Mitral Prolapse: An Old Mysterious Entity - The Incremental Role of Multimodality Imaging in Sports Eligibility.

Mitral valve prolapse is generally a benign condition characterized by fibromyxomatous changes of the mitral leaflet with displacement into the left atrium and late-systolic regurgitation. Although it is an old clinical entity, it still arouses perplexity in diagnosis and clinical management. Complications, such as mitral regurgitation (MR), atrial fibrillation, congestive heart failure, endocarditis, ventricular arrhythmias, and sudden cardiac death (SCD), have been reported. A large proportion of the overall causes of SCD in young competitive athletes is explained by mitral valve prolapse. Recent studies have shown the fibrosis of the papillary muscles and inferobasal left ventricular wall in mitral valve prolapse, suggesting a possible origin of ventricular fatal arrhythmias. Athletes with mitral valve prolapse and MR should undergo annual evaluations including physical examination, echocardiogram, and exercise stress testing to evaluate the cardiovascular risks of competitive sports and obtain the eligibility. In this setting, multimodality imaging techniques - echocardiography, cardiac magnetic resonance, and cardiac computed tomography - should provide a broad spectrum of information, from diagnosis to clinical management of the major clinical profiles of the disease.

INTRODUCTION

Mitral valve prolapse (MVP) was first identified, as a pathological entity, in the 1960s when the mid-systolic click and the late-systolic murmur were correlated with the demonstration of angiographic protrusion of the mitral leaflets into the left atrium (LA) and late-systolic regurgitation.[1] The cause of this anomalies remains controversial, and many theories have been proposed. Although MVP is generally a benign condition, the outcome is widely heterogeneous, and complications, such as mitral regurgitation (MR), atrial fibrillation, congestive heart failure (CHF), endocarditis, ventricular arrhythmias, and sudden cardiac death (SCD), have been reported.[234] Particularly, MVP has been reported to explain for a large proportion (as high as 11%) of the overall causes of SCD in young competitive athletes.[4] In this review, we summarize our current knowledge of the diagnosis, pathophysiology, genetics, epidemiology, and prognosis and MVP, with a focus on potential implications in sports eligibility.

MITRAL VALVE PROLAPSE: A SINGLE DEFINITION?

MVP is present in approximately 4% of the general population and is most prevalent in young women.[5] MVP is a clinical entity characterized by typical fibromyxomatous changes in the mitral leaflet tissue with superior displacement of one or both leaflets into the LA.[36] Barlow entered in the international cardiology scene in 1963, with his observations on the mid-systolic click and late-systolic murmur associated with billowing of the mitral valve (MV) leaflets and MR, which was subsequently known as the Barlow syndrome.[7] Barlow never liked using the term “prolapse” and preferred the term “billowing” of the mitral leaflet. In 1966, Criley et al. introduced the term “prolapse,” recognizing cine-angiographically an MR [Figure 1], which occurs in association with a murmur in the latter part of systole or marked accentuation of a soft holosystolic murmur in late systole.[8] He sustained that the difference between billowing and prolapse might merely be semantic or only a matter of degree, with one condition merging into the other.[8] The introduction of the term “prolapse” has contributed to the general confusion. Then, Alain Carpentier defined the essential differences between prolapse and billowing: he restricted the use of the term “prolapse” to the failure of the leaflet edges to oppose normally.[9] Such partial loss of apposition may occur with or without abnormal billowing of the bellies of the leaflets, and MR, albeit mild, or even minimal, will inevitably result. If the billowing of the mitral leaflet is extreme with very voluminous leaflets and elongated chordae, the term “floppy” is appropriate.[9] Leaflet “flail” implies coaptation failure with eversion of the free edge of a leaflet into the LA, usually consequent to chordal rupture.[910] When symptoms, electrocardiographic changes, arrhythmias, or other features occur, the recognition of a syndrome is justified.[9]

Figure 1

Cine-angiographically mitral regurgitation in MVP. Left heart cineangiocardiography demonstrated aneurysmal bulging of one or both leaflets of the mitral valve into the left atrium in early systole, followed by mitral regurgitation in the latter part of systole. *Mitral regurgitation

In the early days of 2D echocardiography, the MVP was overdiagnosed, in part for the erroneous assumption that the MV was planar. In the late 1980s, using 3-dimensional echocardiographic imaging, Levine and colleagues established that the mitral annulus was saddle shaped and in four-chamber view, the leaflets can appear to “break” the annular plane (creating the appearance of prolapse) when they are normal.[11] Echocardiographic MVP has since been defined as single-leaflet or bileaflet prolapse of at least 2 mm beyond the long-axis annular plane, with or without mitral leaflet thickening. Prolapse with thickening of the leaflets >5 mm is called classic prolapse whereas prolapse with lesser degrees of leaflet thickening is regarded as nonclassic prolapse.[311]

