Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet

INTRODUCTION — An understanding of the natural history of chronic mitral regurgitation (MR) is an essential part of any medical or surgical management plan. The natural history is variable, depending upon the etiology and the stage at which the disease is first diagnosed.

The major causes of MR are primary diseases of the valve apparatus and secondary (functional) MR due to cardiomyopathy or coronary disease. The causes of primary MR include mitral valve prolapse (MVP), rheumatic heart disease, infective endocarditis, and trauma, which can lead to a flail (or partial flail) mitral leaflet. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation", section on 'Etiology' and "Chronic secondary mitral regurgitation: General management and prognosis".)

The best natural history data that are presently available have come from studies of patients with MVP and flail mitral leaflet, which is usually a consequence of degenerative mitral valve disease (eg, MVP). These findings may not apply to MR of other causes, especially ischemic and functional MR.

This topic will review the natural history of chronic primary MR caused by MVP and of flail mitral leaflet. The indications for surgery in chronic MR are discussed separately. (See "Chronic primary mitral regurgitation: Indications for intervention".)

NATURAL HISTORY OF MITRAL VALVE PROLAPSE

Overview — The estimated prevalence of MVP using modern echocardiographic techniques is 0.6 to 2.4 percent [1,2]. The natural history of MVP is generally benign, but serious complications do occur; the most common are infective endocarditis, cerebrovascular accidents, the need for mitral valve surgery, heart failure, and death. (See "Mitral valve prolapse: Overview of complications and their management".)

In the 1970s, clinicians relied on the physical examination and phonocardiogram for the diagnosis of MVP. Reports from that era indicate that serious complications occurred at the rate of about 1 percent per year [3,4]. In the 1980s, with increasing use of echocardiography, clinical investigators described higher complication rates of approximately 2 to 4 percent per year [5-8]. These patients, seen at tertiary referral centers, presumably had more serious disease.

Although leaflet thickness >5 mm by M-mode echocardiography was associated with increased risk for complications in some series [5,8], a larger later series using 2D echocardiography found that leaflet thickness was not an independent predictor of mortality and valvular morbidity [9]. In this community study of 833 patients diagnosed with asymptomatic MVP and followed longitudinally in the Olmsted County, cardiac mortality was best predicted by presence of MR and left ventricular dysfunction at the time of diagnosis, while risk factors for cardiac morbidity (defined as occurrence of heart failure, thromboembolic events, endocarditis, atrial fibrillation, and need for cardiac surgery) included age ≥50 years, left atrial enlargement, MR, flail leaflet, and atrial fibrillation present at baseline echocardiography.

Our current understanding is that patients with MVP constitute a heterogeneous group in which risk factors for a widely varying prognosis can be identified [10,11]. This was best illustrated in a community-based retrospective review of the course of 833 residents of Olmsted County, Minnesota who were first diagnosed with asymptomatic MVP between 1989 and 1998; the patients had little comorbidity or cardiovascular history [10]. The presence of MVP was suspected from auscultatory findings in 67 percent and was confirmed in all patients by echocardiography, which was performed for other reasons in 33 percent.

At a median follow-up of 5.4 years, the estimated 10-year overall and cardiovascular mortality were 19 and 9 percent, respectively. Cardiovascular morbidity occurred in 30 percent and MVP-related events (death or heart failure related to MVP, endocarditis, or mitral valve surgery) occurred in 20 percent. Valve surgery was performed in 65 patients (7.8 percent).

Risk factors — The major risk factor for cardiovascular mortality in the Olmsted County study was moderate to severe MR by echocardiography, which was present in 131 patients (16 percent) (movie 1 and movie 2) [10]. Similar findings were noted in another report in which the likelihood of developing MVP-related complications was directly related to the severity of the MR (figure 1) [12].

A less common primary risk factor for cardiovascular mortality in the Olmsted County study, present in 3.7 percent of patients, was a left ventricular ejection fraction (LVEF) less than 50 percent [10]. Secondary risk factors that were independently predictive of cardiovascular morbidity were slight MR, left atrial dimension ≥40 mm, flail leaflet, atrial fibrillation (AF), and age ≥50 years.

