Idiopathic Degeneration of the Aortic Valve: A Common Cause of Isolated Aortic Regurgitation

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1 lacc Vol. 5. No.2 February 1985: Idiopathic Degeneration of the Aortic Valve: A Common Cause of Isolated Aortic Regurgitation JEFFREY B. LAKIER, MD, FACe, FACC, HAROLD COPANS, MD, FACC, HOWARD S. ROSMAN, MD, FACC, RONALD LAM, MD, GERALD FINE, MD, FAREED KHAJA, MD, FAce, SIDNEY GOLDSTEIN, MD, FAce Detroit, Michi/{an Michi!{an To establish the etiology of isolated aortic valvular regurgitation, histologic examination was carried out on 27 consecutive surgically removed aortic valves from patients with aortic regurgitation. In 12 patients, the regurgitation was due to rheumatic or syphilitic valvular disease or a congenital bicuspid aortic valve. In the remaining 15, no etiology was apparent. In the lattergroup, seven aortic valves were identified by the surgeon as redundant and eight as thickened and retracted. Despite these gross differences, the histologic features of the 15 valves were similar and consisted of increased and disorganized elastic and collagen fibers, with variable quantities ofacid mucopolysaccharide and calcium. Although small foci of myxomatous stroma were present, they did not differ substantially from those observed in age-matched competent aortic valves removed at necropsy, nor were they as extensive as described in reports of floppy aortic valves. Idiopathic degeneration was the most common cause of aortic regurgitation, occurring in more than half of the surgically treated patients. An underlying defect in the synthesis of collagen or elastic fibers, similar to that described in mitral valve prolapse, may be an important feature in aortic valve degeneration. (J Am Coil CardioI1985;5:47-5l) A number of recognized pathologic processes may cause isolated aortic regurgitation. Over the last two decades, a change in the relative frequency of these processes in medically developed countries has been recognized (1-), with a decline in the proportion of patients with syphilitic and rheumatic valvular disease and an increase in those having aortic regurgitation without a specific etiology. Histopathologic description of the valves in this latter group is scant. A similar change in the etiology of mitral valve disease has occurred, with idiopathic degeneration or mitral valve prolapse, or both, occurring more frequently. Controversy exists as to whether the degenerative changes in connective tissue (4) or myxomatous stroma (5) are the primary abnormality in mitral valve prolapse. Similar uncertainty surrounds isolated aortic regurgitation, where it is unclear whether the aortic root or the cusps are first involved. In this report, we describe the gross and microscopic appearance of the aortic valves removed at surgery from patients with isolated aortic regurgitation of uncertain ori- From the Divisions of Cardiovascular Medicine and Pathology, Pathology. Henry Ford Hospital. Detroit. Detroit, Michigan. Manuscript received April ; revised manuscript received August 1. 1, 1984, accepted August 2. 2, Address for reprints: Jeffrey B. Lakier, MD, Cardiovascular Division, Henry Ford Hospital, Hospital West Grand Boulevard. Detroit. Michigan (01985 by the American College of Cardiology gin. We discuss the natural history of the degenerative process involving the aortic valve and emphasize the relative importance of this process as a cause of aortic regurgitation. Methods Study patients. Twenty-seven consecutive symptomatic (New York Heart Association functional class II to IV) patients requiring valve replacement at our institution for isolated severe aortic regurgitation were evaluated from January 1976 to January Patients with associated coronary artery disease, mitral valve disease, hypertrophic cardiomyopathy or subaortic stenosis were excluded. The cause of the regurgitation was apparent in 12 (44%) from study of clinical, surgical and pathologic data (Table I). Five had rheumatic disease, three had syphilitic aortitis, three had infective endocarditis and one had a congenital bicuspid aortic valve. In the other 15 IS patients, who form the basis of this study, the cause of aortic regurgitation was not determined. None of these 15 patients had rheumatic heart disease, Marfan's syndrome, serologic evidence of syphilis, clinical or laboratory evidence of rheumatoid arthritis, spondyloarthritis or severe long-standing hypertension. Cardiac catheterization. All 27 patients underwent left and right heart catheterization using fluid-filled catheters and spon /851$ /X5/$. 0

2 48 LAKIER ET AL. JACC Vol. 5. No.2 No, 2 February 1985:47-51 Table 1. Etiology of Aortic Regurgitation in 27 Patients No. of Patients % Rheumatic 5 19, 19. Syphilis II Congenital bicuspid aortic valve I Endocarditis with "normal valve" II Idiopathic degeneration standard angiographic technique. Cardiac output was measured by thermodilution. Surgery. The macroscopic appearance of the aortic valve was recorded by the surgeon before removal. On the basis of this, the 15 patients without an etiologic diagnosis were divided into two groups: those with obviously redundant valves and those with thickened and retracted valves (nonredundant). Pathologic assessment. The valves were examined by two pathologists who were aware of the clinical and surgical diagnoses. Hematoxylin-eosin, Verhoeff's elastic, alcian blue (at ph 2.5 with and without prior testicular hyaluronidase digestion) and periodic