Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death
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.
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 arrhythmic MVP”3,4 triggered a debate on its definition and clinical implications in terms of diagnosis, risk stratification, and treatment. The patient at risk is usually female, with non-syndromic mostly bileaflet myxomatous degeneration of the mitral valve, ECG repolarization abnormalities, and complex ventricular arrhythmias with polymorphic/right bundle branch block morphology.3,4 The echocardiographic features are those of classic MVP (ie, single-leaflet or bileaflet displacement >2 mm beyond the long-axis annular plane, with >5 mm leaflet thickening),5,6 accompanied by morphofunctional abnormalities of the mitral annulus (ie, mitral annular disjunction [MAD] and systolic curling).7 Moreover, the morphology is consistent with that of MVP attributable to myxomatous degeneration (ie, the accumulation 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 prevention of sudden cardiac death (SCD) has drawn attention 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 occurrence 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 Furthermore, studies in which MVP has been associated to SCD hypothesize the role of coexisting pathophysiologic risk factors of electrical instability, rendering it difficult to define these associations as causative.
| 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 |
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 absence of a systematic evaluation with prolonged ECG recording.36,38–44
It is well known that a high degree of valve regurgitation 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 ventricular 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, localized reentry, abnormal automaticity, and triggered activity 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 produced 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 alternating 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 ventricular outflow tracts. In our autopsy series of SCD attributable 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, fascicular tissue and outflow tract, as well as by T-wave inversion 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
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 originating 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.
The origin of ventricular arrhythmias in MVP remains controversial in the absence of valve regurgitation 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-related factors comprise changes at the level of both the valve and the LV.
| 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 |
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 hypothesized 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, ventricular 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 However, 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 Arrhythmogenesis
Electrophysiologic study in bileaflet MVP syndrome patients 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 anecdotal cases.51,53,61,71 In particular, by extending the histopathological 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 subpopulation of living MVP patients with complex ventricular arrhythmias, closely overlapping the histopathological features observed in SCD victims.4 A relative hypertrophy of the LV inferobasal wall in comparison with the adjacent midportion was also found. In a previous publication on MVP patients with a history of arrhythmias, most of whom had moderate to severe mitral regurgitation, 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 electrophysiologic 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 instability.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
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.
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 consistent localization of PVB foci and abnormal tissue with slow conduction to the vicinity of the subvalvular mitral apparatus indeed suggests a structural association. Presumably, 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 myocardial imaging with electrophysiological substrates in different patient populations are mandatory. The frequent observation of T-wave abnormalities on inferolateral leads on 12-lead ECG suggests a disturbed repolarization 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 Arrhythmias
The 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 palpitations 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 displacement of the point of insertion of the posterior mitral 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 distributed 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 significantly 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 apparatus. The concept of MAD was dismissed and remained a matter of speculation for pathologists76 until the 2000s when Erikson et al77 and Carmo et al78 demonstrated that it is also easily detectable and measurable by routine transthoracic echocardiography (Figure 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.
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.
We provided the first evidence that MAD is associated with arrhythmic MVP (Figure 4).7 MAD was more pronounced, and the end-systolic and end-diastolic mitral annular diameters were larger in MVP patients with arrhythmias and LGE than in those without arrhythmias and LGE. At the same time, histological analysis revealed a longer MAD in 50 SCD cases with MVP and LV fibrosis as compared with that in control hearts.
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, Histology: 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.
Furthermore, in 1976, Gilbert et al79 provided the first echocardiographic demonstration of a peculiar functional abnormality of the mitral annulus in MVP patients (ie, an unusual systolic curling of the posterior mitral annulus on the adjacent myocardium, such that the systolic 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, demonstrating that the curling of the mitral annulus is typically associated with MAD and leads to annular hypermobility7 (Movie in the online-only Data Supplement).
Our morphofunctional data clearly show that in patients with arrhythmic MVP, the mitral valve apparatus is characterized by MAD, systolic curling, and myxomatous leaflet thickening.7 We, along with others, also previously demonstrated the association of LV fibrosis with life-threatening electric instability.4,71,80 On the basis of 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 phenomena 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
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.
Notably, the long-standing theory of an occult cardiomyopathy evolved into that of a localized mechanical 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 abnormalities correspond with mitral valve annular dilatation. A potential mechanism for these findings can be suggested 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 evidence, demonstrating a high occurrence of arrhythmias in patients with MAD, without a difference in the prevalence 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 systolic 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, patients 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 ventricular arrhythmias was particularly high.1,2 Whether the presence of click, MAD, and curling in MVP patients without arrhythmias can predict valve disease progression and the onset of complex ventricular arrhythmias requires further investigation.
Risk Stratification
The 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, referrals, and false-positive results, only MVP patients with red flags, particularly MAD and systolic curling, besides arrhythmic presentation, will undergo further investigation, including contrast-enhanced or T1 mapping CMR and a strict arrhythmia surveillance for proper management 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 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.
