Mitral Valve Prolapse Associated with Mitral Annular Disjunction: Diagnosis, Prognosis, and Arrhythmic Risk

Abstract

Mitral valve prolapse (MVP) is the most common valvular heart disease, with a reported prevalence of 2–3% in the general population, and represents the leading structural cause of mitral regurgitation in Western countries. MVP has long been considered predominantly a benign condition; however, it may be associated with adverse clinical events, including severe mitral regurgitation, atrial fibrillation, congestive heart failure, endocarditis, stroke, and ventricular arrhythmias, potentially leading to sudden cardiac death.

The so-called malignant MVP syndrome has been described in a subset of patients, predominantly young women, characterized by bileaflet MVP, a mid-systolic click, biphasic or inverted T waves in the inferior leads, and complex ventricular arrhythmias with polymorphic or right bundle branch block morphology, in the absence of significant mitral regurgitation. In addition to electrocardiographic and clinical features, myocardial fibrosis involving the basal inferolateral wall and the papillary muscles has been documented. Fibrosis in these two specific myocardial regions plays a crucial role and, in clinical practice, can be identified in vivo by contrast-enhanced cardiac magnetic resonance imaging. Distinct morpho-functional abnormalities of the mitral annulus, including annular disjunction and systolic curling, have been described in patients with arrhythmic MVP and are considered possible primum movens of alterations in mitral valve apparatus mechanics, leading to leaflet remodelling and myocardial injury/fibrosis.

Mitral valve prolapse (MVP) is the most common valvular disease, with a reported prevalence of 2–3% in the general population, and represents the leading structural cause of mitral regurgitation in Western countries.¹ Although it has historically been regarded as a predominantly benign condition, a subset of individuals is characterized by ventricular arrhythmias and sudden cardiac death (SCD), the risk of which remains difficult to quantify. This subgroup of patients is affected by so-called malignant MVP, in which the arrhythmic burden outweighs the severity of valvular regurgitation.²

The so-called ‘malignant MVP syndrome’ has been described in a subset of patients, predominantly young women, characterized by bileaflet MVP, a mid-systolic click, biphasic or inverted T waves in the inferior leads, and complex ventricular arrhythmias with right bundle branch block or polymorphic morphology, in the absence of significant mitral regurgitation.² Comparative analyses of clinico-pathological data, correlating autopsy findings with cardiac magnetic resonance (CMR) imaging in patients with arrhythmic MVP, have revealed well-defined and distinctive anatomical and structural features of this entity. The main anatomical characteristics include both tissue abnormalities (fibrosis of the papillary muscles and of the inferolateral wall of the left ventricle) and anatomo-functional alterations (mitral annular disjunction-MAD- and the so-called systolic curling motion).^3,4

In addition to these anatomical aspects, from an electrophysiological standpoint, patients with MVP and a history of cardiac arrest have been shown to be characterized by premature ventricular beats originating from Purkinje tissue, which act as triggers for ventricular fibrillation.⁵

The term MAD was originally introduced by Bharati et al.⁶ to describe an anatomical abnormality of the fibrous mitral annulus observed in a patient with MVP and a long history of palpitations and a mid-systolic click who died suddenly. MAD was subsequently systematically investigated by Hutchins et al. in the 1980s,⁷ who defined it as a displacement of the insertion point of the posterior mitral leaflet, resulting in a marked separation between the left atrial wall–mitral valve junction and the left ventricular myocardium.

Furthermore, in 1976, Gilbert et al. provided the first echocardiographic evidence of a distinctive functional abnormality of the mitral annulus in patients with MVP, namely an unusual systolic ‘curling’ motion of the posterior mitral annulus towards the adjacent myocardium. Specifically, the systolic motion of the annulus was predominantly downward, with little or no anterior displacement, resulting in a characteristic curled appearance when observed in real-time imaging. The authors concluded that the cause of this curling phenomenon in MVP was uncertain because, in contrast to previous reports, they did not identify abnormalities in left ventricular wall motion by either echocardiography or angiography.⁸

The presence of MAD is a well-recognized finding, particularly for its implications in the surgical correction of mitral valve disease; however, its role in arrhythmogenesis emerged from an electrophysiological perspective following the observation that MAD is associated with annular hypermobility. Morpho-functional data clearly demonstrate that, in patients with arrhythmic MVP, the mitral valve apparatus is characterized by the coexistence of MAD, systolic curling, and myxomatous leaflet thickening. Although myocardial fibrosis represents a robust marker associated with electrical instability, as observed in other clinical settings, major ventricular arrhythmias have also been documented in individuals without fibrosis but with MAD and systolic curling, even in the absence of significant mitral regurgitation. These findings support the concept of a multifactorial arrhythmogenic mechanism.⁹

