Floppy mitral valve chordae tendineae: Histopathologic alterations

Original Contributions Floppy Mitral Valve Chordae Tendineae: Histopathologic Alterations PETERB, BAKER,MD, GIRRAJ BANSAL,MD, PHD, HARISIOSBOUDOULAS, MD, ALBERTJ, KOLIBASH,MD, JAMES KILMAN, MD, AND CHARLES F, WOOLEY, MD Pathologic studies of floppy or myxomatous mitral valves have focused primarily on changes in the valve cusps, with little attention given to the chordae tendineae. In a systematic study of the histopathology of floppy mitral valve chordae tendineae, 128 nonruptured chordae from 8 severely regurgitant floppy mitral valves were compared to 152 chordae from 10 normal control mitral valves and to 152 chordae from 8 control mitral valves with severe regurgitation due to ischemic heart disease. Collagen alterations were observed in 2% of normal mitral valve chordae and 3% of control regurgitant mitral valve chordae compared to 38% of floppy mitral valve chordae. Moderate or severe acid mncopolysaccharide accumulation was observed in 2 % of normal mitral valve chordae and 3% of control regurgitant mitral valve chordae compared to 39% of floppy mitral valve chordae. Nonuniform histopathologic alterations, rare in normal and control regurgitant mitral valve chordae tendineae, were frequent in floppy mitral valve chordae tendineae (p < 0.001). Histopathologic alterations provide the basis for abnormal physical properties previously demonstrated in floppy mitral valve chordae tendineae and may predispose to chordal elongation and rupture. HUM PATHOL 19:507--512, 1988.

valve chordae tendineae have provided conflicting i n f o r m a t i o n . 3'5'11'12'14'~5 In addition, these studies provide little information concerning the frequency, distribution, and severity of collagen alterations in floppy mitral valve chordae tendineae. Because elongation and rupture of floppy mitral valve chordae t e n d i n e a e may c o n t r i b u t e to p r o g r e s s i o n f r o m mild valvular prolapse to severe valvular regurgitation, 2'~6-~s demonstration of the nature and extent of histopathologic changes in the chordae tendineae should result in a better understanding of the pathogenesis and natural history of floppy mitral valves. The present study systematically evaluated the histopathologic alterations in chordae tendineae from floppy mitral valves, normal control mitral valves, and mitral valves from patients with severe mitral valve regurgitation due to ischemic heart disease. METHODS Floppy mitral valves were obtained from eight patients, four men and four women, aged 50 to 73 years (mean age, 60), who underwent mitral valve replacement for pure, isolated, severe mitral valve regurgitation. Preoperative angiography had demonstrated voluminous mitral valve cusps prolapsing into the left atrium during systole. ~9 Gross and microscopic findings were typical of floppy mitral valves. 1-I3 A single ruptured chorda was identified in two of the eight floppy valves. Control normal mitral valves were obtained at autopsy from 10 patients, 6 men and 4 women, aged 25 to 85 years (mean age, 60), who died of noncardiac diseases. These patients had normal coronary arteries, heart valves, and myocardium by gross and histologic examination. A second control group consisted of mitral valves from 8 patients, 6 men and 2 women, aged 43 to 72 years (mean age, 62), who had isolated severe mitral valve regurgitation secondary to ischemic heart disease. Mitral valve regurgitation had been present for 5 years in 2 patients, 1 to 1.5 years in 4 patients, and 3 to 4 weeks in 2 patients. In each patient, angiography demonstrated severe narrowing in at least two major coronary arteries and segmental left ventricular dysfunction. A ventricular aneursym was present in 2 patients and a ruptured papillary muscle in 1 patient. The valves were obtained following mitral valve replacement in 7 patients and cardiac transplantation in 1 patient. Pathologic evaluation of the mitral valves revealed no

