MORPHOLOGICAL EVALUATION OF THE SURGICALLY EXCISED AORTIC AND MITRAL VALVES (Abstact): In 2001, of the 114 valves surgically excised at the Iasi Center of Car1diology from 59 men and 54 women (mean age 51 years; age range: 25 to 78 years), half  were aortic and the other half mitral valves. The 57 aortic valves, from 20 women and 37 men (mean age 51.1; age range 25 to 78 years), had been surgically replaced. Functionally, 57.63 percent (30) were stenotic, 21.05 percent (12) were incompetent, and 26.31 percent (15) were both stenotic and incompetent (aortic disease). Pure stenosis was related to calcification of   degenerative (73.3 percent), bicuspid (3.33 percent), post-inflammatory (20 percent), and undetermined (3.33 percent) causes. Pure regurgitation was not related to calcification and causes included infective endocarditis (50 percent), bicuspid valve (16.66 percent), postinflammatory (16.66 percent), aortic root dilatation (8.33 percent), and undetermined (8.33 percent). Aortic disease was secondary to postinflammatory etiologies (40 percent), degenerative calcification (33.33 percent), bicuspid and undetermined (13.33 percent each) causes. The reminder of 57 mitral valves, from 35 women and 24 men (mean age 45.5 years; age range 28 to 71 years), were surgically replaced. Functionally, 40.35 percent (23) were purely stenotic, 19.29 percent (11) were purely regurgitant, and 40.35 percent (23) both stenotic and regurgitant (mitral disease). The causes of pure stenosis were postinflammatory (presumably rheumatic) disease in 91.3 percent (21 cases) and degenerative disease in 8.7 percent  (3 cases). Pure regurgitation etiology involved floppy valves in 45.45 percent (5 cases), degenerative disease in 27.27 percent (3 cases), postinflammatory disease in 18.18 percent  (2 cases) and infective endocarditis 9.1 percent (1 case). Key words: AORTIC VALVE, MITRAL VALVE, VALVE DISEASE

INTRODUCTION
     The valvular dysfunction may result from a variety of mechanisms including calcification, fibrosis, scar retraction, perforation, and congenital malformation (1, 2). Previous studies of the valves removed surgically at different centers have shown substantial changes in the relative frequency of the various etiologic categories by evaluating the pathologic features of surgically excised aortic and mitral valves (3-6). In general, conclusions regarding the underlying etiology have been based on gross inspection of the entire valve, removed during valve replacement procedures (7, 8). 
     Thus, the current investigation was undertaken in view of determining an accurate etiologic diagnosis, and for assessing the etiological trend of valve disease in further investigations, having this paper as a reference. 

MATERIALS AND METHODS
     All aortic and mitral valves excised at the Iasi Center of Cardiology (CCI) during 2001 were assessed by gross and histological means, as recommended by Davies and Roberts. Based on morphological criteria each valve was classified as degenerative, post-inflammatory (presumably rheumatic), congenitally bicuspid, associated with aortic root dilatation, or involved by active or healing endocarditis. Valves that could not be confidently classified under one of the above categories were considered to be of undetermined etiology.  For each specimen the patient's chart was reviewed and the following information was recorded: age, gender, pertinent clinical diagnosis, valvular functional state (assessed by electrocardiography and at operation), the surgeon's description of the valve and aortic root, and the results of the histological examination of the excised tissue. In assessing the functional state of the valves, mild degrees of either stenosis or incompetence were not taken into account. Thus, the functional state was recorded as pure stenosis when the valve was moderately or severely stenotic, and pure regurgitant when the valve was moderately or severely regurgitant. Although the incidence of aortic and mitral disease (combined valvular disease) etiology is a little different from isolated valvular disease etiology, the etiological chart of aortic and mitral disease is relatively similar with that of pure aortic and mitral regurgitation. 

