Calcific Aortic Valve Disease and Stenosis

The prevalence of valvular heart disease in the adult population of the USA is more than five million people [13, 14]. Aortic valve disease is now the third most common cause of cardiovascular disease. There are an estimated 95,000 surgical valve procedures performed each year in the USA. Aortic valve disease is responsible for more than 25,000 annual deaths. Untreated, calcific aortic stenosis has a fatal outcome within 2–5 years once the patient presents with angina, syncope, or heart failure due to the valve lesion.

Degeneration and calcification of a congenitally bicuspid aortic valve leads to clinical presentation of aortic stenosis in middle age whereas the disease process involving a tricuspid aortic valve progresses to clinical significance in older individuals (Figs. 1.1 and 1.2). The overall prevalence of degenerative aortic valve disease has risen as life expectancy has increased [6, 7, 13, 14].

The pathogenesis of calcific aortic stenosis involves a response of the valve to injury with common features to the pathogenesis of atherosclerosis (see schema below) [15–17]. Modulation of valvular interstitial cells (VICs) by transforming growth factor-ß is an important mechanism contributing to valve fibrosis. Subsequent expression of molecules that promote calcification occurs at a later stage. This basic information has led to therapeutic trials of interventions involving control of risk factors and use of statins, metal metalloproteinase inhibitors and angiotensin converting enzyme inhibitors [13]. Most experience has been obtained with statin therapy for lipid control. Although the randomized trials did not confirm slowing of the progression of aortic stenosis, the largest trial did demonstrate improvement in primary end points of ischemic vascular disease [18].

Floppy Valve (Myxomatous Degeneration) and Connective Tissue Dyscrasias

Mitral valve prolapse is a common disorder with a strong hereditary component which occurs in approximately 2% of the general population [19]. Mitral valve prolapse occurs in various genetic syndromes and as an idiopathic, non-syndromic condition with an autosomal dominant inheritance pattern [20]. The pathological correlate is myxomatous valvular degeneration.

Although myxomatous degeneration has been described in tricuspid, aortic, and pulmonary values, the mitral value is most commonly involved, and the posterior leaflet is affected more often and more severely than is the anterior leaflet. Grossly, the most outstanding feature is marked increase in surface area of the affected leaflets (Fig. 1.3), which are voluminous, hooded, and white; however, they transilluminate with ease, especially before fixation. On sectioning, the myxomatous consistency of the center of the leaflet is often apparent on gross examination. Small foci of ulceration with occasional superimposed thrombi may be noted on the atrial surface of the affected mitral leaflet [1, 3, 4]. The chordae tendineae often are elongated and thin; however, some localized thickening may be present at their insertions into the valve leaflets (Fig. 1.4). Rupture of the chordae tendineae is common in myxomatous degeneration of the mitral valve: less frequently, myxomatous degeneration may result in aneurysmal dilatation and rupture of a mitral leaflet. Commissural fusion is not a feature of the floppy valve. Because these valves are predisposed to infective endocarditis, gross evidence of this complication must be sought by the surgical pathologist, so that appropriate sections can be obtained for culture before fixation of the valve.

Microscopically, the spongiosa contains stellate cells embedded in a matrix rich in proteoglycans (Fig. 1.5). Characteristically, there is focal to extensive replacement of the normal dense, homogeneous collagen of the fibrosa by this myxomatous tissue. This histologic pattern is in contrast to that seen in most valvular heart diseases, in which the spongiosa of the leaflets is partially or completely replaced by dense fibrous tissue. The collagen in the chordae tendineae may show changes similar to those in the fibrosa. The atrialis of the leaflet generally contains a variable degree of fibroelastic proliferation, and superficial ulceration with microscopic fibrin deposition is not uncommon. Unless there is superimposed infective endocarditis, there is no evidence of inflammation or vascularization. Ultrastructurally, there is focal loss of the normal orderly cross-banding of collagen fibers. Microscopically, small areas of myxomatous degeneration may be found near the free edges of normal or diseased valves and should not be confused with the diffuse findings in floppy valves.

