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Rev. Cardiovasc. Med. 2022; 23(4): 117
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Review
Mitral Annular Disjunction: Pathophysiology, Pro-Arrhythmic Profile
and Repair Pearls
Dimos Karangelis1,*,†, Konstantinos S. Mylonas2,†, Argyris Krommydas3, Spiros Loggos4,
Vasiliki Androutsopoulou1, Dimitrios Stakos5, Dimitrios Mikroulis1, Aphrodite Tzifa6,7,
Fotios Mitropoulos4
1Department of Cardiac Surgery, Democritus University of Thrace, University Hospital of Alexandroupolis, 68100 Alexandroupoli, Greece
2Third Department of Cardiac Surgery, Onassis Cardiac Surgery Center, 10671 Athens, Greece
3Department of Echocardiography, Mitera Hospital, 15123 Athens, Greece
4Department of Cardiac Surgery, Mitera Hospital, 15123 Marousi, Athens, Greece
5Cardiology Department, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece
6Department of Congenital Cardiology, Mitera Hospital, 15123 Marousi, Athens, Greece
7School of Biomedical Engineering & Imaging Sciences, King’s College London, NW3 3 London, UK
*Correspondence: dimoskaragel@yahoo.gr;dkarange@med.duth.gr (Dimos Karangelis)
†These authors contributed equally.
Academic Editor: Peter A. McCullough
Submitted: 20 December 2021 Revised: 14 February 2022 Accepted: 25 February 2022 Published: 30 March 2022
Abstract
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.
Keywords: mitral disjunction; mitral valve prolapse; mitral regurgitation; lethal arrhythmias; ventricular arrhythmias; mitral valve
repair; mitral surgery
1. Definition and Anatomical Considerations
Mitral valve prolapse (MVP) is the most frequent
cause of primary mitral regurgitation (MR) affecting 2.4%
of the general population [1]. The observed leaflet redun-
dancy which is regarded as the main structural abnormality
present in MVP, was thought to be the only mitral valve-
related aberration that could predispose to complex ventric-
ular arrhythmias and sudden cardiac death [2]. Recently,
another type of mitral pathology termed mitral annular dis-
junction (MAD) was reported in patients with MVP and
complex arrhythmias [3]. MAD is a cardiac structural ab-
normality characterized by a distinct separation of the mitral
valve annulus—left atrial wall apparatus and the basal as-
pect of the posterolateral left ventricle (LV) [4]. Disjunction
was first described in 1981 by Bharati et al. [5] in a brief
communication paper delineating the case of a 45-year-old
patient with a floppy mitral valve who died suddenly after
a long history of palpitations [5]. Five years later, Hutchins
et al. [6] identified MAD in 92% of 25 heart autopsies
with mitral valve prolapse (MVP). At that time, MAD was
thought to be of little clinical consequence and received
little attention [6]. In the 90s MAD became a theoretical
and speculative matter in pathological reports [7]. Subse-
quently, it started to gain interest due to the fact that routine
transthoracic echocardiography made it easy to detect and
quantify MAD. One important preliminary paper which in-
troduced echocardiography in the assesment of MAD was
the report by Carmo and colleagues [4]. The authors found
that the function of the mitral annulus was substantially im-
paired in patients with MAD and also correlated the severity
of MAD with the occurrence of non-sustained ventricular
tachycardia [4].
To this day, the pathophysiology of MAD is still not
fully understood. It is well known, however, that the mitral
valve (MV) annulus is not actually a discrete, fibrous, ring-
like structure but rather represents the attachment line of
mitral leaflets to the atrioventricular junction. In this con-
text, the mobility and pattern of contraction of the MV an-
nulus is dictated by the LV contractility and the aortic root
[8]. Therefore, in regular circumstances, the MV annulus
moves in systole towards the LV apex and in diastole to-
wards the left atrium [9].
In the presence of MAD, the annulus is functionally
disengaged from the left ventricle, and a paradoxical an-
nular movement occurs as the annulus moves consistently
with the left atrium during the cardiac cycle (instead of the
LV). Expanding and flattening of the annulus occurs in sys-
tole, causing the segment of the left ventricular wall which
is adjacent to the disjunction area to move outwards in sys-
tole and inwards in diastole. This prominent flattening of
the MV annulus in systole imposes mechanical stress on
the leaflets of the valve as well as the chordae tendineae,
which can lead to valvular degeneration [10].
