INTRODUCTION — Management of patients with chronic primary mitral regurgitation (MR) requires an understanding of the pathophysiology and natural history of the disease (table 1) and the efficacy and timing of treatment, particularly mitral valve repair and replacement.
Primary MR is caused by a primary abnormality of one or more components of the valve apparatus (leaflets, chordae tendineae, papillary muscles, annulus) in contrast to secondary MR, which is caused by another cardiac disease (such as coronary heart disease or a cardiomyopathy) (table 2). Identification of the cause and type (primary or secondary) of MR is required for appropriate management of MR as well as any associated conditions.
The only effective treatment for MR is valve repair or valve replacement [1,2]. Recommendations for treatment of severe chronic primary MR differ from those for severe secondary MR (also known as functional MR). The indications for corrective surgery in severe chronic primary MR will be reviewed here. The types of procedures that are available, the factors that determine the choice of procedure, an overview of the natural history and management of chronic primary MR, and issues related to mitral valve prolapse, ischemic MR, functional MR, and MR in elderly patients are discussed separately. (See "Surgical procedures for severe chronic mitral regurgitation" and "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet" and "Management of chronic primary mitral regurgitation" and "Valvular heart disease in older adults" and "Management and prognosis of chronic secondary mitral regurgitation".)
APPROACH TO IDENTIFYING CANDIDATES FOR INTERVENTION — Corrective mitral valve intervention is indicated only in selected patients with chronic severe primary MR (table 3). (See "Clinical manifestations and diagnosis of chronic mitral regurgitation", section on 'Diagnosis and evaluation'.)
The optimal timing of corrective surgery for chronic severe MR is determined by a number of factors, including [3]:
●The presence or absence of symptoms.
●The severity of the MR.
●The functional state of the left ventricle (LV) – Clinically, this is generally assessed by measurement of the LV ejection fraction (LVEF), as well as end-systolic dimension or end-systolic volume.
●The feasibility of valve repair.
●The presence of atrial fibrillation (AF).
●The presence of pulmonary hypertension at rest or with exercise.
●The preferences and expectations of the patient.
For patients with flail or partial flail mitral leaflet and chronic severe MR, indications for corrective surgery are similar to those for most patients with severe MR.
Use of LVEF as a criterion for valve intervention requires identification of the range of LVEF in a population with no heart disease. The broad range of normal is approximately 5 to 75 percent, and values in the range of 50 to 60 percent are considered to be in a low-normal range. Thus, an EF >60 percent is normal. Patients with chronic MR and a low-normal EF have been shown to have depressed LV intrinsic contractility, which appears to be associated with suboptimal outcomes [4] after otherwise successful corrective mitral surgery [5].
Randomized trials have not been performed comparing medical therapy to surgery in patients with severe chronic MR who meet the indications for corrective surgery. However, symptoms are clearly improved after surgery and a survival benefit has been suggested on multivariate analysis in observational studies in which some patients had undergone surgery.
With better definition of the indication for corrective surgery and improved surgical techniques, outcomes for patients with severe chronic MR treated surgically have improved, and the threshold for corrective surgery has declined. There is, however, some lack of agreement about the indications for surgery in an asymptomatic patient. As a result, the general guidelines presented in this review should be modified depending upon local experience and outcomes from surgery.
The following recommendations for surgery in patients with severe chronic nonischemic MR are in broad agreement with those in the 2020 American College of Cardiology/American Heart Association and 2021 European Society of Cardiology guidelines [1,2]. Recommendations for the management of chronic secondary MR are presented separately. (See "Management and prognosis of chronic secondary mitral regurgitation".)
THE SYMPTOMATIC PATIENT
The patient with mild symptoms — Dyspnea and fatigue, even if mild (New York Heart Association [NYHA] functional class II) (table 4), are an indication for corrective surgery in patients with severe chronic MR (table 5) [1].
Decision making is more difficult in patients with mild symptoms who have only moderate MR by echocardiographic evaluation. Because there is considerable variability in the accuracy of echocardiographic regurgitant severity, some of these patients may have hemodynamically severe disease. This issue is not directly addressed in major society guidelines.
In patients with "moderate" mitral regurgitation and symptoms, careful evaluation for other causes of symptoms, including pulmonary disease, should be the first step. If no other cause of symptoms is present, other evidence for adverse hemodynamic consequences of mitral regurgitation (suggesting regurgitation is in fact severe) should be evaluated. This evidence includes LV dilation or systolic dysfunction, the presence of persistent or intermittent AF, or early pulmonary hypertension. When the likelihood of valve repair is high and the clinical evidence is consistent with symptoms due to mitral regurgitation, valve repair or replacement should be considered [6]. Measurement of LV volumes, regurgitation fraction, and ejection fraction by cardiovascular magnetic resonance (CMR) imaging also may be helpful in these patients for more accurate quantitation of regurgitation severity and ventricular size and function. A conservative nonsurgical approach is suggested for the patient with no or mild symptoms and moderate MR; careful clinical follow-up is indicated.