PATHOPHYSIOLOGY AND HISTOLOGY

There is a variety of biological, biochemical, and biomechanical factors involved in the development of MVP. Morphologic alteration of the MV apparatus leads to enhancement of localized stress and tissue degeneration. The underlying mechanisms for the development of MVP and MR in association with MV tissue remodeling are still unclear. Myxomatous transformation is the most important mechanism responsible for MVP and the associated click.[1] It is characterized by disruption and loss of normal valvular architecture with thickening of the spongiosa, which is rich in acid mucopolysaccharides. The thickened spongiosa encroaches on the fibrosa, interrupting it focally and causing a basic weakness of this supporting structure, and leading to redundancy and prolapse.[12] Similarly, myxoid replacement of the collagen of chordae tendineae is frequent, leading to their rupture.[6] Furthermore, the expression of proteoglycans and catabolic enzymes is increased, included matrix metalloproteinases (MMP-1, MMP-2, MMP-9, and MMP-13) that contribute to the fragmentation of elastin and collagen fibers.[10] Myxomatous MV tissue generally exhibits lower stiffness values with lower failure stresses compared to normal MV tissue. The MV annulus is usually enlarged.[13] The so-called “Barlow disease” is an extreme form of degenerative mitral valve disease, characterized by excess connective tissue, redundant, thickened leaflets, marked annular dilatation, elongated, and thin (or thick/calcified) chordae.[10] On the other side, the fibroelastic deficiency is associated with thin, translucent leaflets, with collagen, elastin, and proteoglycans deficiency, moderate annular dilatation, and focal chordal elongation or rupture.[14]

Many studies in patients with MVP who died suddenly have shown a possible role for annular circumference, leaflet length and thickness, and the presence of endocardial plaques in the SCD.[1516] More recently, Basso et al. have shown that fibrosis of the papillary muscles and inferobasal left ventricular (LV) wall, suggesting a myocardial stretch by the prolapsing leaflet, is the structural hallmark of ventricular arrhythmias origin and contrast-enhanced cardiac magnetic resonance may help to identify in vivo this concealed substrate for risk stratification.[17]

CLASSIFICATION OF MITRAL VALVE PROLAPSE

MVP can be distinguished into primary MVP and secondary or syndromic MVP, in the presence of connective tissue disorders such as Marfan syndrome (MFS), Loeys–Dietz syndrome, Ehlers–Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, and the recently reported aneurysms-osteoarthritis syndrome.[31819202122] MVP has also been observed in hypertrophic cardiomyopathy.[23]

MFS is a multisystemic genetic condition affecting connective tissue. It has a worldwide prevalence of about 1 in 5000 and affects all races equally.[24] It results from heterozygous mutation in the gene that encodes fibrillin-1, which is the most important component of the extracellular matrix.[10] The connective tissue is “weak,” which accounted for the dilatation of the sinuses of Valsalva, aortic dissection, dislocation of the lens, scoliosis, and pneumothoraces. Patients with MFS often have MV elongation and thickening-like Barlow disease morphology.[25] Reports demonstrate that MV dysfunction is present in 80% of patients with MFS, and by age 30 years, moderate to MV occurs in 1 in 8 of them.[2627] If severe, MVP and regurgitation may evolve as progressive LV dilation and dysfunction and eventually, heart failure. Mas-Stachurska et al. showed increased collagen deposition and fibrosis in the LV myocardium of Marfan mice.[28] They demonstrated, in the murine model, the positive impact of moderate dynamic exercise on Marfan cardiomyopathy as evidenced by an antihypertrophic effect and the absence of deleterious effects on LV myocardial fibrosis.[28] Athletes with MFS can participate in low and moderate static/low dynamic competitive sports if they do not have aortic root dilatation, moderate-to-severe MR, and family history of dissection or SCD in a Marfan relative.[29]

Loeys–Dietz syndrome, which has phenotypic overlap with MFS, is characterized by aortic aneurysm, dissection, arterial tortuosity, hypertelorism and often long-bone overgrowth, and MVP.[10] It is associated with mutations of gene encoding the components of family of TGF-beta receptors.[10] Aneurysms-osteoarthritis syndrome is a very similar condition, associated with mutations of gene encoding Smad3 proteins, in which MVP is reported in 50% of patients.[3031]