The floppy or myxomatous mitral valve is the most common cause of isolated, pure, chronic mitral valve regurgitation.~ Pathologic studies of floppy mitral valves have d o c u m e n t e d thick, voluminous, hooded valve cusps and thin, elongated chordae tendineae. ~-~3 Histopathologic alterations in the valve cusps include expansion of the spongiosa layer, accumulation of acid mucopolysaccharides, and focal disruption of the flbrosa layer. 6-9'11'12 A l t h o u g h macroscopic and histopathologic changes in floppy mitral valve cusps have been well documented, relatively little attention has been given to histopathologic changes in the chordae tendineae. Previous microscopic descriptions of floppy mitral From the Department of Pathology; Department of Medicine, Division of Cardiology; and Department of Surgery, Division of Thoracic Surgery, Ohio State University College of Medicine, Columbus, Ohio. Revision accepted for publication 30 July 1987. Supported by the Overstreet Cardiovascular Teaching and Research Laboratory in the Division of Cardiology at The Ohio State University College of Medicine and by a Young Investigatorship Award to Dr. Baker from the Central Ohio Heart Chapter of the American Heart Association, Columbus, Ohio. Address correspondence and reprint requests to Dr. Baker: The Ohio State University Medical Complex, Room M368 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Keywords:chordae tendineae, collagen, floppy mitral valve, histopathology. 9 1988 by W.B. Saunders Company. 0046-8177/88 $0.00 + .25

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gross abnormalities. Each mitral valve was excised intact, including the tips of the anterior and posterior papillary muscles. T h e chordae tendineae were categorized according to their site of attachment on the valve cusp, by the classification of Lain et al. 2~ Commissural chordae have branches that insert into the anterior and posterior cusps in the anterolateral and posteromedial commissures. Cleft chordae have branches that insert into two adjacent posterior cusp scallops. Basal chordae arise f r o m the left ventricular wall and insert into the posterior cusp base. All the remaining chordae are classified as anterior cusp or posterior cusp rough zone chordae. T h e lengths of the chordae were measured f r o m the papillary muscle tip to the valve cusp attachment site. Basal chordae were measured from the valve cusp attachment site to the severed end. Twelve to 21 n o n r u p t u r e d chordae were selected from each valve for histologic study. Randomly selected anterior and posterior cusp r o u g h zone chordae and posterior cusp cleft chordae were studied in each valve. T h e anterolateral and posteromedial commissural chordae were studied in all valves except one floppy valve in which the commissural chordae could not be identified because of partial separation of the valve cusps at the time of surgery. T h e chordae were severed at their attachment sites on the papillary muscle and valve cusp. Each chorda was divided 3 m m from the distal end. T h e shorter distal segment was oriented to obtain crosssectional histologic sections, and the longer proximal segment was oriented to obtain longitudinal histologic sections. A total o f 128 chordae from floppy valves, 152 f r o m normal valves, and 152 f r o m control regurgitant mitral valves were studied. Following fixation in 10% b u f f e r e d formalin, the chordae were paraffin e m b e d d e d by routine methods, and 4-txm-thick sections were prepared. Sections f r o m each chorda were stained with hematoxylineosin, Mowry's colloidal iron, Jones' m e t h e n a m i n e silver, M a s s o n ' s t r i c h r o m e , a n d W e i g e r t ' s elastic stains. 21 Accumulation of acid mucopolysaccharides was d e m o n s t r a t e d by Mowry's colloidal iron stain. Collagen alterations were best d e m o n s t r a t e d by the Jones' silver 12 and Masson's trichrome stains. T h e his-

topathologic alterations were g r a d e d semiquantitatively by one investigator (PBB) who was blinded to valve type and chorda attachment site. T h e histologic grades were d e t e r m i n e d by estimating the percentage of cross-sectional or longitudinal profile area with acid mucopolysaccharide accumulation or collagen alterations according to the following criteria: grade 0, 0%; grade 1, <25%; grade 2, 25 to 50%; grade 3, >50%. Collagen alterations were characterized by attenuation of collagen content a n d by fragmentation and separation o f collagen bundles. Statistical evaluation of chordal length was done by the unpaired Student's t test. T h e Wilcoxon ranksum test was used for statistical evaluation of acid mucopolysaccharide accumulation and collagen alteration.

