2.1. Search Strategy

A comprehensive search of all echocardiographic studies estimating MVP prevalence in various cohorts of individuals, regardless of the time period, was carried out by two independent reviewers (A.S. and M.L.) through August 2024 by using Medline and EMBASE databases. The search strategy included the following terms: “mitral valve prolapse” OR “MVP” AND “prevalence” AND “cardiac function” AND “echocardiography” OR “M-mode echocardiography” OR “two-dimensional (2D) echocardiography” OR “three-dimensional (3D) echocardiography”. The search was limited to full-text articles published in English.

2.2. Eligibility Criteria

All echocardiographic studies evaluating MVP prevalence in various cohorts of individuals, regardless of the time period, were included. Conversely, imaging studies conducted on MVP individuals that did not analyze MVP prevalence, non-clinical articles, animal studies, duplicate articles, case reports, conference presentations, reviews, correspondences, editorials, letters without data, and abstracts, were excluded.

2.3. Study Selection and Data Extraction

Two reviewers (A.S. and M.L.) screened the databases according to the inclusion criteria and performed data extraction independently. The following information concerning MVP individuals was independently collected by the two reviewers: (1) demographics (age and sex); (2) anthropometrics [waist-to-hip ratio (WHR), body mass index (BMI), and eventual chest shape abnormalities, such as straight back syndrome (SBS) and pectus excavatum (PE), or inherited connective tissue disorder, such as Marfan Syndrome (MFS), asssociated with MVP]; (3) the prevalence of the most common cardiovascular risk factors (hypertension, smoking, type 2 diabetes mellitus, and dyslipidemia); (4) auscultatory findings (mid-systolic click and/or late systolic murmur) and hemodynamics (heart rate, systolic and diastolic blood pressure); (5) subjective symptoms, such as chest pain, palpitations, dyspnea, and/or syncope; (6) electrocardiographic (ECG) findings, particularly ST-T-wave abnormalities in inferior leads, ventricular premature beats (VPBs), atrial premature beats (APBs), and/or atrial fibrillation (AF); (7) left ventricular (LV) internal dimensions, LV systolic and diastolic function, and left atrial (LA) size assessed by 2D-TTE; (8) MVP prevalence in each study group; (9) complications associated with MVP, including arrhythmias, MR, IE, HF, and sudden cardiac death; (10) concomitant valvulopathies; (11) current medical treatment; and (12) follow-up data (if any). A third author (G.L.N.) checked the extracted data for accuracy and resolved possible discrepancies between reviewers.

4.2. Possible Explanations for the Divergent Findings between the Studies Performed before and after the Year 1999

The true prevalence of MVP in the general population may have been systematically overestimated by the older echocardiographic studies performed before the year 1999 due to a number of technical issues. First, these studies were subject to selection bias in the cohorts of participants evaluated. Indeed, the studies that reported higher prevalences of this disorder included volunteers who were concerned about their cardiac status because of affected family members, who had a history of heart murmur or subtle symptoms, and who were well known to the examining physician [17,18,20]. Moreover, the high frequency of complications associated with MVP, such as severe MR, IE, and stroke, was generally described in patients selected from large clinics or hospital practices rather than from the general population [25]. Therefore, the high prevalence of MVP in such studies is likely not reflective of the real prevalence of this disorder in the general community.

Another major reason for the overestimation of the true prevalence of MVP in older studies can be attributed to the use of poorly defined M-mode and 2D-echocardiographic diagnostic criteria. With regard to M-mode echocardiography, several false positive diagnoses of MVP could be related to the inherent spatial limitations of this technique in representing the mitral valve leaflets, mitral annulus, and left atrium simultaneously; indeed, several artifacts may occur in M-mode echocardiography when the transducer is not perpendicular to the valve leaflets but has a high or low position relative to the mitral valve [38]. Therefore, the results of M-mode echocardiography vary widely depending on the orientation of the transducer [39]. Moreover, an inconsistent correlation of the M-mode echocardiographic pattern with auscultatory findings or clinical symptoms of MVP has been repeatedly reported [12,24,26].

