Spectrum of structural abnormalities in floppy mitral valve echocardiographic evaluation

Spectrum of structural abnormalities in floppy mitral valve echocardiographic evaluation Michael J. Malkowski, MD, Harisios Boudoulas, MD, Charles F. Wooley, MD, Ruiqiang Guo, MD, and Anthony C. Pearson, MD, with the technical assistance of Peter G. Gray Columbus, Ohio

Posterior displacement of the mitral valve with billowing into the left atrium has been the major echocardiographic criterion used for the diagnosis of mitral valve prolapse (MVP). However, the current criteria are limited by the influence of hemodynamic factors on the degree of prolapse, whereas complications such as mitral regurgitation, endocarditis, and need for surgery have been associated with redundancy or thickening of the leaflets. Sixty-eight normal subjects (mean age, 40 years; range, 18 to 76 years) were compared with 58 patients with MVP (mean age, 37 years, range, 18 to 83 years). Leaflet displacement across the annular plane in the parasternal long-axis view was mandatory for the diagnosis of MVP. Transthoracic echocardiographic measurements of anterior and posterior leaflet thickness, leaflet length, and chordal length were made from the parasternal long-axis view and the mitral annular diameter, from the apical four-chamber and two-chamber views. The MVP group had greater anterior thickness (4.1 ± 0.4 mm vs 5.3 ± 0.7 mm; p-0.0001), posterior thickness (3.2_+0.4 mm vs 4.7 ± 0.9 mm; p = 0.0001), anterior length (22.8 ± 2.0 mm vs 25.7 _+ 1.7 mm; p = 0.0001), posterior length (12.8 ± 1.0 mm vs 15.7 ± 2.5 mm; p = 0.0001), chordal length (25.6 ± 2.7 mm vs 28.0±2.5 mm; p=0.0001), and annular diameter (29.1 ± 1.5 mm vs 31.3 ± 2.6 mm; p = 0.0001). Of the MVP group, >80% had at least one abnormality identified and >50% had at least two abnormalities. In addition, patients with MVP with significant regurgitation had greater anterior thickness (5.2 _~ 0.7 mm vs 5.8 _+0.8 ram; p= 0.015), posterior thickness (4.5 _+0,9 mm vs 5.3 ± 0.7 mm; p = 0.024), posterior length (15.1 _+ 1.6 mm vs 17.9 ± 4.2 mm; p = 0.004), and annular diameter (36.0 ± 2.0 mm vs 33.3 _+2.1 mm; p = 0.0001). The majority of patients with floppy mitral valves resulting in MVP have structural abnormalities that may be defined by echocardiography. A spectrum of floppy valve structure is demonstrated by echocardiography, with mitral regurgitation occurring more frequently in patients with multiple and more severe anatomic abnormalities. In addition to the presence of prolapse and regurgitation, the assessment of leaflet thickness, leaflet length, annular diameter, and chordal length is fundamental to the definition and stratification of patients with MVP associated with the floppy mitral valve. (Am Heart J 1996;132:145-51.) From The Ohio State University, Division of Cardiology. Received for publication Aug. 30, 1995; accepted Oct. 6, 1995. Reprint requests: Anthony C. Pearson, MD, 1654 Upham Drive, Rm. 657, Columbus~ OH 43210-1228. Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 4/1/71357

Myxomatous infiltration of the floppy mitral valve resulting in mitral valve prolapse (MVP) is a common valvular abnormality with a variable clinical course. 1-~ Although posterior displacement of the mitral valve with billowing into the left atrium or across the mitral annulus has been the major echocardiographic criterion used for the diagnosis of MVP, 4 the degree of billowing is influenced by postural maneuvers, 5 hydration status, 6 and ventricular volume 7 and has not been shown to have prognostic importance 8 or relate to symptoms attributed to MVP. 9 Complications associated with these floppy mitral valves that result in MVP, including mitral regnrgitation, endocarditis, arrhythmia, and death have been associated with redundancy or thickening of the mitral leaflets. 8, 10-13 The separation of imaging criteria from the spectrum of mitral valve disorders previously described 14-19has resulted in controversy regarding the diagnosis and treatment of these patients. Our study was performed to identify the frequency of structural abnormalities and assess the relation between valvular disorders and function. Our hypothesis was that, in the subset of patients with MVP, structural abnormalities are frequently present, and the functional status of the mitral valve is related to the severity of these abnormalities. METHODS Population selected. The 126 patients (68 normal, 58