It is noteworthy that despite the propensity of MVP to cause life-threatening ventricular arrhythmias, the American Heart Association, American College of Cardiology, Heart Rhythm Society, and the European Society of Cardiology 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 Prolapse
The clinical decision making in a young subject with MVP and symptomatic ventricular arrhythmias is difficult and still empiric, relying on the expertise of the medical team in each center.
From a lifestyle viewpoint, it has recently been demonstrated that only a small proportion of competitive athletes with MVP develop adverse cardiovascular events (0.5% per year).87 The worst prognosis was reported in those who had both regurgitation and ventricular arrhythmias, suggesting a cautious restriction of competitive sports. However, when MVP is isolated, the prognosis is excellent, and no exercise or sport restriction is required. Noteworthy, SCD in MVP patients usually occurs while at rest or during sleep.4
Medical therapy based on β-blockers may be theoretically beneficial, even if there are no randomized studies available in arrhythmic MVP patients. Prospective studies are warranted to assess the therapeutic role of implantable cardioverter defibrillators (ICDs), targeted 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 arrest, after the exclusion of other underlying reversible cardiac diseases. However, data on the rate of recurrent cardiac arrest are not yet available and are warranted. The therapeutic management of a symptomatic 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.
The possibility of an invasive electrophysiological evaluation leading to radiofrequency ablation has been recently assessed. Syed et al70 demonstrated that ablation is feasible in MVP patients with symptomatic, drug-refractory 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 frequent 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 annulus. 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 ventricular arrhythmias after surgery could result from an improvement of mitral incompetence with LV remodeling. Furthermore, when treating less severe forms of MVP, without a surgical indication merely based on regurgitation, surgery would theoretically reduce ventricular arrhythmias attributable to mechanical stretch by relieving traction on the PM. Remarkably, it has been demonstrated that experimental PM traction in a canine 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 activity, 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 regurgitation secondary to bileaflet MVP.100 Surgery did not uniformly reduce ventricular arrhythmia frequency, but patients who had a >10% reduction in PVB frequency 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 outcome. 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 treatment options advocate for a better recognition of PM-based ectopy in MVP patients. The use of multiple imaging modalities including CMR, coupled with electrophysiologic 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).
Conclusions
The 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 morphofunctional abnormalities of the mitral annulus. Prospective 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.
Sources of Funding
Drs Basso and Thiene are supported by the Registry for Cardio-cerebro-vascular 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 Ricerca dei Dipartimenti-BIRD162733, University of Padua, Padova, Italy.
Disclosures
None.
Footnotes
References
- 1.
Barlow JB, Bosman CK . Aneurysmal protrusion of the posterior leaflet of the mitral valve. An auscultatory-electrocardiographic syndrome.Am Heart J. 1966; 71:166–178. doi: 10.1016/0002-8703(66)90179-7CrossrefMedlineGoogle Scholar - 2.
Barlow JB, Bosman CK, Pocock WA, Marchand P . Late systolic murmurs and non-ejection (“mid-late”) systolic clicks: an analysis of 90 patients.Br Heart J. 1968; 30:203–218. doi: 10.1136/hrt.30.2.203CrossrefMedlineGoogle Scholar - 3.
Sriram CS, Syed FF, Ferguson ME, Johnson JN, Enriquez-Sarano M, Cetta F, Cannon BC, Asirvatham SJ, Ackerman MJ . Malignant bileaflet mitral valve prolapse syndrome in patients with otherwise idiopathic out-of-hospital cardiac arrest.J Am Coll Cardiol. 2013; 62:222–230. doi: 10.1016/j.jacc.2013.02.060CrossrefMedlineGoogle Scholar - 4.
Basso C, Perazzolo Marra M, Rizzo S, De Lazzari M, Giorgi B, Cipriani A, Frigo AC, Rigato I, Migliore F, Pilichou K, . Arrhythmic mitral valve prolapse and sudden cardiac death.Circulation. 2015; 132:556–566. doi: 10.1161/CIRCULATIONAHA.115.016291LinkGoogle Scholar - 5.
Freed LA, Levy D, Levine RA, Larson MG, Evans JC, Fuller DL, Lehman B, Benjamin EJ . Prevalence and clinical outcome of mitral-valve prolapse.N Engl J Med. 1999; 341:1–7. doi: 10.1056/NEJM199907013410101CrossrefMedlineGoogle Scholar - 6.
Freed LA, Benjamin EJ, Levy D, Larson MG, Evans JC, Fuller DL, Lehman B, Levine RA . Mitral valve prolapse in the general population: the benign nature of echocardiographic features in the Framingham Heart Study.J Am Coll Cardiol. 2002; 40:1298–1304. doi: 10.1016/s0735-1097(02)02161-7CrossrefMedlineGoogle Scholar - 7.
Perazzolo Marra M, Basso C, De Lazzari M, Rizzo S, Cipriani A, Giorgi B, Lacognata C, Rigato I, Migliore F, Pilichou K, . Morphofunctional abnormalities of mitral annulus and arrhythmic mitral valve prolapse.Circ Cardiovasc Imaging. 2016; 9:e005030. doi: 10.1161/CIRCIMAGING.116.005030LinkGoogle Scholar - 8.
