Mitral annular disjunction (MAD) is defined as an abnormal displacement of a hinge point of one or both mitral valve leaflets away from the ventricular myocardium into the left atrium.1 MAD often coexists with mitral valve prolapse (MVP) and is estimated to be present in 30% of MVP patients.1 Although relatively uncommon in the general population, MAD remains a clinically important diagnosis due to its association with an increased risk of malignant ventricular arrhythmias leading to sudden cardiac death (SCD).1 Despite this known association with malignant arrhythmias, there remains a lack of standardized guidelines regarding appropriate screening, diagnosis, and management strategies for patients with MAD.
MAD was first described in the 1980s in autopsy studies of patients with myxomatous MVP, with one series noting MAD in 92% of patients with MVP.2,3 For many years, MAD was viewed as an anatomic abnormality only seen on autopsy without much clinical relevance. Recently, with advances in imaging technology and detection, MAD has gained increasing recognition in the cardiology literature, with a growing number of reports.4
We report the case of a 37-year-old man incidentally diagnosed with MAD, and also summarize the most relevant available literature, discuss screening, diagnostic, and management strategies, and highlight important gaps in current professional society guidelines and high-quality data.
Methods
A literature review was performed to gather current knowledge on MAD. We searched PubMed for English-language articles using the keywords ‘mitral annular disjunction,’ ‘mitral valve prolapses AND arrhythmia,’ ‘mitral valve prolapse AND sudden death,’ and ‘mitral valve prolapse AND MRI.’ Reference lists of relevant articles, including original research, review articles, and case series, were screened for additional sources. Priority was given to high-impact cardiology journals and imaging studies that specifically addressed the incidence, imaging characterization, and clinical outcomes of MAD. Key data from multimodality imaging studies (echocardiography, cardiac MRI, CT) and electrophysiological studies were extracted. We included observational cohort studies that examined the relationship between MAD and arrhythmic events or mitral regurgitation (MR), as well as surgical series detailing the operative management of MAD. Given that MAD is a relatively recent re-emerging topic, much of the available data comes from retrospective analyses and case reports; no randomized trials or large prospective studies were available. For this narrative review, we synthesized the findings qualitatively. No institutional review board approval was required for this literature-based study.
Case Presentation
A 37-year-old man presented to transfer his primary care from another facility with the primary complaint of increasing seizure frequency. His past medical history was notable for traumatic brain injury sustained during military service 16 years prior, seizure disorder diagnosed 10 years prior, and paroxysmal AF (pAF), which was documented during his index hospitalization for seizure disorder. Vital signs, including heart rate, blood pressure, and BMI, were within normal limits. Social history was negative for tobacco, alcohol, or recreational drug use, and family history was unremarkable for prior seizure disorder or cardiac disease. The physical examination was unremarkable, and a review of systems was negative for palpitations, syncope, chest pain, or other cardiac disease. Given his reported history of pAF at a young age, a 12-lead ECG and transthoracic echocardiogram (TTE) were ordered. The 12-lead ECG demonstrated normal sinus rhythm with non-specific ST changes inferiorly (Figure 1). TTE revealed preserved biventricular systolic function with left ventricular ejection fraction of 50–55%. Also noted on TTE was atrial displacement of the hinge point of the lateral mitral valve annulus and lateral tissue Doppler S′ of the mitral valve >15 cm/s, consistent with MAD (Supplementary Video 1 and Figure 2). The patient was subsequently referred to a cardiology clinic.
Given the known association between MAD and malignant arrhythmias, there was significant concern that the patient’s reported seizures may actually represent undiagnosed ventricular arrhythmias or convulsive cardiogenic syncope. After thorough discussion with the patient, the decision was made to proceed with implantable loop recorder placement (ILR). At the 2-month follow-up, the patient continued to suffer frequent seizure-like activity. ILR confirmed a pAF burden of 1%, but has thus far not demonstrated any ventricular arrhythmias, effectively excluding malignant arrhythmias as the underlying etiology of the patient’s seizure-like activity. Follow up, including discussions regarding pAF ablation versus antiarrhythmic therapy, is ongoing.
Prevalence and Epidemiology of MAD
Initial impressions may suggest that MAD is a rare entity; however, emerging data indicate it is more prevalent than previously thought. The lack of consensus about the definition makes determining the prevalence of MAD challenging, and establishing a clear threshold for MAD is important in distinguishing clinically significant MAD from incidental MAD. How we truly define MAD is vital in risk stratifying these patients for potential management and the prevention of adverse events.