with MVP)were retrospectively studied from the clinical and research echocardiography databases at The Ohio State University. Normal patients were reviewed from two clinical studies that recruited normal healthy volunteers who had no known history of cardiovascular disease and a normal resting echocardiogram. Patients with MVP were identified by searching the clinical database for patients whose indication for echocardiography was to evaluate for MVP from August 1, 1993, to April 11, 1994. We were able to identify 241 patients whose only indication was to confirm MVP. After exclusion of patients without echocardiographic evidence of prolapse, and those with significant cardiac abnormalities, a study group of 58 patients re145

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Table I. Clinical characteristics and structural analysis by echocardiography in normal subjects and patients with mitral valve prolapse Normal

Age (yr) BSA (m2) Sex (M/F) Anterior leaflet (ram) Mid thickness Margin thickness Leaflet length Posterior leaflet (ram) Margin thickness Leaflet length Chordal length (ram) Mitral annulus (ram) Two-chamber Four-chamber

p Value

40 ± 18 1.81 _+0.23 41/27

MVP

36 ± 16 1.80 ± 0.22 22/36

2.0 ± 0.3 4.1 ± 0.4 22.8 ± 2.0

0.0001 0.0001 0.0001

2.7 -+ 0.4 5.3 ± 0.7 25.7 ± 1.7

3.2 ± 0.4 12.8 ± 1.0 25.6 +- 2.7

0.0001 0.0001 0.0001

4.7 ± 0.9 15.7 +_2.5 27.9 ± 2.5

29.1 ± 1.5 28.9 ± 1.5

0.0001 0.0001

31.3 _+2.6 31.0 ± 2.3

BSA, Body surface area; F, female; M, male.

mained. Patients were included for study if they were found to have MVP as their only abnormal echocardiographic finding, were in normal sinus rhythm, and had a normal blood pressure. Echocardiographic assessment. Two-dimensional and color Doppler echocardiograms were obtained with a Hewlett-Packard (Andover, Mass.) model Sonos 1500 imaging system and an Advanced Technologies Laboratory (Bothell, Wash.) Ultramark-9 imaging system with 2.5 to 3.5 MHz transducers in standard parasternal and apical views. Gain was minimized and processing was optimized to allow clear visualization of the valvular structures. MVP was diagnosed if either leaflet protruded into the left atrium or crossed the mitral annulus in ventricular systole from the parasternal long-axis view, as previously described. 4 The presence of MVP was confirmed in all cases by an independent reader (R. G.). Thickness of the mitral valve was measured from the anterior leaflet of the mitral valve in diastole from the parasterna] long-axis view from a diastolic still frame when the anterior leaflet was most perpendicular to the transducer. A midanterior leaflet thickness was measured from the leading edge to the trailing edge at the midpoint from the mitral annulus to the leaflet tip (Fig. 1, A). The marginal leaflet thickness was measured from the leading edge to the trailing edge at the thickest aspect of the leaflet tip (Fig. 1,A). The maximal posterior thickness was also measured from a diastolic still frame, but because of the shorter length of the posterior leaflet, a mid thickness was not measured. Leaflet length was measured from the tip of the leaflets to the insertion at the annulus in diastole (Fig. 1, B). Chordal length was measured from the tip of the anterior papillary muscle to the insertion of the anterior leaflet at end systole (Fig. 1, C). Mitral annular diameter was measured from the apical four-chamber and twochamber views from the insertion point of each leaflet in diastole (Fig. 1, D). Mitral regurgitation was detected from color Doppler