Levine RA, Hagége AA, Judge DP, Padala M, Dal-Bianco JP, Aikawa E, Beaudoin J, Bischoff J, Bouatia-Naji N, Bruneval P, ; Leducq Mitral Transatlantic Network. Mitral valve disease–morphology and mechanisms.Nat Rev Cardiol. 2015; 12:689–710. doi: 10.1038/nrcardio.2015.161CrossrefMedlineGoogle Scholar - 9.
Pomerance A . Ballooning deformity (mucoid degeneration) of atrioventricular valves.Br Heart J. 1969; 31:343–351. doi: 10.1136/hrt.31.3.343CrossrefMedlineGoogle Scholar - 10.
Davies MJ, Moore BP, Braimbridge MV . The floppy mitral valve. Study of incidence, pathology, and complications in surgical, necropsy, and forensic material.Br Heart J. 1978; 40:468–481. doi: 10.1136/hrt.40.5.468CrossrefMedlineGoogle Scholar - 11.
Dollar AL, Roberts WC . Morphologic comparison of patients with mitral valve prolapse who died suddenly with patients who died from severe valvular dysfunction or other conditions.J Am Coll Cardiol. 1991; 17:921–931. doi: 10.1016/0735-1097(91)90875-aCrossrefMedlineGoogle Scholar - 12.
Rizzo S, Basso C, Lazzarini E, Celeghin R, Paolin A, Gerosa G, Valente M, Thiene G, Pilichou K . TGF-beta1 pathway activation and adherens junction molecular pattern in nonsyndromic mitral valve prolapse.Cardiovasc Pathol. 2015; 24:359–367. doi: 10.1016/j.carpath.2015.07.009CrossrefMedlineGoogle Scholar - 13.
Delling FN, Vasan RS . Epidemiology and pathophysiology of mitral valve prolapse: new insights into disease progression, genetics, and molecular basis.Circulation. 2014; 129:2158–2170. doi: 10.1161/CIRCULATIONAHA.113.006702LinkGoogle Scholar - 14.
Narayanan K, Uy-Evanado A, Teodorescu C, Reinier K, Nichols GA, Gunson K, Jui J, Chugh SS . Mitral valve prolapse and sudden cardiac arrest in the community.Heart Rhythm. 2016; 13:498–503. doi: 10.1016/j.hrthm.2015.09.026CrossrefMedlineGoogle Scholar - 15.
Burke AP, Farb A, Tang A, Smialek J, Virmani R . Fibromuscular dysplasia of small coronary arteries and fibrosis in the basilar ventricular septum in mitral valve prolapse.Am Heart J. 1997; 134(2 Pt 1):282–291. doi: 10.1016/s0002-8703(97)70136-4CrossrefMedlineGoogle Scholar - 16.
Drory Y, Turetz Y, Hiss Y, Lev B, Fisman EZ, Pines A, Kramer MR . Sudden unexpected death in persons less than 40 years of age.Am J Cardiol. 1991; 68:1388–1392. doi: 10.1016/0002-9149(91)90251-fCrossrefMedlineGoogle Scholar - 17.
Anderson RE, Hill RB, Broudy DW, Key CR, Pathak D . A population-based autopsy study of sudden, unexpected deaths from natural causes among persons 5 to 39 years old during a 12-year period.Hum Pathol. 1994; 25:1332–1340. doi: 10.1016/0046-8177(94)90094-9CrossrefMedlineGoogle Scholar - 18.
Van Camp SP, Bloor CM, Mueller FO, Cantu RC, Olson HG . Nontraumatic sports death in high school and college athletes.Med Sci Sports Exerc. 1995; 27:641–647.CrossrefMedlineGoogle Scholar - 19.
Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO . Sudden death in young competitive athletes: clinical, demographic, and pathological profiles.JAMA. 1996; 276:199–204. doi: 10.1001/jama.1996.03540030033028CrossrefMedlineGoogle Scholar - 20.
Wisten A, Forsberg H, Krantz P, Messner T . Sudden cardiac death in 15-35-year olds in Sweden during 1992-99.J Intern Med. 2002; 252:529–536. doi: 10.1046/j.1365-2796.2002.01038.xCrossrefMedlineGoogle Scholar - 21.
Morentin B, Suárez-Mier MP, Aguilera B . Sudden unexplained death among persons 1-35 years old.Forensic Sci Int. 2003; 135:213–217. doi: 10.1016/S0379-0738(03)00212-3CrossrefMedlineGoogle Scholar - 22.
Doolan A, Langlois N, Semsarian C . Causes of sudden cardiac death in young Australians.Med J Aust. 2004; 180:110–112. doi: 10.5694/j.1326-5377.2004.tb05830.xCrossrefMedlineGoogle Scholar - 23.
Eckart RE, Scoville SL, Campbell CL, Shry EA, Stajduhar KC, Potter RN, Pearse LA, Virmani R . Sudden death in young adults: a 25-year review of autopsies in military recruits.Ann Intern Med. 2004; 141:829–834. doi: 10.7326/0003-4819-141-11-200412070-00005CrossrefMedlineGoogle Scholar - 24.