Myxomatous degeneration of the cardiac valves, with resulting insufficiency, often occurs in connective tissue dyscrasias such as Marfan syndrome, osteogenesis imperfecta, cutis laxa, and relapsing polychondritis. This group of diseases may also be associated with cystic medial degeneration of the aorta. Adults with Marfan syndrome most commonly have myxomatous degeneration of the aortic valve; in children, however, the mitral valve is more commonly involved [21]. The affected mitral and aortic leaflets contain an accumulation of myxoid material mainly in the spongiosa. Recent studies have shown the importance of matrix metalloproteinases in the pathogenesis of these lesions in the Marfan syndrome [22]. The Ehlers-Danlos syndrome is a heterogeneous group of several genetically distinct disorders of connective tissue synthesis, which differ in major clinical features, inheritance patterns, and biochemical defects. Cardiovascular lesions have been described in types I–IV; however, myxomatous degeneration and prolapse of the mitral valve appear to be more common in type III, the benign hypermobile form [21]. The most common valvular lesion in osteogenesis imperfecta is aortic regurgitation; mitral regurgitation and combined aortic and mitral regurgitation are less common. The aortic regurgitation results from dilatation of the aortic root and deformity of the valvular leaflets, which become abnormally translucent, weak, and elongated. Aneurysms of the sinuses of Valsalva also occur. The mitral annulus is dilated, the mitral leaflets are attenuated and redundant and tend to prolapse, and the chordae tendineae may rupture [21]. In cutis laxa, the most common cardiac lesions involve the aorta, pulmonary artery, and pulmonary veins; less commonly, there may be myxomatous degeneration of the aortic or mitral valves [2]. The aortic and mitral valves are the cardiac valves most commonly involved in relapsing polychondritis. Lesions may be microscopically identical to those in the other connective tissue dyscrasias [1].

The pathogenesis of myxomatous degeneration is thought to involve abnormal homeostasis of the valvular extracellular matrix related to complex genetic factors. The hypothesis has been advanced that genetic defects present at the time of valve morphogenesis, coupled with individual variation in genetic background, may lead to progressive alterations leading to clinical disease [23, 24].

Endocrine and Metabolic Valvular Diseases

In carcinoid heart disease , there is either focal or diffuse plaque-like thickening of valvular and mural endocardium and, occasionally, of the intima of the great veins, coronary sinus, pulmonary trunk, and main pulmonary arteries. The fibrous tissue is atypical and limited in the majority of instances to the right side of the heart. When the pulmonary valve is involved, deposition is almost exclusively on the arterial aspect of the valve cusps (Fig. 1.6). When the tricuspid valve is involved, however, the fibrous tissue is located predominantly on the ventricular aspect, often causing the leaflets to adhere to the adjacent ventricular wall [25]. Similar lesions may be observed in the mitral and aortic valves in patients with a patent foramen ovale or a functioning bronchial carcinoid tumor [26]. In some patients with predominant right-side carcinoid heart disease, the mitral and aortic valves also may be involved to a lesser degree. Microscopically, these lesions contain fibroblasts, myofibroblasts, and smooth muscle cells embedded in a distinctive stroma, which is rich in collagen and proteoglycans but lacking in elastic fibers. Blood vessels, often thick-walled, may be immediately adjacent to the valve leaflets. Lymphocyts and plasma cells are frequently located adjacent to these blood vessels.

Histologically, similar valvular and endocardial lesions have been described in patients taking methysergide [27] and ergot [28]; however, the mitral and aortic valves are most commonly involved in these cases. A decade ago, similar valvular lesions were described in patients taking fenfluramine and phentermine for appetite suppression [29].