In most cases, the disjunction is subtle (a few millimeters) and located in the anterior or inferior aspect of the annulus. The clinically ‘classic’ MAD in the inferolateral annular region is less common, occurring in only 5% of individuals.4 These asymptomatic individuals highlight that minor degrees of annular disjunction can be a normal anatomic variant. Thus, a key challenge that is currently being undertaken is distinguishing clinically significant MAD from trivial ‘physiologic’ disjunction that can be present in many asymptomatic individuals. Current evidence suggests that small disjunctions are common and benign, whereas larger disjunctions are rarer but associated with a significantly increased risk of arrhythmia, especially in symptomatic individuals with other comorbidities.4
Another area that has been studied in detail is the prevalence of MAD in patients with MVP, given the proposed link between MAD and arrhythmic ‘malignant’ MVP. Multiple imaging cohorts indicate that a substantial number of MVP patients have MAD, although reported percentages vary widely depending on the imaging modality used and the population studied. The most accessible modality, TTE, tends to yield the lowest prevalence: for example, in one series of 131 patients with MVP and significant MR, TTE detected MAD in approximately 17.3% of patients.5 The use of transesophageal echocardiography (TEE) in that same cohort increased detection to 25.5%, and cardiac MRI identified MAD in 42% of patients.5 These findings suggest that many cases of MAD go unrecognized on standard TTE (due to limited visualization of the posterior annulus and challenges with image quality in many patients due to body habitus, lung disease, or other imaging characteristics) and that a multimodal imaging approach may be necessary when clinical suspicion is increased.
Data suggest that the prevalence of MAD may be increased among patients with connective tissue disorders or other structural heart diseases. For example, MVP is common in those with Marfan’s syndrome and, as a result, so is MAD. One study of Marfan patients reported MAD in approximately 42% of patients overall and in up to 85% of those who had MVP, an important correlation and possible population for future studies regarding routine screening for MAD.6 Interestingly, MAD was present even in a significant proportion of Marfan patients without overt MVP, suggesting an inherent abnormality of the mitral annulus in connective tissue disease. Pediatric patients with Marfan’s syndrome had particularly high rates of MAD, with one report noting MAD in approximately 50% of children with Marfan’s syndrome compared with approximately 26% of adults.7 Geographically, many epidemiological studies have been conducted in tertiary referral centers in North America and Europe; thus, the prevalence of MAD in non-White individuals of non-European ancestry may be under- or overestimated.1,4,5,7
Diagnostic Modalities
As discussed above, there is no clear consensus regarding the optimal definition or diagnostic criteria for clinically significant MAD. In an effort to address this, several studies have examined the strengths and weaknesses of various imaging modalities in relation to MAD diagnosis. As with many other areas of cardiology, there has been an emphasis on the role of multimodal imaging when appropriate.5
Before diagnostic modalities are discussed, it is important to mention that MAD can manifest as either a true structural abnormality or a disjunction caused by leaflet motion (the difference between true MAD and pseudo-MAD). True MAD is an anatomic separation where the posterior mitral annulus hinge point is actually displaced onto the left atrial wall and is visible throughout the entirety of both diastole and systole.8 In contrast, pseudo-MAD is seen only during systole and presents as billowing of the posterior mitral leaflet as it folds up against the atrial wall, creating the illusion of annular separation despite a normal annular attachment in diastole.9 On echocardiography, pseudo-MAD is far more common with concomitant myxomatous MVP and tends to accompany advanced leaflet redundancy and mitral regurgitation.
Transthoracic Echocardiography
TTE, as used in our patient, is the most common mode of cardiac imaging and the most common diagnostic study where MAD is identified. MAD is most clearly identified in the parasternal long-axis (PLAX) view of the mitral valve. In this view, MAD presents a separation between the posterior mitral leaflet–atrium hinge point and the base of the inferior left ventricular wall during systole (Figure 3). This appears as an echo-lucent gap or ‘step-off’ between the bright echo of the leaflet hinge point and the ventricular wall. The disjunction distance can be measured at end-systole by measuring perpendicularly from the atrial wall/leaflet hinge point to the origin of the basal left ventricle.3 Most commonly, MAD involves the posterior annulus, making the PLAX view (which captures the posterior leaflet and inferolateral wall) the standard measurement. However, a single PLAX view may not capture disjunction if it is localized elsewhere or if the ultrasound beam is not aligned optimally. A comprehensive TTE with careful attention to the mitral annulus in all available views is vital to avoid underdiagnosis of MAD.