These findings, which were similar whether the diagnosis was made by auscultation or incidental echocardiography, were then used to identify patients in different prognostic groups for both cardiovascular mortality and morbidity:

●The 430 patients (52 percent of the population) with 0 to 1 secondary risk factors and no risk factor for mortality had a generally good prognosis. The 10-year mortality was 5 percent, which was not significantly different from expected, and the rates of cardiovascular and MVP-related morbidity were 0.5 and 0.2 percent per year.

●The 250 patients (30 percent) with ≥2 secondary risk factors and no risk factor for mortality had a 10-year cardiovascular mortality similar to that expected but higher rates of cardiovascular and MVP-related morbidity (6.2 and 1.7 percent per year).

●The 153 patients (18 percent) with a risk factor for mortality (moderate to severe MR or LVEF <50 percent) had marked increases in the rate of overall and cardiovascular mortality (4.5 and 3.4 percent per year) and cardiovascular and MVP-related morbidity (18.5 and 15 percent per year).

●The five-year rate of cardiovascular mortality or morbidity in the low, moderate, and high-risk groups were 1, 22, and 49 percent, respectively, in patients under age 50; the values were 3, 26, and 66 percent in older patients.

The potential prognostic value of serum concentrations of brain natriuretic peptide (BNP) and N-terminal pro-BNP in patients with MR is discussed separately. (See "Chronic primary mitral regurgitation: General management".)

Sex differences — Although more women than men have MVP [2,10], complications have been reported more frequently in men [13-15]. Sex differences in MVP presentation and outcomes were evaluated in a Mayo Clinic study of 4461 women and 3758 men diagnosed with MVP by echocardiography from 1989 to 1998 [16].

●Compared with men, women had less posterior prolapse (22 versus 31 percent), less flail (2 versus 8 percent), more valve thickening (32 versus 28 percent), and less frequent severe regurgitation (19 versus 23 percent).

●Among patients with severe regurgitation, women were less likely than men to undergo mitral valve surgery (52 versus 60 percent).

●At 15 years, women with no or mild MR had better odds of survival than men (87 versus 77 percent) but those with severe regurgitation had worse survival than men (60 versus 68 percent). Survival 10 years after surgery was similar in women and men (77 versus 79 percent).

Development of atrial fibrillation — As noted in the Olmsted County study, AF is one of the secondary risk factors for mortality [10]. Another report from Olmsted County assessed the rate of development of AF in 89 patients with MVP (and grade 3 or 4 MR) and 360 with flail leaflets; all of the patients were in sinus rhythm at diagnosis [17]. The rate of development of AF was approximately 5 percent per year with both types of lesions; the major independent risk factors were age ≥65 years and baseline left atrial dimension ≥50 mm. The onset of AF was associated with increases in cardiac mortality and morbidity with medical management.

Another report evaluated the prevalence of AF in patients with MVP who were about to undergo mitral valve repair or valve replacement [18]. Among 246 such patients, 37 (15 percent) were in AF and another 32 (13 percent) had a history of AF that reverted to sinus rhythm either spontaneously or with antiarrhythmic drug therapy.

Mitral regurgitation — Because of its relatively high prevalence (0.6 to 2.4 percent in the general population [1,2]), MVP is the most common valvular cause of chronic MR (ie, primary MR). In the community-based Olmsted County study cited above, moderate to severe MR was present in 16 percent of patients [10]. A similar rate of moderate to severe MR on echocardiography (23 percent) was noted in a much smaller series from the Framingham Heart Study [19].

The valvular lesion in MVP is characterized by thickening and degeneration of the leaflets and chordae (movie 3A-B). These changes reflect repeated damage to the valve leaflets, which deforms the valve, thereby preventing proper coaptation of the leaflets. The mitral annulus gradually dilates as regurgitation worsens. An increase in prolapse may further stretch and damage the chordae tendineae. Weakened chordae can rupture suddenly, producing a flail or partial flail mitral leaflet and severe MR. (See 'Natural history of flail mitral leaflet' below.)

