INTRODUCTION — Mitral regurgitation (MR) is the most frequent valve disease in the United States population [1], with mitral valve prolapse (MVP) the most common cause of MR requiring surgical correction [2]. While the diagnosis of MVP is relatively simple (the clinical finding of a systolic click and/or murmur leads to confirmatory echocardiography), the medical literature is somewhat confusing. This is related to the overlap between denomination of MVP clinical syndromes, etiology and mechanisms, and to a change in echocardiographic diagnostic criteria for MVP. (See "Mitral valve prolapse: Clinical manifestations and diagnosis".)
Major nonarrhythmic complications of MVP including MR, heart failure, infective endocarditis, and cerebrovascular accidents will be reviewed here. Other conditions associated with MVP are discussed elsewhere. (See "Arrhythmic complications of mitral valve prolapse" and "Mitral valve prolapse syndrome".)
It has been estimated that the overall risk of serious complications in MVP is approximately 1 percent per year in patients with clinically and echocardiographically diagnosed disease; this is a not a cumulative risk since some patients have multiple complications [3]. However, patients with MVP can be divided into widely variable risk groups, with the high-risk group having a cardiovascular mortality of 3.4 percent per year [4].
The most important risk factors for mortality are presence of moderate to severe MR and left ventricular ejection fraction less than 50 percent [4]. The severity of MR also correlates with the requirement for valve replacement and the incidence of infective endocarditis, cerebral embolism, and death (figure 1) [4,5]. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet", section on 'Natural history of mitral valve prolapse'.)
MITRAL REGURGITATION — Primary mitral valve prolapse (MVP) is the most common etiology of pure mitral regurgitation (MR), accounting for over 50 percent of cases; it also accounts for over 60 percent of patients with ruptured chordae tendineae [6].
MR in MVP is a consequence of myxomatous degeneration of the leaflets and chordae, leading to loss of mitral valve competence. The severity of leaflet dysfunction can progress as the abnormal leaflet tissue stretches, resulting in further prolapse and increasing regurgitation. The ventricular and atrial consequences of MR are initiated by volume overload with increased preload and left ventricular and left atrial enlargement. Impedance to ejection is reduced (due to regurgitation into the lower pressure left atrium), and therefore impaired systolic function may be masked by preservation of the left ventricular ejection fraction. Indeed, in patients with MVP and severe MR, borderline normal ejection fraction (50 to 60 percent) and increased end-systolic diameter imply overt left ventricular dysfunction. The left ventricular dysfunction is unmasked at time of surgery, with a postoperative average immediate ejection fraction drop of approximately 10 percent [7,8]. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet", section on 'Natural history of mitral valve prolapse'.)
The majority of patients with MVP have only trace or mild MR [9]; hemodynamically significant MR is uncommon, occurring in only 2 to 7 percent of cases [9-11]. However, the relatively high prevalence of MVP accounts for the observation that more than 25 percent of MVP surgeries are currently performed for severe MR secondary to myxomatous degeneration of the valve and subvalvular structures. Progression of MR may occur in patients with all degrees of MR at baseline but tends to be more intense in patients with pre-existent MR (as MR begets more MR). In patients with MR at baseline, the regurgitant volume increases by a mean of 7 mL/beat per year [12].
The mechanisms of progression of MR are varied. In patients with chronic MR, with the progressive enlargement of cavities the left atrium compliance increases so that, with the same regurgitant orifice, the regurgitant volume increases as the V wave in the left atrium declines. Development of chronic progressive enlargement of the mitral annulus or new ruptured chords will tend to separate the mitral leaflets further during systole, leading to progressive increase in the regurgitant orifice.
Acute severe MR (such as occurring after chordal rupture with large unsupported segments) is poorly tolerated and usually requires rapid surgical intervention.
Role of quantification — Formal quantification of MR is endorsed by all major society guidelines (including the American College of Cardiology, European Society of Cardiology, and American Society of Echocardiography) [13-16]. Our observations that quantitative measures of MR (regurgitant volume and orifice) are essential predictors of outcome [17] have been confirmed in two independent prospective studies totaling, with our own, more than 1000 patients followed long term [18,19]. Echocardiography is the key diagnostic modality; formal quantification requires comprehensive integration of color-flow imaging and pulsed and continuous wave Doppler-echocardiography.
