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Mitral Annular Disjunction: Associated Pathologies and Clinical Consequences

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Purpose of Review To provide an overview of mitral annular disjunction (MAD) and to discuss important challenges in diagnosis and management of MAD. Recent Findings MAD has regained interest in the context of sudden cardiac death (SCD) in patients with mitral valve prolapse (MVP), coined as the “arrhythmic” MVP syndrome. In addition, MAD in isolation was recently suggested to be associated with severe arrhythmia and SCD. Summary There is a lack of consensus on the definition of MAD and the imaging modality to be used for diagnosing MAD, and the therapeutic implications of MAD remain uncertain. Furthermore, the exact mechanism underlying the association of MAD with SCD remains largely unexplored.
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https://doi.org/10.1007/s11886-022-01806-1
CARDIAC PET, CT, ANDMRI (P CREMER, SECTION EDITOR)
Mitral Annular Disjunction: Associated Pathologies andClinical
Consequences
JonasVerbeke1 · AnthonyDemolder1 · JulieDeBacker1 · FrankTimmermans1
Accepted: 10 October 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Purpose of Review To provide an overview of mitral annular disjunction (MAD) and to discuss important challenges in
diagnosis and management of MAD.
Recent Findings MAD has regained interest in the context of sudden cardiac death (SCD) in patients with mitral valve
prolapse (MVP), coined as the “arrhythmic” MVP syndrome. In addition, MAD in isolation was recently suggested to be
associated with severe arrhythmia and SCD.
Summary There is a lack of consensus on the definition of MAD and the imaging modality to be used for diagnosing MAD,
and the therapeutic implications of MAD remain uncertain. Furthermore, the exact mechanism underlying the association
of MAD with SCD remains largely unexplored.
Keywords Mitral annular disjunction· Mitral valve prolapse· Mitral regurgitation· Sudden cardiac death
Introduction
Mitral valve prolapse (MVP) affects 1–2% of the general pop-
ulation and, in the absence of significant mitral regurgitation
(MR), it is usually considered a benign degenerative disease
[19, 10••]. Over the years, an increased risk of sudden car-
diac death (SCD) has been reported in patients with MVP,
including patients with mildor no MR [1119]. The risk
of SCD appears to be confined to a small subset of patients
with MVP featuring specific electrocardiographic and
echocardiographic signs, coined as the “arrhythmic MVP”
syndrome (aMVP) [1923]. Patients with aMVP are typi-
cally young with bileaflet MVP and extensive leaflet redun-
dancy, and present with electrocardiographic abnormalities
(T wave inversion and ST-segment depression) and (marked)
mitral annular disjunction (MAD). Among these features,
MAD has received particular interest in recent years.
In MAD, there is a discontinuation between the attach-
ment of the mitral valve leaflet and the myocardium of the
left ventricular (LV) free wall (“ventricular crest”) (Fig.1)
[24, 25]. Although the original description is often credited
to Hutchins etal. [24], other authors already documented
this anatomic alteration several years before [2629]. How-
ever, the association with MVP or SCD appeared spurious,
and soon after the landmark report, Angelini reiterated MAD
as a normal anatomical variant, reassuring the cardiac com-
munity [30, 31]. Although the number of reports on MAD
are rapidly expanding, many questions on this topic remain,
in particular, regarding the pathophysiology of MAD, its
assessment, its relation with MVP, and the potential thera-
peutic consequences. The purpose of this review is to pro-
vide an overview on the pathophysiology of MAD, and to
discuss the diagnostic and therapeutic challenges in patients
with MAD.
Challenges inDiagnosis ofMAD
The prevalence of MAD varies considerably among reports.