The aorto-mitral continuity (aorta and the anterior MV
leaflet) is less prone to dilation due to the support of two
robust fibrous trigones. On the other hand, the posterior
part of the MV annulus appears to be significantly more
susceptible to the effects of mechanical stress. These fea-
tures largely explain why MAD affects the territory directly
under the posterior MV leaflet (specifically the P1 and P2
scallops) [11,12]. MAD has a dynamic nature and it is de-
tectable in systole as the myocardium of the ventricle con-
tracts. This nature of the ventriculoannular detachment ex-
plains the paucity of pathological studies on flaccid hearts
[6]. It is also quite obvious why surgeons may not notice
this anatomical variation unless the posterior leaflet is sep-
arated.
2. Incidence and Pathophysiology
MAD accompanies various types of mitral pathology.
In a 2019 systematic review that included 19 studies, the
pooled incidence of MAD was estimated to be 51% in pa-
tients with myxomatous mitral valves, 32.6% in the con-
text of MVP, and 25.9% in severe mitral valve regurgitation
and floppy MV [13]. Severe myxomatous disease involv-
ing bileaflet MVP and marked leaflet redundancy have been
independently associated with annular disjunction [14].
The pathophysiology behind disjunction and the rea-
son why it varies in incidence among different patient
groups has still to be defined. To date, it remains unclear
whether MAD constitutes an acquired structural abnormal-
ity or it has a congenital substrate. As delineated above,
there is a higher proportion of patients with MAD who have
a myxomatous mitral valve compared to patients with a
structurally normal heart [13]. Some speculate that substan-
tial mechanical stress and stretch placed upon the MV annu-
lus and apparatus favor excess tissue formation and leaflet
mobility, ultimately resulting in billowing and prolapse [6].
3. Diagnosis and Imaging
It should be emphasized that the diagnostic cut-off for
disjunction is not unanimously accepted. In the original
histological report by Hutchins et al. [6] wide separation
(>5 mm) was required to diagnose MAD. This descrip-
tion was initially adopted in two-dimensional (2D) [12,15]
and three-dimensional (3D) transesophageal echocardio-
graphic (TEE) studies [10]. However, in recent years
a threshold of >2 mm for two-dimensional transthoracic
echocardiography (TTE) measurements was proposed and
is gradually gaining traction [16].
Taking it a step further, Tani et al. [17] classified dis-
junction according to the degree of separation, as follows:
type 0 in which no MAD is apparent, type I which refers to
a hypermobile basal left ventricular segment and no MAD,
type II which corresponds to MAD less than 5 mm, and type
III in which MAD is more than 5 mm [17]. MAD can be
diagnosed using non-invasive imaging, including TTE or
TEE studies, computed tomography (CT), and cardiac mag-
netic resonance (CMR). By definition, MAD is seen only in
systole when the posterolateral portion of the LV contracts
and the MV annulus “slides” thereby detaching from the LV
myocardium.
When transthoracic echocardiography is utilized,
MAD is assessed by measuring the distance from the site of
the posterior leaflet insertion into the left atrial wall, which
corresponds to the upper border of the disjunction, to the
point where the left atrium associates with the ventricular
myocardium (lower border of the disjunction). This is best
achieved in a parasternal long axis TTE view at end-systole.
By means of 2D TTE, the degree of annular displacement
can be best measured at the P2 level by using a 4-chamber
mid-esophageal view at 0 degrees during systole [12].
CMR not only has high sensitivity in identifying MAD
but can also provide instrumental data regarding the distri-
bution and extent of myocardial and papillary muscle fi-
brosis [18]. Interestingly, Dejgaard et al. [19] utilized
CMR and found that the circumferential extension of MAD
ranges between 30◦–240◦(median 150◦), meaning that
MAD can take up to 2/3 of the annular circumference [19].
Lastly, cardiac CT has also been used to confirm the pres-
ence and quantify the degree of MAD by rotating the view
plane around the center of the MV to visualize the disjunc-
tion along the annular circumference [20].
