INTRODUCTION
Mitral valve prolapse (MVP) is a common cardiac valvular disorder occurring in 1.2%–3% of the general population. The characteristics of mid-systolic click were already described in 1887 by Cuffer and Barbillon [1]. In 1936, Barlow further attributed the physical finding to the mitral valve-chordal origin, describing mitral insufficiency in these patients [2]. The prolapse, as a distinct syndrome, was later described using surgical and autopsy specimens [3], and since then, it has remained a clinical and scientific challenge.
MVP has at least two histological types. The first MVP is caused by fibromyxomatous changes in the valve leaflets characterized by alterations in collagen organization and an increase in glycosaminoglycans causing thickening of the leaflets. This gives the valve the pathological appearance designated “myxomatous degeneration”. The second, termed fibroelastic deficiency, is more prevalent in elderly people and is characterized by thickening of the spongiosa and accumulation of collagen [4]. These changes lead to biomechanically impaired leaflets, resulting in redundancy and prolapse into the left atrium (Figure 1) [5, 6]. This further creates abnormal strain on the chordae, which may lead to rupture and worsen the regurgitation.
ETIOLOGY
MVP genetics
MVP can be classified as sporadic (isolated cardiac presentation), familial or syndromic. Syndromic MVP, also referred to as secondary MVP, is the presence of MVP and other known disorders, most commonly, a connective tissue disease. The prominent related syndromes include Marfan syndrome [7], Loeys–Dietz syndrome, Ehlers–Danlos syndrome, and osteogenesis imperfecta, among others [8]. A summary of the main syndromes is presented in Table 1.
|
Genes |
Gene’s function |
Presence of MVP |
Inheritance mode |
Main features |
|
|
Marfan syndrome |
FBN1 |
Structural component in the extracellular matrix |
40%–80% |
AD |
MVP is one of the diagnostic criteria |
|
Loeys–Dietz syndrome |
TGF-β receptor 1 (TGFBR1); TGFBR2; SMAD3; TGFB2; TGFB3 |
TGF-β singling — well-established pathway for connective tissue disorders |
25% |
AD/AR |
Lower rate of MVP in comparison to FBN1 |
|
Ehlers–Danlos syndrome |
COL5A1 or COL5A2 or COL1A1 and TNXB |
Connective tissue components |
AD |
Mainly vascular phenotype, MVP in ~6% |
|
|
Williams–Beuren syndrome |
ELN |
Encode major structural protein involved in organization of vascular smooth muscle |
6% |
AD |
Cardiac phenotype includes supravalvular and pulmonary stenosis (45%–75%) and MVP (6%) |
|
Osteogenesis imperfecta |
COL1A1, COL1A2, CRTAP, and P3H1 |
Proteins involved in the extracellular matrix of connective tissues |
5.4% |
AD |
Cardiac phenotype includes aortic root dilatation and aortic valve abnormalities |
|
Trisomies |
Trisomies in chromosomes 18, 13, and 15 |
Most cases are sporadic |
Sever global phenotype (including growth retardation and cognitive impairment) |
||
|
Stickler syndrome |
COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3 |
Proteins involved in the extracellular matrix of connective tissues |
4% |
AD/AR |
Familial MVP is diagnosed whenever MVP is present as an isolated malformation in a first-degree relative. About 35%–50% of MVP cases are familial, suggesting a strong genetic component in its etiology. The prevalence of MVP among first-degree relatives is higher than in the general population and is estimated at 5%–20%. Familial studies of non-syndromic MVP suggest an autosomal dominant mode of inheritance with incomplete and age-dependent penetrance [9–12].
Genes that are associated with non-syndromic MVP are detailed in Table 2. The first genetic mutation for non-syndromic MVP has been successfully linked to FLNA (filamin A mutations) in the family with X-linked inheritance [13]. The FLNA gene encodes an actin-binding protein that crosslinks actin filaments and links them to membrane glycoproteins. Later on, mutations in the DCHS1 gene were also identified as causing MVP [14]. DCHS1 is a member of the cadherin superfamily that encodes calcium-dependent cell-cell adhesion molecules. Using zebrafish and mouse models, it has been demonstrated that mutated valves exhibit abnormal planar cell polarity architecture in the valve matrix resulting in myxomatous degeneration and prolapse. Six loci reached genome-wide statistical significance in a genome-wide association study (GWAS) of 1412 MVP cases and 2439 controls. Through functional analysis, clinical importance was demonstrated for two genes: LMCD1 (LIM and cysteine-rich) and TNS1 (tensin1) by altered valve phenotype in zebrafish. A recent study found that mutations in the DZIP (DAZ interacting zinc finger protein 1) gene, involved in primary cilia formation, can cause MVP. Combining analyses of mitral valve development in mice with human genetic data suggested that MVP can be caused by abnormal cilia function [15]. Recent studies have also found epigenetics involvement in the pathogenesis of MVP [16], such as evidence from in vivo and in vitro studies demonstrating a regulatory role for microRNAs (miRNAs) [17]. While these genetic findings point out potential mechanisms for myxomatous degeneration, they currently lack clinical implications.