CLINICAL AND ELECTROCARDIOGRAPHIC FINDINGS

MVP is usually asymptomatic and with benign natural history. Chest pain, dyspnea, fatigue, dizziness, palpitation, and neuropsychiatric disorders are encountered in patients with MVP[1] and might originate from neuroendocrine and autonomic dysfunction. This neurophysiological association of the heart in case of MVP, renal, and adrenal function with the autonomic nervous system is described in the literature as a “neuroendocrine cardiovascular process,” which may explain many symptoms including heart rhythm disorders.[32]

Auscultatory findings

There are seven major auscultatory manifestations of MVP as follows: isolated mid-systolic click, mid-systolic click followed by a late-systolic murmur, early systolic click, isolated late-systolic murmur, pansystolic murmur, precordial honk, and “silent” form. Physiologic and pharmacologic maneuvers can alter the timing of the click and murmur.[1] The mid-to-late systolic click is generally accepted as the diagnostic hallmark of this syndrome.[1] The general physical appearance in MVP may be entirely normal. However, certain features, that is, asthenic body habitus, high-arched palate, and thoracic skeletal abnormalities (straight back, pectus excavatum, and scoliosis), are frequently noted and heighten suspicion of this condition.[33]

Electrocardiographic findings

Initially, inverted or totally inverted T waves with or without ST-segment depression, primarily in the inferior limb leads might be present in the electrocardiogram of MVP patients. Biphasic or negative T waves might be present but are not uncommon in the athletes and are not necessarily due to MVP.[1] Ventricular and atrial arrhythmias are probably the most common manifestation of MVP. Ventricular fibrillation is the probable mechanism of SCD, a rare occurrence in MVP;[17] however, its mechanism is not clear.

The classical MVP was followed by more frequent and potentially malignant cardiac rhythm disorders compared to the nonclassical primary prolapse of the mitral valve.[32] Recently, Caselli et al. have analyzed twenty-four-hour ambulatory ECG monitoring of 188 athletes with MVP.[34] They have noted that ventricular arrhythmias, which were detected in 29% of MVP athletes, were likely an epiphenomenon of increased myocardial stress and hemodynamic load, as suggested by the larger LV and LA size, mild increase in pulmonary artery systolic pressure, and more frequent MR.[34]

NONINVASIVE IMAGING

Transthoracic echocardiography

MVP is defined by abnormal systolic bulging or “billowing” of one or both leaflets toward the LA with displacement of coaptation point into the LA (>2 mm beyond a line connecting the annular hinge point, ideally in parasternal long-axis view) [Figure 2]. The diagnosis of MVP should be avoided in the apical four-or two-chamber windows as these windows image the MV annulus along the low points of the saddle-shaped MV annulus, falsely making the leaflets appear to be displaced into the LA from the annular plane.[3536] MVP regurgitation is typically in mid-to-late systole, while functional MR is often seen during early-to-mid systole.[37] Other findings might be evaluated by transthoracic echocardiography (TTE):

Figure 2

Transthoracic echocardiography parasternal long-axis view with and without color Doppler. Mitral valve prolapse (A2 and P2 scallops) with severe mitral regurgitation

Leaflet length and thickness: normal length is 22–23 mm for the anterior leaflet and 12–13 mm for the posterior. The thickness should be calculated in the parasternal long-axis view in tele-diastole and normally is 2–3 mm. In patients with MVP, leaflets are generally elongated and thickened. “Classic MVP” is characterized by a leaflet thickening >5 mm[10]

Mitral annulus diameter: normal value is between 28 and 30 mm.[10] In patients with MVP, the annulus is usually enlarged.[10] Fukuda et al. demonstrated the basal predominance of LV dilatation and reduced contraction in MVP using 2-dimensional TTE and speckle tracking.[38] They showed that the reduction of basal wall motion was proportional to the annular dilatation but not associated with LV ejection fraction or MR volume, suggesting that annular dilatation is associated with basal LV abnormality and annuloplasty might improve the basal LV wall motion.[38] Annular dilatation is also associated with annular flattening[39] and mitral annular disjunction (MAD) [Figure 3]. The normal annulus contracts and increases in saddle-shaped planarity during systole, but in MVP annular flattening increases stress on the leaflets and chordae, which can accelerate the degenerative processes. Normally, the motion of the annulus is passively determined by contraction and relaxation of adjacent ventricular musculature and by the motion of the aortic root.[40] MAD is an anatomic abnormality of the annulus described pathologically as a wide separation between the atrium–MV junction and the LV attachment that is appreciable on both gross and histologic examination.[40] During the surgery, MAD can be detected as superior displacement or atrialization of the posterior leaflet base, and both TTE and transesophageal echocardiography (TEE) can recognize it[40414243]