4. The Impact of MAD on MVP
According to some authors MAD has been considered
to precede occurrence of MVP [6], while others support that
it is developed either independently of MVP [16,19] or even
as a side-product of myxomatous MVP [12]. MAD preva-
lence and associated MVP phenotypes were recently ana-
lyzed in a large cohort of 595 patients with isolated MVP
[14]. Besides the common presence of MAD in patients
with MVP (31%), the authors reported that advanced myx-
omatous degeneration characterized by marked leaflet re-
dundancy and bileaflet prolapse was the most dominant fea-
ture of MVP in MAD [14]. The frequency of bileaflet pro-
lapse in patients with disjunction has also been described
by Mantegazza and colleagues, who further noted that pa-
tients with MVP have been shown to develop significant
mitral regurgitation at an earlier age when MAD is present
[11]. Furthermore, the researchers noted that the incidence
of MAD was higher in patients with Barlow’s disease com-
2
pared to fibroelastic deficiency (22% vs 6%), although the
maximum distance of MAD was similar between these two
phenotypes of degenerative mitral disease [11].
A 2021 study by the Mayo Clinic assessed annular,
valvular and ventricular dynamics in MVP with severe re-
gurgitation stratified by presence of MAD [21]. Patients
with evident MAD had significantly larger diastolic annular
areas (mean, 1646 ±410 vs 1380 ±348 mm2), circumfer-
ences (mean, 150 ±19 vs 137 ±16 mm), and intercommis-
sural diameters (mean, 48 ±7 vs 43 ±6 mm) compared to
those without disjunction. Moreover, the mid- and late sys-
tolic excess intercommissural diameter, circumference en-
largement, and annular area were significantly linked with
MAD. Additionally, MAD was associated with dynami-
cally annular slippage, a statistically significant larger pro-
lapse volume and height (p≤0.007), as well as a larger
leaflet area (mean, 2053 ±620 vs 1692 ±488 mm2,p=
0.01) [21].
Moreover, it has been shown that the incidence of
chordal rupture was reduced in patients with MAD and
MVP (52–61%) compared to prolapse alone (73–75%)
[10,11]. Despite the fact that the presence of MAD did not
affect ejection fractions/LV strain, in the setting of disjunc-
tion, the systolic basal posterior thickness was observed to
be increased (mean, 19 ±2 vs 15 ±2 mm, p<0.001),
with higher systolic thickening of the basal posterior wall
(mean, 74 ±27% vs 50 ±28%) and greater ratio of basal
wall thickness to diameter (p≤0.01) [11].
5. Association with Ventricular Arrhythmias
A growing body of literature has shown a strong as-
sociation between ventricular arrhythmias and MAD. Im-
pressively, 15% of patients with cardiac arrest and no iden-
tifiable cause seem to have underlying MAD (which may
have precipitated the event) [13]. Furthermore, patients
with more extensive MAD and circumferential area seem
to carry an even greater risk of ventricular arrhythmias
[19,22]. Indeed, a disjunction of >8.5 mm has been shown
to strongly predispose to ventricular tachycardia (OR: 10;
95% CI: 1.2–78.1) [4].
Late gadolinium enhancement suggests myocardial fi-
brosis and scarring, which may further predispose to ven-
tricular arrhythmias. A study by Perazzolo Marra and col-
leagues reported that there was a higher extend of late
gadolinium enhancement within the LV with greater MAD
diameters in patients who suffered sudden cardiac death
[23]. Essayagh et al. [22] also associated MAD with ven-
tricular arrhythmias and reported that late gadolinium en-
hancement was detected within the papillary muscles in
84% of the patients [22]. In a more contemporary report,
the same group also suggested that MAD over time con-
tributes significantly and independently to arrhythmic MVP
occurrence likely due to progressive fibrosis of the mitral
apparatus [24].
Dejgaard et al. [19] conveyed that gadolinium en-
hancement in papillary muscles (OR: 4.09; 95% CI: 1.28–
13.05), as well as increased longitudinal MAD distance in
the posterolateral LV wall (OR: 1.16; 95% CI: 1.02–1.33)
are predictive of ventricular arrhythmias. In their series,
late gadolinium enhancement in the anterolateral papillary
muscle was firmly combined with severe arrhythmic events
(OR: 7.35; 95% CI: 1.15–47.02) [19]. Syed and coau-
thors also suggested that excessive mobility of the basal
anterolateral and posterolateral LV segments may generate
a greater degree of mechanical stress on mitral valve an-
nulus and therefore produce myocyte hypertrophy and fi-
brosis. Subsequently, this may induce electrical instability
[25]. Picklehaube’s sign refers to lateral MV annular sys-
tolic velocity more than 16 cm and is observed with exces-
sive pulling of the posterolateral LV wall. This sign may be
valuable in detecting substantial hypermobility which may
predispose patients with MAD to ventricular arrhythmias
[26].
