Pontos importantes sobre doença aórtica adquirida:
- “Nodular calcific aortic stenosis” is the most common cause of aortic stenosis in the elderly, and consists of nodules of calcification on the aortic surface of the valve leaflets, with sparing of the free edges and commissures. A diagnosis of “nodular calcific aortic stenosis, trileaflet valve” is appropriate on surgical specimens, and histologic evaluation is not necessary unless there is a suspicion of superimposed endocarditis or if there are possible vegetations.
- “Nodular calcific aortic stenosis” also occurs on bicuspid aortic valves with similar pathogenesis, but accelerated, occurring 10-15 years earlier on average. A diagnosis of “nodular calcific aortic stenosis, congenitally bicuspid valve” is warranted (see chapter 30).
- Post-inflammatory disease is less common in developed countries, and typically involves the mitral valve as well (often there are two valves replaced, or at autopsy mitral disease is evident). There is thickening of the leaflets with far less calcification, and commissural fusion may necessitate removal of the valve in one piece. A diagnosis of “post-inflammatory (post-rheumatic) aortic valve disease” is appropriate. Often there is no clear history of rheumatic fever, so the more non-specific diagnosis of “post-inflammatory” is indicated unless there is a history. Postinflammatory aortic disease is often a combination of stenosis and insufficiency, and there are pure forms of aortic stenosis and aortic insufficiency.
- Acquired bicuspid aortic valve may be due to post-inflammatory (post-rheumatic) disease, or post-infectious, or idiopathic. The gross distinction between acquired and congenital bicuspid valve partly depends on angle of the fused leaflets: it is generally acute in acquire disease, and the raphe forms an obtuse angle in congenital bicuspid valve.
- Aortic insufficiency is typically caused by aortic root dilatation (unless there is endocarditis, see chapter 35). The specimen typically consists of stretched, thin, pliable unremarkable leaflets. If there is a portion of aorta, the presence of dissection should be noted, and histologic evaluation of the aortic wall is warranted to evaluate for the presence of cystic medial necrosis and exclude rare causes of aortic root dilatation, such as aortitis. A diagnosis on the valve specimen could be simply “aortic valve, replacement: changes consistent with aortic insufficiency”. Histologic evaluation is generally not necessary unless there are vegetations.
- Review of operative notes is always helpful to obtain the surgeon’s impression of the intact valve.
- Other causes of acquired aortic valve disease are rare.
TEXTO PARA REVISÃO (DO LIVRO PRACTICAL CARDIOVASCULAR PATHOLOGY):
The two most common causes of acquired aortic valve disease are degenerative calcific aortic stenosis and post-inflammatory aortic disease. Degenerative calcific stenosis is the most common cause for aortic valve replacement, especially in older adults. Post-inflammatory valve disease is etiologically linked to prior rheumatic fever and is typically seen in association with mitral stenosis (see chapter 33). Autoimmune valve sclerosis can also occur in the setting of ankylosing spondylitis and HLA B27 disease. The diseased aortic valve can show both stenosis and insufficiency. In addition to these more common causes of aortic disease, there are a number of rare entities related to iatrogenic causes (anorexigen drugs, ergotamine, radiation induced valve disease), systemic diseases (ochronosis and carcinoid) that may produce acquired aortic valve disease and are discussed below.
Aortic sclerosis, which is clinically defined as valve thickening without obstruction to outflow, is present in about 25% of patients over 65 years of age. The incidence of symptomatic stenosis is approximately 5 in 10,000, and is generally a disease of the elderly. Congenitally bicuspid valves are over 20 times more likely to become stenotic than normally formed aortic valves, and calcify at a younger age (see Chapter 30). Risk factors that increase the incidence overlap with those predisposing to atherosclerosis, and include hypercholesterolemia and elevated C-reactive protein levels. Recently, there has been an association with elevated serum fetuin levels (1,2).