The older 2D-echocardiographic studies evaluating MVP prevalence did not consider the saddle-like shape of the mitral annulus and used nonspecific 2D-echocardiographic criteria, including displacement of the anterior leaflet in the apical four-chamber view, to diagnose MVP. Studies describing the three-dimensional shape of the mitral annulus [9,10] have allowed for the refining of the 2D-echocardiographic criteria. Based on the saddle-shaped configuration of the mitral annulus, leaflets can appear to ascend above the mitral annulus in the apical four-chamber view without actual leaflet displacement above the high points of the annulus contained in the long-axis view [9,10,13] (Figure 2).

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Figure 2

An example of superior anterior mitral leaflet displacement in the apical four-chamber view (panel (A)), absent in the parasternal long-axis view (panel (B)), accepted as the diagnostic standard of mitral valve prolapse before the year 1999. The red line indicates the mitral annular plane in each of the two orthogonal views. Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Eliminating the use of the apical four-chamber view reduces false positive diagnoses [13]. According to the more specific 2D-echocardiographic criteria, MVP is actually defined as the systolic displacement of one or both mitral leaflets > 2 mm above the mitral annulus plane, visualized from the parasternal long-axis view [12] (Figure 3).

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Figure 3

Transthoracic echocardiography. Parasternal long-axis view showing the systolic billowing of both mitral leaflets > 2 mm above the mitral annulus plane, compatible with bileaflet MVP. The red line indicates the plane of the mitral annulus. Ao, aorta; LA, left atrium; LV, left ventricle; MVP, mitral valve prolapse; RV, right ventricle.

The increased prevalence of MVP among healthy young adult females reported by the older studies was likely related to both selection bias and the use of poorly defined M-mode and/or 2D-echocardiographic criteria for MVP adopted by these studies. Similarly, the high frequency of complications associated with MVP described before the year 1999 [1,2,3,4] could be ascribed to the improper selection of cohorts of individuals referred to large hospital centers for complications under investigation.

4.3. Implications for Clinical Practice

The echocardiographic detection of MVP should be specifically focused on individuals who are tall and lean, with a low BMI and WHR, and with various degrees of anterior chest wall deformity. In this regard, it is noteworthy that MVP is commonly associated with several thoracic skeletal abnormalities (TSAs), such as PE, pectus carinatum, scoliosis, SBS, and connective tissue disorders, such as MFS [40]. These TSAs may be encountered in clinical practice more frequently than commonly expected, particularly in their forms of minor severity. The objective evidence of a concave-shaped chest wall in an individual who is tall and thin may indicate the clinical suspicion of MVP, especially in the presence of frequent isolated VPBs and nonspecific ST-T-wave abnormalities in inferior leads on resting ECGs. The MHI represents a simple and noninvasive method to quantify the degree of anterior chest wall deformity. It is obtained by dividing the latero-lateral maximum external thoracic diameter by the A-P minor internal thoracic diameter, without using CXR, thus avoiding exposure to ionizing radiation (Figure 4).

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Figure 4

An example of modified Haller index assessment in an individual with mitral valve prolapse. Panel (A): The L-L thoracic diameter, measured with the individual in the standing position and with open arms, using a rigid ruler in centimeters coupled to a level (the measuring device) placed at the distal third of the sternum at the point of maximum depression of the sternum. Panel (B): The A-P thoracic diameter, obtained with the individual in the left-lateral decubitus position during conventional transthoracic echocardiography by placing a 2.5 mHz transducer near the sternum in the left third or fourth intercostal space to obtain a parasternal long-axis view, and measuring the distance between the true apex of the sector and the anterior surface of the vertebral body. The vertebral body is identified by using, as a reference point, the posterior wall of the descending thoracic aorta, visualized behind the left atrium. Ao, aorta; A-P, antero-posterior; Asc, ascending; Desc, descending; LA; left atrium; L-L, latero-lateral; LV, left ventricle; RV, right ventricle.

