Relation between severity of mitral regurgitation and prognosis of mitral valve prolapse: Echocardiographic follow-up study

Relation between severity of mitral regurgitation and prognosis of mitral valve prolapse: Echocardiographic follow-up study

Seungbum Kim, MD, Toshio Kuroda, MD, Masanori Nishinaga, MD, Masanori Yamasawa, MD, Shintaro Watanabe, MD, Takeshi Mitsuhashi, MD, Sou Ueda, MD, and Kazuyuki Shimada, MD Tochigi, Japan

We investigated the relation between the severity of mitral regurgitation and the development of complications and cardiac events by using two-dimensional and color Doppler echocardiography in 229 consecutive patients with mitral valve prolapse. The frequency of moderate and severe mitral regurgitation was significantly higher in patients with a prolapsed posterior leaflet (61%) than in patients with a prolapsed anterior leaflet (25%), and the older the patient, the greater the severity of mitral regurgitation. The occurrence of complications, such as atrial fibrillation, congestive heart failure, and chordal rupture, was significantly greater in prolapsed posterior leaflet cases than in prolapsed anterior leaflet cases, and the occurrence was closely associated with the degree of severity of mitral regurgitation. Multiple logistic regression analysis showed that the severity of mitral regurgitation is a strong prognostic indicator for developing complications. Furthermore, in a subgroup of 49 patients tracked for a mean of 4.8 years, the new development of complications was significantly higher in patients who showed a progression in the severity of mitral regurgitation (52%) than in patients without progression in severity (8%). The initial severity of mitral regurgitation was related to the occurrence of cardiac events (mitral valve replacement, infective endocarditis, cerebral embolism and death). The data indicated that the progression of mitral regurgitation is closely associated with the development of complications and cardiac events and suggest that the severity of mitral regurgitation is an important prognostic indicator for the development of complications and cardiac events in patients with mitral valve prolapse. (Am Heart J 1996;132:348- 65.)

Long-term follow-up studies have indicated that patients with primary mitral valve prolapse may have a poor prognosis. Some patients with mitral valve prolapse are at high risk for severe mitral regurgita-

From the Department of Cardiology, Jichi Medical School. Received for publication May 19, 1995; accepted Nov: 11, 1995. Reprint requests: Toshio Kuroda, MD Department of Cardiology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-machi, Kawachi-gun, Tochigi, Japan 329-04. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/1/72009

tion and for complications such as infective endocarditis, cerebral embolic events, malignant ventricular arrhythmias, and sudden death, i'5 Recent reports show that a prolapse of the mitral valve is the most common cause ofmitral regurgitation requiring surgery. 6s Mitral regurgitation is the most frequent hemodynamic complication in patients with mitral valve prolapse and unfavorably affects the patient's prognosis. 9"n In particular, enlargement of the left atrium and the development of chronic atrial fibrillation caused by the progression of mitral regurgitation may signal clinical deterioration and the need for surgical intervention.

Mitral regurgitation may worsen as the severity of the mitral valve prolapse increases. Labovitz et al. i2 reported that the more severe the prolapse, the greater the likelihood of echocardiographic evidence of significant regurgitation. Therefore monitoring patients for the development and progression of mitral regurgitation is important in assessing and treating mitral valve prolapse. Although several studies have shown that the severity of mitral regurgitation may be an important prognostic factor in patients with mitral valve prolapse, 11-14 the relation between the severity and progression of mitral regurgitation and the prognosis has not been fully studied.

Echocardiography is considered to be the most useful technique for evaluating patients with mitral valve prolapse. The development of color Doppler echocardiographic techniques has made it possible to evaluate the severity of mitral regurgitation semi- quantitatively.i5, 16 A l t h o u g h the clinical usefulness of color Doppler flow imaging for the assessment of the severity ofmitral regurgitation has been demon- strated,13,17-19 few studies have related the severity of mitral regurgitation to the development of complications and cardiac events, which could help predict the prognosis of a patient with mitral valve prolapse.

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Volume 132, Number 2, Part 1 American Heart Journal -~i/7~ e t al. 349

Fig. 1. Typical examples ofmitral valve prolapse observed on two-dimensionallong-axis echocardiograms. Anterior mitra] leaflet was superiorly displaced into left atrium during systole (arrow, left). Posterior mitral leaflet bulged into left atr ium beyond line of mitral annulus during systole (arrow, right) AML, An- terior mitral leaflet; PML, posterior mitral leaflet.