echocardiography. A semiquantitative estimate of the severity of mitral regurgitation was determined by estimating the jet-to-left-atrial area ratio in the view that demonstrated the most severe regurgitation. 2° The grading of mitral regurgitation was performed by a reader unaware of the structural measurements. Interobserver variability. Two-dimensional echocardiograms from 10 normal patients were analyzed independently by two investigators (P.G.G. and R.G.). The coefficient of variability was calculated by dividing the standard deviation of the mean difference by the mean value of the specific parameter (leaflet thickness, 13%; leaflet length, 6%; chordal length, 6%). Absolute values correlated closely between the two investigators with r values ranging from 0.87 to 0.95. Data analysis. Patients were separated into two groups, control and MVP. The numeric mean and standard deviation Of the anterior and posterior leaflet thickness, anterior and posterior leaflet length, annular diameter, and chordal length were calculated for both groups. An unpaired t test was performed to identify significant differences between groups. In addition, an unpaired t test was performed on patients with and without mitral regurgitation graded as ->2 to evaluate the effect of mitral valve thickness on severity of regurgitation in MVP. Abnormal leaflet thickness, leaflet length, chordal length, and annular diameter were considered to be present when values were greater than the mean normal value +2 SD.

RESULTS T h e clinical c h a r a c t e r i s t i c s a n d m i t r a l v a l v e struct u r a l m e a s u r e m e n t s of t h e two groups a r e p r e s e n t e d in T a b l e I. B o t h t h e m a r g i n a l a n d midleaflet thickn e s s of b o t h t h e a n t e r i o r a n d posterior leaflets w e r e significantly g r e a t e r in p a t i e n t s w i t h M V P t h a n in control subjects (Table I). A n t e r i o r m i d l e a f l e t thickn e s s w a s a b n o r m a l in 48% of p a t i e n t s w i t h MVP, w h e r e a s a n t e r i o r a n d posterior m a r g i n t h i c k n e s s w e r e a b n o r m a l in 57% a n d 66%, respectively. Agea d j u s t e d n o r m a l limits of a n t e r i o r leaflet t h i c k n e s s w e r e calculated for p a t i e n t s y o u n g e r t h a n 45 y e a r s a n d p a t i e n t s 45 y e a r s or older. W h e n p a t i e n t s w i t h MVP were analyzed with the age-adjusted upper limits of n o r m a l , 72% h a d a b n o r m a l middle thickn e s s a n d 76% h a d a b n o r m a l m a r g i n t h i c k n e s s comp a r e d w i t h 48% a n d 57%, respectively, w h e n age-adj u s t e d n o r m a l v a l u e s w e r e not used. A n t e r i o r leaflet l e n g t h a n d posterior leaflet l e n g t h w e r e also g r e a t e r in M V P t h a n in control p a t i e n t s (Table I). F o r t y - e i g h t p e r c e n t of p a t i e n t s w i t h M V P displayed a b n o r m a l posterior length, a n d a b n o r m a l a n t e r i o r l e n g t h w a s p r e s e n t in 21%. C h o r d a l length w a s g r e a t e r in p a t i e n t s w i t h M V P t h a n in controls (Table I). A b n o r m a l chordal l e n g t h w a s p r e s e n t in 9% of p a t i e n t s w i t h MVP. C h o r d a l l e n g t h did not correlate w i t h age b u t did w e a k l y correlate w i t h

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Fig. 1. Measurements of mitral valve apparatus made from two-dimensional echocardiograms. A, Mid and margin anterior leaflet thickness. B, Anterior leaflet length. C, Length of chordal tendineae. D, Annular diameter from apical four-chamber view.