RESULTS Measurement of C h o r d a e Tendineae T h e chordae tendineae at each attachment site except basal were significantly longer in floppy mitral valves than in normal and control regurgitant mitral valves (table 1). No difference was f o u n d in chordal length between normal and control regurgitant mitral valves. Normal a n d Control Regurgitant Mitral Valve C h o r d a e Tendineae

Normal chordae tendineae had two distinct connective tissue layers (fig. l). T h e fibrous layer, a large central core composed of dense collagen bundles, was s u r r o u n d e d by the elastic layer, a thin layer o f compact elastic fibers. T h e r e was no zone of loose connective tissue comparable to the spongiosa of the valve cusp. T h e results of histologic grading are presented in table 2. Collagen alterations were absent and acid mucopolysaccharides were either absent (grade 0) or present in small deposits (grade 1) in 149 of 152 (98%) normal mitral valve chordae. Similar histologic grading results were obtained for control regurgitant mitral valve chordae. Endocardial thickening was observed in 12 (8%) control regurgitant mitral valve chordae (fig. 2).

TABLE t. Average Lengths of Chordae Tendineae Floppy Mitral Valves (n = 8)

Anterior cusp Rough zone Posterior cusp Rough zone Cleft Basal Commissural Anterolateral Posteromedial

Normal Mitral Valves (n = 10)

Control Regurgitant Mitral Valves (n = 8)

Length (cm)

Chordae Measured (n)

Length (cm)

Chordae Measured (n)

Length (cm)

Chordae Measured (n)

2.30 -+ 0.35

48

1.54 -+ 0.33*

59

1.54 -+ 0.40*

65

2.35 -+ 0.30 2.19 +- 0.28 1.90 -+ 0.57

51 12 3

1.38 + 0.23* 1.34 -+ 0.23* 1.00 -+ 0.36

57 11 5

1.41 -+ 0.33* 1.35 -+ 0.32* 1.30 -+ 0.50

52 16 3

2.17 -+ 0.44 2.16 -+ 0.38

7 7

1.29 -+ 0.31" 1.39 -+ 0.40?

10 10

1.34 -+ 0.29* 1.27 -+ 0.36*

8 8

*p < 0.001, compared with floppy mitral valves. ? p < 0.005, compared with floppy mitral valves.

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eae. Most of these chordae had either grade 0 or grade 1 acid mucopolysaccharide accumulation. Thus, many of the floppy mitral valve chordae had a histologic appearance that was indistinguishable from normal mitral valve chordae. For statistical analysis of the histopathologic data, grade 0 collagen alteration and grades 0 and 1 acid mucopolysaccharide accumulation were accepted as normal. In each valve, the percentage of chordae with collagen alteration and abnormal acid mucopolysaccharide accumulation determined the ranking order. Comparison of floppy mitral valves with normal and control regurgitant mitral valves showed significant differences (p < 0.001) for both collagen alteration and acid mucopolysaccharide accumulation.