The patient with moderate to severe symptoms — If the patient presents with serious symptoms (NYHA functional class III or IV), (table 4), surgery is almost always indicated unless there is severe LV dysfunction (LVEF ≤30 percent) (table 5). A valve repair procedure is preferable, regardless of the LVEF.
Delaying surgery until moderate to severe symptoms occur is associated with increased perioperative and long-term mortality. The potential magnitude of this effect was illustrated in a retrospective study that compared the outcome after surgery in 199 patients in NYHA class I/II with 279 patients in class III/IV (table 4) [7]. Compared with those in class I/II, patients in class III/IV had a significantly higher surgical mortality (5.4 versus 0.5 percent) and a significantly lower 10-year survival (48 versus 76 percent). These differences were independent of all baseline characteristics, including LVEF (figure 1) and concomitant coronary artery bypass grafting (figure 2), and were seen in patients undergoing valve replacement or repair, although the outcomes were better with valve repair (figure 3).
Patients with an LVEF below 30 percent are not likely to have an optimal result, especially if valve replacement is necessary. In such patients, medical management, including vasodilator therapy, may be preferable. In patients who do not respond to medical therapy, surgical intervention may be considered if the mitral annular-papillary muscle continuity can be maintained (which helps maintain LV systolic function) either by valve repair or replacement with perseveration of the chordal apparatus [1]. These observations illustrate the importance of careful monitoring to detect patients before such an advanced state is reached.
THE ASYMPTOMATIC PATIENT — In the absence of symptoms, management decisions and the indications for surgery rest largely upon the echocardiographic assessment of LV size and function as well as careful confirmation of the severity of MR [1,2]. Some degree of LV and left atrial enlargement are to be expected in severe chronic MR; thus, mild to moderate LV chamber enlargement alone is generally not an indication for surgery in patients with severe chronic MR . Indeed, the absence of LV enlargement suggests less than severe MR.
Some consideration of body size should be included in any assessment of LV dimension or volume, since smaller females are less likely to reach the published criteria, which were largely established in males [1,2]. However, simply normalizing for body surface area can lead to misleading conclusions, especially in patients with obesity. In general, somewhat lower values should be considered in very small patients and somewhat higher values in very large patients.
Normal left ventricular function — Asymptomatic patients with severe chronic MR and normal LV systolic function (defined as LVEF ≥60 percent and/or LV end-systolic dimension <40 mm) are usually followed and managed conservatively. Such patients should be seen every 6 to 12 months or sooner if symptoms occur; repeat transthoracic echocardiography should be obtained at these visits [1]. (See "Management of chronic primary mitral regurgitation", section on 'Monitoring'.)
Patients with a borderline or low-normal LVEF or a technically limited study will require radionuclide, contrast angiography, or CMR imaging to assess LV function and regurgitant severity. (See "Tests to evaluate left ventricular systolic function".)
Exercise stress testing may add objective evidence about symptoms, and a change in exercise tolerance may be particularly useful if an adequate history of exercise capacity is difficult to obtain. Measurement of MR severity and pulmonary artery pressure during or immediately after exercise may also be helpful.
Mitral valve surgery is reasonable in some asymptomatic patients with chronic severe MR and low-normal LV systolic function, defined as an EF between 50 and 60 percent [4]. The 2020 American College of Cardiology/American Heart Association (ACC/AHA) guidelines concluded that the weight of evidence or opinion was in favor of mitral valve repair in such patients, especially if they have one or more of the following [1,2]:
●New-onset AF in this context denotes documented new-onset AF in a prospectively followed patient with severe MR or presence of AF when the diagnosis of severe MR is made.
●Pulmonary hypertension, defined as pulmonary artery systolic pressure >50 mmHg at rest.
●At experienced centers with more than a 95 percent likelihood of successful mitral valve repair without residual MR. (See "Surgical procedures for severe chronic mitral regurgitation", section on 'Valve repair'.)
The 2021 European Society of Cardiology (ESC) guidelines reached similar conclusions, the main difference being that left atrial dilation ≥60 mL/m2 with sinus rhythm is included as a weak indication for consideration of mitral valve repair [2]. A higher threshold for surgery is used if valve replacement is required [1,2].