Hemodynamic progression — MR in moderate to severe MVP tends to progress, leading to a worsening of hemodynamic status and ultimately to clinical symptoms. Progression is usually gradual but can be abrupt if chordal rupture occurs. The severity of MR is an essential determinant of the hemodynamic alterations, left ventricular remodeling, and outcome. (See "Chronic primary mitral regurgitation: Indications for intervention".)

The course of MR in MVP was evaluated in a prospective study of 74 patients with organic MR (64 with MVP, 10 of whom developed a new flail leaflet) who underwent two Doppler echocardiographic examinations that were separated by an average of 1.5 years. The following results were noted [20]:

●Decrease in the regurgitant volume by more than 8 mL occurred in 11 percent.

●Increase in the regurgitant volume by more than 8 mL occurred in 51 percent.

●The mean rate of increase in regurgitant volume was 5.9 mL per year in patients with stable MVP and 18.4 mL per year in the patients with MVP who developed a new flail leaflet.

●The effective regurgitant orifice increased by a mean of 6.2 mm² per year in patients with stable MVP and 10.6 mm² per year in the patients with MVP who developed a new flail leaflet.

In multivariate analysis, there were two independent predictors of increased regurgitant volume:

●Progression of the valvular lesion, particularly a new flail leaflet, which occurred in 10 of the 64 patients (16 percent) with MVP.

●Progressive increase in mitral annulus diameter, usually due to left ventricular and left atrial enlargement, and which reduces leaflet coaptation.

On the other hand, the major predictor of a reduction in regurgitant volume was a fall in blood pressure. However, no significant effect from treatment was seen, a finding consistent with the uncertain benefit of oral vasodilator therapy in patients with chronic MR.

Clinical outcome — It has been estimated that as many as 10 percent of patients with MVP will require mitral valve surgery in their lifetime [21]. Findings indicative of increased risk include greater magnitude of MR, flail leaflet, AF, and age ≥50 [10,11,22]. (See 'Risk factors' above.)

The magnitude of MR (quantified as the regurgitant volume or regurgitant fraction) is an important determinant of prognosis [22]. The regurgitant volume is determined by the magnitude and duration of the pressure gradient across the valve, the duration of regurgitation, as well as the size of the regurgitant orifice and the magnitude of the systolic pressure gradient across the mitral valve, and the effective orifice area (EROA) [23,24]. In patients with MVP, the MR may be holosystolic or mid to late systolic and thus the duration of MR is an important variable. Hence, the effective orifice area (EROA) is important, but it is not the sole factor affecting regurgitant volume. This distinction may be one explanation for why baseline EROA predicted outcome in some studies [25], but not in others [22]. In addition, there are limitations and technical challenges associated with EROA measurements [26].

The predictive value of EROA was suggested by a prospective study of 456 patients with isolated primary MR [25]. Eighty percent had MVP, nine percent AF, the mean age was 63 years, the mean LVEF was 70 percent, and the mean duration of follow-up with medical therapy was 2.7 years. Clinical management proceeded according to each patient's treating physician. Cardiac surgery was eventually performed in 232 patients (51 percent) and was independently associated with increased survival (adjusted odds ratio 0.28). Quantitative grading of the severity of MR by measurement of the EROA was the most powerful predictor of outcome as illustrated by the following observations:

●The 198 patients (43 percent) with an EROA ≥40 mm² (mean 64 mm²) had significantly higher rates of all-cause mortality (adjusted risk ratio [RR] 2.90), cardiac death (adjusted RR 5.21), and cardiac events (adjusted RR 5.66) compared with 129 patients with an EROA <20 mm² (mean 11 mm²). The estimated rates of five-year overall mortality and cardiac mortality in the two groups were 42 versus 9 percent and 36 versus 3 percent, respectively.

●Of note, the patients with an EROA ≥40 mm² had higher regurgitant volumes (101 versus 29 mL/beat with an EROA <20 mm²) as well as greater left atrial volumes, higher systolic pulmonary pressures, and were more likely to have MVP (98 versus 48 percent).

●Mortality rates at five years were significantly higher than expected among medically treated patients with an EROA ≥40 mm² (42 versus 22 percent) as well as in those with an EROA of 20 to 39 mm² (34 versus 16 percent).

