The pathology of mitral valve prolapse

 The gross criteria for diagnosing prolapsing mitral valve are: 

1. interchordal hooding of the involved leaflets, 

2. hooding or doming of leaflets towards the left atrium, 

3. elongation of the involved leaflets resulting in an increase in valve area, 

4. dilatation of the valve annulus in patients with severe mitral regurgitation. 

The posterior leaflet is most frequently affected. The involved leaflets, in general, are thickened, soft, greyish white and have a smooth atrial surface. 

Chordae tendineae are described as elongated, tortuous and attenuated or thinned. Deviations from normal chordal insertion have recently been observed which possibly appear to represent the underlying abnormality. 

Microscopic findings include significant thickening of the spongiosa and the fibrosa, changes in dense collagen fibers in the atrialis layer, occasionally, with fibrin platelet deposits. 

Histochemical characterization of changes in the spongiosa may also be helpful in the diagnosis. Ultrastructurally, there may be changes in collagen and elastic fibers as well as myxoid areas. On comparison of findings in surgically-removed mitral valves with those of control specimens from autopsy patients with no cardiac abnormalities, the length of the anterior and posterior leaflet as well as the annular ring diameter was larger in the valves with prolapse. 

Two-dimensional echocardiography accurately assessed leaflet length when compared to morphologic measurements, however, the annular diameter during systole or diastole was smaller. In patients with mitral regurgitation requiring surgery, mitral valve prolapse is the most common cause. Annular ring dilatation and chordae tendineae rupture appear to contribute substantially to incurrence of the mitral regurgitation. The heart weight is increased in the majority of patients with symptomatic mitral valve prolapse but normal, however, in those without symptoms. The most frequent complication of mitral valve prolapse is mitral regurgitation with or without congestive heart failure. Patients with redundant leaflets may be at high risk of sudden death. Young women with abnormal resting ECG, prolonged Q-T interval, family history of sudden death or complex ventricular arrhythmias may also be at a greater risk of sudden death. The incidence of infective endocarditis appears higher in those with redundant than in those with nonredundant valves. The incidence of cerebral ischemic events is low.

Mitral valve (MV) prolapse (MVP) is a common disorder, afflicting 2% to 3% of the general population. 1, 2 It is characterized by typical fibromyxomatous changes in the mitral leaflet tissue with superior displacement of 1 or both leaflets into the left atrium. 3, 4 With a prevalence of 2% to 3%, MVP is expected to affect ≈7.8 million individuals in the United States and >176 million people worldwide.

Epidemiology and Pathophysiology of Mitral Valve Prolapse.

New Insights Into Disease Progression, Genetics, and Molecular Basis.

Introduction

Mitral valve (MV) prolapse (MVP) is a common disorder, afflicting 2% to 3% of the general population. It is characterized by typical fibromyxomatous changes in the mitral leaflet tissue with superior displacement of 1 or both leaflets into the left atrium. With a prevalence of 2% to 3%, MVP is expected to affect ≈7.8 million individuals in the United States and >176 million people worldwide. MVP can be associated with significant mitral regurgitation (MR), bacterial endocarditis, congestive heart failure, and even sudden death.

MVP is a clinical entity that is not fully understood, despite being known for more than a century. A “midsystolic click” was first described in 1887 by Cuffer and Barbillon. In 1963, Barlow and Pocock9 demonstrated the presence of MR by angiography in patients with the “click-murmur” syndrome. Criley et al subsequently coined the term MVP.

MVP may be familial or sporadic. Despite being the most common cause of isolated MR requiring surgical repair, little is known about the genetic mechanisms underlying the pathogenesis and progression of MVP. Studies on the heritable features of MVP have been limited by the analysis of relatively small pedigrees and by self-referral and selection biases, including a preponderance of data from hospital-based cohorts. Nonetheless, the majority of data favor an autosomal-dominant pattern of inheritance in a large proportion of individuals with MVP. Despite the variability in clinical features, familial MVP might be considered a prevalent mendelian cardiac abnormality in humans. Although filamin-A has been identified as causing an X-linked form of MVP, the causative genes for the more common form of autosomal-dominant MVP have yet to be defined. In this review, we summarize our current knowledge of the diagnosis, epidemiology, prognosis, pathophysiology, and genetics of MVP, with a focus on potential future research directions.