In addition to the above indications, it has been suggested that the effective regurgitant orifice area (EROA) and functional capacity (cardiopulmonary exercise testing) may identify asymptomatic patients with isolated severe chronic MR who would benefit from surgery before they develop LV systolic dysfunction, AF, and/or pulmonary hypertension [8,9].
Effective regurgitant orifice — The predictive value of a large EROA, indicating severe MR, was suggested by a prospective observational study of 465 patients with isolated primary MR (80 percent mitral valve prolapse), a normal LVEF (mean value 70 percent), absence of pulmonary hypertension, and, in all but 9 percent, absence of AF [8]. An EROA ≥40 mm2, which was present in 43 percent of cases, was associated with a significantly higher regurgitant volume (101 versus 29 mL/beat with an EROA <20 mm2) and was a powerful predictor of an adverse outcome, including all-cause mortality, cardiac events, and undergoing cardiac surgery.
Similarly, a prospective observational study of 447 asymptomatic patients with severe MR and normal LV function found that EROA, baseline grade of pulmonary hypertension, and age were independent predictors for development of an indication for MV surgery or heart failure [9].
EROA use is subject to technical limitations, and the EROA does not account for the duration of regurgitation (mid-late systolic versus holosystolic).
Left atrial size — The prognostic significance of left atrial volume indexed to body surface area (LA index) was suggested by a prospective observational study of 492 patients with isolated primary MR (81 percent mitral valve prolapse) in sinus rhythm at baseline [10]. Five-year survival with medical management was 80 percent. LA index was an independent predictor of mortality and of cardiac events in patients receiving medical management. Patients with LA index ≥60 mL/m2 had lower five-year survival (53 percent) than those with LA index of 40 to 59 mL/m2 (84 percent) and those with LA index <40 mL/m2 (90 percent). LA index remained a significant predictor of mortality and cardiac events after adjustment by EROA.
In this cohort, mitral surgery was associated with decreased mortality (hazard ratio [HR] 0.46, 95% CI, 0.26-0.84) and cardiac events (HR 0.38, 95% CI 0.23-0.62). Postoperative outcomes were not significantly different in patients with LA index ≥60 mL/m2 compared with those with LA index <60 mL/m2 (five-year mortality 9.1 versus 8.7 percent and cardiovascular events 20 versus 16.8 percent).
These findings suggest that LA index may be a useful parameter for risk stratification of patients with MR, although this study did not evaluate whether it provides predictive value beyond current monitored parameters such as pulmonary artery systolic pressure.
Functional capacity — The potential value of quantitative assessment of functional capacity (FC) using cardiopulmonary exercise testing (CPET) with determination of gas exchange was assessed in 134 asymptomatic patients with MR (57 percent severe) who underwent CPET and echocardiographic quantitation of MR (including the EROA), as well as measurement of left ventricular systolic and diastolic function [11]. At three years, clinical events and the combined end point of clinical events and surgery were significantly more common in the 25 percent of patients with markedly reduced FC. This is not surprising, since decreased exercise tolerance is often the first symptom of severe MR, and, as discussed below, symptomatic patients have worse outcomes.
Reduced left ventricular function — Corrective surgery is indicated in asymptomatic patients with severe chronic MR if there is definite and reliable evidence of LV contractile dysfunction or significantly increased LV end-systolic dimension. One or both of the following criteria for LV dysfunction is sufficient to warrant mitral valve surgery [1,2]:
●An LVEF ≤60 percent
●An LV end-systolic dimension ≥40 mm (ACC/AHA) or >45 mm (ESC)
Exercise echocardiography may be useful when there is a concern that symptoms may be occurring or there are borderline echocardiographic findings [12].
The importance of surgical repair before there is a significant impairment in left ventricular function or more than mild symptoms was illustrated in a report of 409 patients who underwent surgery for isolated organic MR [4]. Ten-year survival was 72, 53, and 32 percent in patients with a preoperative LVEF of ≥60 percent, 50 to 59 percent, and less than 50 percent, respectively. Among patients with an LVEF ≥60 percent, survival was higher in patients with NYHA class I or II compared with class III or IV (82 versus 59 percent).
Serial echocardiographic studies have shown that preoperative LV end-systolic dimension ≥40 to 45 mm or a low-normal (50 to 60 percent) or abnormal/depressed LVEF (<50 percent) is predictive of persistent postoperative LV enlargement and systolic dysfunction (table 1) [1,2,4,13-16].