acid-schiff stains (with and without prior diastase digestion) were performed on all valves. Aortic valves obtained at necropsy from four age-matched individuals without clinical heart disease were used as controls. Results Evaluation at surgery. At operation, the 15 valves had three identifiable cusps without commissural fusion. Val- vular surface area was considered to be redundant in seven patients and thickened, retracted and distorted in eight patients. Only two patients (Cases 10 and 15) had anular dilation as assessed by the surgeon at the time of valve replacement. The two groups of patients were of similar age and sex. Five of the seven patients with a redundant valve were men with an average age of 59 years (range 28 to 72). Seven of the eight patients with a fibrotic valve were men with an average age of 58 years (range 8 to 72). Histologic evaluation. The histologic findings in the valves from both groups were similar (Table 2). All valves had fibrotic leaflets with varying degrees of change in the ventricularis, spongiosa and fibrosa (Fig. I and 2). Elastic tissue and collagen were increased and disorganized. Microscopic foci of myxomatous stroma, present in all the valves and to an equal degree in both groups, did not differ from foci in age-matched aortic valves from control subjects (Fig. ). There was, however, more extensive calcification in the valves from patients with a thickened, retracted valve. Hemodynamic evaluation. There were no differences in the hemodynamic characteristics of the two groups (Table ). All patients had severe aortic regurgitation clinically and angiographically, with variable degrees of cardiac decompensation. Hemodynamically significant aortic stenosis was absent in all patients. Two patients had pressure differences of 14 and 20 mm Hg, respectively, across the aortic valve, but both had a calculated valve area greater than 2 cm 2 using angiographically derived left ventricular output. Severe hypertension, defined as routinely measured systolic blood Table 2. Summary of Histopathologic Changes of 15 Aortic Valves With Idiopathic Degeneration Age (yr) Case &Sex& Thickness Fibrosis Calcification Redundant Valve I 67M M M M F M F Nonredundant Valve 8 56M M M II 69M M M M F F = female; M = male; 0 = none; + = mild; + + = moderate; = marked.

3 studied. but these were not a prominent feature. Although an objective assessment of increase in myxomatous tissue is difficult,, we believe that the spectrum of pathologic findings described reflects the stage in the natural history of the degenerative process at which the valves are examined. At an early stage of degeneration, the valve may be redundant, with little or no regurgitation. In some. some, the aortic regurgitation may be severe, particularly if a cusp has prolapsed. Repetitive hemodynamic stresses imposed over many years could predispose to further degenerative change, change. with the end result being a thickened,, calcified, distorted and often grossly insufficient valve.. Microscopically, at an early point in the degenerative process, myxomatous tissue may appear increased. increased, while later the calcific process would be more prominent. Only 2 of our 15 patients had obvious dilation of the aortic ring, suggesting that root dilation was not a major cause of the aortic regurgitation. Myxomatous degeneration and aortic regurgitation. McKay and Yacoub (10) described II patients with a "floppy" aortic valve and histologic evidence of "diffuse myxomatous tissue" in the valve cusps. These findings are in contrast with ours and may be explained by different subsets of patients or different stages at which patients with aortic regurgitation underwent valve replacement. Aortic regur- lacc Vol. 5. No.2 2 February I'iX5: X5: LAKIER ET AI.. AL. 49 Figure l. Marked fibrosis of aortic valve. A small myxomatous area (M) is present in the nodule of Arantius. The spongiosa (5) (S) is thin. F = fibrosa; V Y = ventricularis. (Hematoxylin-eosin stain: stain; original magnification x 11; II; reduced by 22%.). ""'I..0\ ~ -s pressures greater than 180 mm Hg or diastolic blood pressures greater than 80 mm Hg, was absent in all patients.. Discussion Etiology. Recognized causes of isolated aortic regurgitation have included congenital bicuspid valve. rheumatic and rheumatoid valvular disease, syphilis (1.2.6) (1,2.6) and severe hypertension (7), but an etiology has not been established in as many as 2% of patients (2). A changing causal frequency influenced by geographic and socioeconomic factors has been observed over the last 20 years (1,2),, but recent investigations (1,2,9).,2,9), with few exceptions (,8).,8), continue to consider rheumatic valvular disease as the primary cause of aortic regurgitation. Degenerative change and aortic regurgitation. Evidence of rheumatic valvular disease was found in only 5 of our 27 patients. Nonspecific degenerative change was found in 15 of the 27 patients and was the leading cause of aortic regurgitation. Our inability to find meaningful histologic and histochemical differences between the redundant and nonredundant valve groups suggest that these gross appearances represent different stages in the same disease. Small areas ofmyxomatous change were present in all valves Figure 2. Severe fibrocalcification (Fe) involves the base of the aortic valve. The remainder ofthe aortic valve is ofnormal thickness. S 5 = spongiosa. (Hematoxylineosin stain; original magnification x II; ; reduced by 2%.)