RESULTS AND DISCUSSIONS 
AORTIC STENOSIS (AS)
     Age and gender distribution: The mean age for the entire group with aortic stenosis was 62.5 years (50 to 75 years) with little variation in mean age for patients in the major etiologic categories. Sex distribution revealed a male predominance (17 to 13). Males also predominated for degenerative disease (13 to 10).
     Morphology and etiological classification: Obstruction of the aortic valve orifice generally results from fibrocalcific processes that produce cusp thickening or commissural fusion impeding cusp excursion. In our study, according to Waller (9), the three most common causes of aortic stenosis in surgical specimens were, in decreasing order, degenerative calcification, calcification of congenital bicuspid valve, and calcification of postinflammatory valves. 

1. We found the degenerative calcification as the most common cause of aortic stenosis, accounting for 73.3 percent (22 of 30) of the cases. Such a calcification in a tricuspid aortic valve is best known as "senile" or tricuspid aortic valve stenosis.  According to Waller's description (9), our studied degenerative aortic valves showed, as common features, fibrosis and calcification. The calcified lesions were arranged as nodular arch-like ridges along the aortic aspect of each cusp, that is anchored to the annulus. As a result, degenerative lesions gave rigidity to the cusps and favored the development of stenosis. Commissural fusion was minimal or absent.  Waller (9) considers that this feature serves to differentiate the degenerative forms of aortic valve disease from other causes, particularly the post-inflammatory state. Waller reported, in his institution, from 980 surgically excised aortic valves, 9.5 percent were involved by degenerative calcification and 55 percent of them occurred in men. 

2. The frequency of post-inflammatory disease in our surgical population was of 20 percent (6 patients). Morphologically, two pathological processes characterize chronic rheumatic aortic valve stenosis: cusp fibrosis and fusion of the commissures. In our cases, cusp fibrosis was diffuse rather than focal, leading to cusp thickening and rigidity; secondary calcification, produced as diffuse and nodular pattern, involving either cusps or commissures, was responsible of valve stenosis. In some of our cases, the calcific mass underwent ulceration permitting the secondary development of superimposed surface small thrombi. The post-inflammatory form of aortic valve disease was a chronic, apparently non-infectious fibrosing process that produced valvular distortions, resembling with chronic rheumatic valvulitis (fig. 1) . Davies (10) considers that this entity should not be designated as rheumatic unless there is a clinical history of previous acute rheumatic fever, because nonrheumatic disorders (such as rheumatoid arthritis, systemic lupus erythematosus), or possibly even viral valvulitis may produce similar lesions. Waller (9) reported that of 980 surgically excised aortic valves 48 percent were involved by post-inflammatory disease; of these, 35 percent were purely stenotic. In agreement with Virmani and Burke (11), we concluded that the present lower rheumatic incidence might be related to several factors including the decreasing incidence of acute rheumatic fever in many Western countries. Waller (9) also noticed that post-inflammatory involvement tended to occur in patients less than 70 years, with 57 percent in men. 

3. We found in our study only one case of congenital aortic stenosis (CAS) (fig. 2) . Generally, CAS is the result of valvular dysplasia and hypoplasia, regardless of the number of cusps (3). The congenital bicuspid state was the single anomaly of the aortic valve encountered in our study. Davies (10) appreciated that the term CAS should be used only when the obstruction is present at or soon after birth. In rest, only 1 percent of the population could present a risk of developing aortic valve stenosis, at 40 to 50 years of age, by producing secondary dystrophic calcification of a congenital bicuspid valve. Burke (11) showed there must be a considerable variation in the susceptibility of individuals to develop cusp calcification, the causes of which are unknown yet. 
     The morphological study of the bicuspid aortic valve (BAV) revealed that one cusp was larger than the other, the larger cusp containing a shallow ridge or raphe; this could represent the line of congenital fusion of the two cusps. Like Waller (1), we noticed in our case the calcification occurring on the raphe and along the aortic aspect of the nonconjoined cusp contributing to cusp rigidity. Waller (9) reported that among his 980 surgically excised aortic valves 33 percent were congenitally bicuspid and 75 percent of them occurred in men. Burke (11) observed that CAS affect men three to four times more frequently that women, and also tend to occur in patients less than 70 years old. 