The a im of this s tudy was to inves t iga te the re la t ion be tween the echocardiographic g rade of mi t r a l regurg i ta t ion and the deve lopment of complicat ions and cardiac events and to clarify a predict ive significance of the sever i ty of mi t r a l r egurg i t a t ion in the prognosis of pa t i en t s wi th mi t r a l va lve prolapse.

METHODS Patient population. We identified 425 patients with

echocardiographic evidence of mitral valve prolapse from 14,376 patients referred to the Jichi Medical School Hos- pital between April 1986 and August 1993. The patients were assessed for symptoms and signs suggestive ofmitral valve prolapse, including atypical chest pain, systolic murmurs, and ventricular premature beats. We excluded 196 patients with congenital heart disease, Marfan's syndrome, rheumatic heart disease, coronary artery disease, and cardiomyopathy. Therefore the study population con- sisted of 229 consecutive patients with primary mitral valve prolapse (124 women and 105 men; mean age 50.8 years, aged 14 to 88 years).

Echocardiographic studies. Two-dimensional and color Doppler echocardiography was performed by using a Toshiba SSH-65A, 140A or 160A system with a 2.5- or 3.75-MHz transducer (Tokyo, Japan). The echocardiographic morphologic characteristics of the mitral leaflets were estimated in images obtained from parasternal long- axis and short-axis views and apical four-chamber and long-axis views. We mainly used the parasternal long-axis two-dimensional echocardiogram to assess the location of prolapsed leaflets. Two-dimensional echocardiographic evidence of prolapsed leaflets was defined as a superior pro- trusion of the mitral leaflets into the left atrium, crossing the plane of the mitral annulus, with the coaptation point of the leaflets remaining at or superior to the mitral annu- lar plane during systole. 12, 2o Fig. 1 shows two typical examples of prolapsed leaflets of the mitral valve from the

long-axis view of the parasternal two-dimensional echocardiograms. We measured the left atrial dimension, left ventricular end-diastolic dimension, and ejection fraction on M-mode tracing according to the recommendation of the American Society of Echocardiography. 21

The severity of mitral regurgitation was estimated by color Doppler echocardiography with a 2.5-MHz transducer. The degree of mitral regurgitation was assessed in terms of the distance in the left atrium reached by regurgitant flow from the mitral valve orifice, 15 the maximum regurgitant jet area expressed as a percentage of the left atrial area, 16"1s and the proximal isovelocity surface area 19 visible in any view. Mitral regurgitation was classified as trivial, mild, moderate, or severe (Table I).

Complications and cardiac events. We noted the occurrence of complications such as atrial fibrillation, congestive heart failure and chordal rupture, and cardiac events including mitral valve replacement, infective endocarditis, cerebral embolism, and cardiac death. We then examined the relations between the incidence of complications and the location of prolapsed mitral leaflets and the severity of mitral regurgitation. To clarify the association between the progression of mitral regurgitation and the occurrence of complications, a follow-up study was con- ducted in 49 patients with mild to moderate regurgitant flow. We assessed the prolapsed leaflets; changes in the left atrial dimension, the left ventricular end-diastolic dimension, and the ejection fraction; the progression of mitral regurgitation; and the development of complications. We also investigated the relation between the development of cardiac events and the initial severity of mitral regurgitation during a follow-up period. The follow-up data were obtained from hospital charts, physicians' office records and telephone interviews over a maximum period of 76 months.

Statistics. Data are expressed as mean ± SEM. Differ- ences in the incidence of complications were analyzed by the chi-squared test. p Values of <0.05 were considered

August 1996 350 Kim et al. American Heart Journal

Table I. Color Doppler echocardiographic criteria for grade of mitral regurgitation

Grade of mitral regurgitation

Method Trivial Mild Moderate Severe

Distance in left a t r ium 1/4 2/4 3/4 4/4

Maximal je t area (%) <20 20-40 40< Left atr ial area

Proximal isovelocity <30 30-100 100< surface area (mm 2)

statistically significant. Logistic regression analysis was used to assess the univariable association of clinical and echocardiographic data with the development of complications. A multiple regression model was then developed to identify the independent variables predicting the development of complications. The cumulative cardiac event-free rate was estimated by the Kaplan-Meier method.