Fibrosis may represent a late stage of the malignant pathological process, whereas mechanisms other than fibrosis per se likely act as substrates for malignant arrhythmias in the early stages of MVP. Based on these observations, data derived from patients with arrhythmic MVP without valvular insufficiency suggest that abnormal contractility of the basal left ventricular wall, reflected by the characteristic systolic curling motion, exerts both direct and indirect effects (the latter mediated by late gadolinium enhancement, LGE) on arrhythmia generation. In other words, arrhythmias in MVP appear to be related not to a single factor such as LGE, but also to mechanical abnormalities, highlighting the need for additional risk stratification protocols.⁹

In recent years, evidence has emerged demonstrating that MAD, as assessed by CMR, is associated with arrhythmic MVP. MAD extent and mitral annular diameters measured at end-systole and end-diastole were greater in patients with arrhythmic MVP and left ventricular LGE compared with patients with MVP without arrhythmias and without myocardial LGE. Concurrently, histological analysis revealed a more extensive region of MAD in 50 cases of SCD associated with MVP and left ventricular fibrosis compared with control subjects¹⁰ (Figure 1).

Figure 1.

Anatomical and cardiac magnetic resonance visualization of mitral annular disjunction (MAD). Panel A illustrates the normal anatomical relationship between the left atrium and left ventricle in a healthy subject without MVP. Panel B shows a thickened myxomatous mitral valve with the presence of MAD. Panel C depicts systolic MAD (red line) as visualized by cardiac magnetic resonance imaging in the three-chamber view. Image modified from Circulation: Cardiovascular Imaging 2016; 9:e005030.⁴

An additional piece of the puzzle was provided by Dejgaard et al., who demonstrated a high prevalence of arrhythmias in patients with MAD in the absence of MVP, with no significant difference in arrhythmic burden between patients with MAD with and without MVP. Importantly, these findings further support a pivotal role of MAD in arrhythmogenesis, attributable to mechanical myocardial stretch that is independent of MVP itself.¹¹

Considering the clinical and prognostic implications, the existence and significance of MAD have been widely debated in the literature. Study populations have included heterogeneous degrees of mitral regurgitation, making definitive conclusions challenging. Moreover, the assessment of MAD using different imaging modalities—such as two-dimensional and three-dimensional echocardiography, transoesophageal echocardiography, computed tomography, and CMR—contributes to limited comparability among studies and hampers the achievement of a definitive consensus. In this context, which has historically shifted focus from the mitral valve to the left ventricular myocardium through the identification of MAD, novel mechanisms have been proposed to explain arrhythmogenesis in arrhythmic MVP.

Although the incidence of SCD in MVP is low, reported estimates range from 0.2% to 4%. Early identification of asymptomatic individuals with MVP who may be at high risk of developing life-threatening ventricular arrhythmias or SCD represents the true clinical challenge. Risk stratification in this setting is complex, largely because the mechanisms underlying ventricular arrhythmias and SCD in MVP are not yet fully understood. Indeed, although CMR has, in recent years, provided a unique opportunity to visualize myocardial fibrosis in vivo as a true arrhythmogenic substrate, this imaging modality cannot be considered a screening tool in patients with MVP. To avoid the consequences of increased costs, unnecessary referrals, and false-positive findings, only MVP patients presenting with specific warning signs should ideally be selected for further investigations, including CMR, electrophysiological study, and a rigorous arrhythmic surveillance programme, in order to ensure appropriate management and prevention of SCD.

A different clinical context is represented by arrhythmias occurring in MVP associated with significant mitral regurgitation, in which left ventricular volume overload constitutes the major trigger for electrical instability and the development of myocardial fibrosis.

The wide range of reported prevalence of SCD in MVP is attributable, at least in part, to variability in the definition of SCD. A recent prospective study employing long-term continuous cardiac monitoring demonstrated that annual incidence rates of severe ventricular arrhythmias—including aborted cardiac arrest, ventricular fibrillation, appropriate or aborted implantable cardioverter-defibrillator (ICD) therapy, sustained ventricular tachycardia, or non-sustained ventricular tachycardia with haemodynamic instability—were as high as 4% in patients with arrhythmic MVP without prior major events.

Another recent study showed that 29% of athletes with MVP engaged in competitive sports exhibited evidence of ventricular arrhythmias. Athletes with MVP and ventricular arrhythmias had larger left ventricular and left atrial dimensions (with comparable left ventricular systolic function) and a higher prevalence of MAD (16% vs. 3%; P < 0.001) compared with athletes with MVP but without ventricular arrhythmias. The incidence of major adverse events—including mitral valve surgery, ischaemic stroke, atrial fibrillation, and SCD—was low in this population (0.5% per year); however, all individuals who experienced adverse events had evidence of ventricular arrhythmias at baseline.