Aortic stenosis: clinical findings
Patients with calcific degenerative aortic stenosis present in the 6th to 9th decades and account for more than 70% of the patients undergoing valve replacement in the United States. There are two subsets of patients: those with congenitally bicuspid valves, who are usually younger (chapter 30) and those with trileaflet (normally formed) valves, who are usually older than 70 years. There is an approximate equal incidence between the two groups of aortic stenosis, and the pathologic process of nodular calcification is the same in both. However, there is a significant difference in the onset of symptomatic disease. Nodular calcific aortic stenosis in bicuspid valves typically presents in the 60’s, whereas degenerative calcific changes on trileaflet valves generally become symptomatic when patients are in the 70’s or 80’s. Patients with chronic renal failure and secondary hyperparathyroidism have symptomatic disease at an earlier age, because of an increased risk for tissue calcification.
There is a male predominance ranging from 1.6:1 to 4:1, depending on etiology. Clinically, most patients have stenosis or combined stenosis and insufficiency. The natural history of aortic stenosis is characterized by a prolonged period in which the disease is only incidentally detected. The rate of progression is slow, but seems to be more rapid in patients with degenerative calcific disease compared to patients with congenital or post-inflammatory valve disease (3). 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. The development of symptoms usually signifies advanced disease with hemodynamic compromise. Patients usually present at this later stage with a systolic murmur. Echocardiography is used to quantitate the degree of gradient, assess the degree of valve thickness (sclerosis), and measure the size and function of the left ventricle. It can also be used to follow patients with established diagnosis of aortic stenosis to assess progression of disease.
In symptomatic patients with severe aortic stenosis due to calcific disease, aortic valve replacement is indicated, as the surgery improves symptoms and survival (4). Because of the risk of sudden death, valve replacement should be performed promptly after symptoms appear. Most sudden death patients were symptomatic prior, but sudden death has been reported to occur rarely in asymptomatic patients (3,5). The decision replace the valve in asymptomatic patients is more difficult when the risks of the surgery, longevity of bioprosthetic valves and morbidity related to mechanical valves are considered. In young patients, percutaneous balloon valvotomy may be elected. This is a safe procedure with debatable results in the elderly however, as restenosis and recurrence of symptoms occurs within 6 to 12 months in a great proportion of the elderly population (6,7).
Calcific aortic stenosis, trileaflet valve
Gross pathology, autopsy
Aortic sclerosis with leaflet calcification and little or no stenosis is a common incidental finding at autopsy in the elderly. If there was clinical evidence of valve disease, or if the cause of death is uncertain, then the degree of stenosis should be estimated, based on valve findings and degree of ventricular hypertrophy. If there are other potential causes for left ventricular hypertrophy, such as hypertension, then a description of the valve is especially important in determining to what degree it contributed as a cause of death. Assessment of size of aortic valve orifice is not generally feasible, especially in fixed specimens. However, before opening of the left ventricular outflow, approximate dimensions of the functional opening should be made, and the degree of stenosis estimated by passage of a little finger, which should encounter no resistance in a normal valve. The normal aortic orifice valve area as determined echocardiographically is >2.0 cm2. A valve area of 1.5-2.0 cm2 is considered mild aortic stenosis, 0.8-1.5 cm2 corresponds to moderate stenosis, and <0.8 cm2 corresponds to severe stenosis.
The evaluation should also document degree and location of calcified deposits (Figures 1-3), presence of median raphe that would indicate a bicuspid valve, commissural fusion, status of the aortic annulus and evaluation of the aortic root for signs of dilatation. Heart weight and measurements of left ventricular free wall and left ventricular chamber diameter (excluding papillary muscles) are important to document the degree of cardiac hypertrophy and remodeling. In about 5% of patients, there is asymmetric hypertrophy with an increase in septal:free wall ratio.
Gross pathology, resection
Surgically excised valves for nodular calcific aortic stenosis may be fragmented during surgical procedure due to heavy calcification, or the valve leaflets may be relatively intact (Figures 4-7). The calcification usually begins in the base of the cusp and spares the free margins, thus commissural fusion is rare. Gross inspection and documentation of degree of calcification is sufficient for a diagnosis of degenerative calcific aortic disease. A median raphe is absent, and represents a reliable sign in the differential diagnosis of congenital bicuspid aortic disease. Unless endocarditis is suspected, histologic examination is not always necessary.
