Author + information
- aCardiovascular Pathology Unit, Azienda Ospedaliera, Padova, Italy
- bDepartment of Cardiac, Thoracic, and Vascular Sciences, University of Padua Medical School, Padova, Italy
- cClinical Cardiology Unit, Azienda Ospedaliera, Padova, Italy
- ↵∗Address for correspondence:
Dr. Cristina Basso, Cardiovascular Pathology, Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua Medical School, Via A. Gabelli, 61 35121 Padova, Italy.
- cardiac magnetic resonance
- mitral annulus disjunction
- mitral regurgitation
- mitral valve prolapse
- ventricular arrhythmia
Function of the mitral valve (MV) requires a complex interplay among the annulus, leaflets, and subvalvular apparatus (1). Mitral annulus is a 3-dimensional saddle-shaped structure exhibiting dynamic conformational change during the cardiac cycle. Morphologically, it is a fibrous structure conventionally divided into an anterior and posterior portion, although the real mitral annulus is along the atrioventricular junction that serves as hinge point for the mural leaflet of MV. The anterior portion is between the right and the left trigones, at the level of the so-called “mitro-aortic fibrous continuity.” As a fibrous structure, the motion of the annulus is passive and is determined by the contraction and relaxation of adjacent atrial and ventricular musculature, as well as by the motion of the aortic root (1).
The Concept of Mitral Annular Disjunction
Mitral annular disjunction (MAD) was originally described by Bharati et al. (2) in a 45-year-old physician who died suddenly with a long history of palpitations, midsystolic click, and late systolic murmur, affected by mitral valve prolapse (MVP). This anatomic appearance of the fibrous mitral annulus was then systematically investigated by Hutchins et al. (3), who defined MAD as a variation in the attachment of the posterior MV leaflet, accounting for a wide separation between left atrium wall-MV junction and the left ventricular (LV) free wall. It is still a matter of debate whether it should be considered an abnormal or normal variation in embryological development of the mitral annulus (4).
In the pathological study of 900 hearts from adult autopsies, 25 (3%) had a morphologically typical floppy MV and 23 of them (92%) showed a MAD; Hutchins et al. (3) not only provided a morphological description of MAD in the context of MVP, but also postulated the pathogenetic hypothesis that this peculiar anatomy of the annulus could trigger a mechanical stress on the leaflets leading, with time, to myxomatous degeneration as a consequence of an excessive mobility of MV apparatus (3).
In vivo, MAD can be visualized by 2-dimensional transthoracic echocardiography on parasternal long-axis view during end systole (5), even if the transesophageal echocardiography technique seems to be more accurate (6). Recently, the 3-dimensional structure of MAD in MVP has also been reported (7).
Despite the initial pathological interest in MAD prevalence related to MVP coexistence (2,3), the clinical relevance of MAD remained confined to its role in MV regurgitation from a surgical point of view. In 2005, Eriksson et al. (6) observed MAD by direct surgical inspection in some patients undergoing MV repair with advanced myxomatous disease. By applying a standardized transesophageal echocardiography protocol, the authors found a 98% prevalence of MAD in a surgical series of MVP patients with severe mitral regurgitation. Furthermore, a positive correlation between the extent of MAD and the number of diseased MV scallops was detected, supporting an association between MAD and the severity of MVP. The effect of MAD on mitral annular function and the possible increased failure after MV repair because of an unrecognized MAD were also demonstrated, so that Eriksson et al. (6) modified their surgical repair technique to optimize long-term results. More recently, it has been suggested that evaluation of the presence and extent of MAD should become an essential part of pre-procedural planning of surgical and transcatheter MV repair (7).
It is noteworthy that an abnormal movement of mitral annulus in MVP was also already noted (8). Normally, the motion of the mitral annulus is passive and determined by the contraction and relaxation of adjacent atrial and ventricular musculature. As a consequence, in normal conditions, the posterior mitral ring and its adjacent myocardium move downward and anteriorly in systole, in synchrony with the remainder of the LV. On the contrary, a peculiar functional abnormality of the mitral annulus was described in MVP patients (i.e., an unusual systolic curling of the posterior mitral ring on the adjacent myocardium), so that the systolic movement of the ring was primarily downward with little, if any, anterior motion, thus resulting in a curled appearance when visualized in real-time motion (9). In a unified perspective, MAD and curling seem to be the 2 sides of the same coin.
MAD and Arrhythmic MVP Syndrome
In the setting of MVP, Carmo et al. (5) for the first time demonstrated an increased frequency of premature ventricular beats and nonsustained ventricular tachycardia in patients with MAD versus those without by routine 2-dimensional transthoracic echocardiography. The wider the magnitude of MAD, the higher the incidence of nonsustained ventricular tachycardia. We also provided the evidence that MAD was associated with arrhythmic MVP. More in detail, a quantifiable MAD was always detectable in our series of arrhythmic MVP, both clinically by CMR and at postmortem, with late gadolinium enhancement (LGE) and fibrosis mostly located close to the mitral annulus in the inferobasal LV wall (10,11).
Based upon our histological and clinical observations in arrhythmic MVP patients, we postulated a cascade of events initiated by MAD and eventually leading to electrical instability. The presence of MAD accounts for systolic curling motion, possibly representing the basis for the paradoxical increase of the MV annulus diameter during systole, the myxomatous degeneration of MV leaflets, and the myocardial stretch in the LV inferobasal wall and papillary muscles, with relative hypertrophy and fibrosis (11).
Isolated MAD and Ventricular Arrhythmias: Are We Ready for an Arrhythmic MAD Syndrome?
Until now, the association between MAD and ventricular arrhythmias has been demonstrated only as a part of MVP. In this issue of the Journal, Dejgaard et al. (12) provide an original piece of the puzzle of the arrhythmic significance of MAD. The authors describe, in a cross-sectional multicenter study of patients with MAD, the clinical presentation of MAD, its morphology, and the association with MVP and ventricular arrhythmias (12). The analysis included not only the echocardiographic, but also the CMR evaluation, with circumferential assessment of MAD in the annular plane, longitudinal MAD distance, and myocardial fibrosis. Of 122 patients screened, 116 patients were eventually included, 77 of whom with LGE evaluation. The reasons for initial cardiac examination included typical arrhythmic symptoms such as palpitations, syncope, and ventricular arrhythmias. By CMR, the longitudinal MAD distance was 3.0 mm (interquartile range: 0 to 7.0 mm). The authors found a high occurrence of ventricular arrhythmias in patients with MAD. Longitudinal MAD distance in posterolateral wall and papillary muscle fibrosis assessed by CMR remained markers of arrhythmias in multivariate analysis. Not surprisingly, the authors found that 22% of the patients did not have MVP, and the prevalence of ventricular arrhythmias did not differ between MAD patients with and without concomitant MVP. Other papers demonstrated that the presence of MAD is not necessarily associated with MVP. In the pathologic series by Hutchins et al. (3), MAD was detected in 42 hearts without floppy MV (5%). Because these patients were significantly younger than those with a floppy MV, the authors suggested that this anatomic variation could play a role in the pathogenesis of myxomatous valve degeneration through increased mechanical stress induced by the excessive mobility of the MV apparatus. Recently, Konda et al. (13) described a prevalence of 8.7% of MAD in a series of 1,439 patients referred to echocardiography and only 12% of them had MVP.
Similarly, Dejgaard et al. (12) found that MAD patients with MVP were older than those without, and more frequently had moderate or severe mitral regurgitation. These observations confirm and extend previous data, supporting the concept of MVP as a “progressive” disease, with an age-related phenotype.
The study of Dejgaard et al. (12) carries important clinical implications. First, the comprehensive use of CMR encourages the application of this imaging tool for both mechanics and tissue characterization purposes, introducing a complete assessment of mitral annulus circumference by long-axis cine sequences. Second, the data support a key role of MAD in altered mechanics of the mitral annulus by confirming the presence of curling movement of the inferobasal LV wall in patients with MAD and its relationship with arrhythmias. Most probably, in the younger arrhythmic patients, the authors intercepted a subset of patients with “concealed” MVP, but with an arrhythmogenic substrate potentially leading to develop an overt “malignant” MVP variant with time.
The puzzle is being discovered only partially, but the contours have been delineated. To complete the picture, the arrhythmic presentation of patients with MAD should be investigated in larger and unselected populations. We previously hypothesized papillary muscle and inferobasal wall stretch and fibrosis as arrhythmic mechanisms in MVP, based upon the observation of premature ventricular beats originating from these LV sites (10,11). Dejgaard et al. (12) confirm the association between LV fibrosis and ventricular arrhythmias in MAD, independently from MVP, to indicate that MAD itself can account for mechanical stretch of the myocardium and arrhythmogenesis. A careful prospective study addressing ECG changes, ventricular arrhythmias morphology, and electrophysiological data in MAD patients with and without LGE and with and without MVP should provide the missing data and shed light on the arrhythmogenic role of this anatomic variation of the mitral valve.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
- Angelini A.,
- Ho S.Y.,
- Anderson R.H.,
- Davies M.J.,
- Becker A.E.
- Lee A.P.,
- Jin C.N.,
- Fan Y.,
- Wong R.H.L.,
- Underwood M.J.,
- Wan S.
- Nutter D.O.,
- Wickliffe C.,
- Gilbert C.A.,
- Moody C.,
- King S.B. 3rd.
- Gilbert B.W.,
- Schatz R.A.,
- VonRamm O.T.,
- Behar V.S.,
- Kisslo J.A.
- Basso C.,
- Perazzolo Marra M.,
- Rizzo S.,
- et al.
- Perazzolo Marra M.,
- Basso C.,
- De Lazzari M.,
- et al.
- Dejgaard L.A.,
- Skjølsvik E.T.,
- Lie Ø.H.,
- et al.
- Konda T.,
- Tani T.,
- Suganuma N.,
- et al.