Transesophageal Echocardiography
TEE provides superior image quality and allows for multiplanar reconstruction and 3D imaging, which can improve MAD detection. MAD can be assessed by TEE in mid-esophageal long-axis views and in two-chamber or commissural views that image the posterior annulus. Due to the invasive nature of TEE and the inherent risks of sedation, proper patient selection remains paramount. For example, in patients undergoing surgical repair or replacement, intraoperative TEE is routinely used and may lead to improved detection of MAD in this high-prevalence group.10
Cardiac CT
Cardiac CT has complementary value in assessing patients with MAD. This imaging modality is useful, especially in situations where cardiac magnetic resonance (CMR) is contraindicated. Cardiac CT provides high-resolution 3D imaging of the mitral apparatus. Although CT lacks the tissue characterization capabilities of CMR (discussed below), it plays an important role in preprocedural planning for mitral valve interventions and may be used in conjunction with the other imaging modalities to form a comprehensive assessment of patients with in MAD. In addition, the superior spatial resolution of cardiac CT compared with MRI provides more reliable assessment of the degree of disjunction.
Cardiac Magnetic Resonance
CMR has emerged as the standard modality for the identification of MAD due to excellent spatial resolution and dynamic imaging. These characteristics allow high-fidelity 3D visualization of the mitral annulus and precise measurement of disjunction length. Unlike echocardiography, which may have image quality limitations in certain planes, CMR has the particular advantage of being able to survey the entire annular circumference for disjunction. A landmark CMR study that systematically measured the degree of MAD at four annular sites (anterior, inferior, anterolateral, inferolateral) in thousands of individuals demonstrated how CMR can detect disjunction in locations beyond the inferolateral wall that echocardiography traditionally focuses on.4 In patients with MVP, CMR often reveals that what appeared as an isolated posterior MAD on echocardiography is part of a broader annular abnormality.
Late Gadolinium Enhancement
CMR is best at detecting replacement fibrosis, most commonly located in the basal inferolateral wall or papillary muscles. The presence of late gadolinium enhancement (LGE) has been independently associated with a higher incidence of ventricular arrhythmias, serving as a marker of underlying myocardial compromise.11 Although LGE is highly specific, its absence does not rule out arrhythmic burden, because some patients do exhibit diffuse fibrosis or mechanical abnormalities without a visible scar. In the absence of LGE, the use of T1 and T2 parametric mapping may also aid in the identification of clinically significant myocardial fibrosis.9
Fluorodeoxyglucose PET
PET scans can add another dimension to risk stratifying patients with MAD by uncovering inflammatory activity in the myocardium, suggesting that arrhythmogenic MVP is an active disease process rather than a static scarring condition.12 PET–MRI imaging of the arrhythmic MVP can demonstrate subclinical myocardial inflammation that may coexist with areas of myocardial fibrosis in patients with severe degenerative MR, even in asymptomatic patients.12 This warrants further investigation in order to establish the role of PET in management, but it can play a role in early risk stratification if used in the correct subset of patients at risk of arrhythmic triggers.
Other Modalities and Considerations
Other imaging modalities and characteristic findings are also useful in the evaluation of MAD. For example, 3D echocardiography improves visualization of the saddle-shaped mitral annulus and can help identify MAD by allowing en face views. A quantitative 3D echocardiographic study found that MAD was associated with abnormal annular dynamics, specifically reduced annular contraction and higher systolic strain on the posterior annulus.3 Strain imaging and speckle-tracking echocardiography may eventually play a role in quantifying the mechanical impact of MAD on the myocardium. Tissue Doppler imaging can reveal the Pickelhaube sign, an unusually high tissue Doppler S′ velocity (>16 cm/s) of the lateral mitral annulus during systole, which correlates with the severity of MAD and MVP.
Together, these reports indicate that a multimodal approach is often necessary to identify the presence and severity of MAD. TTE remains widely available, cost-effective, and non-invasive and is the preferred first-line modality for the diagnosis of MAD. When image quality is suboptimal or the findings warrant further anatomical assessment of the mitral valve, TEE and/or CMR offer distinct advantages and improved diagnostic yield.
