Aortic Stenosis Pathology

Aortic stenosis can be caused by acquired conditions, be the result of a congenital malformation, or be a result of a combination of acquired and congenital processes. Acquired stenosis of the aortic valve, which affects adults, is most often caused by calcification of the leaflets themselves and is considered an age-related or degenerative process. Postrheumatic aortic stenosis is another common cause of acquired aortic stenosis, and is a result of remote infection from group A streptococci that triggers an autoimmune process resulting in scarring of the valve leaflets. Radiation and ochronosis are rare causes of acquired aortic stenosis.

Congenital aortic stenosis is classified as valvular, subvalvular, and supravalvular. Congenital aortic stenosis becomes symptomatic in childhood.

Bicuspid and unicuspid aortic valve disease are congenital conditions. Bicuspid and unicommissural unicuspid valves generally function normally for the first few decades, after which superimposed degenerative changes occur, at a faster rate that normal trileaflet aortic valves. The pathologic findings, clinical symptoms, and treatment are similar to degenerative aortic stenosis in trileaflet valves.

Evaluation of valve disease is typically performed by echocardiography. Hardening of the aortic valve, usually by degenerative calcification, with a jet velocity of less than 5 mm/second is considered aortic sclerosis and is asymptomatic. Greater jet flow velocity with a gradient of less than 20 mm Hg is considered mild stenosis. A gradient of between 20 and 40 mm Hg is considered moderate, and more than 40 mm Hg severe aortic stenosis, according to American Heart Association guidelines.[1]

See also Aortic Stenosis, Pediatric Valvar Aortic Stenosis, Pediatric Rheumatic Heart Disease, and Pathology of Rheumatic Heart Disease.

Calcific aortic stenosis has been also termed “degenerative aortic stenosis” and "fibrocalcific aortic stenosis." Calcific aortic valve disease occurs on previously normally-functioning valves, either bi- or trileaflet, and less commonly on unicuspid valves. Calcification is an intrinsic part of the degenerative process.

Molecular studies have pointed to proteins related to osteoblastic differentiation in the pathogenesis of calcific degenerative valve disease,[2] as well as inflammatory pathways involving proteoglycan matrix.[3] Degenerative aortic stenosis is currently the most common indication for valve surgery, as the population ages and newer techniques, such as minimally invasive surgery and transcutaneous methods, become available.

Epidemiology and risk factors

At present, the most common cause of valve replacement in the United States is aortic stenosis secondary to calcification. Aortic sclerosis, which is clinically defined as valve thickening without obstruction to outflow, is the most prevalent valve disease in developed countries, being present in about 25% of patients over age 65 years. The incidence of symptomatic stenosis, a more advanced form of sclerosis that causes symptoms, is approximately 5 in 10,000 and is generally a disease of the elderly. There is a male predominance ranging from 1.6:1 to 4:1. The mean age at presentation is around 75 years.[4, 5]

Risk factors that increase the incidence overlap with those predisposing to atherosclerosis and hypertension, smoking, and diabetes and obesity.[6] The role of hyperlipidemia and statin treatment in the prevention of aortic stenosis is unclear, although hypercholesterolemia is an often cited risk factor.

Clinical findings

Patients with severe calcific degenerative aortic stenosis can be categorized into three clinical groups at the time of diagnosis: those without evidence of congestive heart failure, those with chronic congestive heart failure, and those with acute heart failure requiring hospitalization. The first group accounts for about 60% of patients, with the other two about 20% each. The prognosis is especially poor in the setting of acute heart failure, for which aortic valve replacement provides the least benefit.

Most patients have stenosis or combined stenosis and a minor degree of insufficiency. The natural history of aortic stenosis is characterized by a prolonged period in which the disease is only incidentally detected. During the initial phases, the left ventricle adapts to the increased systolic pressure overload and develops hypertrophy with normal chamber volume. This is followed by concentric left ventricular hypertrophy, which may cause reduced coronary blood flow and subendocardial ischemia, even in the absence of epicardial coronary disease. Eventually, symptoms of angina, syncope, and heart failure develop—these usually signify advanced disease with hemodynamic compromise.