Severely impaired left ventricular function — A separate issue is surgery in patients with severe chronic MR and severe LV dysfunction (LVEF <30 percent and/or LV end-systolic dimension >55 mm) in whom surgery may improve symptoms but may not alter long-term mortality rates or need for LV assist device support or transplantation. Such patients may have primary mitral valve disease with irreversible depression of ventricular contractility due to long-standing volume overload. Alternatively, the MR may be secondary to LV dysfunction (secondary/functional MR). In either case, LV systolic function usually does not improve after mitral valve surgery in patients with severely impaired LV function.
The ACC/AHA guidelines concluded that the weight of evidence or opinion was in favor of mitral valve surgery in such patients if the severe MR is due to a primary abnormality of the mitral apparatus (not secondary/functional MR) and mitral valve repair is highly likely [1]. The weight of evidence or opinion in favor of surgery is not well established for mitral valve repair in patients with severe LV dysfunction who have severe chronic functional MR and persistent NYHA class III to IV symptoms despite optimal therapy for heart failure, including biventricular pacing.
Watchful waiting — Watchful waiting is appropriate for asymptomatic patients with chronic severe MR without any of the above indications for valve intervention. A decision on watchful waiting must consider patient preference, the presence of other risk factors (new AF or pulmonary hypertension), and whether mitral valve repair, the preferred approach, can be performed.
Such patients should undergo physical examination and echocardiography every 6 to 12 months or any time symptoms occur. The six-month interval is preferred if stability has not been documented, there is evidence of progression, or measurements are close to the echocardiographic cutoff values. Surgery may be offered earlier in patients with borderline values in whom access to such monitoring is limited.
The optimum timing of surgery is uncertain in asymptomatic patients with chronic severe MR with borderline or low-normal LV function (LVEF 50 to 60 percent) or a borderline end-systolic dimension (40 to 45 mm). Some of these asymptomatic patients remain asymptomatic and stable for years, but some develop irreversible LV systolic dysfunction [3]. Surgical decisions in asymptomatic patients with preserved LV function depend upon associated factors, including the preferences of the patient. In this setting, surgery is suggested for patients with new onset AF, pulmonary hypertension (pulmonary artery systolic pressure at rest >50 mmHg), or high likelihood of successful mitral valve repair [1,2].
Serial clinical monitoring for symptoms and echocardiographic monitoring of LV size and systolic function ("watchful waiting") are recommended for patients with severe MR who are treated medically [17]. Any trend indicating a decline in LVEF below normal is an indication for surgery.
The safety of watchful waiting in asymptomatic patients with severe chronic MR who do not meet guideline recommendations for mitral valve surgery was evaluated in the following three observational series. The first study suggested that outcomes with watchful waiting may be acceptable, although no comparator group was available. The latter two studies suggested that early surgery may prolong survival and reduce onset of heart failure as compared with watchful waiting. However, residual confounding cannot be excluded and the early surgery approach is applicable only to centers with similarly high rates of successful mitral valve repair and low rates of operative mortality.
●In the earliest report, 132 consecutive patients (mean age 55 years) with degenerative disease (mitral valve prolapse or flail leaflet) were followed prospectively for development of an indication for surgery [18]. Criteria for surgery included symptoms, LV end-systolic diameter ≥45 mm or 26 mm/m2 body surface area, LVEF <60 percent or fractional shortening <32 percent, systolic pulmonary artery pressure >50 mmHg, or recurrent AF.
•During a mean follow-up of 5.2 years, criteria for surgery were met in 38 patients (29 percent). Mitral valve repair was performed in 29 (83 percent) of the 35 patients who underwent mitral valve surgery.
•Overall survival was not statistically different from expected in the overall group or in the 58 patients with flail leaflet. However, there was no direct comparator group that underwent early surgery.
●A later prospective observational study found that in a setting with high success rate of mitral valve repair and low operative mortality, a strategy of early surgery in patients with asymptomatic severe mitral regurgitation was associated with longer survival. Outcomes following watchful waiting (with referral for surgery for development of exertional dyspnea, LVEF <60 percent, LV end-systolic dimension >45 mm, pulmonary artery pressure >50 mmHg, or AF) were compared with results following early surgery in 447 consecutive asymptomatic patients with severe degenerative MR (with flail leaflet in 39 percent), LVEF ≥60 percent, LV end-systolic dimension ≤45 mm, and no other indication for surgery [9].
•In the early surgery group, mitral valve repair was performed successfully in 151 (94 percent) and 10 (6 percent) underwent mitral valve replacement. In the conventional treatment group, survival free of indications for surgery was 76 and 67 percent at five and seven years, similar to the rates noted in the previous study.