leaflet length (r -- 0.44;p < 0.01). The mitral annulus diameter was greater in patients with MVP than in controls in both the apical two-chamber and apical four-chamber views (Table I). Abnormal mitral annular diameter was present in 33% of patients in the four-chamber view and 29% in the two-chamber view. Structural abnormalities and mitral regurgitation in MVP. Among the patients with MVP, anterior and

posterior leaflet thickness, posterior leaflet length, and mitral annular diameter were significantly greater in patients with mitral regurgitation (Table II). Anterior and posterior leaflet thickness were increased in 91% and 88%, respectively, of patients with significant regurgitation compared with 48% and 66% in patients without regurgitation (Fig. 2). In addition, 55% and 58% of patients with MVP and regurgitation displayed abnormal posterior leaflet length and annular diameter, respectively, com-

pared with 48% and 26% in patients without regurgitation (Fig. 3)° The spectrum of abnormalities in MVP with floppy mitral valves. In analyzing each patient for the number

of structural abnormalities, including leaflet thickness, leaflet length, chordal length, and annular diameter, nearly 80% had at least one abnormality, and >50% had two or more abnormalities (Fig. 4). In addition, patients with MVP with significant mitral regurgitation were more likely to demonstrate multiple abnormalities than were patients without regurgitation (Fig. 5). DISCUSSION

Individual aspects of the echocardiographic assessment of abnormal valvular architecture have been addressed in previous reports. 13 Our study applied a multidimensional approach t ° the definition and stratification of floppy mitral valves resulting in

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et al.

Structural characteristics of patients with mitral valve prolapse with and without regurgitation Table II.

7.5

~"

7.0

[]

6.5

m

6.0

.~

5.5

I-.c

Mitral valve Mitral valve prolapse without prolapse with regurgitation p Value regurgitation

5.0

!

4.5 =_

.=o

4.0

3.5 <

3.0

io

Anterior leaflet (mm) Margin thickness Leaflet length Posterior leaflet (ram) Margin thickness Leafletlength Chordal length (ram) Mitral annulus (mm) Two-chamber Four-chamber

z~

°

0 o

2.5

Normal

MVP Without Regurgitation

MVP With Regurgitation

7.0-

r't

E~ 6.0. E v 5.5.

==

5.0.

.o_

4.5-

.c~ 4.0. o~ 3.5o o.

2.0

5.8 ± 0.8 26.2 + 1.6

4.5 ± 0.9 15.1 +_1.6 27.9 ± 2.6

0.024 0.004 NS

5.3 ± 0.7 17.9 ± 4.2 27.8 ± 2.2

30.8 +_2.2 30.6 +_2.0

0.0001 33.9± 2.6 0.0001 33.3-+2.1

z~

A

................................................................

.................................................................

2 so

13

3.0-

2.5-

0.015 NS

13

6.5-

m

5.2 ± 0.7 25.6 +_1.7

o Normal

MVP Without

MVP With

Regurgitation

Regurgitation

Fig. 2. A, Anterior leaflet margin thickness for normal subjects and patients with MVP with and without mitral regurgitation. Mean and standard error bars are displayed for each group. Dashed line, 2 standard deviations above normal mean. B, Posterior leaflet thickness for normal subjects and patients with ~ with and without mitral regurgitation. Mean and standard error bars are displayed for each group. Dashed line, 2 standard deviations above normal mean. MVP. The results are consistent with previously reported surgical and autopsy findings 14-19 of structural abnormalities of the mitral apparatus, including increased leaflet thickness, leaflet length, chordal length, and annular diameter in patients with floppy mitral valves and MVP. In addition, we present echocardiographic data t h a t confirm a spectrum from nearly normal valvular structure to valves with marked structural changes t h a t adversely influence valvular function in this patient population. Leaflet thickness. The most common mitral valve structural abnormality in MVP in our study was increased anterior and posterior leaflet thickness. Multiple echocardiographic studies demonstrated increased complications, including regurgitation, endocarditis, arrhythmia, and need for valve replacement in patients with increased leaflet thickness.S, lo, 11 In contrast to the normal mitral valve with tightly packed, organized collagen fibers with a