Clinical Implications
MAD has important clinical ramifications, particularly in the context of MVP. The presence of MAD can influence a patient’s arrhythmic risk profile, the progression of mitral regurgitation, and event management decisions. The primary clinical concern regarding MAD is its association with ventricular arrhythmias and SCD. In recent years, a syndrome of arrhythmogenic MVP has been described, where patients (often middle-aged women with bileaflet MVP) experience complex ventricular ectopy, non-sustained ventricular tachycardia (VT), and SCD often discordant from the degree of mitral valve regurgitation. MAD has emerged as a high-risk feature of this syndrome.1 A pivotal study by Dejgaard et al. evaluated 116 patients with MAD (with and without MVP) and documented a high incidence of arrhythmic events.1 Clinically, the arrhythmias associated with MAD and MVP range from frequent premature ventricular contractions and non-sustained VT (often polymorphic or originating from the papillary muscles) to sustained VT and ventricular fibrillation. Patients may present with palpitations, exercise intolerance, presyncope/syncope, or, in the worst case, sudden cardiac arrest. On ECG or Holter monitoring, high-risk features include frequent polymorphic premature ventricular contractions (particularly those originating from the left ventricular outflow tract or papillary muscle region) in a patient with known MAD. Another diagnostic clue is the presence of T-wave inversions in the inferolateral leads, which have been noted in patients with arrhythmogenic MVP with myocardial fibrosis.13 Although rare, SCD in MVP occurs at higher rates than in healthy controls without MVP. Retrospective autopsy studies of individuals with MVP-SCD typically reveal bileaflet myxomatous prolapse, fibrotic changes in the papillary muscles, and MAD.14 For example, pathologic series have reported the incidence of MAD in individuals with MVP-SCD to be high, implicating it as a high-risk feature in patients with MVP.15 However, not all patients with MAD develop arrhythmia; many have no arrhythmic symptoms at all, especially if the MAD is minimal.
Current data suggest that a combination of factors confers higher risk: MAD (especially with disjunction >5 mm), redundant mitral valve tissue associated with prolapse, frequent complex premature ventricular contractions, myocardial fibrosis on CMR, and perhaps certain demographic features (younger age, female sex).1,9 MAD has the potential to significantly alter the clinical landscape of MVP management. Its presence identifies patients who may be at higher risk of malignant ventricular arrhythmias (regardless of the degree of valvular regurgitation), thereby warranting closer monitoring and possibly prophylactic measures. It may also influence the behavior of the mitral valve, potentially accelerating regurgitation or complicating repair. Clinicians managing patients with MAD should maintain vigilance for arrhythmias (through Holter monitoring and patient education on symptoms) and ensure the timely follow-up of valve status. The concept of MVP/MAD syndrome is now recognized, describing patients with bileaflet MVP, MAD, frequent ventricular ectopy, fibrosis on imaging, and sometimes mid-systolic clicks or audible arrhythmic beats on auscultation.16 Early identification of this syndrome is crucial so that interventions (medical or surgical) can be considered before a catastrophic arrhythmic event.
Proper risk stratification in MAD patients remains a challenge and an active area of research. MAD in an asymptomatic patients should not be dismissed as only an incidental finding because it may portray an arrhythmogenic substrate, especially when accompanied by other abnormalities, as in our patient. CMR with LGE delineates myocardial fibrosis, a proven marker of malignant ventricular arrhythmias in MVP/MAD. The presence of fibrosis on CMR, either in the form of replacement fibrosis on late gadolinium sequences or interstitial fibrosis on T1 mapping, and extracellular volume measurement have also been shown to predict malignant arrhythmias.17 Global longitudinal strain and novel strain patterns, such as the double-peak sign, detect subtle mechanical dysfunction. The double-peak pattern in particular has emerged as a potent predictor of ventricular arrhythmias, even independent of scar burden.17 The above modalities each provide a piece of the risk stratification puzzle that is present in asymptomatic MAD patients. In practice, a comprehensive and multimodal approach would be best used to incorporate all these findings. For example, an asymptomatic patient with MAD who has bileaflet MVP with redundant leaflets, reduced global longitudinal strain, and fibrosis on CMR would be viewed very differently from a patient with an isolated small MAD and normal strain and CMR. In an asymptomatic patient, one or more of the above findings should prompt a lower threshold for obtaining ambulatory ECG monitoring to look for occult ventricular ectopy.12 If complex or frequent ventricular arrhythmias are found, escalation of care with referral to electrophysiology, consideration of beta-blockers or antiarrhythmics, and, in select cases, ICD may be appropriate.12
Management and Treatment Strategies
The management of MAD patients must be individualized in order to appropriately identify patients who would benefit from early intervention and SCD prevention (i.e., ILR monitoring, or ICD implantation) while avoiding overtreatment and procedural complications in lower-risk individuals. Currently, no professional society guidelines focus on MAD; thus, clinicians rely on general MVP management principles and expert consensus to appropriately treat patients. In patients with incidentally discovered MVP without MAD, significant valvular regurgitation, or high-risk symptoms, reassurance with periodic physical examination and TTE is reasonable. Patients with MAD may benefit from additional imaging and should likely undergo at least one-time ambulatory cardiac rhythm monitoring to assess for occult ventricular arrhythmias with consideration of longer-term ILR placement if there are high-risk features. Surveillance TTE should also be performed in these patients at least annually, with evaluation at shorter intervals if high-risk features or symptoms develop.