Diagnosis of MVP

Physical examination and 2-dimensional (2D) echocardiography are the diagnostic gold standards for MVP.

 Various symptoms (including atypical chest pain, exertional dyspnea, palpitations, syncope, and anxiety) and clinical findings (low blood pressure, leaner build, and electrocardiographic repolarization abnormalities) have been associated with MVP, and their constellation has been called the MVP syndrome. Of the numerous reported correlates, only the association with leaner body mass has been reproducibly associated with MVP in the literature. Abnormal autonomic function has been reported as the mechanism explaining symptoms in patients with MVP, but given its absence in asymptomatic MVP patients, it remains unclear whether MVP is directly related to autonomic dysfunction or any reported association is purely incidental. Hypomagnesemia and dysregulation of the renin-angiotensin-aldosterone system have also been demonstrated in MVP syndrome, albeit in small patient samples.

The classic auscultatory finding in MVP is a dynamic, midsystolic to late systolic click frequently associated with a high-pitched, late systolic murmur. A careful physical examination is highly sensitive for making a diagnosis of MVP, but its specificity is limited (with echocardiography used as the gold standard). Redundant leaflets or chordae may produce an audible click without echocardiographic evidence of leaflet prolapse, giving false-positive physical findings. Finally, echocardiographic prolapse may exist without significant auscultatory findings. Patients with physical examination findings that suggest MVP should undergo confirmatory testing with 2D echocardiography.

In the early days of 2D echocardiography, the diagnosis of MVP occurred with a prevalence ranging from 5% to 15% and in as many as 35% of those undergoing imaging. In part, this overdiagnosis was the result of the erroneous assumption that the MV was planar; thus, any sonographic view that showed excursion of the leaflets superior to the mitral annulus was deemed pathological. Pivotal echocardiographic work in the late 1980s redefined normal mitral anatomy. Using 3-dimensional echocardiographic imaging, Levine and colleagues established that the mitral annulus was in fact saddle shaped. Therefore, in the anterior-posterior axis, the mitral annulus is concaved upward, whereas medially to laterally, the annulus is concaved downward. This mitral geometry creates the possibility that, in a sonographic 4-chamber view, the leaflets can appear to “break” the annular plane (creating the appearance of prolapse) when in reality they are normal. 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 (Figure 1A). 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.

Figure 1. Prolapse of the intermediate posterior mitral valve scallop (P2) shown in a long-axis view of (A) a 2-dimensional (2D) transthoracic echocardiogram, (B) a 2D transesophageal echocardiogram (TEE) with (C) associated severe, eccentric, anteriorly directed mitral regurgitation, and (D) a 3-dimensional TEE surgical view. AO indicates aorta; LA, left atrium; LV, left ventricle; and RV, right ventricle.

Transthoracic echocardiography (TTE) may not adequately visualize the entire MV anatomy. Anatomically, the posterior and anterior leaflets of the MV each may be divided into 3 sections. Carpentier’s widely recognized nomenclature describes 3 posterior leaflet scallops, the lateral (P1), middle (P2), and medial (P3), and 3 anterior segments, the lateral (A1), middle (A2), and medial (A3; Figure 1D). Most cases of prolapse involve the posterior middle scallop, which is easily identified on long-axis TTE images (Figure 1A). However, the posterior lateral scallop (P1) is not clearly seen on long-axis images but is best visualized in the apical 4-chamber view. As noted above, superior leaflet displacement in a 4-chamber view should not be regarded as diagnostic of prolapse. Thus, TTE can confirm the diagnosis of MVP but may not be able to exclude prolapse of all scallops. Although the Carpentier nomenclature is based on leaflet indentation, in the Duran classification, scallops are grouped on the basis of chordal attachments.

 Specifically, the anterior leaflet is divided into 2 segments (A1 and A2) and the posterior into 4 segments (P1, PM1, P2, and PM2). Segments A1, P1, and PM1 attach to the anterolateral papillary muscle, and segments A2, P2, and PM2 attach to the posteromedial papillary muscle. The modified Carpentier classification is a combination of the Carpentier and Duran nomenclatures. Although the Duran and modified Carpentier classifications are anatomically more precise than the classic Carpentier scheme, they are less widely used.