Quantitative assessment by continuity equation or proximal isovelocity surface area method allows measurement of effective regurgitant orifice area (ERO) and regurgitant volume (RVol); severe MR is present with ERO >40 mm2 and RVol >60 mL. Quantitation of regurgitation severity must also take into account the highly dynamic nature of ERO with MVP. Indeed, some patients have virtually no regurgitation in the initial part of systole, with a sudden increase in ERO (sometimes to very large values) during late systole [20]. We have shown that patients with MVP and purely mid-late systolic MR have a more benign outcome than those with holosystolic MR. In mid-late systolic MR, regurgitant volume provides information more reflective of MR severity than ERO [21].
Quantitative assessment of MR is evolving in parallel with development of new technologies. Three-dimensional (3D) echocardiographic techniques are increasingly used for MR quantitation (3D vena contracta area, 3D proximal isovelocity surface area [PISA], and 3D volumetric estimation of left ventricular and left atrial volumes), but their predictive value for patient outcomes remains to be established. Cardiac magnetic resonance imaging for quantitation of MR is now recommended when assessment by echocardiography is suboptimal or discordant with clinical findings [16]. In addition, with the advent of percutaneous intervention on the mitral valve, numerous quantitative parameters have been proposed to assess feasibility and predict success of percutaneous mitral valve repair (mitral valve annulus and mitral valve opening areas, coaptation and leaflet length, flail gap and flail width, etc) [22]. These are now possible with the progress in 3D echocardiography, but are time consuming, and should be reserved for patients considered for percutaneous intervention.
In addition to increasing the likelihood of valve replacement/repair, presence of moderate to severe MR with MVP has been implicated as a marker for complications such as infective endocarditis, arrhythmias, and cardiovascular mortality, including sudden death [3-5]. Most of the increased risk of arrhythmias and sudden death is directly related to valvular insufficiency, although cases of sudden death have been reported in patients in whom minimal prolapse was the only abnormality found at autopsy [23-25]. (See "Arrhythmic complications of mitral valve prolapse", section on 'Sudden cardiac death'.)
Natural history and role of surgery — The natural history of MR in MVP and the indications for mitral valve surgery in such patients are discussed in detail separately [13,14]. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet" and "Indications for intervention for chronic severe primary mitral regurgitation".)
PROLAPSE OF OTHER VALVES — Mitral valve prolapse (MVP) may be accompanied by myxomatous degeneration and prolapse of other valves, particularly the tricuspid valve. Although data are limited, small studies suggest that there is concurrent tricuspid valve prolapse in approximately 40 percent and aortic and pulmonic valve prolapse in up to 10 percent [13,14,26,27]. These lesions occur with or without valvular regurgitation [28].
The role of concurrent tricuspid repair in patients undergoing mitral valve surgery for MVP with severe mitral regurgitation is discussed separately. (See "Management and prognosis of tricuspid regurgitation", section on 'Indications'.)
INFECTIVE ENDOCARDITIS — Infective endocarditis (IE) occurs at an increased frequency in patients with MVP when compared with those with a normal mitral valve, although the absolute risk of infection is low.
Incidence — Over the last few decades, there has been a shift in the spectrum of underlying cardiac lesions in patients with IE, as mitral valve prolapse (MVP) has replaced rheumatic heart disease as the most common disorder in developed countries [29,30]. One study, for example, compared patients with IE in the 1970s with those diagnosed in the 1980s: The incidence of MVP rose from 6 percent in the earlier group to 22 percent in the later group [29]. In a systematic review of all patients undergoing surgery for native valve endocarditis at Mayo Clinic between 1984 and 2005, MVP was present in 43 percent of patients with mitral valve endocarditis and was an independent risk factor for development of endocarditis [31].
The exact risk of developing IE in patients with MVP is difficult to determine, but estimates can be made based on the presumed incidence of IE in the general population of 1 per 20,000 per year. An overview of available series indicates a fivefold relative risk for the development of IE in the presence of MVP, and a much higher risk if a systolic murmur of mitral regurgitation (MR) is also present [32]. (See "Auscultation of cardiac murmurs in adults".)
●The absolute risk of developing IE among patients with MVP has been estimated to be 1 in 5725 patients per year, assuming a 4 percent prevalence of MVP in the general population [32].
●Based upon similar assumptions, the annual risk of developing IE is 1 in 1920 in the presence of MR diagnosed by auscultation and 1 in 21,950 in the absence of a murmur [32].
Risk factors — Male gender, older age, thickened and redundant mitral valve leaflets, and the presence of a MR murmur, especially in older patients, predispose individuals with MVP to the development of IE [33,34]. A retrospective study of 319 subjects with thickened mitral valve leaflets revealed that 11 patients had developed IE versus none in patients with MVP who had normal valve thickness [34].
Prophylaxis — Endocarditis prophylaxis is no longer recommended by the current American College of Cardiology/American Heart Association (ACC/AHA) guidelines for patients with MVP [35].
Although MVP is associated with an increased risk of endocarditis, there are no convincing data that antibiotic prophylaxis is effective in preventing episodes of endocarditis. IE can occur in spite of antibiotic prophylaxis, and many cases of failure of prophylaxis have been reported with bacteria sensitive to the antibiotic given preventively [36]. Furthermore, transient everyday episodes of bacteremia account for a large proportion of cases of endocarditis. In one survey, only 44 percent had clear, predisposing events that might have been an indication for antibiotic prophylaxis [29]. Studies in the Netherlands have also concluded that only a small number of cases of IE are prevented by antibiotic prophylaxis [37].
Further supporting restricted use of antibiotic prophylaxis, the incidence of endocarditis caused by group viridans streptococci in Olmsted County has, if anything, decreased after the 2007 publication of the updated guidelines [38].
Recommendations — We concur with the 2007 AHA and 2006 ACC/AHA guidelines on IE, which recommend endocarditis prophylaxis for patients only at the highest risk [39]. Patients with MVP, including those with MR, are not included in this highest-risk group. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)
TRANSIENT ISCHEMIC ATTACKS AND CEREBRAL VASCULAR ACCIDENTS
Does a relationship exist between stroke and MVP? — Clinical studies suggest a weak relationship between mitral valve prolapse (MVP) and stroke. A study from the Mayo Clinic examined the clinical course of 777 patients with MVP (mean age 49 years) who were followed for a mean of 5.5 years [40]. Ischemic neurologic events occurred in 30 patients (4 percent). This event rate was significantly increased compared with the expected rate of neurologic events in the community (relative risk 2.2, 95% CI 1.5-3.2). However, this high life-time risk of ischemic cerebral events was not uniformly distributed. The risk was non-detectable in MVP without leaflet thickening, mild for MVP with leaflet thickening under medical management, and high after either atrial fibrillation or cardiac surgery. The estimated 10-year risk of an embolic event (including events after mitral surgery) was significantly greater than the expected community event rates for patients over age 50, for those who developed atrial fibrillation, and for those with thickened mitral valve leaflets (adjusted relative risks 2.3, 5.9, and 3.5, respectively) [40].
Other reports using current echocardiographic criteria for MVP have found no relationship between MVP and cerebral events [9,41]. In a case-control study comparing 213 patients 45 years old or younger with ischemic stroke or transient ischemic attacks with 263 control subjects, the prevalence of MVP was similar in the two groups (1.9 and 2.7 percent; odds ratio adjusted for age and sex was 0.59; 95% CI 0.12-2.50).
These observations indicate that cerebrovascular events are rare in young patients with MVP and the attributable risk to MVP of strokes in young patients is very low.
Potential mechanisms — The association between thromboembolic events and MVP most likely is related to the prevalence of other risk factors for embolism, primarily atrial fibrillation, which may be paroxysmal and asymptomatic. The current guidelines for therapy are based upon this view.
Other mechanisms have been proposed but have not been confirmed in larger studies: The presence of fibrinous exudates on myxomatous mitral valve leaflets [42] or at the angle formed by the prolapsing posterior mitral valve leaflet and the left atrial wall [43]. Endothelial denudation of valve leaflet surfaces or chordal attachment sites may predispose to platelet deposition and embolization. Abnormal platelet function has been documented in some, but not all, studies of patients with MVP with mitral regurgitation (MR) [44].
Recommendations for antithrombotic therapy — Given the uncertainty about the association of MVP and cerebral vascular events, there is no consensus regarding prophylactic aspirin or warfarin therapy. The 2014 American Heart Association/American College of Cardiology (AHA/ACC) and 2012 European Society of Cardiology valve guidelines do not comment on antiplatelet/antithrombotic therapy in MVP [13,16]. Our approach is consistent with the 2006 ACC/AHA valve guidelines with 2008 focused update (table 1) [13,14]:
●Antithrombotic therapy is not recommended in patients without a history of systemic embolism, unexplained transient ischemic attacks, ischemic stroke, or atrial fibrillation. However, aspirin therapy (75 to 325 mg) may be considered for patients in sinus rhythm with echocardiographic evidence of high risk MVP.
●Aspirin (75 to 325 mg/day) is recommended in patients with unexplained transient ischemic attacks in sinus rhythm with no atrial thrombi. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)
●Anticoagulation is recommended in patients with documented systemic embolism or recurrent transient ischemic attacks despite aspirin therapy.
•Embolic events in adults with MVP and only mild MR are presumed due to paroxysmal atrial fibrillation and should be treated according to general guidelines for atrial fibrillation. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)
•In patients with MVP and moderate to severe MR, documented atrial fibrillation or embolic events due to presumed paroxysmal atrial fibrillation should be treated with warfarin anticoagulation (goal International Normalized Ratio 2.5, range 2.0 to 3.0). The use of new oral anticoagulants (direct thrombin and Xa inhibitors) has not been studied in these patients.
General discussions of antithrombotic therapy for atrial fibrillation and stroke are presented separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Secondary prevention for specific causes of ischemic stroke and transient ischemic attack".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Mitral valve prolapse (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Patients with mitral valve prolapse (MVP) may develop a nonarrhythmic complication such as hemodynamically significant mitral regurgitation (MR), heart failure, infective endocarditis, or transient ischemic attack or stroke. The overall risk of serious complications of MVP is approximately 1 percent per year. (See 'Introduction' above.)
●MVP is the most common etiology of primary isolated MR, accounting for over 50 percent of cases; it also accounts for over 60 percent of patients with ruptured chordae tendineae. The majority of patients have only trace or mild MR; hemodynamically significant MR is uncommon in MVP, occurring in only 2 to 7 percent of cases. (See 'Mitral regurgitation' above.)
●In addition to increasing the likelihood of the need for valve surgery, the presence of moderate to severe MR with MVP has been implicated as a marker for complications such as infective endocarditis, arrhythmias, heart failure, and cardiovascular mortality, including sudden death. (See 'Mitral regurgitation' above.)
●MR severity should be formally quantified by comprehensive echocardiography, as jet Color Doppler appearance may be misleading. Regurgitant orifice area and volume have prognostic implications.
●Presence of severe left atrial enlargement and pulmonary hypertension in patients with MR due to MVP is associated with increase in cardiovascular morbidity and mortality.
●Infective endocarditis occurs at an increased frequency in patients with MVP when compared with those with a normal mitral valve, although the absolute risk of infection is low. Antibiotic prophylaxis is, however, no longer recommended for patients with MVP. (See 'Infective endocarditis' above.)
●The association between thromboembolic events and MVP is most likely related to the prevalence of other risk factors for embolism, including atrial fibrillation, which may be paroxysmal and asymptomatic. (See 'Transient ischemic attacks and cerebral vascular accidents' above.)
●Aspirin is recommended in patients with unexplained transient ischemic attacks in sinus rhythm with no atrial thrombi. (See 'Recommendations for antithrombotic therapy' above.)
●Anticoagulation is recommended in patients with atrial fibrillation or systemic embolism and in those with recurrent transient ischemic attacks despite aspirin therapy. (See 'Recommendations for antithrombotic therapy' above.)
•Embolic events in adults with MVP and only mild MR are presumed due to paroxysmal atrial fibrillation and should be treated as in other cases of non-valvular atrial fibrillation. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)
•In patients with MVP and moderate to severe MR, documented atrial fibrillation or embolic events due to presumed paroxysmal atrial fibrillation should be treated with warfarin anticoagulation (goal International Normalized Ratio 2.5, range 2.0 to 3.0). The use of newer oral anticoagulants (direct thrombin and Xa inhibitors) has not been studied in these patients because adults with valvular heart disease were excluded from clinical trials of these agents.