Puranik R, Chow CK, Duflou JA, Kilborn MJ, McGuire MA . Sudden death in the young.Heart Rhythm. 2005; 2:1277–1282. doi: 10.1016/j.hrthm.2005.09.008CrossrefMedlineGoogle Scholar - 25.
di Gioia CR, Autore C, Romeo DM, Ciallella C, Aromatario MR, Lopez A, Pagannone E, Giordano C, Gallo P, d’Amati G . Sudden cardiac death in younger adults: autopsy diagnosis as a tool for preventive medicine.Hum Pathol. 2006; 37:794–801. doi: 10.1016/j.humpath.2006.03.008CrossrefMedlineGoogle Scholar - 26.
Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO . Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006.Circulation. 2009; 119:1085–1092. doi: 10.1161/CIRCULATIONAHA.108.804617LinkGoogle Scholar - 27.
Eckart RE, Shry EA, Burke AP, McNear JA, Appel DA, Castillo-Rojas LM, Avedissian L, Pearse LA, Potter RN, Tremaine L, ; Department of Defense Cardiovascular Death Registry Group. Sudden death in young adults: an autopsy-based series of a population undergoing active surveillance.J Am Coll Cardiol. 2011; 58:1254–1261. doi: 10.1016/j.jacc.2011.01.049CrossrefMedlineGoogle Scholar - 28.
Margey R, Roy A, Tobin S, O’Keane CJ, McGorrian C, Morris V, Jennings S, Galvin J . Sudden cardiac death in 14- to 35-year olds in Ireland from 2005 to 2007: a retrospective registry.Europace. 2011; 13:1411–1418. doi: 10.1093/europace/eur161CrossrefMedlineGoogle Scholar - 29.
Winkel BG, Holst AG, Theilade J, Kristensen IB, Thomsen JL, Ottesen GL, Bundgaard H, Svendsen JH, Haunsø S, Tfelt-Hansen J . Nationwide study of sudden cardiac death in persons aged 1-35 years.Eur Heart J. 2011; 32:983–990. doi: 10.1093/eurheartj/ehq428CrossrefMedlineGoogle Scholar - 30.
Pilmer CM, Porter B, Kirsh JA, Hicks AL, Gledhill N, Jamnik V, Faught BE, Hildebrandt D, McCartney N, Gow RM, . Scope and nature of sudden cardiac death before age 40 in Ontario: a report from the cardiac death advisory committee of the office of the chief coroner.Heart Rhythm. 2013; 10:517–523. doi: 10.1016/j.hrthm.2012.12.003CrossrefMedlineGoogle Scholar - 31.
de Noronha SV, Behr ER, Papadakis M, Ohta-Ogo K, Banya W, Wells J, Cox S, Cox A, Sharma S, Sheppard MN . The importance of specialist cardiac histopathological examination in the investigation of young sudden cardiac deaths.Europace. 2014; 16:899–907. doi: 10.1093/europace/eut329CrossrefMedlineGoogle Scholar - 32.
Risgaard B, Winkel BG, Jabbari R, Behr ER, Ingemann-Hansen O, Thomsen JL, Ottesen GL, Gislason GH, Bundgaard H, Haunsø S, . Burden of sudden cardiac death in persons aged 1 to 49 years: nationwide study in Denmark.Circ Arrhythm Electrophysiol. 2014; 7:205–211. doi: 10.1161/CIRCEP.113.001421LinkGoogle Scholar - 33.
Bagnall RD, Weintraub RG, Ingles J, Duflou J, Yeates L, Lam L, Davis AM, Thompson T, Connell V, Wallace J, . A Prospective study of sudden cardiac death among children and young adults.N Engl J Med. 2016; 374:2441–2452. doi: 10.1056/NEJMoa1510687CrossrefMedlineGoogle Scholar - 34.
Basso C, Aguilera B, Banner J, Cohle S, d’Amati G, de Gouveia RH, di Gioia C, Fabre A, Gallagher PJ, Leone O, ; Association for European Cardiovascular Pathology. Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology.Virchows Arch. 2017; 471:691–705. doi: 10.1007/s00428-017-2221-0CrossrefMedlineGoogle Scholar - 35.
Nishimura RA, McGoon MD, Shub C, Miller FA, Ilstrup DM, Tajik AJ . Echocardiographically documented mitral-valve prolapse: long-term follow-up of 237 patients.N Engl J Med. 1985; 313:1305–1309. doi: 10.1056/NEJM198511213132101CrossrefMedlineGoogle Scholar - 36.
Düren DR, Becker AE, Dunning AJ . Long-term follow-up of idiopathic mitral valve prolapse in 300 patients: a prospective study.J Am Coll Cardiol. 1988; 11:42–47. doi: 10.1016/0735-1097(88)90164-7CrossrefMedlineGoogle Scholar - 37.
Boudoulas H, Schaal SF, Stang JM, Fontana ME, Kolibash AJ, Wooley CF . Mitral valve prolapse: cardiac arrest with long-term survival.Int J Cardiol. 1990; 26:37–44.CrossrefMedlineGoogle Scholar - 38.