By taking into account several planes of imaging, 2D transesophageal echocardiography (TEE) is more effective in identifying prolapsing MV segments (Figure 1B). Three-dimensional TEE has the additional advantage of simulating the surgeon’s view of the MV, with the aortic valve at the 11 o’clock position (Figure 1D), and has become an essential tool in the intraoperative setting.

Cardiac magnetic resonance (CMR) represents a novel, albeit still not widely used, noninvasive imaging method that identifies MVP with a sensitivity and specificity of 100% with 2D TTE used as the gold standard (Figure 2A). In addition, CMR can quantify MR using phase-contrast velocity mapping. Because CMR can reliably provide quantitative determination of ventricular volumes and function, it is becoming an important clinical tool for following up patients with MVP-related moderate to severe MR and for surgical decision making. Finally, CMR provides novel insight into the biology of the MV and its linked myocardium through improved spatial resolution provided by 3-dimensional acquisition of images with delayed gadolinium enhancement. Such enhancement occurs when the kinetics of gadolinium excretion is different in 2 adjacent compartments so that over time 1 compartment enhances more than the other. This has been a powerful tool for delineating infarcted and scarred myocardium, which excrete gadolinium more slowly than viable tissue. The presence of gadolinium enhancement has been shown in both the MV and in papillary muscle tips in patients with MVP but not in normal control subjects (Figure 2B). It has been speculated that the papillary muscle is altered in MVP by repetitive traction exerted by the prolapsing leaflets, which has been shown experimentally to lower the threshold for arrhythmias. Although more frequent complex arrhythmia on 24-hour ambulatory Holter monitor has been demonstrated in MVP patients with scarring of the papillary muscles, its clinical significance remains to be established.

Figure 2. Cardiac magnetic resonance steady state free processing long-axis view of bileaflet mitral valve prolapse (A). Short-axis view with 3-dimensional late-gadolinium enhancement (3D-LGE) showing fibrosis of the papillary muscle tips. Adapted from Han et al with permission from the publisher. Copyright © 2008 Elsevier B.V. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

Clinical Classification and Prevalence of MVP

MVP can be distinguished into primary or nonsyndromic MVP and secondary or syndromic MVP. In the latter case, MVP occurs 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. MVP has also been observed in hypertrophic cardiomyopathy (HCM) and may contribute to the pathophysiology of obstruction typical of this myopathy.

Nonsyndromic MVP

Based on revised echocardiographic diagnostic criteria, the prevalence of MVP and its clinical associations were examined in the community-based Framingham Heart Study (FHS). The sample analyzed consisted of 3491 participants in whom routine 2D echocardiograms were available and adequate for the evaluation of the MV. Forty-seven individuals (1.3%) had classic and 37 (1.1%) had nonclassic MVP, yielding an estimated overall prevalence of 2.4%. The prevalence of MVP was distributed fairly evenly among individuals in each decade of age from 30 to 80 years of age. With respect to sex, MVP was equally distributed between men and women. These findings differed from older studies based on M-mode diagnostic criteria or observations of pedigrees that reported that MVP preferentially afflicted women and older individuals. Although the genetic predisposition to develop MVP may be present at birth, MVP is not found in newborns, and its prevalence is low among children (0.3%) and young adults (0.6%). These findings suggest that MVP is a progressive disease affecting predominantly middle-aged individuals. Participants with MVP in FHS were leaner compared with those without MVP. An important limitation of the FHS sample is that it is predominantly white. A similar prevalence of MVP was described in a population-based sample of American Indians (the Strong Heart Study), and in a different sample of Canadians of South Asian, European, and Chinese descent (the SHARE study). Although these recent studies were based on revised echocardiographic criteria, the prevalence of MVP in blacks was based on older M-mode criteria and nonstandard 2D echocardiographic views. A systematic review of the published literature did not reveal prior studies that have evaluated the prevalence of MVP in Hispanic samples.

Tricuspid valve prolapse has been observed in up to 40% to 50% of patients with primary or nonsyndromic MVP, but isolated tricuspid prolapse has rarely been reported.