4. In 33.3 percent of our cases the etiology was undetermined, being considered as unspecific cause.

AORTIC INCOMPETENCE OR AORTIC REGURGITATION 
     Age and gender distribution: The mean age was 49.5 years (25 to 66), with little variation between the major etiologic categories. Sex distribution showed male predominance (10 to 2). Males also predominated in the categories of infective endocarditis (5 to 1). We found this degenerative aortic stenosis at a mean age of 67 years, while Davies (10) observed this senile entity was rare under the age of 70 years, generally occurring in older patients.
     Morphology and etiological classification: It is well known that in aortic regurgitation (AR) the aortic orifice exceeds in total area the root of the aorta. The both recognized causes of the AR were present in our study: the aortic valve disease (A) and the ascending aortic disease (B). 

A1. In our study the most common cause of AR was infective endocarditis, encountered in 50 percent of the cases (6 patients), and represented healed forms of endocarditis and not active ones. Morphologically, the valvular lesions included fibrous thickening, cusp erosions, and scar retractions corresponding with the areas of previously treated infection. We had in all cases a clinical history of infective endocarditis. These cases suggest that an aortic infective endocarditis is not always fatal if the patient has been treated with antibiotics. Waller (9) reported that among 980 aortic valves surgically excised in his institution 3.2 were involved by endocarditis, and 93 percent of these occurred in men.

A2. The second identified cause of AR in our surgical specimens was post-inflammatory disease, which accounted for 16.66 percent (2 patients) of the cases (fig.3) . Grossly, the aortic valves showed cusp fibrosis producing scar retraction of the cusps; there was no commissural fusion, thereby resulting a valvular incompetence. In his work, Davies (10) revealed the formation of small rigid cusps is characteristic for chronic rheumatic disease, and Waller (9) registered purely AR in 25% of post-inflammatory aortic valve disease.

A3. According to Davies (10), the patients with bicuspid aortic valves usually develop stenosis, but only a small proportion develops pure regurgitation. In our study, the two cases (16.66 percent) were characterized by a marked disproportion in cusp size, containing a small amount of calcium salts. Among his 319 congenital bicuspid aortic valve, Waller (9) identified that 17 percent were purely regurgitant.

A4. Of the regurgitant aortic disease cases, only one case, accounting for 33,33 percent of all cases, was without specific etiology.
B. In our study we found only one case of surgically excised aortic valve with pure AR, caused by aortic root dilatation in a patient with Marfan syndrome. The patient was a 45 years old male, having a clinical history of dilated ascending aorta. In this case aortic valve incompetence was secondary to the dilatation of the aortic wall at the commissural level, so that the cusps could not converge during systole.

AORTIC DISEASE
     Age and gender distribution: The mean age for patients with degenerative disease was of 66,5 years (ranges 55 to 78), for those with bicuspid valves of 45 years (34 to 56), and of 58,5 years (49 to 68) for post-inflammatory disease. Males predominated for post-inflammatory disease (4 to 2) and for degenerative disease (3 to 2). 
Morphology and etiological classification: For the 15 cases displaying both stenosis and regurgitation the most common etiology was post-inflammatory disease – 40 percent (6 patients) followed by degenerative disease - 33,33 percent (5 patients). Other frequently observed causes included bicuspid valves 13,3 percent (2 patients) and undetermined etiology - 13,3 percent (2 patients). 

MITRAL STENOSIS (MS)
     Age and gender distribution: The mean age for the entire group of mitral stenosis was 49.5 (28 to 71 years) with little variation between the major etiologic categories. There was a female predominance (24 to 35) in the entire mitral stenosis group, women also predominating in the post-inflammatory disease category.
Morphology and etiological classification: 