MVP individuals are generally diagnosed with an MHI > 2.5 due to a narrow A-P thoracic diameter (generally <13.5 cm) [41]. Both MVP and anterior chest wall deformity may have a common developmental origin, since the primordia of the mitral valve undergo differentiation to their final form around the 5th to 6th week of gestation, the same period during which the vertebral column and the thoracic cage start their chondrification and ossification. A defect in growth patterns at this stage of development might affect both the mitral valve and the bony thorax [42,43]. The narrow A-P thoracic diameter may explain the reduced LV internal dimensions detected in several MVP individuals and, most of all, the frequent occurrence of arrhythmias detected in such individuals. Indeed, the basal sternal compression continuously exerted on cardiac chambers may have a preponderant role in generating mitral annular distortion and MVP, with consequent abnormal traction on papillary muscle tips and increased occurrence of both VPBs and symptoms, such as palpitations, atypical chest pain, and dyspnea. In addition, it is not uncommon to detect wall motion abnormalities in MVP individuals on both resting 2D-TTE and ESE. A careful evaluation of these myocardial asynergies may allow them to be considered more properly as areas of intra- and/or inter-ventricular dyssynchrony due to modified heart motion, cardiac rotation, and tilting, rather than areas of hypokinesia or akinesia due to myocardial ischemia. The dyssynchronous cardiac motion within a narrow A-P thoracic diameter may be enhanced by physical exercise, in the absence of obstructive CAD [44,45]. This mechanical theory is supported by the evidence of a weak association between MVP and CAD [12,46,47].

The studies included in this systematic review have also highlighted that the MR associated with MVP is generally mild or mild-to-moderate, and is rarely severe. MR severity may be overestimated by 2D-TTE, particularly in MVP individuals with a concave-shaped chest wall, due to the small size of all cardiac chambers, mostly the left atrium as the receiving chamber [48]. In MVP individuals, jets are often very eccentric, and poor alignment with an eccentric jet may lead to overestimation of both the vena contract and the effective regurgitant orifice area, especially when the left atrial size is small [49,50].

From a clinical viewpoint, in the presence of nonspecific ST-T-wave abnormalities on ECG, atypical chest pain, and mild-to-moderate MR due to MVP on 2D-TTE, ESE could be particularly useful for excluding obstructive CAD and for evaluating the impact of MR on pulmonary hemodynamics. As detected by our study group in a large cohort of individuals referred to perform ESE for suspected CAD [51], a preliminary chest shape assessment by the MHI method together with pre-test probability estimation might help clinicians to identify, among MVP individuals, those with a lower probability of exercise-induced myocardial ischemia and with an increased probability of non-hemodynamically significant MR.

4.4. Syndromic Mitral Valve Prolapse

In the majority of cases, MVP is isolated and not associated with other conditions. However, MVP can also be seen as part of connective tissue disorders, such as Marfan syndrome (MFS), Loeys–Dietz syndrome (LDS), Ehlers–Danlos syndrome (EDS), osteogenesis imperfecta (OI), and aneurysms–osteoarthritis syndrome [52]. The prevalence of MVP is much higher in these conditions compared to the general population [53]. Notably, MVP may affect 40% of MFS patients [54], 15–41% of LDS patients [55], 6% of EDS patients [56], 7% of OI patients [57], and 45% of patients affected by aneurysms–osteoarthritis syndrome [58]. MFS, LDS, and EDS patients have an increased risk of aortic dissection and severe MR due to the progressive degeneration of the valve and chordae, with myxomatous infiltration and fibroelastic and collagen alterations [59]. Moreover, the association between MAD, arrhythmic events, and mitral valve surgery has been consistently reported in the MFS population [60,61]. MVP has also been reported in 2% of patients with long QT syndrome (LQTS) [62] and in 9–26% of patients with QT interval prolongation [63]. Finally, MVP has been associated with left ventricular noncompaction (LVNC) and ion channelopathies [64]. Two authors have described the concomitance of sinus bradycardia, LVNC, and MVP [65,66]. This overlapping phenotype is caused by the mutations and dysfunction of the hyperpolarization-activated cyclic nucleotide channel 4 (HCN4), a major constituent of the pacemaker current (If) in the sinoatrial node [67]. QT interval prolongation and cardiac ion channelopathies may increase the risk of malignant VAs and sudden cardiac death (SCD) in MVP individuals [68].