This probably relates to the lack of a universal definition of
MAD, the characteristics of the specific study population
Julie De Backer and Frank Timmermans contributed equally to the
manuscript
This article is part of the Topical Collection on Cardiac PET, CT,
and MRI
* Jonas Verbeke
jdverbek.verbeke@ugent.be
1 Department ofCardiology, Ghent University Hospital,
Corneel Heymanslaan 10, 9000Ghent, Belgium
Current Cardiology Reports (2022) 24:1933–1944
/ Published online:4 November 2022
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... LV dilation has been documented in patients with non-syndromic MAD/MVP, even in the absence of significant mitral regurgitation [4,28,29]. Verbeke et al. describe several possible explanations including the presence of underlying connective tissue disease (such as MFS), underestimation of mitral regurgitation, frequent unrecognized ectopy, or a separate myocardial disease [30]. Bui et al. have also previously described both LV dilation and more diffusely shortened postcontrast T1 times concerning for global fibrosis in a group of adults with non-syndromic MVP [31], and more recently, Karur et al. have demonstrated longer T1 times in a small cohort of pediatric MFS and Loeys-Dietz patients [32]. ...
Article
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Background Mitral annular disjunction (MAD) has increasingly been recognized as a marker for adverse cardiovascular events in Marfan syndrome (MFS). As recent adult data links MFS with left ventricular (LV) dilation and reduced ejection fraction (LVEF), we hypothesized that MAD may be associated with LV dilation in pediatric MFS patients. Methods A retrospective analysis was performed among MFS patients < 19 years old at initial cardiac MRI (CMR). MAD and mitral valve prolapse (MVP) were assessed by CMR or most proximate echo. CMR-derived left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volumes were measured. Indexed volumes, absolute and indexed z-scores, and LVEF were calculated. The combined volume load from mitral and aortic regurgitation was indexed to LV stroke volume, allowing exclusion of patients with greater than mild volume load or prior MV intervention. MAD association with LV volumes and z-scores was then assessed. Results Forty-two patients were analyzed (median age 13.5 years old, IQR [10.9, 15.3]). MAD was present in 28 patients (66.7%), and MVP was present in 13 patients (31.0%). Absolute LVEDV z-score was > 2 in 35.7% of patients, LVESV z-score was > 2 in 42.9%, and LVEF was < 55% in 45.2%. In multivariable analysis including MVP, MAD remained independently associated with elevated absolute LVESV z-score > 2 (RR 3.88, 95% CI 1.02–14.69, p = 0.046). Conclusion MAD was associated with CMR-derived volume-load-independent LV dilation among pediatric MFS patients. Prospective studies are needed to further understand this association and its relationship with LV dilation over time.
... The incidence of a-MAD in previous clinical studies varies depending on the patient population, imaging modality, and the criteria of for defining a-MAD [29,30]. The most common noninvasive imaging modality to detect MAD is transthoracic echocardiography. ...
Preprint
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Background Mitral annular disjunction (MAD) has increasingly been recognized as a marker for adverse cardiovascular events in Marfan syndrome (MFS). As recent adult data links MFS with left ventricular (LV) dilation and reduced ejection fraction (LVEF), we hypothesized that MAD may be associated with LV dilation in pediatric MFS patients. Methods A retrospective analysis was performed among MFS patients < 19 years old at initial cardiac MRI (CMR). MAD and mitral valve prolapse (MVP) were assessed by CMR or most proximate echo. CMR-derived left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volumes were measured. Indexed volumes, absolute and indexed z-scores, and LVEF were calculated. The combined volume load from mitral and aortic regurgitation was indexed to LV stroke volume, allowing exclusion of patients with greater than mild volume load or prior MV intervention. MAD association with LV volumes and z-scores was then assessed. Results Forty-two patients were analyzed (median age 13.5 years old, IQR [10.9, 15.3]). MAD was present in 28 patients (66.7%), and MVP was present in 13 patients (31.0%). Absolute LVEDV z-score was > 2 in 35.7% of patients, LVESV z-score was > 2 in 42.9%, and LVEF was < 55% in 45.2%. In multivariable analysis including MVP, MAD remained independently associated with elevated absolute LVESV z-score > 2 (RR 3.88, 95% CI: 1.02–14.69, p = 0.046). Conclusion MAD was associated with CMR-derived volume-load-independent LV dilation among pediatric MFS patients. Prospective studies are needed to further understand this association and its relationship with LV dilation over time.