1. According to Waller (9), who appreciated that rheumatic disease accounted for more than 99% of all etiologies and this had been considered synonymous with mitral stenosis, we found among 23 operatively excised stenotic mitral valves 21 cases (91.3 percent) with rheumatic etiology. 
     Morphologically, the rheumatic mitral valve involvement (fig. 4)  was characterized by diffuse fibrous thickening, affecting the margins of closure, the entire posterior and anterior leaflets; one or both commissures were fused, reducing the size of the valve orifice. In older patients we also found the association of a variable calcification contributing significantly to obstruction. The calcification located in the cusps and commissures developed both as nodules and as a more diffuse form along the closure line. Virmani (11) theorized that persons with heavy calcific deposits had higher levels of total serum cholesterol than did persons without calcific deposits.
     Histologically, the leaflet tissue was composed of dense collagen with varying amounts of calcific deposits producing major distortion of the normal leaflet layers. Like Pomerance (12), we consider that the pathology of chronic rheumatic mitral disease is not specific, being also encountered in nonrheumatic inflammatory fibrosis. On one side, the Aschoff nodule, which is pathognomonic for acute rheumatic heart disease, is rarely found within valves. On the other side, in the chronic phase of the disease the life cycle of the Aschoff nodule continues with a gradual decrease in cellular content and an increase in collagen. So, establishing the etiology of "end stage" valve disease is impossible in individual cases. We agree with Pomerance (12) and Olsen (13) to call the chronically inflammatory fibrotic mitral valves as rheumatic only in the presence of a clinical history of previous acute rheumatic fever. Another point of view supporting this etiology refers to the concomitant involvement of two valves in inflammatory process, such as mitral and aortic valves. 
     In some cases we observed a significant valvular deformation. Referring to this, Waller (9) appreciated that the fibrous thickening and distortion of the leaflet could be a sequel of any severe valvulitis. Pomerance (12) also postulated that the progression of valve deformation is independent of continued inflammatory activity, and is secondary only to continued trauma and repeated surface thrombus deposition and its transformation to fibrous tissue resulting a continuing valvular thickening. In our opinion, both factors are very important in the progression of the lesion. 
     Of 759 surgically excised stenotic mitral valves studied by Waller (9), all cases (100 percent) were classified as rheumatic in etiology, while among 452 mitral valve stenoses diagnosed by Olsen (13), the great majority, meaning 99 %, were rheumatic in etiology.

2. In our study, the etiology in the reminder of 2 mitral stenosis cases  (8,7 percent) was a degenerative disease. In these two cases the mitral stenosis was produced by massive deposits of calcium in the mitral annulus and the mitral leaflets having only focal areas of fibrous thickening.

MITRAL INCOMPETENCE OR MITRAL REGURGITATION (MR)
     Age and gender distribution: The mean age for entire group with mitral regurgitation was 49.5 years with appropriate variation between different etiologic groups, and with relatively equal proportions between the two sexes. 
     Morphology and etiological classification: Our study showed that in contrast to mitral stenosis, in which rheumatic disease accounts for more than 90 percent of surgically excised valves, the causes of pure mitral regurgitation were multiple, being represented in decreasing order by floppy mitral valve (FMV), degenerative lesions, rheumatic disease, and infective endocarditis. 
     FMV is used generally synonymously with mitral valve prolapse (MVP) and myxomatous degeneration. Several morphologic definitions use strictly histological criteria, others use morphometric criteria, and still others use a combination of both criteria for separating floppy and non-floppy etiology of pure MR, considering MVP: floppy as hereditary disease or primary MVP and non-floppy, as aging disease, or secondary MVP.  MVP (fig. 5)  was recognized pathologically and clinically by its dome or ballooned shape due to the expansion of the cusp area and elongated thin chordae, which may prolapse into the left atrium during systole and sometimes may spontaneously rupture. 
     At the histological examination of these valves we found a large portion of the central mitral valve containing a mucopolysaccharide material, appearing as myxoid degeneration resulting in a valvular disorganized structure. But, the amount of mucopolysaccharide material is increasing with advancing age. So, for differentiating floppy from non-floppy valves, Waller (9) proposed a morphological and morphometric analysis, the mucopolysaccharide material being graded from 1+ to 3+. According to Waller’s (9) indications and using only histological evaluation, we diagnosed the FMV etiology of MR in the presence of large myxoid areas (3+) with valvular architecture disorganization due to an increase in the spongiosa component and by replacing of the valvular fibrosa with mixoid material. We considered as non-FMV etiology of MR when the myxoid degeneration was focal (1+) and the spongiosa never invaded the fibrosa layer, as was the case in the floppy mitral valves. 
     Taking in consideration these morphological features we diagnosed the floppy mitral valves in 5 cases (45.45 percent), and degenerative disease (non-floppy mitral valves) in 3 cases (27.27 percent), the gross appearance being similarly due to secondary changes, including fibrosis of the surfaces of the leaflets and of the chordae tendinae. For both these etiologies the chordal rupture may be a factor in the worsening of pure MR. Davies (10) reported that the majority of patients with chordal rupture had floppy mitral valves and myxoid changes in both cusps and chordae. In his study, Olsen (13) found the FMV etiology of pure MR in 29 percent of the cases. In contrast with him, Waller (9) accounted for only 3 percent of FMV from purely surgically excised regurgitant mitral valves. 
     Regarding FMV, Davies (10) has another point of view, considering FMV as an unique pathoclinical entity with various pathogenesis, such as:  persistence of a fetal type valve structure, an age-related degeneration of collagen, a partial failure of collagen synthesis; this last concept is supported by an association of FMV with all of known genetic defects in collagen synthesis, particularly Marfan syndrome.
     According to Davies (10), the majority of the patients with chordal rupture had FMV. In our study, we also found other causes of chordal rupture, including ischemic disease (1 case of atherosclerotic coronary disease with systemic hypertension) and healed infective endocarditis (1 case).