The heart valves are involved in 50% of patients with cardiac amyloidosis . Valvular involvement is usually minimal, but discrete nodules measuring from 1 to 4 mm in diameter are occasionally present on the valves either in the cusps or in the annulus [21]. Rarely, valvular involvement is diffuse, resulting in thick, rigid cusps and stenotic or regurgitant orifices (Fig. 1.7). The four cardiac valves are affected with almost equal frequency.

All heart valves and valvular annuli, especially the mitral and aortic valves, are sites of heavy pigment deposition in patients with ochronosis [21]. Although the pigment deposition is most prominent at the bases of the mitral and aortic valves and annulus fibrosus, the edges of the cusps may be roughened and fused for 1–2 mm at their bases; the cusps may be focally calcified. The ochronotic pigment appears blue-black on gross examination and yellow-tan in histologic sections. Infective endocarditis may occasionally be superimposed, especially when the valves are heavily calcified.

The cardiac valves may be involved in any of the mucopolysaccharidoses , most frequently in Hurler’s syndrome (mycopolysaccharidosis I) [21]. The valves are considerably thickened, particularly the mitral valve; right-sided cardiac valves are less severely affected than those in the left side of the heart (Fig. 1.8). The valvular thickening is most pronounced at the free margins, which have an irregular, nodular appearance. The commissures are not fused. The chordae tendineae of the atrioventricular valves are moderately shortened and thickened. Calcific deposits occur in the angle just beneath the basal attachment of the posterior mitral leaflet (mitral annular calcification), in the mitral leaflets, and in the aortic aspect of the aortic valve cusps. The valves contain large, oval or rounded connective tissue cells (Hurler cells) filled with numerous clear vacuoles, which are the sites of deposition of acid mucopolysaccharides [21]. This material is extremely soluble and difficult to preserve. In addition, small granular cells are present, which contain membrane-limited electron-dense material associated with fragments of collagen fibrils. The valve thickening is due to the presence of the cells and to an increase in the amount of fibrous connective tissue.

In Fabry’s disease , the glycosphingolipid is deposited within the cardiac valves, occasionally resulting in valvular dysfunction [21]. The mitral and aortic valves are the two valves that most commonly present clinical problems. There may be thickening of the valves with interchordal hooding, or there may be attenuation of the chordae with thickening and ballooning of the mitral valve. Commissural fusion is not a feature of Fabry’s disease.

Type II hyperlipoproteinemia (familial hypercholesterolemia ) exists in homozygous and heterozygous forms, which differ in the severity and age of onset of clinical symptoms. Aortic valvular disease is frequent in homozygous patients but does not usually occur in heterozygous patients. The aortic valve may be markedly stenosed by fibrous tissue, deposits of foam cells, and cholesterol crystals in the cusps. Thickening of the mitral valve, which results in both stenosis and regurgitation, and thickening of the pulmonary valve and endocardium by foam cells also occur [21].

Patients with gout most commonly develop dysfunction due to hypertension secondary to renal damage; however, tophi occasionally may be present in the heart, most commonly in the mitral valve and the endocardium of the left ventricle and, less frequently, in the mitral annulus and aortic and tricuspid valve leaflets [21, 30]. To establish the diagnosis histologically, appreciable amounts of uric acid must be identified in the tophi to distinguish them from small amounts of uric acid that may be deposited on previously existing fibrocalcific lesions. Urate deposits are histochemically identifiable by fixation in absolute ethanol, followed by staining by the De Galantha method .

Collagen Vascular Diseases

Rheumatic Valvulitis

Acute rheumatic fever produces a pancarditis ; however, valvular involvement is responsible for the most important long-term consequences. In the acute phase of rheumatic valvulitis , the most conspicuous lesions are minute, translucent nodules (verrucae) along the lines of closure of the valve cusps (Fig. 1.9). These are most frequently observed in the mitral and aortic valves, less often in the tricuspid, and rarely in the pulmonary valve. They vary in diameter from less than 1 to 3 mm and are located on the atrial surface of the atrioventricular valves and on the ventricular surface of the semilunar valves [25]. Occasionally, a few verrucae may be distributed elsewhere over the cusps. They are also characteristically present on the chordae tendineae, especially those of the mitral valve, and not infrequently, they extend over the posterior leaflet of the mitral valve onto the endocardium of the left atrium. The verrucae tend to conglomerate on the corpora arantii of the aortic valve and extend in a row along the semilunar cusps. Diffuse thickening of the valves, except the pulmonary, is a less conspicuous but frequent gross alteration.