Currently, no trials provide evidence that beta-blockers or Class III antiarrhythmics reduce arrhythmic events in MVP or mitral annulus disjunction; however, beta-blockers and antiarrhythmics may help in symptomatic patients.2 Sotalol or flecainide have been used in some patients, but these drugs must be used with caution in the setting of prolapse and are to be avoided if significant fibrosis or ischemia is suspected. For those who cannot tolerate metoprolol or other beta-blockers, calcium channel blockers as alternative second-line therapy for the symptomatic relief of palpitations can be attempted.2 If a patient experiences episodes of previous sustained VT or survived cardiac arrest, an ICD comes into play as per general guidelines, whereby an ICD is indicated for survivors of SCD or unstable VT.2
Optimal management of high-risk patients with MAD remains controversial. As mentioned above, there are no guidelines regarding primary prevention ICD placement in this population, and therefore, the decision to implant an ICD is individualized based on a patient’s comorbidities and history.18 If there are surgical indications, the goal of surgery is not only to correct associated MVP and eliminate MR but also to address the associated MAD, if possible.
In addition to medication recommendations, patients with comorbid MAD should receive lifestyle and adjunct measures. It is important to emphasize that regular cardiovascular exercise is beneficial for overall heart health and may reduce adrenergic surges at rest; however, it is also important to risk stratify patients based on other comorbid cardiovascular risk factors and to avoid very intense competitive exercise in those at highest risk of SCD. MVP in pregnancy is usually well tolerated in the absence of severe regurgitation and no current recommendations exist regarding prepregnancy counseling in patients with MAD.
Conclusion
MAD, once an obscure anatomic detail, has emerged as an increasingly important entity that may significantly impact SCD risk, particularly in the MVP population. This review highlights our current understanding and emphasizes the several gaps that remain, as well as areas of ongoing debate. A few critical points warrant further discussion and reflection to further classify and eventually create guidelines. These include diagnostic criteria, pathophysiological mechanisms, and risk stratifications in management guidelines, all of which currently face limitations and uncertainties.
The ongoing discussion revolves around the cause–effect relationship between MAD and arrhythmias. Does MR cause malignant arrhythmias, or is it simply a marker of a more diffuse process, such as myxomatous infiltration or a fibrotic tendency that leads to the arrhythmia? Some argue that MAD is an epiphenomenon and that the same genetic or molecular factors causing MVP also lead to weakened annular connections that can result in fibrosis, with both MVP and MAD stemming from the same underlying cause. Others present MAD as a mechanical trigger that causes secondary irritation and friction from the papillary muscles during systole, which facilitates re-entry circuits.2 We currently lack robust risk models to predict which patients with MAD will develop arrhythmias or experience SCD. The novelty of MAD as described in the literature, along with the absence of prolonged longitudinal studies, pose limitations. Most of the current data come from retrospective cohorts often created after an event has occurred.
In regard to the management of MAD, several unanswered questions remain, including when to refer for surgery, or whether surgery is even indicated in the prophylactic setting before an event occurs in patients exhibiting moderate MR and whether that can truly mitigate arrhythmia risk. Although a trial designed to test this hypothesis would be very challenging from an ethical standpoint, it could answer the question of whether earlier surgical intervention could potentially save lives in this patient population by preventing SCD.3
A patient-centered and multidisciplinary approach must consistently provide the best care for this complex condition, particularly in individuals with multiple cardiovascular risk factors. Cardiologists, imaging specialists, electrophysiologists, and cardiac surgeons should work together with high-risk patients requiring implantable device placement or surgery to develop a tailored strategy and assess the risks and benefits of interventions. Educating patients about warning signs such as syncope and ensuring close follow up with primary care and general cardiologists is crucial in preventing catastrophic events by facilitating prompt monitoring interventions with Holter monitors during primary procedures such as ICD implantation if the risk profile increases.
In conclusion, MAD is a crucial piece of the puzzle, alongside arrhythmogenic MVP and degenerative mitral valve disease. Awareness of this condition is still emerging in the literature, and established guidelines for the prevention of arrhythmias have yet to be developed. By integrating various modalities, such as those mentioned above (including advanced imaging, starting with simple TTE, prudent clinical management, and patient education), we can enhance outcomes for patients living with this condition. Ongoing research will hopefully clarify the remaining uncertainties, particularly concerning who to treat, when to treat, and how to potentially alter the course of MAD-related pathology. The evolving insights into MAD highlight the importance of combining imaging findings with the clinical picture, ultimately leading to more personalized and proactive cardiovascular care.