Syndromic MVP: MFS and Other Connective Tissue Disorders

The prevalence of at least mild MV pathology in MFS has been estimated to be ≈75%, whereas the prevalence of more severe myxomatous MV thickening with prolapse is closer to 25% in these individuals. The prevalence of MVP in patients with Ehlers-Danlos syndrome using standard echocardiographic criteria appears to be much lower (6%). The prevalence of MV disease also appears to be lower in patients with the Loeys-Dietz syndrome (relative to MFS). One group reported a direct comparison of MVP prevalence in 71 individuals with transforming growth factor-β (TGF-β) receptor 2 (TGFBR2) mutations (characteristic of Loeys-Dietz syndrome) with that in 243 people with fibrillin-1 (FBN1) mutations (typical of MFS) and in 50 unaffected family members. The investigators observed a substantially higher prevalence of both MVP and MR in the cohort with FBN1 mutations than in the group with TGFBR2 mutations (45% and 56% versus 21% and 35%, respectively). Among affected individuals with the aneurysms-osteoarthritis syndrome, MV abnormalities were common and ranged from mild to severe; 10 of 22 (45%) had MVP and 6 of 22 (27%) had MR. The presence of MVP has also been described in osteogenesis imperfecta and pseudoxanthoma elasticum although the true prevalence of the disease is unclear because standard diagnostic criteria were not used in the initial imaging studies performed on these patients.

Hypertrophic Cardiomyopathy

The largest study assessing the prevalence of MVP in HCM observed it in 3% (of 528 people with HCM), which might suggest that HCM and MVP are 2 distinct conditions that may coexist in some cases. However, the prevalence of other MV abnormalities (leaflet elongation and increased thickness) is much higher in HCM, estimated at 66% in 1 study. This suggests that MV abnormalities are intrinsic to HCM, either as a primary trait or as a secondary adaptive response to shear stress in a turbulent outflow tract or paracrine effects arising in the adjacent hypertrophic ventricle (see below).

Prognosis of MVP

A Controversial Past

The prognosis of MVP has varied in the published literature. In the community-based FHS sample, MVP was described as a benign entity with a low occurrence of adverse sequelae. Specifically, none of the individuals with MVP had a history of heart failure, 1 patient (1.2%) had atrial fibrillation, 1 patient (1.2%) had cerebrovascular disease, and 3 patients (3.6%) had syncope. The prevalence of these outcomes in the subjects without prolapse was 0.7%, 1.7%, 1.5%, and 3.0%, respectively. The frequencies of chest pain, dyspnea, and electrocardiographic abnormalities were similar among individuals with and without MVP. Individuals with MVP had a greater degree of MR than those without prolapse, but typically the valvular regurgitation was classified as trace or mild. In prior studies, MVP was portrayed as a disease with frequent and serious complications, including stroke, atrial fibrillation, heart failure, and MR requiring surgery. These discrepancies may be due to selection biases inherent in evaluating symptomatic patients at referral tertiary care centers compared with observations made on healthier asymptomatic volunteers. Changes in diagnostic criteria for MVP over time may have further exacerbated these differences in the prevalence of MVP. Subsequently, a community-based study from the Mayo Clinic conducted in a primary care setting has underscored the clinical heterogeneity of MVP, including a widely varying prognostic spectrum. Based on primary (depressed left ventricular ejection fraction, moderate/severe MR) and secondary (age >50 years, mild MR, left atrial enlargement, atrial fibrillation, and flail leaflet) risk factors, different groups of MVP with varying prognoses were identified with regard to cardiovascular morbidity and mortality. Overall, young (<50 years of age), medically treated patients presenting with normal left ventricular function and no symptoms have excellent survival, even with severe MR. The benefit of early surgery (ie, valve repair in asymptomatic patients) versus a watchful wait was suggested in observational studies but remains controversial.