Microscopically, the verrucae may have the appearance of either thrombi, formed by the deposition of platelets and fibrin on the surface of the valve, or extruded collagen that has undergone fibrinoid degeneration. The region immediately adjacent to the vegetation shows marked proliferation of fibroblasts, as well as edema and numerous lymphocytes [25]. The inflammatory process is observed most frequently in the auricularis layer of the atrioventricular valves and the ventricularis layer of the semilunar valves. A nonspecific inflammatory process, which may involve the entire valve and ring, consists of edema, increased numbers of capillaries, and a variety of inflammatory cells (mainly lymphocytes; occasionally polymorphonuclear leukocytes predominate). Plasma cells, fibroblasts, and other mononuclear cells are often present in variable numbers. Usually the valve also contains Anitschkow and Aschoff cells, which may be arranged in nodules or in rows and often surround foci of eosinophilic fragmented collagen, fibrinoid, or both. Aschoff cells may be multinucleated [31]. These lesions are typically accompanied by characteristic Aschoff nodules in the myocardium [25, 31, 32].

Gross alterations of the cardiac valves become more pronounced as a result of recurrent rheumatic valvulitis. Thickening, irregularity of the surfaces, and gross vascularization are usually present. This thickening is usually most pronounced in the distal third of the valve leaflets [25]. The chordae tendineae become thicker and shorter, with especially prominent thickening at their insertions into the valve leaflets. Verrucae in various stages of activity and healing may be observed. In addition to being thickened, the aortic cusps may be considerably shortened, with their free margins rolled and inverted toward the sinus pocket. Fibrous adhesions are commonly present at the commissures, and verrucae in various stages of activity may extend across the commissures of aortic cusps. In recurrent valvulitis, there is a higher incidence of verrucae on the valves of the right side of the heart, and microscopic observation reveals considerable fibrosis, an apparent increase in elastic tissue, and inflammatory changes in various stages of activity [25, 32]. The fibrosis and inflammation involve the rings as well as the leaflets. This histologic pattern differs from that of acute valvulitis , in which the thickening of the valves is the result only of edema and inflammation. Also in contrast to the appearance of acute valvulitis are numerous arteries with thick muscular walls in the ring and proximal portion of the valve.

In chronic rheumatic valvulitis , the alterations described in recurrent valvulitis are most advanced. Usually, the diffuse thickening and fibrosis of the valves have resulted in loss of elasticity and in narrowing of the orifice (Fig. 1.10). Thickening, fusion, and shortening of the chordae tendineae of the mitral valve are usually pronounced (Fig. 1.11). In addition, focal deposits of calcium salts may be present. These deposits may be extensive and may project to the atrial and ventricular surfaces, causing further distortion. Ossification, complete with hematopoiesis, may occur, causing further distortion [32]. Verrucae are less frequent in chronic valvulitis than in recurrent valvulitis and are broad and flat. Active inflammation is less pronounced in chronic than in recurrent valvulitis and usually consists of scattered foci of perivascular cuffing with lymphocytes. The grossly apparent thickening is due to an increase in fibrous and elastic tissue throughout the entire leaflet including the rings and the tips of the valves. The fibrous connective tissue is usually homogeneous and hyaline. These valves are vascularized by capillaries and thick-walled vessels, which are most numerous in the superficial layers. The verrucae no longer consist of material showing fibrinoid necrosis, but are organized and contain fibroblasts and collagen fibers. As chronicity progresses, the number of fibroblasts decreases, and the verrucae become dense, hyalinized scars.

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