Figure 3

The scheme shows mitral annular disjunction. Mitral annular disjunction is a structural abnormality of the mitral annulus fibrosus and is pathologically defined by a separation between the atrial wall-mitral valve junction and the left ventricular attachment. Mitral annular disjunction can cause hypermobility of the mitral valve apparatus and is often associated with mitral valve prolapse

MR severity: a determination of MR severity is important since mild regurgitation does not lead to remodeling of cardiac chambers and has a benign clinical course, whereas severe regurgitation is associated with significant remodeling, morbidity, and high mortality.[37] According to recent guidelines, MR evaluation is possible through color Doppler (regurgitant jet area, vena contracta, and flow convergence PISA), continuous wave Doppler, and pulsed wave Doppler.[3744] Color Doppler M-mode is useful for determine temporal variations of the extension of the proximal flow convergence region due to variations of the regurgitant orifice area throughout systole in MR depending largely on the mechanism of regurgitation: in MVP, there is a small proximal flow convergence region during early systole that increased during midsystole and reached a typical maximum in late systole.[4546] To evaluating the hemodynamics consequences of MR, the pulmonary veins flow, and the assessment of LA and LV volumes are necessary.[37] LA dilation is also an expected consequence of severe MR. A normal LA size generally excludes severe chronic MR.[37] LV and LA deformation parameters could help unmask incipient myocardial dysfunction in patients with MVP especially in those with severe MR and yet normal LVEF.[47484950]

Although his limited use for the diagnosis of MVP, on M-mode pansystolic sagging (hammocking) or late-systolic dipping of the mitral valve echo are the characteristic findings. Hammocking is affected by the position of the transducer, being induced by a high position, and masked by a low position.[3537]

A flail leaflet is part of the MVP spectrum and occurs most commonly from rupture of the marginal chords: the leaflet edge is located in the LA with free motion. A flail leaflet almost always denotes severe MR and is clearly associated with adverse outcomes.[3751]

Recently, Muthukumar et al. have described that the “Pickelhaube sign,” the high-velocity systolic signal with tissue Doppler imaging resembling a spiked helmet, was an indicator of a malignant phenotype in MVP.[52] They hypothesize that the tugging of the posteromedial papillary muscle in midsystole by the myxomatous prolapsing leaflets causes the adjacent posterobasal LV wall to be pulled sharply toward the apex, resulting in the observed spiked configuration of the lateral annular velocities.[52] It is possible that this mechanical traction is arrhythmogenic with early electrical dysfunction being recognized during electrophysiological studies even in the absence of gadolinium enhancement on CMR.[53] Table 1 shows the MVP “spectrum”.

Table 1

The table shows the mitral valve prolapse spectrum

Mitral valve prolapse spectrum

Mitral valve prolapse:  Abnormal systolic bulging of one or both leaflets towards the left atrium with displacement of coaptation point into the LA (> 2 mm beyond a line connecting the annular hinge point). Prolapse with thickening of the leaflets >5 mm is called classic prolapse, whereas prolapse with lesser degrees of leaflet thickening is regarded as non-classic prolapse

Flail leaflet prolapse  Coaptation failure with eversion of the free edge of a leaflet into the LA, usually consequent to chordal rupture, although some patients may have extreme chordal elongation without rupture. A less common pathologic lesion resulting in a flail valve prolapse is papillary muscle rupture in the setting of acute myocardial infarction

Myxomatous degeneration: “Barlow disease”  An extreme form of degenerative mitral valve disease, characterized by excess connective tissue, redundant, thickened leaflets, marked annular dilatation, elongated and thin (or thick/calcified) chordae. High likelihood of progressive disease

Fibroelastic deficiency  Associated with thin, translucent leaflets, with collagen, elastin and proteoglycans deficiency, moderate annular dilatation and focal chordal elongation or rupture.

Secondary mitral valve prolapse:  Associated to Marfan syndrome, hypertrophic cardiomyopathy, Ehlers-Danlos syndrome and other connective tissue disease.