RESULTS Prolapsed leaflets and degree of mitral regurgitation,

Of the 229 patients with mitral valve prolapse detected by two-dimensional echocardiography, 147 (64%) had prolapse of the anterior leaflet, 59 (26%) had prolapse of the posterior leaflet, and 23 (10%) had prolapse of both leaflets. Prolapse of the anterior leaflet was 2.5 times greater than prolapse of the posterior leaflet. Mitral regurgitation was present in 212 (93%) of the 229 patients. The mitral regurgitation was trivial in 45 (20%), mild in 83 (36%), moderate in 50 (22%), and severe in 34 (15%). Of the 147 patients with a prolapsed anterior leaflet, the grade of mitral regurgitation ranged from none to mild in 110 (75%) and from moderate to severe in 37 (25%) (Fig. 2). However, moderate to severe regurgitant flow was present in 36 (61%) with a prolapsed posterior leaflet, whereas trivial to mild regurgitation was present in 23 (39%). Among patients with prolapse of both leaflets, 11 (48%) had moderate to severe regurgitant flow. The incidence of moderate and se: vere mitral regurgitat ionwas significantly higher in patients with a prolapsed posterior leaflet compared with patients with a prolapsed anterior leaflet (chi squared = 23.6, p < 0.001).

Relation between age and severity of mitral regurgitation. The severity of mitral regurgitation was closely associated with age (Fig. 3). Patients with trivial mitral regurgitation were significantly older than patients without regurgitation, and patients with moderate to severe mitral regurgitation were significantly older than patients with trivial to mild regurgitation.

Incidence of complications. Atrial fibrillation and

Table II. Incidence of complications associated with prolapsed leaflets in 229 patients with mitral valve prolapse

Leaflet

AML PML Both Complication (n = 147) (n = 59) (n = 23)

Atrial fibrillation 26 (18%) 15 (25%) 5 (22%) Congestive hear t failure 15 (10%) 12 (20%) 3 (13%) Chordal rupture 4 (3%) 9 (15%)* 1 (4%) Cerebral embolism 1 1 Infective endocarditis 1 Pat ients with more 33 (22%) 29* (49%) 7 (30%)

than one complication

AML, Anterior mitral leaflet; PML, posterior mitral leaflet. *p < 0.01 vs AML by chi-square.

congestive heart failure were more common in patients with a prolapsed posterior leaflet than in patients with a prolapsed anterior leaflet (Table II). The incidence of chordal rupture was significantly higher in patients with prolapse of the posterior leaflet than in patients with prolapse of the anterior leaflet. Cerebral embolisms occurred in one patient with prolapse of the anterior leaflet and in one patient with prolapse of the posterior leaflet. Infec- tive endocarditis developed in one patient with a prolapsed posterior leaflet. The incidence of all complications was significantly higher in patients with prolapse of the posterior leaflet than in patients with prolapse of the anterior leaflet. The incidence of complications increased markedly as the severity of mitral regurgitation increased (Fig. 4). Of 34 patients with severe mitral regurgitation, 23 (68%) had more than one complication. Univariable logistic regression analysis of clinical and echocardiographic data found that old age, male gender, involvement of the posterior leaflet, severity of mitral regurgitation, and increased left atrial dimension and left ventricular end-diastolic dimension predicted the development of complications. The multiple logistic regression analysis (Table III) showed that, age, gender, severity of mitrat regurgitation, and increased left atrial dimension were independently associated with the development of complications. The severity of mitral regurgitation was a strong predictor for the development of complications among the variables.

Follow-up of progression of mitral regurgitation. Of the 49 patients who were tracked for more than 2 years, 25 patients showed a progression of mitral regurgitation associated with moderate to severe flow (Table IV). No progression was detected in the other 24 patients. There were no significant differences in sex, age, or the duration of the follow-up period between the two groups. The prolapse of the posterior

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A m e r i c a n Hear t Journa l K i m et al. 351

AML PML AML & PML (n=147) (n=59) (n=23)

[2=no; [ ] =trivial; O =mild; [] =moderate; •=seve re

Fig. 2. Degree ofmitral regurgitation associated with prolapsed leaflets in 229 patients with mitral valve prolapse. AML, Anterior mitral leaflet; PML, posterior mitral leaflet.

60

5O

'¢~ 40

I I

Ill

I I

none trivial mild moderate severe (n=17) (n=45) (n=83) (n=50) (n=34)

Severity of mitral regurgitation Fig. 3. Relation between age and severity of mitral regurgitation in 229 patients with mitral valve prolapse. Mean -+ SEM, *p < 0.05.

leaflet was more frequent in patients with a progression of mitral regurgitation than in patients without progression (52% vs 17%, p < 0.05). The left atrial dimension and the left ventricular end-diastolic dimension increased significantly in patients who showed progression of mitral regurgitation (Fig. 5). The ejection fraction did not change significantly in patients with or without progression. Of the 25 patients with progression of mitral regurgitation, 13

developed more than one complication during the follow-up period (mean 4.9 _+ 0.3 years). In contrast, only 2 of the 24 patients without progression developed complications during the follow-up period (mean 4.7 -~ 0.4 years). The incidence of atrial fibrillation and congestive heart failure was significantly higher in patients with progression than in patients without progression (Table V). Chordal rupture occurred in three patients with progression.