DISCUSSION The present study showed that chordae tendineae in severely regurgitant floppy mitral valves are elongated when compared with normal and control regurgitant mitral valve chordae. Collagen alterations and moderate or severe acid mucopolysaccharide accumulation, rarely found in control mitral valve chordae, were frequently present in floppy mitral valve chordae. However, the histologic a p p e a r a n c e of floppy mitral valve chordae tendineae was nonuniform, ranging from normal to severely altered. A strong association exists between chordal rupture and floppy mitral valves. Although this association has been questioned by some investigators, I6,22,23 recent studies have shown that approximately 90% of patients with r u p t u r e d c h o r d a e t e n d i n e a e have floppy m i tral valves. 2 4 '2 5 In addmon, most ruptured chordae in floppy mitral valves were not due to bacterial endocarditis. 24-26 Pathologic studies have demonstrated chordal rupture in 22 to 80% of floppy mitral valves.l'5'7'9-11,27 - Chordal rupture and prolapse more frequently involve the floppy mitral valve posterior leaflet than the anterior leaflet. 3'4'6'7'9,19'24 The results of an earlier study from this institution, detailing the morphologic and physical characteristics of floppy mitral valves, indicated that increased surface area and histopathologic alterations are comparable in the anterior and posterior leaflets, t2 The present study revealed histopathologic alterations in floppy mitral valve chordae tendineae from all attachment sites without predilection for a particular site. Because histopathologic alterations seem to be similar in anterior and posterior leaflets of floppy mitral valves, other valvular or hemodynamic factors may predispose to prolapse and chordal rupture involving the posterior leaflet. The pathogenesis of chordal elongation and rupture in floppy mitral valves is not completely understood. Marchand 3 described collagen fragmentation in ruptured chordae tendineae but found that adjacent n o n r u p t u r e d chordae had no histopathologic change. Similar observations were made by ScottJupp et al. 14 Lucas and Edwards 11 were "unable to find a consistent explanation based on gross anatomy or histologic study" for chordal abnormalities in -

FIGURE t [top]. Normal mitral valve chorda tendinea, A large central fibrous layer is composed of compact collagen bundles, and a thin peripheral layer is composed of compact darkly stained elastic fibers, [Weigerl's elastic stain, • FIGURE 2 [bottom], Chorda tendinea of regurgitant mitral valve due to ischemic heart disease, The endocardium is thickened with loose fibrous connective tissue, The central fibrous layer and the thin elastic layer show no histopathologic alterations. [Weigert's elastic stain, • 95.]

Floppy Mitral Valve Chordae Tendineae

Floppy mitral valve chordae had a nonuniform histologic appearance, in contrast to chordae from control mitral valves. Collagen alterations were present in 49 of 128 (38%) floppy mitral valve chordae with severe alterations in 16 (12%) (Fig. 3). Grade 2 or 3 collagen alteration was consistently associated with grade 2 or 3 acid mucopolysaccharide accumulation. Within individual chordae, collagen alterations were present in a patchy distribution or involved the entire chordal length. Collagen alterations were present in 18 to 60% of the chordae tendineae in individual floppy mitral valves. At least 20% of the chordae had moderate to severe collagen alterations in six of the eight floppy valves. No collagen alterations were found in the remaining 79 (62%) floppy mitral valve chordae tendin509

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TABLE 2,

Anterior cusp R o u g h zone FMV NMV MVR Posterior cusp R o u g h zone FMV NMV MVR Cleft FMV NMV MVR Basal FMV NMV MVR Commissural FMV NMV MVR Total FMV NMV MVR

Histopathologic Grading of C h o r d a e Tendineae Acid Mucopolysaccharide Accumulation (%)*

Total (n)

Volume 19, No. 5 [May 1988]

0

1

2

48 59 65

21 73 66

31 27 31

25 0 3

51 57 52

33 77 73

31 19 23

12 11 16

17 91 75

3 5 3

Collagen Alterations (%)* 3

0

1

2

3

23 0 0

58 100 97

17 0 3

10 0 0

15 0 0

20 2 4

16 2 0

67 96 98

16 2 2

6 0 0

12 2 0

42 9 19

25 0 0

17 0 6

50 100 94

8 0 0

33 0 6

8 0 0

33 100 66

33 0 33

0 0 0

33 0 0

67 100 100

0 0 0

0 0 0

33 0 0

14 20 16

29 95 100

50 0 0

7 5 0

14 0 0

64 95 100

21 0 0

7 5 0

7 0 0

128 152 152

27 80 73

34 18 24

20 1 3

19 <1 <1

62 98 97

16 <1 2

10 <1 <1

12 <1 <1

ABBREVIATIONS: FMV, floppy mitral valves; NMV, normal mitral valves; MVR, mitral valves with regurgitation due to ischemic heart disease. * Shown as percentage of chordae for each valve cusp attachment site.