The rate of sudden death in patients with aortic stenosis is as high as 1.4% per year in asymptomatic patients. Independent risk factors for sudden death have been reported to include hemodialysis, history of myocardial infarction, and obesity.[7]

Autopsy findings

Degenerative calcific aortic valve disease is characterized by nodules of calcification on the aortic (nonflow) side of the leaflets, usually near the base of the sinuses. The degree of stenosis at autopsy is estimated by evaluating the stiffness of the valves, as assessed by palpation or passage of an instrument or finger prior to opening the outflow tract. The evaluation should also document the degree and location of calcified deposits, presence of a median raphe that would indicate a bicuspid valve, commissural fusion, intimal calcification of the ascending aorta, and evaluation of the aortic root for signs of dilatation.

Aortic Stenosis Pathology. Calcific aortic stenosis, autopsy. There are nodules seen on the leaflet surfaces, as viewed from the aortic aspect. These nodules impede the movement of the cusps, resulting in a pressure gradient across the valve.

In the myocardium in patients with left ventricular hypertrophy secondary to aortic stenosis, the amount of myocardial fibrosis has been shown to affect long-term survival after aortic valve replacement.[8]

Surgical pathology findings

Surgically excised valves for nodular calcific aortic stenosis may be fragmented during the surgical procedure due to heavy calcification, or the valve leaflets may be relatively intact. The calcification begins in the base of the cusp and spares the free margins, thus commissural fusion is rare. Gross inspection and documentation of the degree of calcification is sufficient for a diagnosis of degenerative calcific aortic disease. Endocarditis is an infrequent complication of calcific aortic stenosis but can be easily missed without histologic evaluation.

Aortic Stenosis Pathology. Calcific aortic stenosis, trileaflet valve. There are nodules covering the surfaces of the cusps, which are approximately equal in size. The valve was normal for much of the life of the patient and then gradually calcified and became stenotic.

The histologic findings include nodules of calcification at the base of the leaflets on the aortic surface, which occur on pools of fibrin, similar to nodular calcified plaques seen in nodular calcific deposits in coronary and carotid atherosclerosis. In addition to nodular calcification, there is mild chronic inflammation composed of macrophages, plasma cells and lymphocytes.

Aortic Stenosis Pathology. Calcific aortic stenosis, histologic appearance. The bright pink areas are nodules of fibrin incorporated into the valve which become calcified and harden the valve, resulting in stenosis.

Epidemiology

Congenitally bicuspid aortic valve is present in about 1-2% of the population. There is a male predominance of up to 4:1. Familial studies suggest that congenital bicuspid aortic valves follow autosomal dominant inheritance patterns with reduced penetrance.

Although the rate of complications is not well documented, it has been stated that the majority of patients with bicuspid aortic valve will eventually require surgery before reaching old age. Aortic stenosis is the most common complication of bicuspid aortic valve, as 80% of symptomatic patients have pure stenosis, 10% pure insufficiency, and 10% combined stenosis and insufficiency. The mean age at surgery for bicuspid aortic stenosis is between 60 and 65 years. The pathologic features are identical to degenerative calcific disease occurring at an older age in patients with normal trileaflet valves. The risk factors are also shared, and they include smoking and hyperlipidemia.[9, 10, 11]

Replacement of bicuspid valves occurs at about half the rate to nearly equal the rate of replacement of trileaflet calcified valves. Because of the low prevalence (about 1.5%) of bicuspid valves in the general population, this rate represents a 20-30-fold increased risk for the development of aortic stenosis.