smooth surface, the myxomatous or "floppy" valves display an "undulating" surface t h a t results from collagen disruption, elastin fragmentation, and mucopolysaccharide deposition. These findings also have been identified in systemic abnormalities of connective tissue. 21, 22 The relation between mitral thickening and severity of mitral regurgitation is consistent with pathologic observations of larger mitral valve surface area and enlarged valvular dimensions made by King et al. is in valves requiring replacement for mitral regurgitation. The results confirm the findings of Weissman et al., 13 who found a high prevalence of abnormal leaflet thickness by two-dimensional echocardiography in patients with MVP (49% to 67%), as well as a similar association between leaflet thickness and severity of regurgitation. We also report the prevalence of abnormal anterior thickness from age-adjusted values resulting from our previous report of increasing anterior thickness with advanced age. 23 Our results suggest increased thickness is present in about three quarters of patients with MVP. Leaflet and chordal length. Our study also confirms t h a t mitral leaflet length is increased in MVP. Posterior leaflet length was abnormal in 48% of patients with MVP and was significantly increased in patients with mitral regurgitation. Although Weissman et al. 13 demonstrated increased anterior length in MVP, posterior length was not greater t h a n t h a t in normal subjects. Our finding of greater prevalence of abnormal posterior length and the association of increased posterior length with mitral regurgitation may provide insight into the greater incidence of flail posterior leaflets in patients with severe mitral regurgitation and torn chordae tendineae. To our knowledge, chordal length by two-dimensional echocardiography has not been systematically evaluated in MVP. The pathologic studies from this

Volume 132, Number 1~ Part 1 American Heart Journal

28.

100

Z~

[] •

26. 24E

22"

Z~

18.

A

16'

% Patients

14.

O

Q.

Normals MVP

75

20.

o

149

Malkowski et al.

12.

50

10"

40] 8

Normal

MVP Without Regurgitation

25-

MVP With Regurgitation

38

I ,

0

36

[]

34

H

0

o

E

~5 ==

Normals (%) 85 MVP (%) 21

32" 30. 28" 26.

[]

24 Normal

MVP Without Regurgitation

MVP With Regurgitation

Fig. 3. A, Posterior leaflet length for normal subjects and patients with MVP with and without mitral regurgitation. Mean and standard error bars are displayed for each group. Dashed line, 2 standard deviations above normal mean. B, Diastolic annular diameter from four-chamber view for normal subject and patients with MVP with and without mitral regurgitation. Mean and standard error bars are displayed for each group. Dashed line, 2 standard deviations above normal mean.

rI

1 2 3 Number of Abnormalities

12 29

3 28

4

0 21

0 4

Fig. 4. Percentage of normal subjects and patients with MVP with zero through four structural abnormalities (leaflet thickness, leaflet length, chordae tendineae length, annular diameter). %, Percentage of patients in each group. 100-

[] [] •

75-

% Patients

Normals MVPwithout MR MVPwith MR

50-

25-

institution indicate that chordae tendineae of "floppy' mitral valves are structurally abnormal and significantly elongated. 24 In our study, only 9% of patients with MVP displayed abnormally long chordae attached to the anterior leaflet. Although increased abnormal chordal length was infrequent in MVP, future studies quantitating this measurement may result in a greater understanding of how structurally abnormal chordae tendineae are related to complications. Mitral annulus diameter. Our finding of an increased mitral annular dimension in MVP is consistent with studies by Ormiston et al.25 and Weissman et al. ]3 Our results also support the finding t h a t the mitral annulus diameter is greatest in those patients with significant mitral regurgitation. Roberts et al. 17 reported the presence of significant regurgitation with annular dilatation in patients with and without chordal rupture. The finding t h a t patients with min-

0 Normals (%) MVP without MR (%) MVP with MR (%)

85 26 0

1 2 3 Number of Abnormalities 12 33 17

3 28 25

0 13 50

4 0 2 8

Fig. 5. Percentage of normal subjects and patients with MVP with and without mitral regurgitation with zero through four structural abnormalities (leaflet thickness, leaflet length, chordae tendineae length, annular diameter). %, Percentage of patients in each group.

imal mitral regurgitation and MVP have abnormal annular dimensions may indicate a primary defect in the annulus in addition to the leaflets and chordae tendineae. Implications. The focus of the clinical and echocardiographic evaluation of MVP has been on the

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150 Malkowski et al.