Campbell RW, Godman MG, Fiddler GI, Marquis RM, Julian DG . Ventricular arrhythmias in syndrome of balloon deformity of mitral valve: definition of possible high risk group.Br Heart J. 1976; 38:1053–1057. doi: 10.1136/hrt.38.10.1053CrossrefMedlineGoogle Scholar - 39.
DeMaria AN, Amsterdam EA, Vismara LA, Neumann A, Mason DT . Arrhythmias in the mitral valve prolapse syndrome: prevalence, nature, and frequency.Ann Intern Med. 1976; 84:656–660. doi: 10.7326/0003-4819-84-6-656CrossrefMedlineGoogle Scholar - 40.
Winkle RA, Lopes MG, Popp RL, Hancock EW . Life-threatening arrhythmias in the mitral valve prolapse syndrome.Am J Med. 1976; 60:961–967. doi: 10.1016/0002-9343(76)90567-2CrossrefMedlineGoogle Scholar - 41.
Kligfield P, Levy D, Devereux RB, Savage DD . Arrhythmias and sudden death in mitral valve prolapse.Am Heart J. 1987; 113:1298–1307. doi: 10.1016/0002-8703(87)90958-6CrossrefMedlineGoogle Scholar - 42.
Lévy S . Arrhythmias in the mitral valve prolapse syndrome: clinical significance and management.Pacing Clin Electrophysiol. 1992; 15:1080–1088. doi: 10.1111/j.1540-8159.1992.tb03101.xCrossrefMedlineGoogle Scholar - 43.
Morady F, Shen E, Bhandari A, Schwartz A, Scheinman MM . Programmed ventricular stimulation in mitral valve prolapse: analysis of 36 patients.Am J Cardiol. 1984; 53:135–138. doi: 10.1016/0002-9149(84)90697-0CrossrefMedlineGoogle Scholar - 44.
Devereux RB, Kramer-Fox R, Shear MK, Kligfield P, Pini R, Savage DD . Diagnosis and classification of severity of mitral valve prolapse: methodologic, biologic, and prognostic considerations.Am Heart J. 1987; 113:1265–1280. doi: 10.1016/0002-8703(87)90955-0CrossrefMedlineGoogle Scholar - 45.
Grigioni F, Enriquez-Sarano M, Ling LH, Bailey KR, Seward JB, Tajik AJ, Frye RL . Sudden death in mitral regurgitation due to flail leaflet.J Am Coll Cardiol. 1999; 34:2078–2085. doi: 10.1016/s0735-1097(99)00474-xCrossrefMedlineGoogle Scholar - 46.
Martínez-Rubio A, Schwammenthal Y, Schwammenthal E, Block M, Reinhardt L, Garcia-Alberola A, Sierra G, Shenasa M, Haverkamp W, Scheld HH, . Patients with valvular heart disease presenting with sustained ventricular tachyarrhythmias or syncope: results of programmed ventricular stimulation and long-term follow-up.Circulation. 1997; 96:500–508. doi: 10.1161/01.cir.96.2.500LinkGoogle Scholar - 47.
Avierinos JF, Gersh BJ, Melton LJ, Bailey KR, Shub C, Nishimura RA, Tajik AJ, Enriquez-Sarano M . Natural history of asymptomatic mitral valve prolapse in the community.Circulation. 2002; 106:1355–1361. doi: 10.1161/01.cir.0000028933.34260.09LinkGoogle Scholar - 48.
Savage DD, Levy D, Garrison RJ, Castelli WP, Kligfield P, Devereux RB, Anderson SJ, Kannel WB, Feinleib M . Mitral valve prolapse in the general population. 3. Dysrhythmias: the Framingham Study.Am Heart J. 1983; 106:582–586. doi: 10.1016/0002-8703(83)90706-8CrossrefMedlineGoogle Scholar - 49.
Lichstein E . Site of origin of ventricular premature beats in patients with mitral valve prolapse.Am Heart J. 1980; 100:450–457. doi: 10.1016/0002-8703(80)90656-0CrossrefMedlineGoogle Scholar - 50.
Zuppiroli A, Rinaldi M, Kramer-Fox R, Favilli S, Roman MJ, Devereux RB . Natural history of mitral valve prolapse.Am J Cardiol. 1995; 75:1028–1032. doi: 10.1016/s0002-9149(99)80718-8CrossrefMedlineGoogle Scholar - 51.
Jeresaty RM . The syndrome associated with mid-systolic click and-or late systolic murmur. Analysis of 32 cases.Chest. 1971; 59:643–647. doi: 10.1378/chest.59.6.643CrossrefMedlineGoogle Scholar - 52.
Salazar AE, Edwards JE . Friction lesions of ventricular endocardium: relation to chordae tendineae of mitral valve.Arch Pathol. 1970; 90:364–376.MedlineGoogle Scholar - 53.
Chesler E, King RA, Edwards JE . The myxomatous mitral valve and sudden death.Circulation. 1983; 67:632–639. doi: 10.1161/01.cir.67.3.632LinkGoogle Scholar - 54.