Article
Full-text available
Mitral annular disjunction (MAD) is a structural abnormality defined by a distinct separation of the mitral valve annulus—left atrial wall continuum and the basal aspect of the posterolateral left ventricle. This anomaly is often observed in patients with myxomatous mitral valve prolapse. Importantly, MAD has been strongly associated with serious ventricular arrhythmias and predisposes to sudden cardiac death. Therefore, we have to emphasize the need to diagnose this morphologic and functional abnormality in routine practice in order to facilitate optimal mitral valve repair and minimize patient risks. Nevertheless, clinical knowledge regarding MAD still remains limited. In the present review, we aim to shed light on several aspects of MAD, including distinct anatomical and pathophysiological characteristics, imaging modalities, association with ventricular arrhythmias, and current methods of treatment.
Article
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Purpose Papillary muscle fibrosis may act as an arrhythmogenic substrate in patients with mitral valve prolapse (MVP). Previous studies used conventional bright-blood late gadolinium enhancement cardiovascular magnetic resonance (LGE CMR) imaging to assess papillary muscle fibrosis, although this technique suffers from poor scar-to-blood contrast which may limit its sensitivity, in contrast to dark-blood LGE. This study sought to compare bright-blood and dark-blood LGE for the detection of papillary muscle fibrosis in patients with MVP. Method 60 patients with known isolated MVP referred for CMR were prospectively recruited. A routine CMR protocol was used to obtain cine imaging, dark-blood LGE and bright-blood LGE in three long-axis views and a stack of short-axis views. Flow mapping of the proximal aorta was performed to calculate mitral regurgitant volume. Images were analysed for cardiac volumes, ejection fraction, mitral regurgitation severity, MVP characteristics (mitral annular disjunction, prolapse volume) and presence of LGE at the papillary muscles and myocardium. Results Dark-blood LGE detected significantly more subjects with LGE at the papillary muscles than bright-blood LGE (35% vs 15%, p=0.002). There was no difference between LGE techniques regarding myocardial (non-papillary muscle) fibrosis (present in 25% each). No statistical differences were observed between patients with or without LGE at the papillary muscles regarding demographics, clinical data (including ventricular arrhythmia) and MVP characteristics. Furthermore, no association was found between LGE at the papillary muscles and at the myocardium. Conclusions Compared to bright-blood LGE, dark-blood LGE CMR improves the detection of LGE at the papillary muscles in patients with MVP.
Article
Background Mitral annular disjunction (MAD) is a structural abnormality associated to mitral valve prolapse (MVP). MVP has been associated with malignant ventricular arrhythmia, originating from inferolateral left ventricle (LV) wall. However, the mechanism of these arrhythmias remains partly unknown and QT prolongation is probably a risk factor. Purpose To take advantage of the high prevalence of MVP in Marfan syndrome (MFS) to study the relationship of MVP, MAD, LV basal hypertrophy and QTc. Methods We conducted a prospective, monocentric and observational study. We included all MFS patients older than 14 yo without a history of thoracic surgery seen in the French reference center between 01/01/2015 and 01/01/2017. A standardized transthoracic echocardiography was systematically performed and recorded. We identified presence of MAD and measured its length, measured end-systole and end-diastole mitral annular diameters. MVP was identified on echocardiography as systolic displacement (≥2mm) of a mitral leaflet into the left atrium, beyond the mitral annular plane. Mitral valve billowing was identified as systolic displacement of a mitral leaflet in the mitral annular plane or less than 2 mm into the left atrium. We evaluated LV inferolateral wall thickness: basal inferolateral hypertrophy (BILH) was defined as basal inferolateral thickness ≥12mm and basal to mild wall thickness ratio ≥1.5. A rest 12-lead ECG was performed and used to measure QTc according to Bazet rules. Results 250 MFS patients (median age 30.8 years) were included. Systolic mitral leaflet displacement abnormality (billowing or MVP) was present in 187 (74.8%) patients and MVP in 93 (37.2%). MAD was present in 52/235 (22.13%) and was associated with billowing or MVP in all cases. End-systole mitral annular diameter was larger when billowing or MVP was present (mean: 34.82mm vs. 30.53mm, p<0.0001) and in MAD+ than in MAD− (mean: 37.14mm vs. 32.46mm, p<0.0001) with a correlation between MAD length and end-systole mitral annular diameter (r=0.395, p<0.0001). Whereas mitral annular diameter decreased in systole in MAD−, it increased in MAD+ (mean mitral annular diameter (diastolic–systolic): 3.69mm vs. −0.87mm, p<0.0001). Basal inferolateral wall was thicker in MAD+ than MAD− (mean: 11.39mm vs. 10.11mm, p=0.016). BILH was present in 18/175 (10.29%) patients with billowing or MVP vs. in 1/59 (1.69%) without (p=0.0367) and in 9/50 (18%) MAD+ vs. 10/174 (5.75%) MAD− (p=0.006). No electric abnormality on ECGs was associated with MAD+, billowing or MVP. In contrast, patients with BILH had a longer QTc than patients without hypertrophy (mean: 426ms vs. 411.4ms, p=0.0220). Conclusion In our MFS population, MAD is associated with systolic mitral annular dilatation, MVP or billowing and basal LV hypertrophy, but not with ECG abnormalities. Only patients with basal hypertrophy present a QTc prolongation, a known risk marker for ventricular arrhythmias. Funding Acknowledgement Type of funding sources: None.
Article
Open in new tabDownload slide Potential of genetics in risk assessment and therapy in individuals with mitral valve prolapse.
Article
Open in new tabDownload slide Risk stratification scheme. Risk stratification aiming at assessing the risk of VAs and SCD in patients with MVP, involving two phases based on the clinical and imaging context and the uncovered arrhythmia. In the absence of ventricular tachycardia, phenotypic risk features will trigger the intensity of screening for arrhythmia. Green boxes indicate green heart consensus statements and yellow boxes indicate yellow heart consensus statements. High risk - sustained VT, polymorphic NSVT, fast (>180 bpm) NSVT, VT/NSVT resulting in syncope. ICD = implantable cardioverter defibrillator; LA = left atrium; LGE = late gadolinium enhancement; LV-EF = left ventricular ejection fraction; MAD = mitral annular disjunction; MV = mitral valve; PVCs = premature ventricular contractions; TWI = T-wave inversion; VT = ventricular tachycardia. #Additional ECG monitoring method may be used such as loop recorders.
Article
Background: Patients (pt) with mitral valve prolapse (MVP) due to Barlow disase (BD) have an increased incidence of ventricular arrhythmias (VA; including ventricular tachycardias VT) and sudden cardiac death (SCD). Data on the effect of MV repair on VA are scarce. Methods: Pre- and postoperative VA in severe mitral regurgitation (MR) with MVP due to BD undergoing surgical mitral valve repair were analyzed. Patients with degenerative mitral valve disease not fulfilling BD criteria were excluded. Information was from charts, ECG/Holter ECG and/or pacemaker/ implantable cardioverter defibrillator (ICD) data. SCD, sustained VT >30 sec and/or ventricular fibrillation necessitating an ICD-shock were considered major events. Event probability was calculated using the Kaplan-Meier estimator throughout the follow-up period of 20.7 years. Results: There were 82 pts (61% males), mean age at surgery 62±14 years. Bileaflet MVP was present in 54%, mitral annular dysjunction (MAD) in 37% and left ventricular ejection fraction (LVEF) < 50% in 12%. MV repair included ring annuloplasty in all and artificial chords in 48%. Mean follow-up was 3.1 years (0.2 to 14.2 years). Postoperative rhythm surveillance by Holter ECG and/or pacemaker was available in 67%. A VA load of ≥ 10% and/or any VT was noted in 26% before and 32% after surgery (p=0.44). Postoperative VA load was not predicted by MAD, artificial chords, LVEF of <50%, age at surgery >50 years and/or residual ≥ moderate MR (all p<0.05), it correlated only with bileaflet MVP (p=0.009). Major events occurred in 3 pts: SCD in 2 pts and ICD for sustained polymorphic VT in 1 pt (incidence 1.2%/year). The event probability of receiving a SCD or an ICD-shock was 4.9%. Conclusions: VA burden does not seem to change after MV repair in MVP due to BD. The occurrence of major arrhythmic events can not be predicted reliably, thus, patients with MVP due to BD may need lifelong postoperative follow-up, especially in bileaflet MVP which was an independent risk factor for increased VA burden in this retrospective long-term study in a small but well selected patient group.