3. In only 2 (13.13 percent) of our cases we found the involvement of the rheumatic disease in MR. 
     Morphologically, we noticed that the structural alterations of the purely regurgitant valve were different from those of the stenotic mitral valve.   Purely regurgitant rheumatic (fig. 6)  mitral valve showed diffuse fibrous thickening of the margins of closure and focal areas of fibrous thickening on the remaining portions of the leaflets; these mitral valves had minimal, if any, calcific deposits, and the commissures were not fused. The question is why some mitral valves become stenotic and others purely regurgitant even though the cause of damage, represented by acute rheumatic fever, is the same? The answer is unknown yet. 
     Of 97 patients studied by Waller (9), only 3 percent had surgically excised valves that were rheumatic in etiology. In 46 patients studied by Olsen (13), rheumatic etiology was an infrequent cause of pure MR. 

4. In our study, infective endocarditis producing pure MR was found in 1 patient (9.1 percent of the cases).
     Morphologically, we described only one surgically excised mitral valve with chronic pure MR resulting from healed infective endocarditis, presenting thickened valves by fibrous tissue in the areas of previous infection. In healed mitral infective endocarditis, erosion of the cusp edges and ruptured chordae, as in active endocarditis, were sequels of valvular fibrous tissue destruction. The patient had a history of previous active infective endocarditis. 
     Among 97 patients with surgically excised purely regurgitant mitral valves studied by Waller, healed infective endocarditis was the third most frequent etiology occurring in 5 percent (5 patients) of the cases. In 260 patients with surgically excised mitral valves, studied by Olsen (13), infective endocarditis was the fourth most common etiology, representing 6 percent of his cases. 

MITRAL DISEASE
     Age and gender distribution: The mean age was 44 years (ranges 39 to 49 years) with a minimal variation between the different etiologic categories, and with similar proportions between men and women.
     Morphology and etiological classification: in the 23 cases displaying both stenosis and regurgitation the most common cause was, in decreasing order, the inflammatory disease 69.56 percent (16 patients), degenerative disease 17.39 percent (4 cases), and in equal proportion of 4.34 percent (1 case each) by floppy mitral valve, infective endocarditis, and undetermined cause. 

CONCLUSIONS:

•  Degenerative (senile) disease is the most common cause of aortic stenosis
•  Mitral and aortic post-inflammatory (presumably rheumatic) disease is a relatively common cause in all the three functional categories: stenotic, regurgitant, and a combination of both 
•  Floppy valves is the most common cause of pure mitral regurgitation

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