Pathologic findings

The gross findings of degenerative calcified bicuspid aortic valves are similar to those seen in trileaflet valves, with the exception of the leaflet number and presence of raphes. Fewer than one in four bicuspid valves show equal-sized, symmetric leaflets without raphes. A raphe, or abortive commissure in the midpoint of the fused leaflet, is present in about 75% of bicuspid valves and does not extend to the aortic wall at the level of the sinotubular junction, but lower in the sinus. This feature helps the pathologist distinguish from acquired postinflammatory fusion of one commissure. In those cases, the angle formed by the two leaflets, with the vertex at the commissure, is generally less than 90º, whereas it is >90º in congenitally bicuspid valves.

Aortic Stenosis Pathology. Bicuspid calcific aortic stenosis. Both cusps are approximately the same size. There is a suggestion of a raphe on the slightly larger cusp at the bottom, appearing as a whitish ridge in the center of the leaflet.

Aortic Stenosis Pathology. Bicuspid aortic stenosis, with prominent raphe. There are two commissures, at the left upper and lower, with an incomplete commissure at the right in the middle, called a raphe. The valve was resected for replacement relatively intact in this case.

Fusion of the right and left cusps (type 1 fusion) occurs in more than 80% of cases, between the right and noncoronary (type 2) in about 10-12%, and in the left and noncoronary in less than 5% (type 3). In the most common form, both main coronaries arise from the sinus of the anterior conjoint cusp. In type 2 fusion, the right coronary ostium is often close to the raphe or center of the fused leaflet. In type 3 fusion, the right ostium is often near the commissure of between the noncoronary half of the fused leaflet, and the right leaflet. In all types, but especially types 2 and 3 fusion, the angle between the two coronary ostia is usually greater than 120º. In approximately 12% of patients, the coronary ostia are nearly 180º apart, on opposite sides of the aortic root.[12]

Calcification is a constant finding in bicuspid aortic valve with clinical stenosis. It begins on the raphe and extends to the cusps, forming nodules on the aortic surface. Secondary left ventricular hypertrophy occurs similar to aortic stenosis from any cause.

The histologic findings are identical to those of degenerative changes on trileaflet valves.

The incidence of unicuspid aortic valve is low, estimated at 0.02% of patients referred for echocardiography. In series of resected valves, they represent 2-3% of all aortic valve replacements and 5% of aortic valves resected for stenosis.[13, 14] Ascending aortic repair is often required for associated aneurysm.[13]

Unicommissural aortic valves are heavily calcified with rigid cusps and typically have a “teardrop” shape. They represent a subset of unicuspid valves; individuals without a commissure usually develop symptoms in childhood, although these may present in adulthood. Patients with unicuspid, unicommissural aortic valves may live asymptomatic for decades, after which the valves undergo degenerative calcification. Symptomatic valve disease occurs earlier than with bicuspid valves, and typically before the sixth decade. The mean age at replacement is in the fifth and early sixth decade.[14]

Aortic Stenosis Pathology. Unicuspid aortic valve. The single commissure was present at the bottom, excised at surgery. At about the 10 o'clock and 2 o'clock meridians are white ridges corresponding to raphes, or abortive commissures. In unicuspid valves, two of the three commissures are incomplete, as opposed to bicuspid valve, where only one is incomplete.

The rate of calcification in unicuspid valve is presumed to be 100% by the seventh decade. The most common form is of a single commissure, with 0-2 raphes; in the minority of cases, a single conjoint leaflet with three raphes and a central orifice can be seen. Leaflet dysplasia is common, and calcification variable.

Clinically, the valves are usually both stenotic and insufficient, due to the lack of coaptation of the leaflet. Patients are at risk of developing infective endocarditis and aortic dissection. The risk for aortic dissection is greater than that of bicuspid aortic valves, approximately 14 times the general population.

Degenerative calcific aortic stenosis may also occur on quadricuspid valves, which is an extremely rare anomaly, present in less than .03% of the population.