Thus, EROA was a strong predictor of outcomes in a population of patients in which larger EROA was associated with larger regurgitant volume.

A later study from the same center, evaluating the effect of duration of regurgitation in patients with MVP, found that the regurgitant volume but not EROA was a predictor of clinical outcomes (mortality, cardiac events [cardiac mortality including sudden death, heart failure, new onset atrial fibrillation], and need for mitral valve surgery) [22]. The compared 111 patients with mid to late systolic MR and 90 with holosystolic MR matched for age, gender, AF, ejection fraction and EROA. Mean regurgitant volume was substantially lower in the group with mid to late systolic MR (25 versus 49 mL), despite similar color jet areas and peak MR velocities. The combined event of death or need for surgery occurred more frequently in patients with holosystolic MR than in those with mid-late systolic MR (24 versus 6 percent at one year and 44 versus 31 percent at five years). Regurgitant volume, but not EROA, was an independent predictor of cardiac events.

It has long been known that the determinants of the regurgitant volume are: 1) the regurgitant orifice area, 2) the duration of the regurgitation, and 3) the square root of the pressure gradient across the valve [23,27]. This study confirms the importance of the duration factor [22], while indicating an important limitation of the calculated EROA in patients with mid to late systolic MVP.

Data suggesting that prospective clinical follow-up of patients with severe MR can alter the natural history to achieve good outcomes were provided by a study of 132 asymptomatic patients with severe degenerative MR (including 58 with flail leaflet) [28]. Patients were followed for 62 months and, based on published guidelines, were referred for surgery at the onset of symptoms or AF or pulmonary hypertension or development of echocardiographic criteria for left ventricular systolic dysfunction:

●Mortality rates at two, four, and eight years were 1, 4, and 9 percent for the entire group and 0, 5, and 8 percent for the subgroup with flail leaflet. Cumulative mortality rates were not significantly different from expected rates for either the whole group or the flail leaflet subgroup.

●Survival free of any indication for surgery at two, four, six, and eight years was 92, 78, 65, and 55 percent.

NATURAL HISTORY OF FLAIL MITRAL LEAFLET — The most common cause for a flail mitral valve is ruptured chordae tendineae, often associated with MVP, endocarditis, or trauma. A less common cause is rupture of a papillary muscle in the setting of an acute myocardial infarction. Depending upon the rate and extent of chordae or papillary muscle rupture, flail mitral leaflet may result in acute, subacute or chronic MR. The course of acute MR is discussed separately. (See "Acute mitral regurgitation in adults".)

The diagnosis of flail (or partial flail) mitral leaflet is based upon echocardiographic evidence of a failure of leaflet coaptation with rapid systolic movement of the involved leaflet into the left atrium. In most cases, only a portion of the leaflet is disrupted and the appropriate descriptive term is "partial flail leaflet" (movie 4 and movie 5 and movie 6 and movie 7). Serious MR is usually present, as the regurgitant leak and the left ventricular (and left atrial) volume overload are more severe than in the vast majority of patients with uncomplicated MVP. (See "Echocardiographic evaluation of the mitral valve", section on 'Flail mitral valve'.)

Course — MR may progress more rapidly in the presence of a flail leaflet than among other patients with MVP. In the study cited above of 64 patients with MVP, 10 of whom developed a new flail leaflet, there was a significantly greater rate of progression of MR in the patients with flail leaflet compared with those with stable MVP [20]. In the above cited study of 132 asymptomatic patients with severe degenerative MR, the 58 patients with flail leaflet tended to develop criteria for surgery slightly but not significantly earlier than those with MVP without flail [28].

A retrospective report evaluated the long-term (5 to 15 years) outcomes of 229 patients with flail mitral valve leaflet [13]. Corrective surgery was performed in 62 percent while the remainder received medical therapy. The main indication for surgery was serious dyspnea (107 patients); other indications included physician preference, endocarditis, angina, and thromboembolism.

Within 10 years of the diagnosis, the following findings were noted:

●Ninety percent of the patients had undergone surgery or died; risk factors for decreased survival were New York Heart Association class III or IV (table 1) and a left ventricular ejection fraction (LVEF) <60 percent (figure 2).