4 50 LAKIER ET AL. lacc Vol. 5. No.2 February 1985:47-51 N Figure. Aortic valve section through the nodule of Arantius (N) from a 60 year old woman without clinical or anatomic evidence of valvular heart disease. Calcification (C) in the fibrosa, less than noted in the cases reported, and the varied thickness of the spongiosa (S) are not uncommon findings in the aortic valve in the later decades oflife. The inset illustrates the myxomatous character and cellular paucity of the spongiosa in the area indicated by the arrow. (Verhoeff Van Gieson stain; original magnification x 5; inset magnification x 20; both reduced by 22%.) gitation associated with extensive myxomatous change in the aortic cusps and root has been described frequently in patients with a Marfan's habitus, but otherwise has been considered rare (11, 12). Myxomatous degeneration and mitral prolapse. "Myxomatous degeneration" has been observed in patients with a floppy and prolapsing mitral valve without features of Marfan's syndrome. Davis et al. (4) believe that the essential fault is disruption of the central collagenous layer of the valve, with fragmentation of collagen bundles and secondary accumulation of acid mycopolysaccharides. King et al. (1) demonstrated that collagen dissolution and fragmentation are ubiquitous in mitral valve prolapse. They propose an abnormality in collagen synthesis as the primary defect. Hammer et al. (14) documented an absence of type III and AB collagen in a patient with mitral valve prolapse. Embryologically, the mitral and aortic valves derive from the same tissues, and an inherent collagen disorder. disorder, if it occurred, could be expected to involve both valves. Concurrent progressive degeneration with myxomatous change involving both valves has been reported (10,15). In addition, a spectrum ofdegenerative disease ranging from redundancy to fibrosis has been proposed to occur in the mitral valve (16). We believe a similar process is likely to affect the aortic valve. Bacterial endocarditis and aortic regurgitation. Bacterial endocarditis involving apparently normal valves occurred in of our 27 patients (Table I). Both rheumatic and congenital abnormalities of the aortic valve predispose to endocarditis (17,18). The incidence of endocarditis is also increased in elderly patients with nonspecific degeneration of the aortic valve (19). Aortic valve endocarditis has been documented in younger patients with Marfan's syndrome (20). Our patients do not fit into these categories, and it is possible that unrecognized aortic valve degeneration Table. Hemodynamic Findings in 15 Patients With Idiopathic Degenerative Aortic Regurgitation PA Pressure LV Pressure CA Pressure EF Case HR(beats/min)/Rhythm (mm Hg) (mm Hg) (mm Hg) (%) Grossly Redundant Valve Group I 90/sinus 58/29 (8) /54 (82) 2 88/AF 26/14 (18) / (96) 20 68/sinus (14) (100) /sinus !l5 (2) /64 (100) /sinus 15/4 (5) 174/5 154/54 (88) /sinus 42/24 (2) 12/0 12/50 (86) /AF 5517 (2) 164/8 164/68 (112) 54 Nonredundant Valve Group 8 68/sinus !l6 (20) 210/16 210/80 (120) /sinus 48/20 (0) 14/25 120/ (75) /AF 12/8 (10) 12/8 128/60 (114) 57 II 8/sinus 17/9 (12) 110/4 110/42 (70) /sinus 22/6 (II) 142/6 142/52 (86) /sinus (19) 128/14 128/40 (80) /AF 45/28 (5) 156/ (110) /sinus 0114 (20) /40 (74) 67 AF = atrial fibrillation; CA = central aortic phasic (and mean) pressure; EF = ejection fraction; HR = heart rate; LV = left ventricular phasic pressure; PA = pulmonary artery phasic (and mean) pressure; sinus = sinus rhythm.

