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\begin{document}

\title{MITRAL ANNULAR DISJUNCTION AND ARRHYTHMIC RISK: A CASE REPORT}



\author[1]{Greta Pascariello}%
\author[2]{Nicola Berlinghieri}%
\author[1]{Giuliana Cimino}%
\author[1]{Emiliano Calvi}%
\author[1]{Davide Farina }%
\author[1]{Edoardo Pancaldi}%
\author[1]{Angelica Cersosimo}%
\author[1]{Ludovica Amore}%
\author[1]{Fabio Alghisi}%
\author[1]{Enrico Vizzardi}%
\author[1]{Nicola Bernardi}%
\affil[1]{University of Brescia}%
\affil[2]{Valduce Hospital}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
Mitral annular disjunction (MAD) is a structural abnormality of the
mitral annulus, defined by a detachment of the atrial wall-mitral
valvular junction from the left ventricular (LV) free wall. This
structural abnormality in mitral annulus fibrosus is significantly
associated with the presence of mitral valve prolapse (MVP) {[}1{]}, but
it can be also detected in normal cases as an anatomical variation of
the mitral annulus fibrosus {[}2{]}. The main tools to detect MAD are
echocardiography and cardiac magnetic resonance. Prevalence of MAD in
the general population ranges from 7\% {[}1{]} to 9\% {[}2{]}. Several
studies proved an association between MAD and arrhythmic events,
independently of concomitant mitral valve abnormalities, suggesting the
existence of a novel entity: MAD arrhythmic syndrome {[}3{]}. Herein we
describe a case report of a middle age man with MAD who experienced
ventricular arrhythmias and placement of an implantable
cardioverter-defibrillator (ICD).%
\end{abstract}%



\sloppy


MITRAL ANNULAR DISJUNCTION AND ARRHYTHMIC RISK: A CASE REPORT

Shortened title: MITRAL ANNULAR DISJUNCTION

Authors: \textsuperscript{a} Greta Pascariello, MD;
\textsuperscript{b}Nicola Berlinghieri, MD; \textsuperscript{a} Giuliana
Cimino, MD;\textsuperscript{a} Emiliano Calvi, MD; \textsuperscript{a}
Nicola Bernardi, MD; \textsuperscript{c} Davide Farina, MD;
\textsuperscript{a}Fabio Alghisi, MD; \textsuperscript{a} Edoardo
Pancaldi, MD;\textsuperscript{a} Angelica Cersosimo, MD;
\textsuperscript{a} Ludovica Amore, MD; \textsuperscript{a} Enrico
Vizzardi, MD.

Co-authors: Greta Pascariello and Nicola Berlinghieri contributed
equally to the manuscript.

Author Department and Institutional Affiliations:

\textsuperscript{a} Institute of Cardiology, Department of Medical and
Surgical Specialties, Radiological Sciences, and Public Health,
University of Brescia.

\textsuperscript{b} Institute of Cardiology, Hospital Valduce, Como.

\textsuperscript{c} Institute of Radiology, Department of Medical and
Surgical Specialties, Radiological Sciences, and Public Health,
University of Brescia.

Address for Correspondence:

Greta Pascariello, MD Institute of Cardiology, Spedali Civili, Piazzale
Spedali Civili 1, Brescia BS 25123, Italy

Email: greta.pascariello@hotmail.it

Phone: +393397896876

Conflict of interest: The authors have no conflicts of interest

Availability of data and material: All available information in
contained within the manuscript

Funding: This manuscript was not funded

\textbf{Abstract}

Mitral annular disjunction (MAD) is a structural abnormality of the
mitral annulus, defined by a detachment of the atrial wall-mitral
valvular junction from the left ventricular (LV) free wall.

This structural abnormality in mitral annulus fibrosus is significantly
associated with the presence of mitral valve prolapse (MVP) {[}1{]}, but
it can be also detected in normal cases as an anatomical variation of
the mitral annulus fibrosus {[}2{]}. The main tools to detect MAD are
echocardiography and cardiac magnetic resonance. Prevalence of MAD in
the general population ranges from 7\% {[}1{]} to 9\% {[}2{]}.

Several studies proved an association between MAD and arrhythmic events,
independently of concomitant mitral valve abnormalities, suggesting the
existence of a novel entity: MAD arrhythmic syndrome {[}3{]}.

Herein we describe a case report of a middle age man with MAD who
experienced ventricular arrhythmias and placement of an implantable
cardioverter-defibrillator (ICD).

\textbf{Keywords} : Mitral annular disjunction, ventricular arrhythmias,
echocardiography, cardiac magnetic resonance

\textbf{Case report}

A 55-year-old man has been sent, by his trusted cardiologist, to our
hospital to implant an ICD.

He was affected by paroxysmal atrial fibrillation, not on anticoagulant
therapy, because of a CHADsVASC 0, and not on antiarrhythmic therapy,
except for propafenone `pill in the pocket', with a family history of
Arrhythmogenic Right Ventricular Dysplasia (ARVD) and unobstructed
arteries at the invasive coronary angiogram performed two years before.
In the previous years he also experienced several presyncopal episodes.

His resting echocardiogram showed a normal left ventricular systolic
function, with an ejection fraction of 55\%, and a mild bi-leaflet
mitral valve prolapse with moderate mitral regurgitation. Interestingly,
on parasternal long-axis view, MAD was well seen in the posterolateral
LV region of approximately 11 mm (figure 1). No other significant
structural abnormalities were seen. The trusted cardiologist decided to
carry out a cardiac magnetic resonance, that showed no signs of ARVD and
proved the presence of MAD. End systolic cine MR sequences in 4-chamber
(figure 2) and 3-chamber view (figure 3) demonstrated annular
disjunction of the mitral valve and short-axis Phase-sensitive Inversion
Recovery (PSIR) sequences, after contrast injection (figure 4, 5),
pointed out late gadolinium enhancement of the posterolateral annular
ring and of the posterior papillary muscle.

It was therefore decided to implant a Loop Recorder in the patient, that
after several months recorded an episode of fast ventricular tachycardia
(TV) at 200 bpm for about 5 seconds without symptoms.

In the light of the above findings, we agreed to implant an ICD and the
patient was discharged the day after.

Five months later the patient presented to our hospital because of a
single shock of ICD, due to an episode of ventricular tachycardia. The
patient was then hospitalized and first treated with intravenous
amiodarone and than with amiodarone orally. We performed an ICD
interrogation, which confirmed the episode of ventricular arrhytmia, and
after three days, during which the patient was stable and asymptomatic,
he was discharged home with amiodarone.

\textbf{Discussion}

Our case report deals with an obscure anatomic variation, probably a
congenital abnormality, of the mitral annulus in which there is still
little literature. For the first time, in a study of 900 hearts from
adult autopsies, Hutchins et al. in 1986 reported a strong association
between the mitral annular disjunction and the presence of MVP (92\% of
typical floppy mitral valves showed MAD); they also found out that it
could be detected in approximately 6\% of patients without MVP {[}1{]}.
This feature was also clinically confirmed by Konda et al. in a study
performed in order to investigate frequencies and characteristics of
mitral annular disjunction in patients referred to an echocardiography
laboratory. They even found a significantly larger percentage of cases
(12\%) with mitral annular disjunction but no floppy mitral valve
{[}2{]}. They also reported meaningfully larger distance of the mitral
annular disjunction in patients affected by MVP than in patients without
it and was not founded any relationship between mitral annular
disjunction and the degree of mitral regurgitation (MR).

An increased frequency of premature ventricular beats, chest pain and
non-sustained ventricular tachycardia was firstly demonstrated by Carmo
et al. in patients with MAD in the setting of MVP {[}4{]}; this was
subsequently proved by the examination of 116 patients with MAD by
Dejgaard et al. This is the first large clinical trial on patients with
MAD where the authors examined patients with MAD clinically and by
echocardiography and cardiac magnetic resonance (CMR), in order to
describe the clinical presentation, MAD morphology, association with MVP
and ventricular arrhythmias. The most important finding was, however,
the high occurrence of ventricular arrhythmias in patients with MAD,
independently of concomitant MVP, suggesting the existence of a novel
clinical syndrome: MAD arrhythmic syndrome. They also identified young
age, lower ejection fraction and papillary muscle fibrosis as markers
for severe arrhythmic events. Interestingly, MAD patients with MVP were
less likely to have experienced severe arrhythmic events, unlike other
papers {[}3{]}.

The association between MAD and arrhythmic MVP was provided by Basso and
Perazzolo Marra. They postulated a cascade of events caused by MAD and
leading to electrical instability and also hypothesized papillary
muscle, inferobasal wall stretch and fibrosis as arrhythmogenic areas in
MVP. The reason of this postulation was the observation of premature
ventricular beats originating from these LV sites {[}5{]} {[}6{]}.
Posterior systolic curling caused by MAD might create a mechanical
stretch of the inferobasal wall and papillary muscle (PM), leading to
myocardial hypertrophy and scarring {[}7{]}. The association between LV
fibrosis and ventricular arrhythmias in MAD was than confirmed by
Dejgaard et al. {[}3{]}. MAD itself, even independently from MVP, can
therefore account for mechanical stretch of the myocardium and
arrhythmogenesis {[}8{]}.

The main instruments to detect MAD are echocardiography and cardiac
magnetic resonance. Absence of myocardium during systole between the
posterior mitral valve annulus and adjacent basal segments of the
ventricular wall is representative of MAD. On echocardiography, this is
most commonly seen in the parasternal long-axis view {[}9{]}.

Studies focused on MAD, using CMR, confirmed that in patients with late
gadolinium enhancement (LGE), presence of LV fibrosis at level of
papillary muscle was more frequent in patient with MAD and, according to
other studies, showed that patients with MAD have the tendency to be
younger and with lower ejection fraction (LVEF), irrespectively of MR
severity {[}10{]}.

A review of several studies showed up that the occurrence of ventricular
arrhythmias was higher with a greater extent of MAD distance and
circumferential area, highlighting the link between electrical
instability and extent of MAD {[}9{]}. A MAD with disjunction of
\textgreater{}8.5 mm was revealed to be prognostic of an increased risk
of ventricular arrhythmias {[}4{]}.

Recently, since MAD has been suggested as a possible cause of
ventricular arrhythmias and sudden cardiac death, Scheirlynck et al.
carried out a study to explore the presence of soluble suppression of
tumorigenicity-2 (sST2) and transforming growth factor-\selectlanguage{greek}β\selectlanguage{english}1 (TGF\selectlanguage{greek}β\selectlanguage{english}1) as
stretch-related and fibrosis-related biomarkers in MAD patients. They
found that circulating sST2 levels were higher in patients with MAD and
ventricular arrhythmias, compared with arrhythmia-free patients, while
TGF\selectlanguage{greek}β\selectlanguage{english}1 levels did not differ. Interestingly, they hypothesized that the
combination of sST2, LVEF and LGE assessment might detect high-risk
individuals {[}11{]}.

\textbf{Conclusions}

MAD could be associated to LV morphological and functional remodeling,
which could be the substrate of ventricular arrhythmias and sudden
cardiac death. MAD itself should be considered as an arrhythmogenic
entity, irrespective of the presence of MR or MVP, and implantation of
an ICD, as for our patient, can be life saving.

In conclusion, we can not consider MAD as a well-known entity and more
research and further studies are warranted.

\textbf{Bibliography}

{[}1{]} Hutchins GM, Moore GW, Skoog DK. The association of floppy
mitral valve with disjunction of the mitral annulus fibrosus. N Engl J
Med. 1986 Feb 27;314(9):535-40. doi: 10.1056/NEJM198602273140902. PMID:
3945291.

{[}2{]} Konda T, Tani T, Suganuma N, Nakamura H, Sumida T, Fujii Y,
Kawai J, Kitai T, Kim K, Kaji S, Furukawa Y. The analysis of mitral
annular disjunction detected by echocardiography and comparison with
previously reported pathological data. J Echocardiogr. 2017
Dec;15(4):176-185. doi: 10.1007/s12574-017-0349-1. Epub 2017 Aug 10.
PMID: 28799132.

{[}3{]} Dejgaard LA, Skj\selectlanguage{ngerman}ølsvik ET, Lie ØH, Ribe M, Stokke MK, Hegbom F,
Scheirlynck ES, Gjertsen E, Andresen K, Helle-Valle TM, Hopp E,
Edvardsen T, Haugaa KH. The Mitral Annulus Disjunction Arrhythmic
Syndrome. J Am Coll Cardiol. 2018 Oct 2;72(14):1600-1609. doi:
10.1016/j.jacc.2018.07.070. PMID: 30261961.

{[}4{]} Carmo P, Andrade MJ, Aguiar C, Rodrigues R, Gouveia R, Silva JA.
Mitral annular disjunction in myxomatous mitral valve disease: a
relevant abnormality recognizable by transthoracic echocardiography.
Cardiovasc Ultrasound. 2010 Dec 9;8:53. doi: 10.1186/1476-7120-8-53.
PMID: 21143934; PMCID: PMC3014886.

{[}5{]} Basso C, Iliceto S, Thiene G, Perazzolo Marra M. Mitral Valve
Prolapse, Ventricular Arrhythmias, and Sudden Death. Circulation. 2019
Sep 10;140(11):952-964. doi: 10.1161/CIRCULATIONAHA.118.034075. Epub
2019 Sep 9. PMID: 31498700.

{[}6{]} Basso C, Perazzolo Marra M, Rizzo S, De Lazzari M, Giorgi B,
Cipriani A, Frigo AC, Rigato I, Migliore F, Pilichou K, Bertaglia E,
Cacciavillani L, Bauce B, Corrado D, Thiene G, Iliceto S. Arrhythmic
Mitral Valve Prolapse and Sudden Cardiac Death. Circulation. 2015 Aug
18;132(7):556-66. doi: 10.1161/CIRCULATIONAHA.115.016291. Epub 2015 Jul
9. PMID: 26160859.

{[}7{]} Perazzolo Marra M, Basso C, De Lazzari M, Rizzo S, Cipriani A,
Giorgi B, Lacognata C, Rigato I, Migliore F, Pilichou K, Cacciavillani
L, Bertaglia E, Frigo AC, Bauce B, Corrado D, Thiene G, Iliceto S.
Morphofunctional Abnormalities of Mitral Annulus and Arrhythmic Mitral
Valve Prolapse. Circ Cardiovasc Imaging. 2016 Aug;9(8):e005030. doi:
10.1161/CIRCIMAGING.116.005030. PMID: 27516479; PMCID: PMC4991345.

{[}8{]} Basso C, Perazzolo Marra M. Mitral Annulus Disjunction: Emerging
Role of Myocardial Mechanical Stretch in~Arrhythmogenesis. J Am Coll
Cardiol. 2018 Oct 2;72(14):1610-1612. doi: 10.1016/j.jacc.2018.07.069.
PMID: 30261962.

{[}9{]} Bennett S, Thamman R, Griffiths T, Oxley C, Khan JN, Phan T,
Patwala A, Heatlie G, Kwok CS. Mitral annular disjunction: A systematic
review of the literature. Echocardiography. 2019 Aug;36(8):1549-1558.
doi: 10.1111/echo.14437. Epub 2019 Aug 5. PMID: 31385360.

{[}10{]} Essayagh B, Iacuzio L, Civaia F, Avierinos JF, Tribouilloy C,
Levy F. Usefulness of 3-Tesla Cardiac Magnetic Resonance to Detect
Mitral Annular Disjunction in Patients With Mitral Valve Prolapse. Am J
Cardiol. 2019 Dec 1;124(11):1725-1730. doi:
10.1016/j.amjcard.2019.08.047. Epub 2019 Sep 10. PMID: 31606191.

{[}11{]} Scheirlynck E, Dejgaard LA, Skjølsvik E, et al. Increased
levels of sST2 in patients with mitral annulus disjunction and
ventricular arrhythmias.~\emph{Open Heart} . 2019;6(1):e001016.
Published 2019 Apr 28. doi:10.1136/openhrt-2019-001016.

\textbf{Figure legends}

Figure 1: MAD in parasternal long-axes view (transthoracic
echocardiography)

Figure 2: Annular disjunction of the mitral valve in end systolic cine
MR sequences in 4-chamber (white arrows).

Figure 3: Annular disjunction of the mitral valve in end systolic cine
MR sequences in 3-chamber view (white arrows).

Figure 4 and 5: Short-axis PSIR sequences after contrast injection show
late gadolinium enhancement of the posterolateral annular ring (black
arrows) and of the posterior papillary muscle (arrowhead).\selectlanguage{english}
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