Impact of MR

The common denominator of the studies evaluating prognosis of MVP is the role of MR at the time of diagnosis in determining the risk for adverse events (such as congestive heart failure, atrial fibrillation, ischemic neurological event, and endocarditis) and the need for surgery on follow-up. The Mayo Clinic series highlighted that over a follow-up period of 1.5 years, MR volume increased >8 mL in 51% of 74 individuals with MVP. In this clinical series, the progression of the valvular lesion (particularly a new flail leaflet) and an increase in the mitral annular diameter were the 2 independent predictors of an increase in the regurgitant volume over time. Although mitral leaflet thickness >5 mm on M-mode echocardiography has been associated with increased risk for sudden death, endocarditis, and MR in patients with classic prolapse in some series, a more recent larger series using 2D echocardiography reported that mitral leaflet thickness was not an independent predictor of mortality and valvular morbidity. In this community-based study of 833 individuals diagnosed with asymptomatic MVP and followed up longitudinally in Olmsted County, cardiac mortality was best predicted by the presence of MR and left ventricular dysfunction at the time of diagnosis. Risk factors for cardiac morbidity (defined as the occurrence of heart failure, thromboembolic events, endocarditis, atrial fibrillation, and need for cardiac surgery) included age ≥50 years, left atrial enlargement, MR, the presence of a flail leaflet, and prevalent atrial fibrillation at the time of the baseline echocardiogram.

Impact of a Flail Leaflet

The presence of a flail MV leaflet has been associated with a widely varying prognosis Survival in medically treated asymptomatic patients with MVP presenting with a flail leaflet and normal left ventricular function is excellent. Thus, such patients are at relatively low risk of cardiovascular morbidity. The indications for valve surgery in this group include the development of atrial fibrillation (4%/y) and heart failure (5.7%/y). Older age, the presence of symptoms, and a left ventricular ejection fraction <60% at the time of initial diagnosis increase the risk of developing heart failure and atrial fibrillation and are markers of the need for valve surgery and mortality. As for chronic severe MR in general, management decisions for patients with flail leaflet are based largely on the presence or absence of clinical symptoms, the functional state of the left ventricle, and the feasibility of successful MV repair.

Sex-Related Differences in Outcomes

As noted, the prevalence of MVP was similar in the 2 sexes in the FHS, a referral-free, community-based sample. Conversely, in the Olmsted County population, characterized by a mixed spectrum of community-dwelling and referred patients, with the use of similar echocardiographic criteria, women were diagnosed with MVP more often than men and at a younger age. However, complications (such as the development of a flail leaflet) have been reported more frequently in men. The Mayo Clinic group also underscored the anatomic and functional differences between the 2 sexes in the context of MVP. Women present with more anterior and bileaflet prolapse, more thickened leaflets, fewer flail leaflets, and less MR compared with men. These milder clinical features in women have led to the speculation that an interplay may exist between loading conditions on the valve (such as higher blood pressure in men) and the development of complications in MVP. However, women represent a large proportion of patients with moderate or severe MR. In these severe forms, the assessment of left ventricular enlargement in women is challenged by the differences in weight and height between the 2 sexes and the frequent use of an absolute rather than a body size–adjusted left ventricular size measurement. Consequently, for the same degree of MR, women undergo mitral surgery less frequently and later than men. As a consequence, women exhibit excess long-term mortality but equivalent survival after valve surgery compared with men. Thus, there are important sex-related differences in the morphology, presentation, and prognosis of MVP.

Pathology and Pathophysiology

Myxomatous Valve Degeneration

MVP is characterized by progressive increases in the area and length of the MV tissue and typically progresses with a natural history spanning decades, causing leaflets to thicken anatomically and prolapse superiorly into the left atrium beyond the mitral annulus in systole, leading to MR (Figure 1C). Histologically, the mitral leaflets in MVP are characterized by myxomatous degeneration. A detailed explanation of myxomatous changes requires an understanding of the histology and the development of the normal MV.

Normal MV Histology and Alterations in MVP

The extracellular matrix (ECM) constitutes the fibroskeleton of a normal MV. Normal valve tissue is divided into 3 layers: the atrialis on the atrial side; the spongiosa, which is the middle layer; and the fibrosa on the ventricular side (Figure 3). The atrialis, a dense sheet of elastic fibers, provides elasticity to the valve leaflet. The spongiosa is rich in glycosaminoglycans and proteoglycans within a fine, interweaving, spongy elastin network. It functions to resist compression between the outer layers, gives flexibility to the valve leaflet, and dampens the vibrations resulting from valve closure. The fibrosa, which is the thickest part of the leaflet, is made up primarily of organized collagen fibers that give the valve its tensile strength.