Unfortunately, current knowledge regarding the natural history of the role of MAD in arrhythmogenesis remains incomplete. Mitral annular abnormalities clearly often precede the development of significant mitral regurgitation in the setting of myxomatous MVP, suggesting annular pathology as a common denominator for both disease phenotypes—namely, the form predominantly characterized by progressive regurgitation and the malignant arrhythmic form. Although the temporal progression of MAD itself has yet to be definitively demonstrated, the association between MAD and the progressive development of ventricular arrhythmias appears clinically relevant. Among patients without severe ventricular arrhythmias at the time of MVP diagnosis, those with MAD are at higher risk of developing significant arrhythmias during follow-up.

In the study proposed by Essayagh et al.¹² nearly one-third of patients with MAD but without baseline ventricular arrhythmias developed significant arrhythmic events—defined as ventricular tachycardia, need for catheter ablation for ventricular tachycardia or ventricular ectopy, ICD implantation, or SCD—over a 5-year follow-up. This proportion further increased to 58% at 10 years. By contrast, only 15% and 38% of patients without MAD developed significant arrhythmias at 5- and 10-year follow-up, respectively. Although ventricular arrhythmias appear to progress and accumulate over time, MAD does not seem to be associated with excess mortality during the first 10 years following diagnosis.

Recently, the European Heart Rhythm Association (EHRA) published a consensus document addressing arrhythmic risk stratification in arrhythmic MVP and MAD.¹³ This document proposes a stepwise approach in which clinical evaluation initially identifies ‘high-risk’ patients, defined by the presence of unexplained presyncope or syncope. Subsequently, documentation of ‘high-risk ventricular arrhythmias’—defined as episodes of ventricular tachycardia ≥180 bpm and/or a history of sustained ventricular tachycardia or ventricular fibrillation—by implantable loop recorder is crucial for selecting candidates who may benefit from ICD implantation. In patients without documented ventricular tachycardia, the consensus summarizes the following ‘phenotypic risk features’: T-wave inversion in inferior leads, multiple polymorphic premature ventricular beats, MAD, redundant mitral valve leaflets, left atrial enlargement, left ventricular ejection fraction <50%, and LGE. Nevertheless, clinical decision-making remains complex and is often individualized.

Sudden cardiac death in patients with MVP typically occurs at rest or during sleep at home. From a lifestyle perspective, only a small proportion of competitive athletes with MVP experience adverse cardiovascular events (0.5% per year). The poorest prognosis has been reported in patients with both mitral regurgitation and ventricular arrhythmias, supporting a cautious approach towards restriction from competitive sports in this subgroup. When MVP is isolated, prognosis is excellent, and no restrictions on physical activity or sports participation should be applied.

In patients with MVP who have survived out-of-hospital cardiac arrest, ICD implantation is mandatory as secondary prevention after exclusion of other reversible underlying cardiac diseases. However, data on the recurrence rate of cardiac arrest in this population are still lacking and urgently needed. Management of symptomatic patients with drug-refractory ventricular arrhythmias remains controversial. The predictive value of invasive electrophysiological study has yet to be established; therefore, a personalized risk stratification approach is currently recommended, taking into account family history, arrhythmic burden and morphology, and myocardial imaging findings.

The potential role of invasive electrophysiological evaluation leading to radiofrequency catheter ablation has recently been explored. Syed et al. demonstrated that catheter ablation is feasible in patients with MVP and symptomatic drug-refractory ventricular arrhythmias. Furthermore, ablation was shown to reduce symptomatic premature ventricular beats and appropriate ICD shocks during follow-up. Specifically, in the subgroup of patients with prior cardiac arrest, targeting polymorphic premature ventricular beats acting as potential triggers for ventricular fibrillation reduced appropriate ICD shocks but did not affect the overall burden of ventricular ectopy. In contrast, in patients without prior cardiac arrest, targeting the most frequent polymorphic premature ventricular beats effectively reduced ectopic burden. In both groups, a reduction in symptoms related to polymorphic ventricular ectopy was observed.¹⁴

The ability of imaging techniques to predict the presence of ectopic foci originating from the papillary muscles may assist in procedural planning for ventricular arrhythmia treatment. However, papillary muscle ablation can be technically challenging due to catheter instability, deep intramural sites of origin, and the need to ablate at the papillary muscle base.

Although fascicular and papillary muscle–related premature ventricular beats are often the triggers for ventricular fibrillation, ventricular ectopy originating from the outflow tract or the mitral annulus may be clinically relevant in selected patients. Late recurrences may result from arrhythmic foci not targeted during the initial ablation, underscoring the need for long-term follow-up.

Finally, surgical mitral valve repair or replacement has been shown to reduce the burden of malignant arrhythmias in selected patients with MVP.

Funding

None.

Data availability

No new data were generated or analysed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Il punto sull'insufficienza mitralica con MAD: diagnosi, prognosi e rischio aritmico’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.