floppy mitral valves. Guthrie and Edwards 6 mentioned that "mucinous" alteration was a potential cause of chordal elongation; however, all three studies independently suggested that gross floppy mitral valve chordal abnormalities were probably due to abnormal chordal tension. Other investigators have described generalized collagen alterations in floppy mitral valve chordae tendineae. Caulfield et al. r5 observed connective tissue dissolution in ruptured and nonruptured floppy mitral valve chordae and concluded that chordal rupture was due to collagen dissolution. McKay and Yacoub 5 f o u n d "disorganization" of collagen in floppy mitral valve chordae from "all parts of the valve." King et a1.12 found that collagen dissolution, present in floppy mitral valve chordae, was absent in normal mitral valve chordae. The present study may clarify conflicting histologic observations from previous studies. Because histopathologic alterations in floppy mitral valve chordae were nonuniform, a large number of chordae must be examined to accumulate a representative sample. The number of chordae evaluated was not mentioned in previous studies. Because histopathologic alterations are present in patchy areas within

individual chordae, chordal rupture may occur at an abnormal site while the remainder of the chorda may be histologically normal. We believe, in concurrence with King et al., 12 that collagen alterations represent the primary defect in floppy mitral valves. The presence of similar histologic characteristics in both the normal and control regurgitant mitral valve chordae tendineae indicates that histopathologic alterations in floppy mitral valve chordae cannot be attributed simply to valvular regurgitation. Other investigators have suggested that collagen abnormalities in the supporting structures, including the valve cusp fibrosa and chordae tendineae, are important in the pathogenesis of the floppy mitral valve. ~'5'7'8'2s This concept is supported by the high prevalence of mitral valve prolapse and regurgitation in conditions with generalized connective tissue and collagen defects, including Marfan's s y n d r o m e 29'3~ and Ehlers-Danlos syndrome. 31'32 Although a variety of biochemical alterations in floppy mitral valve collagen c o n t e n t have b e e n described, 33-36 the precise biochemical changes remain unknown. Salisbury et al. 37 demonstrated in experimental studies on dogs that severing some of the mitral valve

FIGURE 3. Top, Cross section of normal [/effJ and floppy [right) mitral valve chordoe tendineae. Compact dense collagen bundles forth the central core of the normal mitral valve chorda on the left. This is compared to severe attenuation of collagen in the floppy mitral valve chorda on the right. The colloidal iron stain demonstrated prominent accumulation of acid mucopolysaccharides in the area of collagen alteration. [Jones' silver stain, x80.] Bottom, Floppy mitral valve chordae tendineae. The chorda on the left has a peripheral zone of loose connective tissue with expansion and disruption of the elastic layer. Collagen in the fibrous layer is focally fragmented [arrows]. The chorda on the right has severe collagen attenuation and separation in the fibrous layer, while the elastic layer is uninvolved. [Weigeffs elastic stain. x 80 .]