billowing of the mitral leaflets into the left atrium or across the mitral annulus in ventricular systole. 4, 28 However, the fundamental abnormality of MVP is the anatomic alteration of the valve structure, which does not always result in billowing. 14-19 Because of the limitation of the physical examination and the finding that mitral valve thickening and redundancy are associated with serious complications, characterization of the valvular structures is critical to the definition and assessment of MVP. Davies et al. 14 in their classic pathologic study on the floppy mitral valve, observed that minor morphologic abnormalities were not clinically significant, whereas more severe abnormalities were associated with serious complications. Valves requiring replacement for significant regurgitation have a larger surface area, annular enlargement, and frequently elongated chordae tendineae, and most other complications have been recognized to occur in patients with the most abnormal valvular structure. 18 Antibiotic prophylaxis for endocarditis is currently recommended for patients with significant mitral regurgitation. 27 However, the presence and degree of mitral regurgitation in MVP is variable and therefore may not reliably predict endocarditis risk. 26 In a recent study that demonstrated significant morbidity and mortality associated with infective endocarditis and MVP, Frary et al.28 reported the recoguition of mitral regurgitation in only 48% of patients who had infective endocarditis. Knowledge of the morphologic characteristics of the mitral valve may provide a more reliable basis for antibiotic prophylaxis. Limitations. Although our study demonstrates the relation between valvular abnormalities and mitral regurgitation, without follow-up assessment, the impact on risk stratification is not known. Clinical studies have demonstrated an increased risk of mitral valve surgery with increasing age, 29 presence of a heart murmur, 24 and recently, exercise-induced regurgitation. 3° Because pathologic studies indicate a relation between need for valvular surgery and structural deformity, 17, lS it is likely that in vivo recognition of abnormality by echocardiography will have important prognostic implications. Measurement of the posterior leaflet thickness is technically difficult when the valve is in close proximity to the posterior ventricular wall in diastole. Although we were not able to measure the posterior leaflet thickness with confidence in 20% of our patients, our results appear to be consistent with pathologic studies.14-19 Conclusions. The majority of patients with MVP associated with floppy mitral valves have structural

abnormalities that may be defined by echocardiography. The results of this study are consistent with pathologic observation that a spectrum of floppy valve structure is demonstrated by echocardiography, with mitral regurgitation occurring more frequently in patients with multiple and more Severe anatomic abnormalities. Therefore, in addition to the presence of prolapse and regurgitation, the assessment of leaflet thickness, leaflet length, annular diameter, and chordal length is fundamental to the definition and stratification of patients with MVP and the floppy mitral valve.

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Volume 132, Number 1, Part 1 American Heart Journal

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25. Ormiston JA, Shah PM, Tel C, Wong M. Size and motion of the mitral valve annulus in man. Circulation 1982;65:713-9. 26. Devereux RB, Kramer-Fox R, Shear MK, Kligfield P, Pini R, Savage DD. Diagnosis and classification of severity of mitral valve prolapse: methodologic, biologic, and prognostic considerations. AM HEART J 1987;113:1265-80. 27. Maron BJ, Isner JM, McKenna WJ. Hypertrophic cardiomyopathy, myocarditis, and other myocardial diseases and mitral valve prolapse: 26th Bethesda Conference: recommendations for determining eligibility for competition in athletes with cardiovascular abnormalities. J Ara Coll Cardiol 1994;24:880-5. 28. Frary CJ, Devereux RB, Kramer-Fox R, Roberts RB, Ruchlin HS. Clinical and health care cost consequences in infective endocarditis in mitral valve prolapse. Am J Cardiol 1994;73:263-7. 29. Kolibash AJ, Kilman JW, Bush CA, Ryan JM, Fontana ME, Wooley CF. Evidence for progression from mild to severe mitral regurgitation in mitral valve prolapse. Am J Cardiol 1986;58:762-7. 30. Stoddard MF, Prince CR, Dillon S, Longaker RA, Morris GT, Liddell NE. Exercise induced mitral regurgitation is a predictor of morbid events in subjects with mitral valve prolapse. J Am Coll Cardiol 1995;25:693-9.

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