Although MAD appears to be profoundly pro-
arrhythmic, the diagnosis of isolated disjunction should not
affect clinicians to acknowledge this as an imminent risk
factor for sudden death in all patients. Essayagh et al. [24]
in their latest study confirmed that survival after MVP di-
agnosis was non-inferior in patients with MAD in the first
10 years following diagnosis. Although this may seem re-
assuring, careful follow up is warranted in most cases.
6. Surgical Repair in Mitral Regurgitation
with MAD
MAD should be thoroughly investigated during as-
sessment of severe MR in MVP as its recognition is im-
portant to achieve optimal surgical repair. Careful surgical
planning and modification of the repair technique, once the
surgeon is aware of MAD is imperative in these challenging
cases. Mitral valve repair can establish complete postoper-
ative MAD resolution. This is achieved by suturing a ring
which affixes the annulus to the ventricular myocardium
and collapses the MAD area (Fig. 1).
The key determinant of a successful mitral repair in
these cases is to firmly suture the ring to the ventricular my-
ocardium in the area of the pre-operative MAD. It has been
shown that MAD per se, does not hinder the feasibility and
quality of valve repair [21]. Nevertheless, some patients
may be left with a degree of residual MAD after the repair
due to incomplete ring sutures that do not properly affix
the annulus to the posterior wall but rather attach it to atrial
wall. In these cases, it is not yet fully clarified whether per-
sistence of MAD post-repair may lead to progressive LV
fibrosis and arrhythmia [21]. Having said that, in the study
by Essayagh et al. [14] successful mitral surgery was asso-
ciated with a trend towards lower rates of observed arrhyth-
mias. More specifically, the authors report that the link be-
tween MAD and arrhythmic events was strong under medi-
cal management (adjusted HR: 3.21; 95% CI: <2.03–5.06;
3
Fig. 1. Transthoracic echocardiogram of a 60-year-old female patient. (A) Preoperative views showing mitral annular disjunction
(left) and severe mitral regurgitation and during systole (right). The distance between mitral valve leaflet-atrial wall and left ventricle is
measured 1.48 cm (yellow bidirectional arrow). (B) Postoperative views after mitral valve repair with a 34 mm ring. No mitral annular
disjunction is identified. No mitral regurgitation is detected. LV, Left Ventricle; LA, Left Atrium; AO, Ascending Aorta; RVOT, Right
Ventricular Outflow Tract.
p<0.0001) but was weaker after mitral surgery (adjusted
HR: 2.07; 95% CI: 1.24–3.43; p= 0.005) [14].
Historically, Tirone David’s group first proposed that
to make mitral repair successful in the setting of MAD, the
posterior leaflet has to be detached and reattached to the
proximal musculature of the LV and then secured with an
annuloplasty ring [15]. Based on the specific pathology at
hand, either the entire posterior leaflet or just P2–P3 are
detached from their insertion. Moreover, the same group
proposes a liberal use of artificial chordae as a means to
increase the durability of the repair.
Although David’s group favors flexible bands for sta-
bilization of the posterior annulus [15], Carpentier has used
exclusively rigid rings to successfully reattach the posterior
leaflet to the endocardium of the LV in patients with calci-
fication of the annulus and MAD [27]. Using the Toronto
repair approach, freedom from valve-related morbidity and
mortality at 1, 5, and 10 years was 94% ±2%, 90% ±2%,
and 78% ±4%, respectively, while the event-free survival
was 94% ±1.6%, 89% ±3%, and 75% ±5%. Based on
these findings, mitral valve repair in the setting of MR with
advanced myxomatous degeneration and valvular disjunc-
tion seems to be enduring but not as enduring as for isolated
prolapse of the posterior leaflet [28]. Interestingly, it seems
to mirror more the outcomes of repair for bileaflet or ante-
rior leaflet prolapse. With regards to rate of reoperation, this
was low, considering that hardly a 3% of the patient popu-
lation presented severe recurrent MR. Nevertheless, 11.6%
of the patients exhibited moderate MR at follow-up, indi-
cating that MV repair may decelerate but does not halt the
degenerative process altogether.