LA=left atrium

Transesophageal echocardiography

TEE is indicated to evaluate MR severity in patients in whom TTE is inconclusive or technically difficult, to identify the localization of MVP and for planning MV surgery or percutaneous valve procedures.[37] More recently, in several studies, it has been demonstrated that three-dimensional (3D)-TEE may be more easy and accurate to identify the locations of MVP [Figure 4]. With 3D-TEE, the entire MV can be visualized in a single image, making it possible to examine both leaflets from the left atrial (surgical) perspective, and allowing more definitive identification of prolapse of individual scallops and segments.[5455] Furthermore, TEE has been used as the primary imaging modality for guiding the various steps of percutaneous catheter-based edge-to-edge mitral valve repair with a mitral clip. TEE has been shown to be essential for transseptal puncture guidance, optimal clip positioning, and assessment of the severity of MR before and after final deployment of the clip.[56] In the procedural guidance, 3D TEE has the unique ability to depict the whole scenario in which the procedure takes place in a single 3D, real-time, and easily understandable perspective [Figure 5].[56]

Figure 4

Two-dimensional transesophageal echocardiography: MVP (A2 and P2 scallops). (a-c) midesophageal views, 120°, 0°, 90°, respectively; (d) 0° and 90° midesophageal views with X-plane technique; (e) 90° midesophageal view with and without color flow; (f) transgastric view 90° with and without color flow. These images show A2 and P2 significant prolapse with severe mitral insufficiency

Figure 5

Transesophageal echocardiography: Three-dimensional presentation of mitral valve – “en-face” view: mitral valve displayed centrally with the aortic valve placed superiorly. Prolapse of P2 segment

Exercise stress echocardiography

In primary asymptomatic MR, exercise testing allows symptom assessment, confident link of symptoms to valve disease severity, safe deferral of surgery for the next 1 year in patients with preserved exercise capacity, insights into the mechanism of exercise-induced dyspnea, and helps in individual risk stratification.[57] Exercise may unmask the presence of symptoms and establish functional capacity in patients who are sedentary or have equivocal symptoms. Failure of LVEF to increase normally with exercise predicts worse postoperative LV function in primary MR.[58] Increased pulmonary artery pressure during exercise (>60 mmHg) may be important in asymptomatic severe primary MR.[3758] Furthermore, the assessment of LV contractile reserve may be useful to improve risk stratification and clinical decision-making in patients with asymptomatic primary MR and seems to be better assessed using exercise-induced changes in LV myocardial longitudinal function rather than in LVEF. In patients with preserved LV function, the absence of LV contractile reserve is independently associated with a two-fold increase in the risk of cardiac events.[59]

Cardiac magnetic resonance

Cardiac magnetic resonance (CMR) is a useful tool for the evaluation of MR severity when an assessment by echocardiography is felt to be unsatisfactory or when there is a discrepancy between MR severity and clinical findings. It has been suggested that CMR is more accurate than echocardiography in assessing organic MR severity, and the CMR-derived quantification portends outcome information.[606162] However, the long-term prognostic data associated with the MRI-derived assessment of organic MR are scarce; however, CMR should be considered in those patients when MR severity as assessed by echocardiography is influencing important clinical decisions such as the decision to undergo MR surgery in complex situations.

CMR may provide additional information about the mechanism of MR and myocardial viability, provides quantitative evaluation of chamber size, regurgitant volume, and fraction.[37] The presence of billowing, prolapse or flail segments can be identified by dedicated cine imaging performed through the different scallops of the MV leaflets [Figure 6].[37] In MVP, it is possible to detect myocardial fibrosis, the presence of the so-called “curling,” defined as an unusual systolic motion of the posterior mitral ring on the adjacent myocardium. Marra et al. have shown that MAD and systolic curling of the posterior MV leaflet are associated with LV fibrosis, accounting for the excessive mobility of the MV apparatus, and systolic stretch of the myocardium closely linked to the valve.[63] They found, in their arrhythmic MVP patients, relative hypertrophy and fibrosis of inferobasal wall at CMR, as a substrate of electric instability.[63] They showed an association between MAD, curling, and LV fibrosis. The LV fibrosis was detected by CMR in MVP patients with an arrhythmic malignant profile and confirmed by histology in SCD patients with MVP.[63] Furthermore, papillary muscle fibrosis was identified using late gadolinium enhancement in patients with MVP with a history of ventricular arrhythmias and at least moderate MR.[64]

Figure 6

Mitral valve prolapse at cardiac magnetic resonance and end-systolic four-chamber view. Evidence of bileaflet mitral valve prolapse

Cardiac multidetector computed tomography

Cardiac multidetector computed tomography has been mainly applied for the diagnosis of valvular heart morphology and function, with simultaneously evaluation of coronary artery. Few studies are available on the diagnostic accuracy for MVP using this tool.[656667] Radiation exposure and poor temporal resolution are some of the important limits of cardiac MDTC for the evaluation of MVP.