5 lacc Vol. 5. No.2 Fchruary 19X5:47-51 LAKIER ET AL. 51 may have been the underlying lesion in these three patients and in others who develop endocarditis without apparent heart disease. As with mitral valve prolapse, we recommend antibiotic prophylaxis against infective endocarditis if clinically evident aortic regurgitation is present. Echocardiographic demonstration of aortic or mitral valve prolapse without a concomitant murmur is not an indication for prophylaxis given our current state of knowledge. The decline in the frequency of the more commonly recognized causes of isolated aortic regurgitation, such as rheumatic heart disease and syphilis, is likely to continue. An increasing awareness of a primary degenerative form of aortic regurgitation, perhaps secondary to a collagen disorder, will undoubtedly lead to greater recognition and understanding of this entity. References I. Rotman M. Morris JJ, Behar VS, Peter RH, Kong Y. Aortic valvular disease: comparison of types and their medical and surgical management. Am J Med 1971:51: Enghoff E. Aortic incompetence: clinical haemodynamic and angiocardiographic evaluation. Acta Med Seand Scand ISuppljI SupplJ 1972:5X: Sugiura M, Matsushita S, Ueda K. A clinicopathological study on valvular diseases in,000 consecutive autopsies of the aged. Jpn Circ J 1982:46: Davies MJ, Moore BP, Braimhridge MV. The floppy mitral valve: study of incidence, pathology and complications in surgical. surgical, necropsy and forensic material. Br Heart J I I978:40:46X-X I. 5. Pomerance A. Ballooning deformity (mucoid degeneration) of atrioventricular valves. Br Heart J 1969:1 : Roherts We, wc, Morrow AG, Mcintosh CL. Jones M, Epstein SE. Congenitally hicuspid aortic valve eausing causing severe, pure aortic regurgitation without superimposed infective endocarditis: analysis of 1 patients requiring aortic valve replacement. Am J Cardiol 19X I:47: I 7. Waller BF, Kishel Je. Jc, Roherts Wc, we. Severe aortic regurgitation from systemic hypertension. Chest 19X2J:65-X. 19X2::65-X. X. Roherts We. Wc, Anatomically isolated aortic valvular disease: the case against its heing of rheumatic etiology. Am J Med 1970:49: DePace NL. Nestico PF, Kotler MS. MS, et al. Comparison of echocardiography and angiography in determining the cause of severe aortic regurgitation. Br Heart J 19X4:51 : McKay R. R, Yacouh MH. Clinical and pathological findings in patients with "floppy" valves treated surgically. Circulation 197:47,4X(suppl 197:47,4Xtsuppl 111): II. Devereux RB. Mitral valve prolapse. Am J Med 1979:67: Read RC, RC. Thai AP, Wendt VE. Symptomatic valvular myxomatous transforination transformation (the!loppy floppy valve syndrome): a possible forme fruste of the Marfan syndrome. Circulation 1965:52:X King BD, Clark MA. MA, Baha N, Kilman JW. JW, Wooley CF. "Myxomatous" mitral valves: collagen dissolution as the primary defect. Circulation 19X2:66:2XX :66:28X Hammer D. D, Leier CV. CV, Baha N, N. Vasko JS, Wooley CF, Pinnei Pinncl SR. Altered collagen composition in a prolapsing mitral valve with ruptured chordae tendineae. Am J Med 1979:67:X Uy SA, Taylor PC. PC, Kramer JR. Progressive myxomatous degeneration of the cardiac valves. Clev Clin Q 1979:46: Wooley CF. Discussion of "mitral valve prolapse: a modem epidemic or a modem enigma"" Medical Times 19XI:I09: :109: Durack DT, Beeson PD. Pathogenesis of infective endocarditis. In: Rahimtoola SH. SH, ed. Infective Endocarditis. New York: Grune & Stratton, 197X:I-5. ton. 1978: Roberts We. Characteristics and consequences of infective endocarditis (active or healed or hoth) learned from morphologic studies. In Ref 17: Theil R, Martin FH, Edwards JE. Bacterial endocarditis in subjects 60 years of age and older. Circulation 1975:51: Soman VR, Breton G, Hershkowitz M, Mark H. Bacterial endocarditis endm:arditis of mitral valve in Marfan's syndrome. Br Heart J 1974J6: :6: