Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden ... · The genesis of malignant ventricular arrhythmias in MVP probably recognizes the combination of the substrate (regional

September 10, 2019 Circulation. 2019;140:952–964. DOI: 10.1161/CIRCULATIONAHA.118.034075952

Cristina Basso, MD, PhDSabino Iliceto, MDGaetano Thiene, MDMartina Perazzolo Marra,

MD, PhD

ABSTRACT: Despite a 2% to 3% prevalence of echocardiographically defined mitral valve prolapse (MVP) in the general population, the actual burden, risk stratification, and treatment of the so-called arrhythmic MVP are unknown. The clinical profile is characterized by a patient, usually female, with mostly bileaflet myxomatous disease, mid-systolic click, repolarization abnormalities in the inferior leads, and complex ventricular arrhythmias with polymorphic/right bundle branch block morphology, without significant regurgitation. Among the various pathophysiologic mechanisms of electrical instability, left ventricular fibrosis in the papillary muscles and inferobasal wall, mitral annulus disjunction, and systolic curling have been recently described by pathological and cardiac magnetic resonance studies in sudden death victims and patients with arrhythmic MVP. In addition, premature ventricular beats arising from the Purkinje tissue as ventricular fibrillation triggers have been documented by electrophysiologic studies in MVP patients with aborted sudden death.

The genesis of malignant ventricular arrhythmias in MVP probably recognizes the combination of the substrate (regional myocardial hypertrophy and fibrosis, Purkinje fibers) and the trigger (mechanical stretch) eliciting premature ventricular beats because of a primary morphofunctional abnormality of the mitral valve annulus.

The main clinical challenge is how to identify patients with arrhythmic MVP (which imaging technique and in which patient) and how to treat them to prevent sudden death. Thus, there is a necessity for prospective multicenter studies focusing on the prognostic role of cardiac magnetic resonance and electrophysiologic studies and on the therapeutic efficacy of targeted catheter ablation and mitral valve surgery in reducing the risk of life-threatening arrhythmias, as well as the role of implantable cardioverter defibrillators for primary prevention.

© 2019 American Heart Association, Inc.

IN DEPTH

Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death

https://www.ahajournals.org/journal/circ

Circulation

Key Words: arrhythmias ◼ cardiac imaging techniques ◼ mitral valve prolapse ◼ sudden cardiac death

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Basso et al Arrhythmic Mitral Valve Prolapse

STATE OF THE ART

Circulation. 2019;140:952–964. DOI: 10.1161/CIRCULATIONAHA.118.034075 September 10, 2019 953

Since the original description by Barlow in the 1960s,1,2 the existence of an arrhythmic variant of mitral valve prolapse (MVP) has been recognized.

The recent introduction of the term “malignant ar-rhythmic MVP”3,4 triggered a debate on its definition and clinical implications in terms of diagnosis, risk strat-ification, and treatment. The patient at risk is usually female, with non-syndromic mostly bileaflet myxoma-tous degeneration of the mitral valve, ECG repolariza-tion abnormalities, and complex ventricular arrhythmias with polymorphic/right bundle branch block morphol-ogy.3,4 The echocardiographic features are those of clas-sic MVP (ie, single-leaflet or bileaflet displacement >2 mm beyond the long-axis annular plane, with >5 mm leaflet thickening),5,6 accompanied by morphofunction-al abnormalities of the mitral annulus (ie, mitral annular disjunction [MAD] and systolic curling).7 Moreover, the morphology is consistent with that of MVP attribut-able to myxomatous degeneration (ie, the accumula-tion of proteoglycans resulting in leaflet thickening and redundancy, and chordae elongation).8–12 Whereas the overall prevalence of MVP in the general population based solely on the echocardiographic definition is 2% to 3%,13 the actual prevalence, risk stratification, and appropriate treatment of patients with arrhythmic MVP remain to be established.

At the same time, the growing interest in the pre-vention of sudden cardiac death (SCD) has drawn at-tention to MVP as a possible substrate of cardiac arrest. In general, MVP has a low prevalence in the pathology series of SCD both in the general population14 and in the young,4,15–33 and often, it is not even considered as one of the causes because of the absence of uniform diagnostic criteria of MVP in the general and forensic pathology practice (Table 1).34 The estimated occur-rence of SCD in patients with MVP is low, 16 to 41 per 10 000 per year (0.2% to 0.4% per year).35–37 Fur-thermore, studies in which MVP has been associated to SCD hypothesize the role of coexisting pathophysi-ologic risk factors of electrical instability, rendering it difficult to define these associations as causative.

A variable prevalence of ventricular arrhythmias has been reported among MVP series, reflecting the different definitions of MVP, the populations studied, the complexity of ventricular arrhythmias, and the ab-sence of a systematic evaluation with prolonged ECG recording.36,38–44

It is well known that a high degree of valve regur-gitation in MVP is an important determinant of the incidence of SCD and that volume overload of the left ventricle (LV) is associated with a high recurrence rate of ventricular arrhythmias.41,45–47 However, the detection of MVP in SCD victims or survivors of life-threatening arrhythmias suggests that an association between hemodynamically uncomplicated MVP and arrhythmic SCD does exist.

Overall, the reported incidence of premature ven-tricular beats (PVBs) in MVP, as evaluated by 24 hours of ECG Holter monitoring, varies from 49% to 85% in the adult population.48 In the genesis of PVBs, local-ized reentry, abnormal automaticity, and triggered ac-tivity have been implicated, with triggering from either a remote PVB focus or a sinus beat. In 1980, Lichstein49 examined the vectorcardiogram of PVBs in MVP and found that the most common site of origin was the posterobasal portion of the LV, a feature consistent with the hypothesis that the mechanical irritation pro-duced by the billowing valves pumping blood into the LV could be the trigger of these arrhythmias.

More recently, in a study on survivors of out-of-hospital cardiac arrest with bileaflet MVP, Sriram et al3 noted a PVB configuration of outflow tract origin alter-nating with papillary muscle (PM) or fascicular origin. The outflow tract PVBs always originated from the LV and in some cases from both the LV and right ventricu-lar outflow tracts. In our autopsy series of SCD attribut-able to myxomatous degeneration of the mitral valve, the documented ventricular arrhythmias were always of right bundle branch block morphology, associated with arrhythmias of left bundle branch block morphology in a minority of cases,4 suggesting once again that most arrhythmias originate in the LV.

Thus, the so-called “arrhythmic MVP” syndrome is characterized, from an electrocardiographic viewpoint, by complex PVBs arising from one or both PMs, fas-cicular tissue and outflow tract, as well as by T-wave in-version in the inferolateral leads3,4 (Figure 1). Moreover, electrophysiologic studies mapped the site of origin of ventricular arrhythmias in the PMs, the LV outflow tract, and the mitral annulus, suggesting that PVBs arising close to the prolapsing leaflet and adjacent structures are the arrhythmic triggers.3

The origin of ventricular arrhythmias in MVP re-mains controversial in the absence of valve regurgita-tion and LV remodeling.41,50,51 MVP-related and MVP-unrelated factors, both functional and structural, have been suggested (Table 2).52–71 Furthermore, MVP-relat-ed factors comprise changes at the level of both the valve and the LV.

Remarkably, angiographic evaluation of MVP patients initially documented LV abnormalities, such as altered contractions causing the posteroinferior aspect of the LV to bulge into the cavity,56 inferior wall indentation,51 and the so-called “ballerina foot” appearance.57,58 In their study on patients with systolic clicks, murmurs, and prolapsed mitral valve leaflets, Gulotta et al59 hy-pothesized the existence of a cardiomyopathy leading to this impaired LV contractility because of the presence of distressing chest pain or troublesome arrhythmias. They postulated that the LV dysfunction was responsible for both MVP and the mid-systolic timing of the mitral regurgitation. Among the MVP-unrelated factors, ven-

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tricular repolarization abnormalities and a prolonged QT interval have also been suggested in arrhythmic MVP patients. The prolongation of the QT interval has been variably reported, ranging from 9% to 26%.39,65–68 How-ever, the association with MVP is not constant, with no evidence of QT prolongation in the Framingham Study.69

THE EMERGING ROLE OF PURKINJE TISSUE AND LEFT VENTRICULAR FIBROSIS IN ARRHYTHMOGENESISElectrophysiologic study in bileaflet MVP syndrome pa-tients with and without cardiac arrest demonstrated that the former were always identifiable by PVBs arising from the Purkinje tissue as ventricular fibrillation triggers.70 The presence of fractionated, split, and delayed Purkinje potentials was in accordance with a diseased Purkinje tissue. MVP patients without a history of syncope or

cardiac arrest, but in whom standard ventricular pacing maneuvers induced sustained ventricular arrhythmias, also showed evidence of fascicular tissue disease.

Our group first provided convincing evidence of a structural myocardial substrate of electrical instability (ie, fibrosis in the LV myocardium closely linked to the mitral valve),4 as only previously suggested in a few an-ecdotal cases.51,53,61,71 In particular, by extending the his-topathological investigation to the myocardium beyond the valve, we found LV scarring at the level of PMs with adjacent free wall in all and of the inferobasal wall in 88% of young SCD victims with MVP4 (Figure 2). The myocardial fibrosis was patchy and interspersed within viable, hypertrophic cardiomyocytes. At the same time, cardiac magnetic resonance (CMR) imaging was able to detect late gadolinium enhancement (LGE) at the level of PMs and inferobasal LV wall in our study subpopu-lation of living MVP patients with complex ventricular arrhythmias, closely overlapping the histopathological

Table 1. Prevalence of MVP in Major (≥100 cases) Autopsy Series of Sudden Cardiac Death in the Young

Authors, Reference Year Time Location Population Age N. SCD Sex, M (%) MVP, N (%)

Valve Disease Details

Burke et al, 15 1991 1981 – 1988 Maryland, United States General 14 – 40 656 501 (76.4) 11 (1.7) Floppy MV

Drory et al, 16 1991 1976 – 1985 Israel General 9–39 162 134 (82.7) 2 (1.2) MVP

Anderson et al, 17

1994 1977 – 1988 New Mexico, United States

General 5 – 39 183 ND 6 (3.3) MVP

Van Camp et al, 18

1995 1983 – 1993 US high schools and colleges

Athletes 13 – 22 100 92 (92) 1 (1)

Maron et al, 19 1996 1985 – 1995 United States Athletes < 35 134 120 (89.5) 3 (2.2) MVP

Wisten et al, 20 2002 1992 – 1999 Swedish General 15 – 35 181 132 (72.9) 4 (2.2) Valve disease

Morentin et al, 21

2003 1991 – 1998 Bizkaia county, Spain General 1 – 35 107 ND 3 (2.8) Valve disease

Doolan et al, 22 2004 1994 – 2002 New South Wales, Sydney, Australia

General < 35 193 125 (64.7) 5 (2.6) Valve disease

Eckart et al, 23 2004 1977 – 2001 Brooke Army Medical Center, San Antonio, Texas, United States

General 18 – 35 126 111 (88.1) 0 (0)

Puranik et al, 24 2005 1995 – 2004 Eastern part of Sydney, Australia

General 5 – 35 241 189 (78.4) 3 (1.2) Valve disease

Di Gioia et al, 25 2006 2001 – 2005 Lazio region, Italy General 1 – 35 100 69 (69) 3 (3) MVP

Maron et al, 26 2009 1980 – 2006 United States Athletes 13 – 25 1049 937 (89.3) 25 (2.4) MVP

Eckart et al, 27 2011 1998 – 2008 Uniformed personnel from the Department of Defense, United States

General 18 – 35 298 282 (94.6) 1 (0.3) MV disease

Margey et al, 28 2011 2005 – 2007 Ireland General 15 – 35 116 90 (77.5) 1 (0.9) MVP

Winkel et al, 29 2011 2000 – 2006 Denmark General 1 – 35 314 210 (67) 8 (2.5) Valve disease

Pilmer et al, 30 2013 2008 Ontario, Canada General 2 – 40 174 133 (76.4) 0 (0)

de Noronha et al, 31

2014 2007 – 2009 United Kingdom General 0 – 35 422 ND 14 (3.3) Valve disease

Risgaard et al, 32 2014 2007 - 2009 Denmark General 12 – 49 439 317 (72.2) 7 (1.6) Valve disease

Basso et al, 4 2015 1982 – 2013 Veneto region, Italy General 1 – 40 650 450 (69.2) 43 (6.6) MVP

Bagnall et al, 33 2016 2010 – 2012 Australia and New Zealand

General 1 – 35 490 353 (72) ND

MV indicates mitral valve; MVP, mitral valve prolapse; ND, not determinable; and SCD, sudden cardiac death.

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Figure 1. Electrocardiographic and arrhythmic findings in MVP patients. A, Typical 12-leads ECG with negative T wave on III-aVF leads in a 32-year-old woman. B, Nonsustained VT with right bundle branch block morphology originat-ing from the posterior PM (superior axis) in a 30-year-old woman with aborted SCD. C, Nonsustained VT with right bundle branch block morphology originating from the LV infero-basal wall near the mitral annulus (inferior axis) in a 33-year-old woman. D, Aborted SCD attributable to polymorphic VT degenerating into ventricular fibrillation in a 38-year-old man. Modified from Basso et al.4 MVP indicates mitral valve prolapse; PM, papillary muscle; SCD, sudden cardiac death; and VT, ventricular tachycardia.

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features observed in SCD victims.4 A relative hypertro-phy of the LV inferobasal wall in comparison with the adjacent midportion was also found. In a previous pub-lication on MVP patients with a history of arrhythmias, most of whom had moderate to severe mitral regurgita-tion, Han et al72 already found 2 LGE sites at the level of PMs, the mid-apical portion and the base/adjacent LV wall. The morphology of arrhythmias and the electro-physiologic evidence that the most common site of PVB origin in MVP is the inferobasal LV wall suggest that the LV myocardial scarring is the substrate of electrical in-stability.3,4,49 The arrhythmogenic role of PM LGE4,72 has been recently confirmed by electrophysiologic study, demonstrating that patients with LGE in the PM region were significantly more likely to have PM-based PVB.73

The LV fibrosis and the Purkinje tissue theories are possibly not mutually exclusive. In fact, it is unlikely that arrhythmic MVP patients with LV myocardial fibrosis have a coincident, unrelated idiopathic ventricular fibrillation with Purkinje triggers amenable to ablation.70 The con-sistent localization of PVB foci and abnormal tissue with slow conduction to the vicinity of the subvalvular mitral

apparatus indeed suggests a structural association. Pre-sumably, the heterogeneity of the tissue on these regions and its unique electrophysiologic properties are a primary abnormality, and the excessive motion and stretch with consequent scarring represent the secondary anomaly.74 Prospective studies that match the scarring on myocar-dial imaging with electrophysiological substrates in dif-ferent patient populations are mandatory. The frequent observation of T-wave abnormalities on inferolateral leads on 12-lead ECG suggests a disturbed repolariza-tion of the area with abnormal contractility, as previously described.3,4 Endocardial and mid-myocardial changes in the PMs and neighboring LV could generate an abnormal repolarization gradient, resulting in inverted T waves. This could be relevant for the type of arrhythmias that cause SCD (ie, polymorphic ventricular tachycardia [VT] rather than monomorphic and inducible reentrant VT).

CLOSING THE CIRCLE: FROM MITRAL ANNULUS DISJUNCTION TO VENTRICULAR ARRHYTHMIASThe terminology of MAD was originally introduced by Bharati et al61 to refer to an anatomic variation, probably a congenital abnormality, of the fibrous mitral annulus while describing a patient with a long history of palpita-tions and mid-systolic click due to MVP who succumbed to SCD. MAD was then systematically investigated by Hutchins et al75 in the 1980s, defining it as a spatial dis-placement of the point of insertion of the posterior mi-tral valve leaflet, which accounts for a wide separation between the left atrial wall–mitral valve junction and the LV attachment. In other words, the posterior annulus appeared stretched and curtain-like as compared with the normal cord-like structure of collagen fibers distrib-uted along the atrioventricular junction.

In the pathological study of Hutchins et al75 on 900 hearts from adult autopsies, 92% of morphologically typical floppy mitral valves showed MAD. In the same series, MAD was rarely found (5%) in hearts without floppy mitral valve. As these patients were significant-ly younger than those with a floppy mitral valve, the authors suggested that this anatomic variation could play a role in the pathogenesis of myxomatous valve degeneration, by means of increased mechanical stress induced by the excessive mobility of the mitral valve ap-paratus. The concept of MAD was dismissed and re-mained a matter of speculation for pathologists76 until the 2000s when Erikson et al77 and Carmo et al78 dem-onstrated that it is also easily detectable and measur-able by routine transthoracic echocardiography (Fig-ure 3), and found an increased frequency of PVBs and non-sustained VT in patients with MAD in comparison to those without MAD. Thus, the wider the magnitude of MAD, the higher the incidence of non-sustained VT.

Table 2. Substrates and Triggers of Ventricular Arrhythmias/SCD in MVP Patients

MVP-related factors

Valve

Elongated mitral leaflet

Bileaflet MVP

Mitral annulus dilatation

Mitral annulus disjunction

Mitral annulus hypermobility/curling

Diastolic depolarization of muscle fibers in redundant leaflets

Spontaneous chordal rupture

Left ventricle

Excessive papillary muscles traction by the prolapsing leaflets

Mechanical stimulation of the endocardium by elongated chordae

Endocardial friction lesions

Connective tissue myxoid changes

Myocardial ischemia due to platelet/fibrin microembolization

Fibromuscular dysplasia of small coronary arteries

LV fibrosis at the level of papillary muscles/postero-basal wall

LV remodeling due to mitral regurgitation with volume overload

QT dispersion

MVP-unrelated factors

Autonomic nervous system dysfunction

Conduction system abnormalities

Long QT

Cardiomyopathy

Purkinje fibers ectopy foci

LV indicates left ventricular; MVP, mitral valve prolapse; and SCD, sudden cardiac death.

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We provided the first evidence that MAD is associ-ated with arrhythmic MVP (Figure 4).7 MAD was more pronounced, and the end-systolic and end-diastolic mi-tral annular diameters were larger in MVP patients with arrhythmias and LGE than in those without arrhythmias and LGE. At the same time, histological analysis re-vealed a longer MAD in 50 SCD cases with MVP and LV fibrosis as compared with that in control hearts.

Furthermore, in 1976, Gilbert et al79 provided the first echocardiographic demonstration of a peculiar func-tional abnormality of the mitral annulus in MVP patients (ie, an unusual systolic curling of the posterior mitral an-nulus on the adjacent myocardium, such that the sys-tolic movement of the annulus was primarily downward with little, if any, anterior motion, thereby resulting in a

curled appearance when visualized in real-time motion). Unlike previous reports, the authors did not visualize LV motion abnormalities, either by echocardiography or angiography, leading to the conclusion that the cause of the curling was uncertain. We recently explored this aspect in our series of arrhythmic MVP patients, demon-strating that the curling of the mitral annulus is typically associated with MAD and leads to annular hypermobil-ity7 (Movie in the online-only Data Supplement).

Our morphofunctional data clearly show that in pa-tients with arrhythmic MVP, the mitral valve apparatus is characterized by MAD, systolic curling, and myxomatous leaflet thickening.7 We, along with others, also previ-ously demonstrated the association of LV fibrosis with life-threatening electric instability.4,71,80 On the basis of

Figure 2. Myocardial fibrosis in arrhythmic MVP patients: comparison between CMR and histology. A, Contrast-enhanced CMR, 3-chamber view: note the midmural LGE in the LV inferobasal region under posterior valve leaflet (black arrow). B, Histopathology: myocardial fibrosis (blue staining) at the level of the inferobasal LV free wall underneath the posterior mitral valve leaflet is visible. C, Contrast-enhanced CMR: LGE of the PM is visible on mid short-axis view (white arrow). D, Histopathology: replacement-type fibrosis (blue staining) of the myocardium is evident at the level of the PM and adjacent free wall. Modified from Basso et al4 and from Perazzolo Marra et al.7 CMR indicates cardiac magnetic resonance; LGE, late gadolinium enhancement; LV, left ventricular; MVP, mitral valve prolapse; and PM, papillary muscle.

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these findings, we hypothesize the following cascade of events, starting with morphofunctional abnormalities of the mitral annulus (Figure 5, the Padua hypothesis): MAD and systolic curling motion are the basis for the paradoxical increase in annulus diameter during systole, progressive myxomatous degeneration of the leaflets, and myocardial stretch in the LV inferobasal segment and PMs, thus confirming, and further extending, the original observation by Hutchins et al.75 The regional area of hypercontraction, originally hypothesized by Nutter et al,81 now has a clear anatomical basis for the phenom-ena of MAD and systolic curling. This association can increase wall stress in the inferobasal wall and PM, as evidenced by hypertrophy and replacement-type fibrosis, both documented at postmortem by histological analysis and confirmed in vivo by CMR imaging.4 The genesis of malignant arrhythmias in MVP probably recognizes the combination of the substrate (myocardial fibrosis) and the trigger (mechanical stretch) eliciting PVBs.4,7,73

Notably, the long-standing theory of an occult car-diomyopathy evolved into that of a localized mechani-cal injury of the myocardium. Fukuda et al82 recently demonstrated by speckle-tracking echocardiography that basal LV contraction is regionally and significantly reduced in patients with MVP. These LV basal abnor-malities correspond with mitral valve annular dilatation. A potential mechanism for these findings can be sug-gested based on the stress-strain relation, providing a mechanical explanation for the fibrosis development in this region, which is similarly related to the origin of ventricular arrhythmias in MVP.

Recently, Dejgaard et al83 provided additional evi-dence, demonstrating a high occurrence of arrhythmias in patients with MAD, without a difference in the preva-lence between MAD patients with and without MVP.

Remarkably, their data further support the key role of MAD in arrhythmogenesis, albeit independently of MVP, because of the mechanical stretch of the myocardium.84

Patients with MVP were initially identified by the auscultatory finding of a mid-systolic click or late sys-tolic murmur.1,2 which is the result of an abrupt tension in the mitral leaflet caused by the abnormal posterior leaflet systolic curling attributable to MAD.7 Thus, pa-tients with MVP and mid-systolic click more frequently have stress-induced inferobasal lesions.4,7 Noteworthy, in the same original studies, the burden of severe ven-tricular arrhythmias was particularly high.1,2 Whether the presence of click, MAD, and curling in MVP patients without arrhythmias can predict valve disease progres-sion and the onset of complex ventricular arrhythmias requires further investigation.

RISK STRATIFICATIONThe major challenge is the early identification, within a large population of patients with echocardiographically detectable MVP, of the asymptomatic individual with MVP who may be at high risk for developing severe ventricular arrhythmias or SCD.

To prevent the exponential increase in costs, refer-rals, and false-positive results, only MVP patients with red flags, particularly MAD and systolic curling, besides arrhythmic presentation, will undergo further investiga-tion, including contrast-enhanced or T1 mapping CMR and a strict arrhythmia surveillance for proper manage-ment and SCD prevention. The prognostic significance of inducible arrhythmias in electrophysiologic studies among MVP patients is unknown, and consequently, the test cannot be routinely recommended in the risk stratification process (Figure 6).

Figure 3. Measurement of MAD. A, Schematic representation of transthoracic echocardiography, parasternal long axis view: the length of MAD is measured from the left atrial wall–MV posterior leaflet junction to the top of the LV posterior wall during end-systole (double-headed gray arrow). B, Two-dimensional transthoracic echocardiography, parasternal long-axis view, showing a bileaflet MVP and posterior MAD (white line) measured during end-systole. Modified from Carmo et al78 and Perazzolo Marra et al.7 LV indicates left ventricular; MAD, mitral annulus disjunction; MV, mitral valve; and MVP, mitral valve prolapse.

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It is noteworthy that despite the propensity of MVP to cause life-threatening ventricular arrhythmias, the Amer-ican Heart Association, American College of Cardiology, Heart Rhythm Society, and the European Society of Car-diology guidelines for ventricular arrhythmias and SCD do not have specific sections on MVP, including distinct criteria for risk stratification and recommendations for the management of ventricular arrhythmias or SCD.85,86

TREATMENT FOR ARRHYTHMIC MITRAL VALVE PROLAPSEThe clinical decision making in a young subject with MVP and symptomatic ventricular arrhythmias is dif-

ficult and still empiric, relying on the expertise of the medical team in each center.

From a lifestyle viewpoint, it has recently been dem-onstrated that only a small proportion of competitive athletes with MVP develop adverse cardiovascular events (0.5% per year).87 The worst prognosis was re-ported in those who had both regurgitation and ven-tricular arrhythmias, suggesting a cautious restriction of competitive sports. However, when MVP is isolated, the prognosis is excellent, and no exercise or sport restric-tion is required. Noteworthy, SCD in MVP patients usu-ally occurs while at rest or during sleep.4

Medical therapy based on β-blockers may be the-oretically beneficial, even if there are no randomized studies available in arrhythmic MVP patients. Prospec-

Figure 4. MAD by CMR and histology in MVP patients vs controls. A, Cine CMR, systolic frame, 3-chamber, long-axis view: control subject without MAD. B, Cine CMR, 3-chamber, systolic frame, long-axis view: MVP patient with MAD measured from the left atrial wall–posterior MV leaflet junction to the top of the LV infero-basal wall during end systole (double-headed white arrow). C, His-tology: a representative section of the mitral annulus in a control heart showing the absence of MAD. D, Histology: elongated mitral annulus with MAD in a MVP patient who had SCD (double-headed black arrow). Modified from Perazzolo Marra et al.7 CMR indicates cardiac magnetic resonance; LV, left ventricular; MAD, mitral annular disjunction; MV, mitral valve; MVP, mitral valve prolapse; and SCD, sudden cardiac death.

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tive studies are warranted to assess the therapeutic role of implantable cardioverter defibrillators (ICDs), tar-geted catheter ablation, and surgical repair in selected MVP patients with a high arrhythmic burden.

ICD is generally indicated as secondary prevention in MVP patients experiencing out-of-hospital cardiac ar-rest, after the exclusion of other underlying reversible cardiac diseases. However, data on the rate of recur-

rent cardiac arrest are not yet available and are war-ranted. The therapeutic management of a symptomat-ic patient with drug-refractory ventricular arrhythmias is controversial. In this case, the predictive value of electrophysiologic study remains to be established, and thus far, a targeted risk stratification for each subject is indicated, considering the type of arrhythmias and myocardial imaging.

Figure 5. Pathophysiology of ventricular arrhythmias in MVP patients: the combination of mechanical trigger and abnormal substrate (the Padua hypothesis). MAD and systolic curling motion are the basis for paradoxical increase of annulus diameter during systole and myocardial stretch in the LV infero-basal segment and PMs, eventually leading to hypertrophy and fibrosis. LV indicates left ventricular; MAD, mitral annular disjunction; MVP, mitral valve prolapse; and PM, papillary muscle.

Figure 6. Arrhythmic MVP: clinical profile and diagnostic tools for risk stratification and targeted therapy (middle). CE indicates contrast enhanced; CMR, cardiac magnetic resonance; EP, electrophysiologic; LGE, late gadolinium enhancement; LV, left ventricular; MAD, mitral annulus disjunction; MV, mitral valve; MVP, mitral valve prolapse; PM, papillary muscle; PVB, premature ventricular beat; RBBB, right bundle branch block; TE, trans-esophageal; and TT, trans-thoracic.

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The possibility of an invasive electrophysiological eval-uation leading to radiofrequency ablation has been re-cently assessed. Syed et al70 demonstrated that ablation is feasible in MVP patients with symptomatic, drug-re-fractory ventricular arrhythmias. Moreover, ablation can reduce symptomatic PVBs and appropriate ICD shocks during follow-up. In fact, in the subgroup of patients with previous cardiac arrest, targeting the PVB triggers resulted in a reduction of appropriate ICD shocks but did not affect the overall PVB frequency; in the subgroup without previous cardiac arrest, targeting the most fre-quent ectopics resulted in a reduction in PVB burden.

The ability to predict the existence of PM-based ectopic foci can facilitate the treatment of ventricular arrhythmias.72 However, ablation at this level can be technically difficult because of catheter instability, deep intramural sites of origin, and the need to ablate at the base of the PMs.88,89 Although fascicular and PM-based ectopics often trigger ventricular fibrillation, ventricular ectopy may also involve the outflow tract and mitral an-nulus. Late recurrence could arise from arrhythmic foci not targeted at the initial ablation, thus requiring long-term patient follow-up.

Finally, surgical mitral valve repair or replacement has been demonstrated to reduce the burden of malignant arrhythmias in MVP patients. However, data are limited to small case series and isolated case reports,90–96 and mitral valve surgery did not always guarantee control of ventricular arrhythmias.97 The reduction of ventricu-lar arrhythmias after surgery could result from an im-provement of mitral incompetence with LV remodeling. Furthermore, when treating less severe forms of MVP, without a surgical indication merely based on regur-gitation, surgery would theoretically reduce ventricu-lar arrhythmias attributable to mechanical stretch by relieving traction on the PM. Remarkably, it has been demonstrated that experimental PM traction in a ca-nine heart model might account for significant regional changes in LV refractoriness.98 Furthermore, Wilde et al,71 by conducting mapping studies in a MVP patient with VT, showed that the mechanism was that of a delayed afterdepolarization-induced triggered activ-ity, with stretch and fibrosis contributing to the origin of ventricular arrhythmias. In a retrospective study of 4477 patients who underwent mitral valve surgery at the Mayo Clinic,99 8 patients with bileaflet MVP had ICDs in place both pre- and postsurgically. In 5 patients with malignant ventricular arrhythmias before surgery (all but 1 undergoing mitral valve repair), a reduction in ventricular fibrillation, VT, and ICD shocks after mitral valve surgery was documented.

The same group evaluated 32 consecutive patients undergoing valve surgery (repair in 92%) for mitral re-gurgitation secondary to bileaflet MVP.100 Surgery did not uniformly reduce ventricular arrhythmia frequency, but patients who had a >10% reduction in PVB fre-

quency tend to be younger than those who did not. These preliminary data suggest that mechanical trauma, either stretch or friction, is not the sole cause; rather, an arrhythmic substrate may progressively develop over time in patients with a long-standing history of MVP.

Thus far, data are derived from small single-center series to draw any conclusions on the impact of early surgery or ablation on the natural history of malignant MVP. Furthermore, no data are available on the role of repair versus replacement in terms of arrhythmic out-come. Finally, the reduction in PVB frequency cannot be equally translated into SCD risk elimination. Future prospective studies are required for these therapeutic options to be considered primarily for the reduction of malignant ventricular arrhythmia in MVP patients.

The availability of either invasive or surgical treat-ment options advocate for a better recognition of PM-based ectopy in MVP patients. The use of multiple imaging modalities including CMR, coupled with elec-trophysiologic mapping data, can be beneficial for the identification of PM sites of PVB/VT origin in arrhythmic MVP patients and for risk stratification (Figure 6).

CONCLUSIONSThe genesis of malignant arrhythmias in MVP probably recognizes the combination of the substrate (regional myocardial hypertrophy and fibrosis, Purkinje fibers) and the trigger (mechanical stretch) because of primary mor-phofunctional abnormalities of the mitral annulus. Pro-spective multicenter studies that match the scarring on myocardial imaging with electrophysiological substrates and assess the therapeutic role of ICD, targeted catheter ablation, and surgical repair/replacement in selected MVP patients with a high arrhythmic burden are warranted.

ARTICLE INFORMATIONThe online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/circulationaha.118.034075.

CorrespondenceCristina Basso, MD, PhD, Cardiovascular Pathology, Azienda Ospedaliera; and Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Uni-versity of Padua Medical School Via A. Gabelli, 61 35121 Padova-Italy. Email [email protected]

AffiliationsCardiovascular Pathology Unit (C.B., G.T.), and Clinical Cardiology Unit (S.I., M.P.M.), Azienda Ospedaliera; and Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, Padova, Italy.

Sources of FundingDrs Basso and Thiene are supported by the Registry for Cardio-cerebro-vas-cular Pathology, Veneto Region, Venice, Italy; Veneto Region Target Research, Venice 933/2015; Target Projects Ricerca Finalizzata-2013-02356762 and 2016-02363774, Ministry Health System; and Budget Integrato per la Ri-cerca dei Dipartimenti-BIRD162733, University of Padua, Padova, Italy.

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DisclosuresNone.

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Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden ... · The genesis of malignant ventricular arrhythmias in MVP probably recognizes the combination of the substrate (regional