LONG-TERM OUTCOME AND TREATMENT

The outcome of MVP was controversial for a long time. Many studies reported great differences in the incidence of cardiovascular events due, above all, to heterogeneous and small studied populations. Most of them were also published to late ‘80 of the last century till early ‘00. More studies are needed to identify what patients with MVP are at risk for complications. Although MVP is generally a benign condition,[6869] complications, such as MR, atrial fibrillation, CHF, endocarditis, and stroke, are well known. Ventricular arrhythmias and SCD have been reported.[70]

The estimated rate of SCD in MVP ranges from 0.2%/years to 0.4%/years in prospective follow-up studies.[1771] LV dysfunction resulting from severe MR identifies a patient subgroup at high risk of SCD.[17] However, life-threatening ventricular arrhythmias also occur in patients with MVP with trivial or absent MR.[17] Basso et al. have shown that the patient with MVP and ventricular arrhythmias at risk of SCD is usually a young adult woman with a mid-systolic click at auscultation, bileaflet involvement of the mitral valve, T-wave abnormalities on inferior leads, and right bundle branch block-type or polymorphic ventricular arrhythmias on electrocardiogram and fibrosis of papillary muscles and inferobasal LV free wall, which correlates well with arrhythmia morphology, pointing to a myocardial stretch by the prolapsing leaflets and elongated chordae.[17]

Several studies have shown that MVP might infrequently become complicated by transient ischemic attacks that are thought to be due to platelet and fibrin embolization originating from the mitral valve especially among young patients.[7273] These studies are very dated, and the MVP diagnosis was based on single-dimensional (M-mode) echocardiographic criteria.[73] It is necessary to reconsider the previously describe associations with two- and three-dimensional echocardiographic criteria. Therefore, Gilon et al. have not demonstrated an association between the presence of MVP and acute ischemic neurologic events in young people with new echocardiographic criteria.[74] Orencia et al., in a cohort study, showed that in the absence of ischemic heart disease, CHF, and diabetes mellitus, there was no increase in the risk of stroke in MVP patient compared with the general population.[75]

Infective endocarditis (IE) is a serious condition associated with severe complications including CHF, stroke, systemic emboli, abscess formation, and death in up to 25% of patients.[76] Dated studies have suggested that patients with MVP exhibit an increased risk of IE; however, these risks have never been directly compared with the general population.[717778] Moreover, these studies were performed at a time when MVP was overdiagnosed due to imprecise echocardiographic criteria. Recently, Katan et al. have identified all adult Olmsted County residents with MVP diagnosed by echocardiography from January 1989 to December 1998 and cross-matched them with the Rochester Epidemiologic Project-identified Olmsted County cases of IE from January 1986 to December 2006 and have retrospectively analyzed and de novo confirmed each IE case using the modified Duke criteria.[79] They concluded that MVP patients with ≥ moderate mitral MR or a flail leaflet are at notable risk of developing IE compared to those without MR.[79]

A subset of patients with MVP develops CHF secondary to progressive MR.[80] Valvular lesions in MVP can worsen with time, regardless of initial clinical and echocardiographic presentation, although older age and higher initial grade of MR were associated with greater risk for progression.[81]

Treatment

According to the European Society of Cardiology (ESC), urgent surgery is indicated in patients with acute severe MR. In the case of papillary muscle rupture as the underlying disease, valve replacement is in general required. In chronic severe MR surgery is indicated in symptomatic patients with severe primary MR with LV ejection fraction (LVEF) ≥30% and in asymptomatic patients with LV dysfunction (LV diastolic diameter [LVESD] ≥45 mm and/or LVEF ≤60%/≥40 mm for the American College of Cardiology/American Heart Association).[82] Surgery should be considered in asymptomatic patients with preserved LV function (LVESD45 mm and LVEF >60%) and atrial fibrillation secondary to MR or pulmonary hypertension.[83] In patients with flail leaflet, an LVESD of 40–44 mm has been reported to predict a worse outcome compared with LVESD <40 mm, and then in these cases, surgery should be considered in asymptomatic patients with preserved LVEF (>60%) and LVESD 40–44 mm when a durable repair is likely, surgical risk is low, and the repair is performed in a heart valve center.[83] Percutaneous edge-to-edge procedure may be considered in patients with symptomatic severe primary MR who fulfill the echocardiographic criteria of eligibility and are judged inoperable or at high surgical risk by the heart team.[83] When feasible, valve repair is the preferred treatment.[83] When surgery is not possible, medical treatment (vasodilators, diuretics, and angiotensin-converting enzyme inhibitors) should be considered for the management of MR and CHF.[8284]