4.5. Mitral Valve Prolapse Complications

Even if MVP is generally a benign condition, a number of serious complications may occur in individuals with MVP.

MVP individuals have an annual risk of SCD, ranging from 0.2% to 1.9% [63,69]. A subset of patients with MVP and an increased incidence of malignant VAs, and SCD has recently been identified [70]. These individuals have myxomatous and bileaflet MVP without significant MR and with the presence of MAD [63]. The latter may trigger frequent and/or complex VAs due to the abnormal tugging on the submitral apparatus resulting in papillary muscle hypertrophy and fibrosis [71,72]. The wider the magnitude of MAD, the higher the incidence of VAs. MVP individuals with myxomatous and bileaflet MVP and with MAD presence should undergo regular 24 h ECG Holter monitoring at diagnosis and during follow-up, with a detailed evaluation of arrhythmias [73]. In selected cases, particularly in MVP patients with abnormal electrocardiographic or Holter findings, a multimodality imaging approach comprehensive of cardiac magnetic resonance (CMR) would improve MAD detection and better define its circumferential extent [74].

The clinical course of MVP may be complicated by the occurrence of AF, particularly in those patients with severe MR [75,76]. AF is a negative prognostic factor, given that patients with AF at the time of MR surgery have worse outcomes compared with patients without AF [77].

MVP may also cause LV dysfunction, and systolic heart failure [78]. The chronic volume overload increases LV wall stress, LV hypertrophy, fibrosis, and LV afterload, with a gradually worsening systolic function [79]. In addition, MR secondary to MVP may determine progressive LA pressure and volume overload [80], resulting in LA enlargement and contributing to AF occurrence [81].

MR is a natural consequence of MVP [82] and MVP is the most common cause of severe MR requiring surgery [83,84]. Worsening regurgitation causes an increase in volume overload, which further increases the annulus diameter and further worsens the amount of regurgitation [85]. MR due to MVP may also develop abruptly as a result of papillary muscle, or chordal rupture (“flail mitral valve”). In this case, MR develops acutely without appropriate compensation by the LA. This leads to acute LA volume overload and causes pulmonary edema and symptoms of respiratory distress [86]. Mitral valve surgery is highly effective at preventing mortality in patients with severe MR [87]. Early surgery is recommended in patients with MR secondary to flail leaflets and is generally associated with a good outcome [88].

Finally, MVP patients have a 3- to 8-fold increased risk of developing IE, although the estimated annual risk is still quite low, at 0.02% [89]. The main risk factors for EI in MVP patients are MR presence, advanced age, male sex, and leaflet thickening/redundancy [89]. Based on the new 2D-echocardiographic criteria for MVP diagnosis, since 2008 [90], prophylaxis against IE has no longer been recommended for patients with MVP without MR or without thickened leaflets on TTE. Conversely, MVP patients with thickened leaflets and documented MR on TTE may benefit from antibiotics during procedures that often lead to bacteremia.

The medical treatment of hemodynamically relevant MR due to MVP is based on angiotensin-converting enzyme inhibitors which promote a reduction in cardiac after-load by decreasing systemic vascular resistance, beta blockers which promote negative inotropic and chronotropic effects, decreasing cardiac demand, and oxygen demand and loop diuretics which promote a reduction in cardiac preload by decreasing the total blood volume [91].

The authors wish to thank Monica Fumagalli for graphical support.