August 1996

352 Kim et al. American Heart Journal

.u ~ m

E 0 ¢d

0

g=

80

60

40

20

none trivial mild moderate severe

Severity of mitral regurgitation

Fig. 4. Incidence of complications related to severity of mitral regurgitation in 229 patients with mitral valve prolapse.

Table III. Multiple logistic regression analysis of development of complications in 229 patients with mitral valve prolapse

Coefficient (95% confidence

Independent variable interval) p Value

Age 0.01 (0-0.013) 0.02 Gender (male) 0.19 (0.12-0.2) <0.05 Involvement of pos- -0.07 (-0.28-0.13) 0.48

terior leaflet Severity of mitral 0.21 (0.11-0.32) 0.001

regurgitation Increased left atrial 0.02 (0-0.03) 0.02

dimension Increased left ven- 0.01 (-0.01-0.02) 0.44

tricular end-diastolic dimension

Follow-up of cardiac events. Cardiac events associ- a ted wi th the init ial severi ty of mi t ra l regurgi ta t ion included mi t ra l valve rep lacement in 18 pat ients , infective endocardit is in one pat ient , cerebral embolism in two pa t ien ts and cardiac dea th in one pa t ien t (Fig. 6). No cardiac events occurred in pa- t ients wi th no or only tr ivial mi t ra l regurgi tat ion. Pa t ien ts wi th modera te mi t ra l regurg i ta t ion showed a significantly h igher incidence of cardiac events when compared wi th pat ients wi th mild mi t ra l regurg i ta t ion over a 76-month follow-up period (18.0% vs 2.4%, p < 0.01). Cardiac events developed most f requent ly in pat ients wi th severe mi t ra l regurgi ta t ion (32.4%).

Table IV. Baseline characteristics of 49 patients with mitral valve prolapse in follow-up on progression of mitral regurgitation

Progression of MR

(-) (+)

Male/female 12/12 14/11 Age (yr) 43.7 +- 3.7 52.7 +- 2.7 Follow-up period (yr) 4.7 +_ 0.4 4.9 _+ 0.3 MR (mild/moderate) 17/7 16/9 AML/PML/Both 16/4/4 8/13/4"

MR, Mitral regurgitation; AML, anterior mitral leaflet; PML, posterior mitral leaflet. *p < 0.05 by chi-square.

DISCUSSION

Severe mi t ra l regurg i ta t ion t h a t requires surgery is one of the most common and serious complications of mi t ra l valve prolapse. Severe regurgi ta t ion is closely associated wi th the severi ty and progression of prolapse. 12"14 Long- term follow-up studies have shown th a t severe mi t ra l regurg i ta t ion occurs among a subset of pa t ien ts wi th mi t ra l valve prolapse. 1-4 The r isk of mi t ra l regurg i ta t ion is re la ted to sex and age and rises steeply af ter the age of 50, par t icular ly in men. 3 I t is therefore impor t an t to observe the progression of mi t ra l regurg i ta t ion in pa t ien ts wi th mi- t ra l valve prolapse. However , there is little da ta on the progression of mi t ra l regurg i ta t ion or the rela- t ion be tween its severi ty and the prognosis of pa- t ients wi th mi t ra l valve prolapse, especially in refer-

Volume 132, Number 2, Part 1 American Heart Journal Kim et al. 353

6 0 - r

40.

20-

0-

60 r - - 7

40

~'~ 20

0

70

6O

50

40

M R p r o g r e s s i o n (.) MR progression (+)

Fig. 5. Changes in left atrial dimension (LAD), left ventricular end-diastolic dimension (LVDd), and ejection fraction (EF) associated with progression ofmitral regurgitation (MR) in 49 patients with mitral valve prolapse during follow-up study. Mean _+ SEM, *p < 0.05, **p < 0.01 vs initial examination. Sp < 0.01 vs MR progression (-). White bars, Initial examination; black bars, last examination.

ence to the development of complications and cardiac events. Our study examined the relation between the severity ofmitral regurgitation and the development of complications and cardiac events and elucidated the prognostic significance of the severity of mitral regurgitation in patients with mitra] valve prolapse.