•During a median follow-up of 5.4 years, there were two repeat surgeries and no cardiac deaths or operative mortality in the early surgery group compared with 12 cardiac deaths, one repeat surgery, and 22 admissions for HF in the conventional treatment group.
•To control for potential bias, actuarial 7-year event-free survival was calculated for 127 propensity score-matched pairs and was significantly higher in the early surgery group compared with the conventional therapy group (99 versus 85 percent).
●Similarly, a study from an international registry of patients with flail mitral valve leaflets also found that among 1021 patients lacking ACC/AHA class I criteria for surgery [1], early MV surgery (defined as occurring within the first three months of follow-up) was associated with higher survival rates at 5-, 10-, and 20-year follow-up than initial medical management [19]. Early surgery was also associated with lower rates of heart failure at 10- and 20-year follow-up but it did not affect the incidence of AF.
MODERATE MITRAL REGURGITATION — Because there is considerable variability in the accuracy of quantitation of regurgitation severity, some patients classified as having moderate MR may have hemodynamically severe disease. This issue is not directly addressed in major society guidelines. If symptoms are present, alternate causes for symptoms should be sought. If no other cause is evident, we suggest watchful waiting in patients with mild symptoms (New York Heart Association functional class II) (table 4) and moderate MR who have preserved LV function (LVEF >60 percent and LV end-systolic dimension <40 mm) and no other risk factors, such as early pulmonary hypertension.
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".)
SUMMARY AND RECOMMENDATIONS
●General approach – The timing of corrective surgery for chronic severe mitral regurgitation (MR) is determined by a number of factors, including the presence or absence of symptoms, the severity of MR, the functional state of the left ventricle (LV), the feasibility of valve repair, the presence of atrial fibrillation (AF), the presence of pulmonary hypertension, and the preferences of the patient.
●Symptomatic patients
•We recommend mitral valve surgery in symptomatic patients with chronic severe chronic MR if the LV ejection fraction (LVEF) is ≥30 percent and the LV end-systolic dimension is ≤55 mm (Grade 1B). (See 'The patient with mild symptoms' above and 'The patient with moderate to severe symptoms' above.)
•If successful repair is highly likely, we suggest mitral valve surgery in patients with severe mitral regurgitation due to primary mitral valve disease (ie, not functional MR) who have New York Heart Association (NYHA) class III to IV symptoms (table 4) and severe LV dysfunction (LVEF ≤30 percent) (Grade 2C). (See 'Reduced left ventricular function' above and 'The patient with moderate to severe symptoms' above.)
●Asymptomatic patients
•We recommend mitral valve surgery in asymptomatic patients with severe chronic MR and an LVEF of 30 to 60 percent and/or an LV end-systolic dimension ≥40 mm (Grade 1C). However, watchful waiting is reasonable in selected patients with borderline values (LVEF 55 to 60 percent and LV end-systolic dimension 40 to 45 mm). (See 'Reduced left ventricular function' above.)
•We suggest surgical mitral valve repair in asymptomatic patients with severe MR and an LVEF >60 percent who have new-onset AF or pulmonary hypertension (defined as a pulmonary artery systolic pressure >50 mmHg at rest or >60 mmHg with exercise) (Grade 2C). New-onset AF in this context denotes documented new-onset AF in a prospectively followed patient with severe MR or presence of AF when the diagnosis of severe MR is made. A somewhat higher threshold for surgery is used if valve replacement is required. (See 'Normal left ventricular function' above.)
•We suggest mitral valve repair in asymptomatic patients with severe MR and preserved LV function (LVEF >60 percent and LV end-systolic diameter <40 mm) if the likelihood of repair without residual MR is >90 percent and surgical risk is low (Grade 2C). Possible findings favoring surgery in such patients are moderate left atrial enlargement (>50 mm) and/or mild pulmonary hypertension (eg, pulmonary artery systolic pressure 30 to 50 mmHg). (See 'Normal left ventricular function' above.)
●Watchful waiting is appropriate for asymptomatic patients with severe chronic MR who do not meet any of the previously mentioned criteria for mitral valve intervention. Because there is variability in measurement of LVEF and end-systolic size, we suggest watchful waiting as an alternate strategy in asymptomatic patients with borderline values of LV function (LVEF 55 to 60 percent and LV end-systolic dimension 40 to 45 mm) on a single study (Grade 2C). These patients should have repeat studies at six-month intervals to determine if there are reproducible changes in LV size or systolic function that would warrant intervention. (See 'Watchful waiting' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William H Gaasch, MD (deceased), who contributed to an earlier version of this topic review.