|
Gene |
Gene function |
Genetic approach |
|
DCHS1 |
Member of the cadherin superfamily that encodes calcium-dependent cell-cell adhesion molecules |
Familial segregation study |
|
FLNA |
Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins |
Familial segregation study |
|
TNS1 |
Encodes for tensin 1, actin-binding protein |
GWAS |
|
LMCD1 |
Transcription factor repressor of GATA6 |
GWAS |
|
DZIP |
Role in primary cilium formation |
Familial segregation study |
|
LMCD1, NMB, and ALPK3 |
Known to be involved in cardiomyopathies |
GWAS |
|
LTBP2, TGFB2, |
Encodes an extracellular matrix protein involved in regulation of TGF-β signaling. LTBP2 is associated with connective tissue disorders |
|
|
SPTBN1 |
Encodes β2-spectrin, a scaffold protein that connects the actin cytoskeleton to the plasma membrane |
Structural mechanisms
The mitral valve annulus has a characteristic saddle-shaped shape, with high anterior and posterior points and concave leaflets toward the left ventricle in the zone of coaptation. This determines the anatomical definition of MVP in which prolapse is defined when the leaflet or leaflets prolapse into the left atrium above the line connecting the two annular high points [6]. The practical aspect of this is that prolapse can only be safely diagnosed by echocardiography (such as in parasternal long-axis view on echocardiography) whenever both high points are in the image plane.
It has been suggested that structural and functional remodeling, as shown by cardiac magnetic resonance, may lead to early focal or diffuse fibrosis of the papillary muscles, which play a role in reentry circuits, leading to a high-risk MVP phenotype [18].
CLINICAL SIGNIFICANCE
MVP is a progressive disease, found with increased rates and severity with age [19]. It has a broad spectrum of clinical presentations, from silent disease to severe cardiac events. While incorrectly considered by many a benign condition, it often manifests from the fourth to sixth decades of life as a severe cardiac event [9]. Clinical symptoms may include atypical chest pain, exertional dyspnea, palpitations, and the classical sign is mid-systolic click. MVP is the most common cause of isolated mitral regurgitation requiring surgical repair. The lifelong serious adverse complication rate for MVP is 30% [20, 21]. MVP often results in mitral regurgitation, which can lead to cardiac chamber dilation, arrhythmias, bacterial endocarditis, and congestive heart failure [22].
Importantly, MVP has recently been recognized as a common cause of arrhythmias, including sudden cardiac death (SCD). This life-threatening phenotype is referred to as “arrhythmogenic” or “malignant” MVP [23], and its exact prevalence is unclear [24, 25]. In our preliminary results, 9.4% of the MVP families had a history of SCD (unpublished data). The risk of SCD in MVP is estimated to be 3-fold higher than in the general population (0.1% per year) [26]. Four percent of SCDs among young athletes are attributed to MVP [27]. Arrhythmogenic MVP has been associated with abnormalities of T-waves, which can be a result of the endocardial and mid-myocardial changes of the papillary muscles or the left ventricle [24]. Other factors include bileaflet involvement, polymorphic inferiorly triggering ventricular premature beats, mitral annular disjunction, Pickelhaube sign on tissue Doppler tracing of the mitral annulus, and female sex [28]. Mitral annulus disjunction (MAD) is an abnormal atrial displacement of the posterior mitral leaflet hinge point. This creates a separation of the mitral valve annulus-left atrial wall. Although MAD is a common finding in MVP and could also be found in normal hearts, it has recently been associated with ventricular arrhythmias and SCD [29]. Few studies have also evaluated the effect of the MAD length, suggesting a cut-off value of 6–8.5 mm on transthoracic echocardiography (TTE) for the predication of arrhythmia [30]. Pickelhaube sign is a high-velocity (usually >16 cm/s) mid-systolic spike in the tissue Doppler velocity profile of the mitral valve annulus in patients with bileaflet MVP.
The high morbidity of MVP leads to a significant economic burden for both the patient and the healthcare system. The annual hospitalization cost for treating mitral regurgitation in France only was €292 million, including surgical and non-surgical cases [31]. The yearly cost for surgical interventions only was estimated at €80 million.
Due to the described variability, further studies to develop a risk-stratification model for MVP are pertinent. This will allow personalized treatment that could address individual risks for adverse outcomes, saving unnecessary interventions.
DIAGNOSIS
The classic physical auscultatory findings of mid-systolic clicks and/or late systolic murmurs are associated with MVP but are not sufficient for diagnosis.