In this study, mitral regurgitation was present in 93% of the patients, and moderate to severe mitral regurgitation was present in 37% of the patients with mitral regurgitation. Panidis et al. 1° reported that 69% of patients with the mitral valve prolapse syndrome showed Doppler echocardiographic evidence of mitral regurgitation, of which only 10% had moderate to severe regurgitation. The difference between these results and those of Panidis et al. may be related to the older age of our patients. In addition, the development of color Doppler echocardiography

has made the detection of mitral regurgitation more specific and sensitive.

The incidence of prolapse was higher in the anterior leaflet than in the posterior leaflet; however, complications occurred more frequently in patients with a prolapsed posterior leaflet. Hickey et al. s also reported that chordal rupture was more common in patients with a prolapsed posterior leaflet. Our data were consistent with theirs. Previous studies have shown that the degree of mitral regurgitation is cor- related with the severity of prolapse. 1214 In this study, the incidence of complications increased markedly as the severity of mitral regurgitation increased. Multiple logistic regression analysis furthermore indicated that the severity of mitral regurgitation was a strong prognostic indicator for developing complications. Therefore observing the development and

August 1996 354 Kim et al. American Heart Journal

100

90

so I 70[

60

50 ,

0 20

I *

40 60

Duration of follow-up 8O

(months )

Fig . 6. Re•ationbetweendeve••pment•fcardiaceventsandinitia•severity•fmitralregurgitati•nin229 patients with mitral valve prolapse during follow-up study. *p < 0.05 vs mild, **p < 0.01 vs moderate mitral regurgitation. Dashed line, No, trivial (n = 62); thin line, mild (n = 83); medium line, moderate (n = 50); thick line, severe (n = 34).

T a b l e V. New development of complications associated with progression of mitral regurgitation in 49 patients during follow-up period

Progression of mitral regurgitation

Complication (-) (+)

Atrial fibrillation 2 (8%) 12 (48%)* Congestive heart 0 5 (20%)?

failure Chordal rupture 0 3 (12%)

*p < 0.01 vs no progression of mitral regurgitation by chi-square. ~p < 0.05.

progression of mitral regurgitation is very important in the prognosis of mitral valve prolapse.

Kolibashi et al. 9 reported that the progression from mild or moderate regurgitation to severe mitral regurgitation is usually gradual, resulting in archi- tectural and performance changes in the left atrium and the left ventricle. We also observed that the left atrial dimension and the left ventricular end-diastolic dimension increased significantly as the severity of mitral regurgitation increased. However, the ejection fraction did not change significantly in patients with or without the progression. This find- ing may imply that left ventricular systolic function decreased in patients with progressive mitral regurgitation because the ejection fraction should increase as the left ventricle adapts to the volume overload. In

addition, our study indicates that the development of complications was closely related to the progression of mitral regurgitation. Atrial fibrillation and congestive heart failure occurred more frequently in patients with progressively worsening regurgitation during the follow-up period. These findings suggest that monitoring of the progression of mitral regurgitation is essential to detect the development of serious complications.

Although several long-term follow-up studies have shown that a subset of patients is at risk of developing severe mitral regurgitation requiring surgery and complications such as infective endocarditis, cerebral embolisms, and cardiac death, 1-4 follow-up studies on the relation between the severity of mitral regurgitation and the development of cardiac events are rare. In our study, cardiac events developed in relation to the initial severity of regurgitation during the follow-up period. Cardiac events occurred more frequently in patients with moderate and severe regurgitation, but not in patients with no or trivial regurgitation.

In conclusion, the severity of mitral regurgitation was related to the location of the prolapsed leaflet. Moderate and severe regurgitation was more frequent in patients with a prolapse of the posterior leaflet than in patients with a prolapse of the anterior leaflet, and the older the patient, the greater the severity of mitral regurgitation. The incidence of complications and cardiac events increased as the severity of mitral regurgitation increased. The oc-

Volume 132, Number 2, Part 1 American Heart Journal I ~ i / ~ E't a / . 3 5 5

currence of complications was closely associated with the worsening of mitral regurgitation. A multiple logistic regression model indicated that the severity of mitral regurgitation is a strong prognostic indicator for the development of complications. The initial severity of the mitral regurgitation influenced the sub- sequent development of cardiac events. Our results suggest that the severity ofmitral regurgitation is an important prognostic indicator for the development of complications and cardiac events during the follow-up of patients with mitral valve prolapse.

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Relation between severity of mitral regurgitation and prognosis of mitral valve prolapse: Echocardiographic follow-up study