 (2.2%) of patients] did not differ significantly (all P >0.05) between no MAD and MAD groups regardless of applied thresholds although MVS was observed exclusively in patients with MAD.

Conclusion: The high prevalence, large extent, and predominantly pan-annular distribution of MAD suggest a systemic annular pathology in MFS. Overall presence of MAD was not associated with changes to left heart parameters, aortic dimensions, and cardiovascular events. However, MAD, taking into account its extent and affected insertion sites, could serve as a potential marker of disease progression given the shown association of localizations and distance with LV dysfunction and remodeling as well as aortic enlargement and the formation of MVP.

Distribution patterns of mitral annular disjunction (MAD).

Number of sites of observed MAD: n (%)	Distribution of MAD when detected	Patients, n (%)
0: 17 (18.7)	No site affected	17 (18.7)
1: 10 (10.9)	Anterior	2 (2.2)
	Anterolateral	5 (5.5)
	Inferolateral	1 (1.1)
	Inferior	2 (2.2)
2: 11 (12.1)	Anterior and anterolateral	1 (1.1)
	Anterior and inferolateral	0 (0)
	Anterior and inferior	7 (7.7)
	Anterolateral and inferolateral	1 (1.1)
	Anterolateral and inferior	2 (2.2)
	Inferolateral and inferior	0 (0)
3: 18 (19.8)	Anterior, anterolateral, inferolateral	1 (1.1)
	Anterior, anterolateral, inferior	2 (2.2)
	Anterior, inferior, inferolateral	6 (6.6)
	Anterolateral, inferolateral, inferior	8 (8.8)
4: 36 (39.6)	All sites	36 (39.6)

Outcome of patients for all patients, patients with mitral annular disjunction (MAD), and patients without MAD. VT=ventricular tachycardia. SCD=sudden cardiac death.

	Overall (n=91)	Patients with MAD (n=74)	Patients without MAD (n=17)	P value
Aortic events, n (%)	13 (14.3)	11 (14.9)	2 (11.8)	0.888
Prophylactic aortic surgery, n (%)	12 (13.2)	10 (13.5)	2 (11.8)	1.0
Aortic dissection, n (%)	1 (1.1)	1 (1.4)	0 (0)	1.0
Mitral valve surgery, n (%)	2 (2.2)	2 (2.7)	0 (0)	1.0
Sustained VT or SCD, n (%)	2 (2.2)	1 (1.4)	1 (5.9)	1.0
All-cause mortality, n (%)	2 (2.2)	2 (2.7)	0 (0)	1.0

Histograms displaying the distribution of mitral annular disjunction (MAD) extent for the four insertion points.
Pearson correlation between the localization and extent of mitral annular disjunction with selected cardiovascular magnetic resonance parameters. Asterisk indicates statistical significance. BSA=body surface area. EDV=end-diastolic volume. ESV=end-systolic volume. LA=left atrium. LV=left ventricle. LVEF=left ventricular ejection fraction. MVP=mitral valve prolapse. STJ=sinotubular junction.