The first-line and most commonly used imaging modality for MVP is TTE. The seminal work by Robert Levine on the saddle shape of the mitral valve annulus informed the definition of MVP in the American Society of Echocardiography guidelines as displacement of 2 mm or more of the valve leaflets above the annular line in the long-axis view during systole (Figure 1A). The European Society of Cardiology (ESC) guidelines refer to the superior displacement of the mitral valve coaptation point relative to the annulus [32, 33].
Transthoracic echocardiography is also the gold standard for assessing the grade of MR severity. Transesophageal echocardiography can define the abnormal position of the mitral leaflets to their surrounding structures based on specific and validated criteria (Figure 1B), and can further delineate MAD. Three-dimensional echocardiographic studies [5, 6] have significantly increased the specificity of diagnostic criteria for MVP.
In recent years, the role of structural imaging is becoming significant as it has the potential to identify patients at risk of complications. Risk features for arrhythmia include thickened leaflets, fibrosis of the papillary muscles and inferobasal wall, and MAD as described above. These may be used for early detection of arrhythmias allowing for appropriate preventative intervention.
Cardiac magnetic resonance for MVP evaluation is currently gaining popularity. It can facilitate diagnosis [34], and with the use of gadolinium, it can offer benefits in better characterizing the tissue, for example detecting myocardial and papillary muscle fibrosis and defining its pattern (macro or diffuse fibrosis). Cardiac magnetic resonance is the gold standard for left ventricular and right ventricular volumetric assessment and can accurately measure regurgitant volume and fraction.
MANAGEMENT
Currently, our arsenal for the management of MVP is mostly surgical. While it is customary to treat MVP with after-load reduction with medications such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, none of the pharmacologic treatments for MVP have ever been shown efficacious in slowing disease progression. The only treatments for MVP that are thought to be efficacious are surgical and thus palliative. The goal of surgical intervention for MVP is to relieve papillary muscle stretching and facilitate ventricular remodeling, which aims to reduce ventricular arrhythmias. The options include mitral valve repair or replacement, with continuous debate in the literature regarding the best method. These interventions carry a significant complication rate and up to 6.5% mortality rate in one study.
For arrhythmic events prevention and treatment, beta-blockers are the first-choice treatment for symptomatic or asymptomatic patients with non-sustained or sustained ventricular arrhythmias. However, high-risk features such as ventricular arrhythmias, hypercontractility, and fibrosis may prompt further electrophysiologic study investigations [23]. Some authors have considered ablation protocols to relieve the arrhythmia burden with high procedural success, although recurrence of ventricular arrhythmia was not uncommon [35].
Interestingly, higher levels of soluble suppression of tumorigenicity-2 serum levels were associated with MAD and ventricular arrhythmias. This biomarker was suggested to indicate myocardial stretch. It may have a potential in arrhythmogenic MVP diagnosis: the prolapsing leaflets in MVP lead to stretching of the papillary muscles and adjacent myocardium, which has been associated with ventricular arrhythmias.
One of the key questions in treating MVP is whether pharmacological interventions are effective in preventing complications, particularly given that MVP is seen as a structural disease. Recent advances in genetic and molecular techniques may enable the identification of genetic mechanisms leading to preventive treatment that reduces disease complications. Marfan syndrome is characterized by a high prevalence of mitral valve myxomatous degeneration leading to MVP [36]. Mice with a missense mutation in Fbn1 are known to phenocopy Marfan syndrome. In one study, both heterozygous and homozygous mice with a fully expressed missense mutation in Fbn1 were compared to wild-type mice. Adult heterozygous mutant mice were shown to have MVP by high-resolution echocardiography. Treatment with a TGFβ-neutralizing antibody successfully normalized morphologic characteristics of myxomatous degeneration in both the length and the thickness of the mitral valve leaflets [37]. These data suggest that in the future medical treatment will be used to modify disease progression.
Cascade screening
The familial presentation of MVP raises the question of “cascade screening” for first-degree relatives of the MVP index case. Cascade screening refers to the common practice of identifying individuals at risk of a genetic condition through the process of systematic screening. It is a common practice for MVP in many centers but has yet to be recommended in guidelines. There are several accepted criteria for screening methods, including clinical significance, cost-effectiveness, test acceptability, and options for early treatment. Screening for MVP by echocardiography is a simple procedure that does not involve risk for the patient or radiation exposure as in other imaging modalities. It has the benefit of detecting MVP or associated pathologies at an early stage. This allows appropriate follow-up and timely intervention. On the other hand, the emotional burden on the patient and his family should also be considered. Cost-effective data is also lacking in this preliminary stage for systematic screening implantation.
CONCLUSIONS
MVP clinical variability poses a great challenge to clinicians who aim to identify high-risk cases at an early stage. In addition to the basic thorough anamnestic, clinical, and echocardiographic examination, a deeper understanding of the disease development and mechanism may be achieved through combining information about genetics, structural features on advanced imaging, and electrophysiological characteristics.
Article information
Conflict of interest: None declared.
Funding: None.
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