EXERCISE PERFORMANCE IN PATIENTS WITH MITRAL VALVE PROLAPSE

During exercise, recruitment in LV function allows to adequately adapt LV forward stroke volume and cardiac output to central and peripheral demands. In addition to chronotropic adaptation, LV improves contractility with an increase in longitudinal shortening, circumferential, and radial thickening. Patients with dynamic primary MR may have intermittent increase in MR. Hence, MR severity evaluated at rest does not correspond to MR severity experienced in daily life activities.[59]

Data on the effects of exercise on LV performance in patients with severe MR secondary to MVP are limited and dated. Moreover, previous studies of exercise responses in patients with severe MR and MVP have included heterogeneous patient populations. Tischler et al. have shown in asymptomatic patients with chronic, severe MR and normal LVEF at rest, there is an improvement in LV function and an increase in forward stroke volume during exercise. These effects are comparable to those observed in normal controls.[85] Gottdiener et al. have analyzed 39 patients with MVP and no significant MR or coronary artery disease (CAD). They observed that the exercise EF was below the lower limits of normal in 23% of the patients. They also observed that chest pain, arrhythmias, and the pattern and extent of MVP by echocardiography are not independently associated with impairment of LV reserve.[86] In the study of Newman et al., the EF response to exercise was considered normal in 12 patients with MVP and angiographically normal coronary arteries and in 11 patients with MVP and low pretest probability of CAD.[87] These studies did not explore the relationship between age and gender to the EF response to exercise. Iskandrian et al. have demonstrated that patients with MVP have an abnormal LVEF response to exercise in the absence of clinically important MR and in the absence of associated CAD. Furthermore, the abnormality in LV functional reserve is related to both age and gender.[88] More recent data have shown that organic MR due to MVP does not have the dynamic component that characterizes ischemic MR. The effective regurgitant orifice (ERO) in MVP patients was stable during exercise and is a major determinant of survival in patients with asymptomatic organic MR.[8990]

ELIGIBILITY IN COMPETITIVE SPORTS

In 2005, the American Heart Association (AHA) and the American College of Cardiology (ACC) released the following recommendations regarding athletic participation in patients with MVP:[29]

Athletes with MVP can engage in all competitive sports without any of the following features: prior syncope, judged probably to be arrhythmogenic in origin; sustained or repetitive and nonsustained supraventricular tachycardia or frequent and/or complex ventricular tachyarrhythmias on ambulatory Holter monitoring; severe MR assessed with color-flow imaging; LV systolic dysfunction (EF <50%); prior embolic event; and family history of MVP-related sudden death.

Athletes with MVP and any of the aforementioned disease features can participate in low-intensity competitive sports only (Class IA). Examples include bowling, golf, and riflery.[29] The ESC not only released similar recommendations for participation in competitive sports but also added that those with long QT interval should not engage in competitive sports.[91] All athletes with MVP should have annual follow-up with cardiology to monitor for any of the above high-risk features or progression of MR.

Beta-blockers can be used for symptom relief from premature atrial or ventricular contractions. Palpitations should be evaluated with ambulatory electrocardiographic monitoring, and the detection of ventricular tachycardia should be followed by electrophysiology testing to determine the need for an implantable cardioverter defibrillator.[91]

Athletes with MR should undergo annual evaluations, including physical examination, echocardiogram, and exercise stress testing, that simulate the amount of activity, they will be participating in.[92] In 2015, the AHA and ACC released the following recommendations regarding athletes with MR:[92]

Athletes with MR should be evaluated annually to determine whether sports participation can continue (Class I; Level of Evidence C)

Exercise testing to at least the level of activity achieved in competition and the training regimen is useful in confirming asymptomatic status in patients with MR (Class I; Level of Evidence C)

Athletes with mild-to-moderate MR who are in sinus rhythm with normal LV size and function and with normal pulmonary artery pressures can participate in all competitive sports (Class I; Level of Evidence C)

It is reasonable for athletes with moderate MR in sinus rhythm with normal LV systolic function at rest and mild LV enlargement (compatible with that which may result solely from athletic training [LVEDD <60 mm or <35 mm/m2 in men or <40 mm/m2 in women]) to participate in all competitive sports (Class IIa; Level of Evidence C)

Athletes with severe MR in sinus rhythm with normal LV systolic function at rest and mild LV enlargement (compatible with that which may result solely from athletic training [LVEDD <60 mm or <35.3 mm/m2 in men or <40 mm/m2 in women]) can participate in low-intensity and some moderate-intensity sports (Classes IA, IIA, and IB) (Class IIb; Level of Evidence C)