Mayo Clinic data also showed that MAD receded fol-
lowing mitral valve repair, and parameters such as LV diam-
eter and wall thickening had no difference between patients
with and without MAD [21].
With regards to which is the most beneficial and ef-
fective method of surgery (i.e., repair or replacement) in
terms of postoperative arrhythmic events there is still not
enough data to support either approach. Both surgical pro-
cedures however, can achieve complete disappearance of
MAD in the postoperative setting in almost all patients, and
have demonstrated to reduce the burden of malignant ar-
rhythmias in MVP patients. This is probably because either
the ring or the prosthesis (in the case of replacement), when
sutured, will join the annulus to the LV myocardium, and
collapse the area of disjunction [12,14].
7. MitraClip in Mitral Regurgitation with
MAD
MitraClip may represent a reasonable palliative
method. Indeed, patients with severe regurgitation, exten-
sive myxomatous degeneration, low ejection fraction, and
myocardial fibrosis may be poor surgical candidates and
could benefit from percutaneous edge-to-edge repair via
MitraClip implantation. Of note, the new version of Mitra-
Clip (XTR) has increased arm length (12 mm from 9 mm),
which improves coaptation and facilitates grasping by two
additional sets of frictional elements at the grippers. Due
to its technical characteristics, it can be applicable in cases
of prolapse with redundant leaflet tissue, and it has already
been reported to be favorable in advanced myxomatous mi-
tral disease with MAD [29,30].
There is a relative dearth of literature regarding the ef-
fect of mitral valve repair with Mitraclip on the occurrence
of ventricular arrhythmias. Use of MitraClips, as shown
in the prospective study by Ledwoch et al. [31] has led to
a substantial decrease of ventricular arrhythmias in a co-
hort of 50 heart failure patients with severe MR. MitraClip
4
implantation clearly adds to the reduction of MR, and im-
provement of LV function [30]. This reduction alone how-
ever, achieved by the edge-to-edge repair, may not be suf-
ficient in the long run in the presence of MAD. The annular
correction during surgical repair does not occur with tran-
scatheter edge-to-edge mitral repair. It seems rather reason-
able that patients with severe MR and MAD will benefit
more from surgical repair, however this has yet to be es-
tablished. Additional future studies are warranted to clarify
whether additive annular therapy for MAD is necessary in
cases dealt with Mitraclips.
8. Conclusions
MAD is a structural aberration defined by a specific
disengagement of the mitral valve annulus—left atrial wall
continuity and the basal aspect of the posterolateral LV. It is
frequently encountered in patients with myxomatous mitral
valve degeneration and MVP. On imaging, MAD is only
recognizable during ventricular systole. Although initially
thought to be of little clinical importance, a growing body
of literature has associated the presence of disjunction with
ventricular arrhythmias and sudden cardiac death. Surgi-
cal MV repair is the standard of care for patients with se-
vere regurgitation. To ensure a durable repair in the setting
of MAD, the posterior leaflet has to be detached and reat-
tached to the proximal musculature of the LV and then se-
cured with an annuloplasty ring. Patients with low contrac-
tility reserves and myocardial fibrosis may be considered
for palliative percutaneous edge-to-edge repair using Mitr-
aClip technology. Irrespective of the repair approach, it is
still unclear whether and to what extent long-term outcomes
are affected by annular disjunction.
Author Contributions
DK and KSM contributed in the writing of the paper;
AK assisted in figure selection/interpretation and provided
echocardiographic images. SL and VA assisted in literature
review; DS and DM contributed in interpretation/analysis
of data and assisted in the writing; AT and FM overlooked
the paper and contributed personal expertise on MAD.
Ethics Approval and Consent to Participate
All subjects gave their informed consent for inclusion
before they participated in the study.
Acknowledgment
Not applicable.
Funding
This research received no external funding.
Conflict of Interest
The authors declare no conflict of interest.
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