Morales AR, Romanelli R, Boucek RJ, Tate LG, Alvarez RT, Davis JT . Myxoid heart disease: an assessment of extravalvular cardiac pathology in severe mitral valve prolapse.Hum Pathol. 1992; 23:129–137. doi: 10.1016/0046-8177(92)90233-sCrossrefMedlineGoogle Scholar - 55.
Burke AP, Farb A, Tang A, Smialek J, Virmani R . Fibromuscular dysplasia of small coronary arteries and fibrosis in the basilar ventricular septum in mitral valve prolapse.Am Heart J. 1997; 134(2 Pt 1):282–291. doi: 10.1016/s0002-8703(97)70136-4CrossrefMedlineGoogle Scholar - 56.
Ehlers KH, Engle MA, Levin AR, Grossman H, Fleming RJ . Left ventricular abnormality with late mitral insufficiency and abnormal electrocardiogram.Am J Cardiol. 1970; 26:333–340. doi: 10.1016/0002-9149(70)90726-5CrossrefMedlineGoogle Scholar - 57.
Gooch AS, Vicencio F, Maranhao V, Goldberg H . Arrhythmias and left ventricular asynergy in the prolapsing mitral leaflet syndrome.Am J Cardiol. 1972; 29:611–620. doi: 10.1016/0002-9149(72)90161-0CrossrefMedlineGoogle Scholar - 58.
Scampardonis G, Yang SS, Maranhão V, Goldberg H, Gooch AS . Left ventricular abnormalities in prolapsed mitral leaflet syndrome: review of eighty-seven cases.Circulation. 1973; 48:287–297. doi: 10.1161/01.cir.48.2.287LinkGoogle Scholar - 59.
Gulotta SJ, Gulco L, Padmanabhan V, Miller S . The syndrome of systolic click, murmur, and mitral valve prolapse–a cardiomyopathy?Circulation. 1974; 49:717–728. doi: 10.1161/01.cir.49.4.717LinkGoogle Scholar - 60.
Sniezek-Maciejewska M, Dubiel JP, Piwowarska W, Mroczek-Czernecka D, Mazurek S, Jaśkiewicz J, Kitliński M . Ventricular arrhythmias and the autonomic tone in patients with mitral valve prolapse.Clin Cardiol. 1992; 15:720–724. doi: 10.1002/clc.4960151029CrossrefMedlineGoogle Scholar - 61.
Bharati S, Granston AS, Liebson PR, Loeb HS, Rosen KM, Lev M . The conduction system in mitral valve prolapse syndrome with sudden death.Am Heart J. 1981; 101:667–670. doi: 10.1016/0002-8703(81)90235-0CrossrefMedlineGoogle Scholar - 62.
Vesterby A, Bjerregaard P, Gregersen M, Fode K . Sudden death in mitral valve prolapse: associated accessory atrioventricular pathways.Forensic Sci Int. 1982; 19:125–133.CrossrefMedlineGoogle Scholar - 63.
André-Fouët X, Tabib A, Jean-Louis P, Anne D, Dutertre P, Gayet C, Huygue de Mahenge A, Loire R, Pont M . Mitral valve prolapse, Wolff-Parkinson-White syndrome, His bundle sclerosis and sudden death.Am J Cardiol. 1985; 56:700. doi: 10.1016/0002-9149(85)91041-0CrossrefMedlineGoogle Scholar - 64.
Martini B, Basso C, Thiene G . Sudden death in mitral valve prolapse with Holter monitoring-documented ventricular fibrillation: evidence of coexisting arrhythmogenic right ventricular cardiomyopathy.Int J Cardiol. 1995; 49:274–278.CrossrefMedlineGoogle Scholar - 65.
Swartz MH, Teichholz LE, Donoso E . Mitral valve prolapse: a review of associated arrhythmias.Am J Med. 1977; 62:377–389. doi: 10.1016/0002-9343(77)90835-xCrossrefMedlineGoogle Scholar - 66.
Bekheit S, Ali A, Deglin S, Jam A . Analysis of QT interval in patients with idiopathic mitral valve prolapse.Chest1982; 81: 620–625.CrossrefMedlineGoogle Scholar - 67.
Hancock EW, Cohn K . The syndrome associated with midsystolic click and late systolic murmur.Am J Med. 1966; 41:183–196. doi: 10.1016/0002-9343(66)90015-5CrossrefMedlineGoogle Scholar - 68.
Puddu P, Pastemac A, Tubau J, Krol R, Farley L, de Champlain J . QT interval prolongation and increased plasma catecholamine levels in patients with mitral valve prolapse.Am Heart J. 1983; 105: 422–428.CrossrefMedlineGoogle Scholar - 69.
Levy D, Savage D . Prevalence and clinical features of mitral valve prolapse.Am Heart J. 1987; 113:1281–1290. doi: 10.1016/0002-8703(87)90956-2CrossrefMedlineGoogle Scholar - 70.
Syed FF, Ackerman MJ, McLeod CJ, Kapa S, Mulpuru SK, Sriram CS, Cannon BC, Asirvatham SJ, Noseworthy PA . Sites of successful ventricular fibrillation ablation in bileaflet mitral valve prolapse syndrome.Circ Arrhythm Electrophysiol. 2016; 9(5). pii: e004005.LinkGoogle Scholar - 71.