Athletes with MR and definite LV enlargement (LVEDD ≥65 mm or ≥35.3 mm/m2 [men] or ≥40 mm/m2 [women]), pulmonary hypertension, or any degree of LV systolic dysfunction at rest (LV ejection fraction <60% or LVESD >40 mm) should not participate in any competitive sports, with the possible exception of low-intensity Class IA sports (Class III; Level of Evidence C)

Athletes with a history of atrial fibrillation who are receiving long-term anticoagulation should not engage in sports involving any risk of bodily contact (Class III; Level of Evidence C).

These recommendations are all Level of Evidence C and reflect expert opinion. They, therefore, should be used within the context of individual cases for any discussions and shared decision-making on restriction from athletic participation. Further study is needed to elucidate the significance of mitral valve disease in athletes.[92] In evaluating the young athlete with MVP, MFS should be ruled out because the risk of aortic rupture and dissection in this syndrome represents a contraindication to competitive activities and contact sports particularly if dilation of the ascending aorta is present.[92]

In Italy since 1982, every athlete had to undergo a clinical evaluation to obtain eligibility for competitive sports.[93] The goal of preparticipation screening of the athletic population is to identify athletes who have cardiovascular abnormalities and consequently to reduce the risk of sudden death during sports activity.[93] According to these guidelines, athletes with MVP should be prohibited from participating in competitive sports if they show the following conditions:

Unexplained syncope, family history of juvenile sudden death, and long QT syndrome

Moderate-to-severe MR

Recurrent supraventricular tachyarrhythmias or complex ventricular arrhythmias at rest and/or during exercise and/or with right bundle branch block morphology[94]

Negative T waves in inferior or lateral electrocardiographic leads.[94]

A 6-month eligibility period for competitive sports activities of Groups A and B (horse riding and sailing) may be considered in athletes with mild MR with redundant or myxomatous leaflets. The above-mentioned exclusion criteria also apply when tricuspid valve prolapse coexists.[9394] Table 2 summarizes the most important eligibility criteria, according to the international societies of cardiology [Table 2].

Table 2

Criteria of competitive sport eligibility according to the most important societies of cardiology

Recommendations: No eligibility
AHA/ACC	ESC	COCIS
Prior syncope; Sustained or repetitive and non-sustained supraventricular tachycardia or frequent and/or complex ventricular tachyarrhythmias on ambulatory Holter monitoring; Severe MR; LV systolic dysfunction (EF <50%); Prior embolic event; Family history of MVP-related sudden death.	Unexplained syncope; Family history of sudden death; Complex supraventricular or ventricular arrhythmias; Long QT interval, Severe MR.	Unexplained syncope; Family history of juvenile sudden death; Long QT syndrome; Moderate-to-severe MR; Recurrent supraventricular tachyarrhythmias or complex ventricular arrhythmias at rest and/or during exercise and/or with right bundle branch block morphology; Negative T waves in inferior or lateral electrocardiographic leads.
ATHLETES WITH MVP: FOLLOW UP/ELIGIBILITY
Athletes with MR should be evaluated annually to determine whether sports participation can continue. Exercise testing is useful in confirming asymptomatic status in patients with MR (Class I; Level of Evidence C).	Annual follow-up with cardiology to monitor for any of the above high-risk features or progression of MR (physical exam, echocardiogram, and exercise stress testing that simulate the amount of activity they will be participating in).	A 6-month eligibility period for competitive sports activities of Groups A and B (horse riding, sailing) may be considered in athletes with mild MR with redundant or myxomatous leaflets. Annually for the other groups.

AHA=American Heart Association; ACC=American College of Cardiology; ESC=European Society of Cardiology; COCIS=Comitato organizzativo cardiologico per l’idoneità allo Sport; MR=mitral regurgitation; LV=left ventricle; EF=ejection fraction; MVP=mitral valve prolapse

CONCLUSIONS

MVP is usually a benign condition that does not require treatment and specific management. SCD is a rare complication, more common in patients with LV dysfunction resulting from severe MR, although recent studies have shown LV and papillary muscles fibrosis in patients with MVP and without moderate-to-severe MR. The American and European societies of cardiology have created recommendations for athletes with MVP, for screening, follow-up, assessment of cardiovascular risks, and progression of MR. In this setting, multimodality imaging techniques have a central role and should provide a broad spectrum of structural and functional information.

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Conflicts of interest

There are no conflicts of interest.