Article
Aims: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. Methods and results: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. Conclusion: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.
Article
Background Mitral valve prolapse (MVP) has been associated with ventricular arrhythmia, originating from inferolateral left ventricle (LV) wall. However, its mechanism remains unclear. Purpose To take advantage of the high prevalence of MVP in Marfan syndrome (MFS) to study the relationship of MVP, mitral annular disjunction (MAD), LV basal hypertrophy and ECG abnormalities. Methods We included all MFS patients (≥ 14 yo) without a history of thoracic surgery seen in our center between 2015 and 2017. MVP was identified on echocardiography according to Levine definition and the other cases of abnormal systolic mitral leaflet displacement were defined as billowing. Basal inferolateral hypertrophy (BILH) was defined as basal inferolateral thickness ≥ 12 mm and basal to mild wall thickness ratio ≥ 1.5. QTc was measured on rest 12-lead ECG (Fig. 1). Results Two hundred and fifty MFS patients were included. Billowing or MVP (BMVP) was present in 187 (74.80%) patients. MAD was present in 52/235 (22.13%) and was associated with BMVP in all cases. End-systole mitral annular diameter was larger when BMVP was present (mean: 34.82 mm vs. 30.53 mm, P < 0.0001) and in MAD+ than in MAD− (mean: 37.14 mm vs. 32.46 mm, P < 0.0001) with a correlation between MAD length and end-systole mitral annular diameter (r = 0.395 P < 0.0001). Whereas mitral annular diameter decreased in systole in MAD−, it increased in MAD+ (mean mitral annular diameter (diastolic–systolic): 3.69 mm vs. −0.87 mm, P < 0.0001). BILH was present in 18/175 (10.29%) patients with BMVP vs. in 1/59 (1.69%) without (P = 0.0367) and in 9/50 (18%) MAD+ vs. 10/174 (5.75%) MAD− (P = 0.006). No electric abnormality on ECGs was associated with MAD or BMVP. In contrast, patients with BILH had a longer QTc than patients without HBIL (mean: 426ms vs. 411.4ms, P = 0.0220). Conclusion In MFS population, MAD is associated with BMVP, systolic mitral annular dilatation, and BILH but not with ECG abnormalities. Only patients with BILH present a QTc prolongation.
Article
Despite what was considered adequate pharmacological treatment, the conditon of six patients with severe mitral valve prolapse but with trivial or no mitral regurgitation deteriorated. These patients had marked weakness, chest pain, dyspnea, and arrhythmias. Because these patients found their condition to be intolerable, the prolapsed mitral valve was repaired. Electrocardiography, treadmill stress testing, and left ventriculography performed following operation showed complete repair of the valve and significant improvement over the preoperative findings in all six patients. Repair of the floppy mitral valve did not eradicate all abnormalities; however, it did significantly improve the chest pain, weakness, dyspnea, and arrhythmias in all six patients. Five patients no longer require any medication. The prolapsed mitral valve contributed significantly to the symptoms and arrhythmias, but it could not have been the sole cause for these patients’ signs and symptoms. With complete correction of the prolapse in all six patients, few of the signs and symptoms of the disease persisted. Repair of severe mitral valve prolapse without mitral regurgitation is recommended only for those patients who continue to be severely symptomatic from chest pain, dyspnea, or ventricular arrhythmias after an extensive trial of adequate medical therapy.