Wilde AA, Düren DR, Hauer RN, deBakker JM, Bakker PF, Becker AE, Janse MJ . Mitral valve prolapse and ventricular arrhythmias: observations in a patient with a 20-year history.J Cardiovasc Electrophysiol. 1997; 8:307–316.CrossrefMedlineGoogle Scholar - 72.
Han Y, Peters DC, Salton CJ, Bzymek D, Nezafat R, Goddu B, Kissinger KV, Zimetbaum PJ, Manning WJ, Yeon SB . Cardiovascular magnetic resonance characterization of mitral valve prolapse.JACC Cardiovasc Imaging. 2008; 1:294–303. doi: 10.1016/j.jcmg.2008.01.013CrossrefMedlineGoogle Scholar - 73.
Fulton BL, Liang JJ, Enriquez A, Garcia FC, Supple GE, Riley MP, Schaller RD, Dixit S, Callans DJ, Marchlinski FE, . Imaging characteristics of papillary muscle site of origin of ventricular arrhythmias in patients with mitral valve prolapse.J Cardiovasc Electrophysiol. 2018; 29:146–153. doi: 10.1111/jce.13374CrossrefMedlineGoogle Scholar - 74.
Noseworthy PA, Asirvatham SJ . The knot that binds mitral valve prolapse and sudden cardiac death.Circulation. 2015; 132:551–552. doi: 10.1161/CIRCULATIONAHA.115.017979LinkGoogle Scholar - 75.
Hutchins GM, Moore GW, Skoog DK . The association of floppy mitral valve with disjunction of the mitral annulus fibrosus.N Engl J Med. 1986; 314:535–540. doi: 10.1056/NEJM198602273140902CrossrefMedlineGoogle Scholar - 76.
Angelini A, Ho SY, Anderson RH, Davies MJ, Becker AE . A histological study of the atrioventricular junction in hearts with normal and prolapsed leaflets of the mitral valve.Br Heart J. 1988; 59:712–716. doi: 10.1136/hrt.59.6.712CrossrefMedlineGoogle Scholar - 77.
Eriksson MJ, Bitkover CY, Omran AS, David TE, Ivanov J, Ali MJ, Woo A, Siu SC, Rakowski H . Mitral annular disjunction in advanced myxomatous mitral valve disease: echocardiographic detection and surgical correction.J Am Soc Echocardiogr. 2005; 18:1014–1022. doi: 10.1016/j.echo.2005.06.013CrossrefMedlineGoogle Scholar - 78.
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; 8:53. doi: 10.1186/1476-7120-8-53CrossrefMedlineGoogle Scholar - 79.
Gilbert BW, Schatz RA, VonRamm OT, Behar VS, Kisslo JA . Mitral valve prolapse. Two-dimensional echocardiographic and angiographic correlation.Circulation. 1976; 54:716–723. doi: 10.1161/01.cir.54.5.716LinkGoogle Scholar - 80.
Kitkungvan D, Nabi F, Kim RJ, Bonow RO, Khan MA, Xu J, Little SH, Quinones MA, Lawrie GM, Zoghbi WA, . Myocardial fibrosis in patients with primary mitral regurgitation with and without prolapse.J Am Coll Cardiol. 2018; 72:823–834. doi: 10.1016/j.jacc.2018.06.048CrossrefMedlineGoogle Scholar - 81.
Nutter DO, Wickliffe C, Gilbert CA, Moody C, King SB The pathophysiology of idiopathic mitral valve prolapse.Circulation. 1975; 52:297–305. doi: 10.1161/01.cir.52.2.297LinkGoogle Scholar - 82.
Fukuda S, Song JK, Mahara K, Kuwaki H, Jang JY, Takeuchi M, Sun BJ, Kim YJ, Miyamoto T, Oginosawa Y, . Basal left ventricular dilatation and reduced contraction in patients with mitral valve prolapse can be secondary to annular dilatation: preoperative and postoperative speckle-tracking echocardiographic study on left ventricle and mitral valve annulus interaction.Circ Cardiovasc Imaging. 2016; 9: pii: e005113. doi: 10.1161/CIRCIMAGING.115.005113LinkGoogle Scholar - 83.
Dejgaard LA, Skjølsvik ET, Lie ØH, Ribe M, Stokke MK, Hegbom F, Scheirlynck ES, Gjertsen E, Andresen K, Helle-Valle TM, . The mitral annulus disjunction arrhythmic syndrome.J Am Coll Cardiol. 2018; 72:1600–1609. doi: 10.1016/j.jacc.2018.07.070CrossrefMedlineGoogle Scholar - 84.
Basso C, Perazzolo Marra M . Mitral annulus disjunction: emerging role of myocardial mechanical stretch in arrhythmogenesis.J Am Coll Cardiol. 2018; 72:1610–1612. doi: 10.1016/j.jacc.2018.07.069CrossrefMedlineGoogle Scholar - 85.
Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, ; ESC Scientific Document Group. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).Eur Heart J. 2015; 36:2793–2867. doi: 10.1093/eurheartj/ehv316CrossrefMedlineGoogle Scholar - 86.
Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, ; American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.Circulation. 2006; 114:e385–e484. doi: 10.1161/CIRCULATIONAHA.106.178233LinkGoogle Scholar - 87.
Caselli S, Mango F, Clark J, Pandian NG, Corrado D, Autore C, Pelliccia A . Prevalence and clinical outcome of athletes with mitral valve prolapse.Circulation. 2018; 137:2080–2082. doi: 10.1161/CIRCULATIONAHA.117.033395LinkGoogle Scholar - 88.
Van Herendael H, Zado ES, Haqqani H, Tschabrunn CM, Callans DJ, Frankel DS, Lin D, Garcia F, Hutchinson MD, Riley M, . Catheter ablation of ventricular fibrillation: importance of left ventricular outflow tract and papillary muscle triggers.Heart Rhythm. 2014; 11:566–573. doi: 10.1016/j.hrthm.2013.12.030CrossrefMedlineGoogle Scholar - 89.
Santoro F, Di Biase L, Hranitzky P, Sanchez JE, Santangeli P, Perini AP, Burkhardt JD, Natale A . Ventricular fibrillation triggered by PVCs from papillary muscles: clinical features and ablation.J Cardiovasc Electrophysiol. 2014; 25:1158–1164. doi: 10.1111/jce.12478CrossrefMedlineGoogle Scholar - 90.
Pocock WA, Barlow JB, Marcus RH, Barlow CW . Mitral valvuloplasty for life-threatening ventricular arrhythmias in mitral valve prolapse.Am Heart J. 1991; 121(1 Pt 1):199–202. doi: 10.1016/0002-8703(91)90976-oCrossrefMedlineGoogle Scholar - 91.
Kay JH, Krohn BG, Zubiate P, Hoffman RL . Surgical correction of severe mitral prolapse without mitral insufficiency but with pronounced cardiac arrhythmias.J Thorac Cardiovasc Surg. 1979; 78:259–268.CrossrefMedlineGoogle Scholar - 92.
Al-Bassam MS, Cooley DA . Arrhythmia with mitral valve prolapse: results of annuloplasty in two patients.Cardiovasc Dis. 1978; 5:397–405.MedlineGoogle Scholar - 93.
Ross A, DeWeese JA, Yu PN . Refractory ventricular arrhythmias in a patient with mitral valve prolapse. Successful control with mitral valve replacement.J Electrocardiol. 1978; 11:289–295.CrossrefMedlineGoogle Scholar - 94.
Missotten A, Dotremont G, Goddeeris P, Piessens J, De Geest H . Mitral valve replacement in a patient with mitral valve prolapse complicated by severe ventricular arrhythmias.Acta Cardiol. 1980; 35:391–399.MedlineGoogle Scholar - 95.
Beroukhim RS, Reed JH, Schaffer MS, Yetman AT . Surgical correction of mitral valve prolapse: a cure for recurrent ventricular tachycardia in Marfan syndrome?Pediatr Cardiol. 2006; 27:755–758. doi: 10.1007/s00246-006-1102-0CrossrefMedlineGoogle Scholar - 96.
Abbadi DR, Purbey R, Poornima IG . Mitral valve repair is an effective treatment for ventricular arrhythmias in mitral valve prolapse syndrome.Int J Cardiol. 2014; 177:e16–e18. doi: 10.1016/j.ijcard.2014.07.174CrossrefMedlineGoogle Scholar - 97.
Vohra J, Sathe S, Warren R, Tatoulis J, Hunt D . Malignant ventricular arrhythmias in patients with mitral valve prolapse and mild mitral regurgitation.Pacing Clin Electrophysiol. 1993; 16(3 Pt 1):387–393. doi: 10.1111/j.1540-8159.1993.tb01599.xCrossrefMedlineGoogle Scholar - 98.
Gornick CC, Tobler HG, Pritzker MC, Tuna IC, Almquist A, Benditt DG . Electrophysiologic effects of papillary muscle traction in the intact heart.Circulation. 1986; 73:1013–1021. doi: 10.1161/01.cir.73.5.1013LinkGoogle Scholar - 99.
Vaidya VR, DeSimone CV, Damle N, Naksuk N, Syed FF, Ackerman MJ, Ponamgi SP, Nkomo VT, Suri RM, Noseworthy PA, . Reduction in malignant ventricular arrhythmia and appropriate shocks following surgical correction of bileaflet mitral valve prolapse.J Interv Card Electrophysiol. 2016; 46:137–143. doi: 10.1007/s10840-015-0090-5CrossrefMedlineGoogle Scholar - 100.
Naksuk N, Syed FF, Krittanawong C, Anderson MJ, Ebrille E, DeSimone CV, Vaidya VR, Ponamgi SP, Suri RM, Ackerman MJ, . The effect of mitral valve surgery on ventricular arrhythmia in patients with bileaflet mitral valve prolapse.Indian Pacing Electrophysiol J. 2016; 16:187–191. doi: 10.1016/j.ipej.2016.10.009CrossrefMedlineGoogle Scholar
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.