Overview of rheumatic valve disease

Postrheumatic or postinflammatory valve disease refers to scarring of the valve that occurs secondary to an autoimmune reaction following infection with group A streptococci. Acute valve disease occurs with the pancarditis of acute rheumatic fever and is associated with small sterile vegetations on the lines of closure of the mitral valve.

Most patients recover from an episode of acute rheumatic carditis without sequelae, but the outcome worsens if the episodes recur. Therefore, overall prognosis is mostly dependent on severity of the carditis and recurrent episodes of rheumatic fever. In all, it is estimated that 60% of patients will at one time in their lives develop chronic heart valve disease, most commonly in the form of mitral valve scarring.

Rheumatic aortic stenosis

Postinflammatory aortic valve disease is virtually always associated with mitral disease. The surgical pathologist usually encounters a mitral valve specimen in addition to the aortic valve, unless the mitral valve was repaired without excision. Postinflammatory aortic stenosis may affect congenitally bicuspid valves as well as trileaflet valves.

Clinical findings

About 40% of symptomatic postinflammatory aortic valves are both stenotic and insufficient; 35% are purely stenotic and 25% are purely insufficient.

Pathologic findings

There is diffuse fibrosis of the valve cups, resulting in shortening that results almost invariably in a component of aortic insufficiency as well as stenosis, by preventing leaflet coaptation. Calcification can be present, but nodules do not typically form at the base, as in degenerative calcification. When present, calcification may occur in the fused commissures and extend to the cusps. Commissures are often fused, in contrast to nodular degenerative calcific aortic stenosis. If commissural fusion is present, the valve was likely mixed stenotic and insufficient. If only one commissure is fused, there may be confusion with congenital bicuspid aortic valve disease. Histologically, there is neovascularization, chronic inflammation, and fibrosis, similar to postinflammatory mitral stenosis.

Aortic Stenosis Pathology. Rheumatic valve disease, histologic appearance. There are neovessels within the leaflet, seen at higher magnification below.

Aortic Stenosis Pathology. Rheumatic aortic stenosis. Note that the fibrosis involves the commissures, with fusion of all three.

Aortic Stenosis Pathology. Rheumatic aortic stenosis. There is fibrosis (thickening) of the leaflets and commissures. In this example, nodules of calcification are also present, most notably at the bottom right.

Alkaptonuria (endogenous ochronosis) is a rare metabolic disorder caused by a deficiency of homogentisic acid oxidase, an enzyme responsible for the metabolic degradation of tyrosine. Patients with alkaptonuria present with arthritis and pigmentation of the ear cartilage and sclera. A small proportion of patients develop cardiac symptoms, primarily valve stenosis. Rarely, aortic valve stenosis is the first symptom. The pathogenesis of cardiovascular ochronosis is unclear but is probably related to the extensive extracellular deposits of homogentisic acid that can lead to an inflammatory reaction and to progressive fibrosis.[15, 16, 17]

Grossly, the valves appear similar to degenerative calcific valve stenosis, with the added feature of black pigment. The homogentisic acid and metabolites are also visible histologically as black pigment deposits.

Aortic Stenosis Pathology. Aortic stenosis caused by ochronosis. There are calcifiied nodules, in addition to black pigment.

Approximately 0.1% of patients with mediastinal radiation develop cardiac complications, usually decades later. Fibrosis with calcification of the aortic valve can lead to stenosis, often in association with coronary ostial stenosis and rarely with diffuse aortic calcification (“porcelain aorta”). Echocardiographically, there is a unique and consistent pattern of thickening of the aortic and mitral valves involving the aortic-mitral curtain. Most reported cases of aortic stenosis after radiation are case reports.[18, 19] The gross and histologic findings are nonspecific and consist of fibrosis with leaflet thickening, usually with less commissural involvement than in rheumatic valve disease.

Aortic Stenosis Pathology. Radiation aortic stenosis. There is diffuse thickening due to fibrosis, which results in a lack of leaflet translucency.