●Among those treated medically, the rate of cardiac mortality was 21 percent at five years and 33 percent at 10 years.

●In a multivariate analysis, mortality was markedly reduced by surgery (hazard ratio [HR] 0.29, 95% CI 0.15-0.56).

A follow-up review from the same authors compared the outcomes of 63 patients who had early surgery and 158 patients who were treated conservatively [29]. Early surgery was associated with a higher rate of overall survival at 10 years (79 versus 65 percent) and a lower incidence of cardiovascular death (8 versus 29 percent), heart failure (27 versus 59 percent), and new chronic atrial fibrillation (AF) (4 versus 26 percent) (figure 3).

Later series have reported lower rates of adverse cardiac events in patients with flail leaflet, which may be due to earlier corrective surgery [28,30]. As an example, a study of 392 patients with flail leaflet, including 102 asymptomatic patients with LVEF ≥60 percent, reported outcomes following 3.9 years of follow-up [30]. Corrective surgery was performed in 80 percent of patients.

●Five-year mortality during medical treatment was relatively low (14 percent), particularly for the subgroup of asymptomatic patients with normal left ventricular function (3 percent).

●Incidence rates during medical management of AF (5.4 percent per year) and heart failure (8 percent per year) were high, even in the asymptomatic, preserved LVEF subgroup (4 and 5.7 percent per year).

●Surgery was independently associated with reduced risk of death (adjusted HR 0.42, 95% CI 0.21-0.84) with benefit largely driven by mitral valve repair. In the asymptomatic, preserved LVEF subgroup, surgery was associated with reduced risk of heart failure (HR 0.20, 95% CI 0.05-0.89) but the impact of surgery on mortality was not statistically significant.

Risk stratification — The preceding findings can be used to develop general guidelines for the identification of patients with flail mitral valve leaflet who are at low and high risk:

Low risk — Survival in medically treated patients presenting with normal LV function and no symptoms is excellent [30]. Thus, such patients are at relatively low risk, although indications for surgery including AF (4 percent per year) and heart failure (5.7 percent per year) are relatively infrequent.

High risk — Patients exhibiting one or more of the following factors at the time of initial diagnosis are at relatively high risk for heart failure, AF, death, or need for surgery [13,30]:

●Older age

●Presence of symptoms

●An LVEF <60 percent

As noted above, the rate of development of AF in patients with flail leaflet who are in sinus rhythm is approximately 5 percent per year [17]. The development of AF is much less frequent in patients who undergo early surgery [29].

These low- and high-risk factors in patients with flail or partial flail leaflet and the rate of development of AF are similar to those in MVP cited above and chronic MR in general. As for chronic severe MR in general, management decisions for patients with flail leaflet are based largely upon the presence or absence of symptoms, the functional state of the left ventricle, as well as the feasibility of successful mitral valve repair. (See "Chronic primary mitral regurgitation: Indications for intervention" and "Chronic primary mitral regurgitation: General management".)

SUDDEN CARDIAC DEATH — Sudden cardiac death is rare (approximately 1 percent per year) in patients with MVP and appears to be more frequent among those with flail mitral leaflet, particularly those with class III to IV symptoms and/or depressed left ventricular systolic function who are managed conservatively. Risk of sudden cardiac death in patients with MVP and flail mitral leaflet is discussed separately. (See "Mitral valve prolapse: Overview of complications and their management".)

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

●The natural history of mitral valve prolapse (MVP) is generally benign, but serious complications include infective endocarditis, cerebrovascular accidents, the need for mitral valve surgery, and rarely, sudden death. (See 'Overview' above.)

●Among patients with MVP, findings indicative of increased risk include moderate to severe mitral regurgitation (MR), left ventricular ejection fraction (LVEF) below 50 percent, increased end systolic diameter, increased left atrial size, atrial fibrillation, flail leaflet, and age ≥50. (See 'Risk factors' above.)

●Among patients with a flail leaflet, findings indicative of increased risk include older age, symptoms, and an LVEF <60 percent (figure 2). (See 'Risk stratification' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William H Gaasch, MD (deceased), who contributed to an earlier version of this topic review.