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c h o r d a e t e n d i n e a e r e s u l t e d in i n c r e a s e d t e n s i o n o n t h e r e m a i n i n g i n t a c t c h o r d a e . C h o r d a l r u p t u r e o r sev e r e a l t e r a t i o n s in t h e c o l l a g e n c o n t e n t o f i n d i v i d u a l c h o r d a e w o u l d also b e e x p e c t e d to p r o d u c e i n c r e a s e d t e n s i o n o n a d j a c e n t c h o r d a e . By this m e c h a n i s m , t h e h i s t o p a t h o l o g i c a l t e r a t i o n s m a y l e a d to p r o g r e s s i v e , generalized chordal elongation. H i s t o p a t h o l o g i c a l t e r a t i o n s r e p r e s e n t t h e basis for abnormal physical properties of floppy mitral v a l v e c h o r d a e t h a t w e r e r e c e n t l y d e m o n s t r a t e d at this i n s t i t u t i o n . B a n s a l a n d c o l l e a g u e s 38 o b s e r v e d t h a t t h e f r a c t u r e stress ( f r a c t u r e l o a d / o r i g i n a l c r o s s - s e c t i o n a l a r e a ) was s i g n i f i c a n t l y b u t n o n u n i f o r m l y r e d u c e d in f l o p p y m i t r a l valve c h o r d a e t e n d i n e a e . T h e s e r e s u l t s a r e c o n s i s t e n t w i t h t h e n o n u n i f o r m n a t u r e o f t h e histopathologic alterations observed in the present s t u d y . H i s t o p a t h o l o g i c a l t e r a t i o n s in f l o p p y m i t r a l valve c h o r d a e t e n d i n e a e p r e d i s p o s e to c h o r d a l e l o n g a t i o n a n d r u p t u r e , w h i c h m a y c o n t r i b u t e to p r o g r e s sive v a l v u l a r p r o l a p s e a n d r e g u r g i t a t i o n in f l o p p y m i t r a l valves.

Acknowledgments. T h e authors thank Virginia Coe for h e r secretarial assistance in p r e p r a t i o n of this manuscript; Max Robinowitz, MD, D e p a r t m e n t of Cardiovascular Pathology at the A r m e d Forces Institute o f Pathology, Washington, DC, for his review of the manuscript; and James Ashton, MS, for p r e p a r i n g the statistical analysis. REFERENCES i. Waller BF, Morrow AG, Maron BJ, et al: Etiology of clinically isolated, severe, chronic, pure mitral regurgitation: analysis of 97 patients over 30 years of age having mitral valve replacement. Am Heart J 104:276, 1982 2. Jeresaty RM: Mitral Valve Prolapse. New York: Raven Press, 1979 3. Marchand P, Barlow JB, DuPlessis LA, et al: Mitral regurgitation with rupture of normal chordae tendineae. Br Heart J 28:746, 1966 4. Pomerance A: Ballooning deformity (mucoid degeneration) of atrioventricular valves. Br Heart J 31:343, 1966 5. McKay R, Yacoub MH: Clinical and pathological findings in patients with "floppy" valves treated surgically. Circulation 47(suppl III):III-63, 1973 6. Guthrie RB, Edwards JE: Pathology of the myxomatous mitral valve: nature, secondary changes and complications. Minn Med 59:637, 1976 7. Davies MJ, Moore BP, Braimbridge MV: The floppy mitral valve: study of incidence, pathology, and complications in surgical, necropsy, and forensic material. Br HeartJ 40:468, 1978 8. Roberts WC: Congenital cardiovascular abnormalities usually "silent" until adulthood: morphologic features of the floppy mitral valve, valvular aortic stenosis, discrete subvalvular aortic stenosis, hypertrophic cardiomyopathy, sinus of valsalva aneurysm and the Marfan syndrome. Cardiovasc Clin 10:407, 1979 9. Olsen EGJ, A1-Rufaie HK: The floppy mitral valve: study on pathogenesis. Br Heart J 44:674, 1980 10. Yacoub M, Halim M, Radley-Smith R, et al: Surgical treatment of mitral regurgitation caused by floppy valves: repair versus replacement. Circulation 64(suppl II): II-210, 1981 11. Lucas RV, Edwards JE: The floppy mitral valve. Curr Probl Cardiol 7:1, 1982 12. King BD, Clark MA, Baba N, et al: "Myxomatous" mitral valves: collagen dissolution as the primary defect. Circulation 288:66, 1982 13. Van der Bel-Kahn J, Becker AE: The surgical pathology of rheumatic and floppy mitral valves. Am J Surg Pathol 10:282, 1986

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