Microscopic evaluation plays a small role in the diagnosis of calcific aortic stenosis, and is not necessary to perform routinely. If there is evidence of thrombosis, vegetation, or discoloration, then histologic assessment is necessary. 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 (Figures 8 and 9). In addition to nodular calcification, there is mild chronic inflammation (8,9). The sparse inflammation is composed of macrophages, plasma cells and lymphocytes. The latter have been implicated as a source of cytokines that recruit additional inflammatory cells that lead to remodeling of the valve tissue matrix (10,11). If there are dense macrophage infiltrates or any neutrophilic inflammation, then superimposed endocarditis should be excluded by special stains or clinical correlation.
Post-inflammatory aortic valve disease
Post-inflammatory aortic valve disease, which is primarily caused by rheumatic heart disease, is virtually always associated with mitral disease. The surgical pathologists usually encounter products of valve repair or replacement in association with the repair of the mitral valve specimen. There is a slight male predominance. Post-inflammatory aortic stenosis may affect congenitally bicuspid valves as well as trileaflet valves. About 40% of symptomatic post-inflammatory aortic valves are both stenotic and insufficiency; 35% are purely stenotic and 25% are purely insufficient.
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 (Figures 10-12). 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 extending to the cusps (Figures 13-14). 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 (Figure 15). However, the angle formed by post-inflammatory stenosis is typically acute (<90°), whereas the angle formed by fused cusps, with the raphe at the apex, is typically obtuse. Furthermore, a raphe indicative of congenital valve fusion is located proximal to the sinotubular junction and typically does not meet the aortic wall. In contrast, normal commissures, as well as commissures fused by prior inflammation, meet the aortic wall at the sinotubular junction.
As in cases of degenerative aortic valve disease, histologic evaluation is not usually necessary in post-inflammatory aortic disease unless endocarditis is suspected. There is neovascularization, chronic inflammation rich in T cells, and fibrosis, similar to post-inflammatory mitral stenosis (see chapter 33). The underlying valve architecture is altered. The fused commissure consists of fibrous connective tissue with disruption of elastic tissue, in contrast to raphes, which (if not heavily calcified) are rich in intact elastic fibers. The degree of myxoid ground substance is variable, and not helpful in diagnosis.
Ankylosing spondylitis and HLAB27 related aortic insufficiency
Several seronegative spondyloarthropathies, such as Reiter’s syndrome and psoriatic arthritis, can affect the heart, but the most common is ankylosing spondylitis. Given the association of these entities with HLA-B27 antigens, HLA-B27-associated heart disease is also a generic used term. (12) The most common site affected by this disease is the ascending aorta, which can progress proximally and involve the aortic root and aortic cusps, causing clinically aortic insufficiency. (13) The incidence of aortic regurgitation in ankylosing spondylitis ranges from 10-50% of affected patients and increases with age, disease duration, and presence of peripheral arthritis. (12,14)
With chronic involvement of the aortic valve by HLA-B27 disease, the valve cusps are thickened and markedly fibrotic, which cause regurgitation. In addition, there is inward rolling of valve cusp free edges that can be seen grossly. A subaortic fibrous ridge can be caused by extension of the inflammatory process downward.(12,15) Aortic root dilatation can be severe in cases of Reiter’s disease and produce severe insufficiency. On histologic sections, chronic inflammation is usually seen.
Aortic insufficiency related to aortic root disease
Aortic insufficiency can be caused by disease of the valve itself or by dilatation of the proximal ascending aorta or of the aortic root. The most common valvar disease resulting in insufficiency is endocarditis (See chapter 35); less commonly, isolated aortic prolapse in the absence of aortic dilatation may result in aortic valve insufficiency. Aortic valve insufficiency is usually caused by dilatation of the ascending aorta, or of the aortic root (annuloaortic ectasia). Valve insufficiency develops in the setting of ascending aortic aneurysm because of dilatation of the annulus (at the sinotubular junction) with outward displacement of aortic valve commissures, preventing the leaflets from coapting (Figure 16) (16,17). In such cases, valve insufficiency can resolve with aneurysm repair; however, when aortic root dilatation is present as well, valve-sparing surgery of the aortic sinuses, sometimes with partial valve resection, or aortic valve replacement may be necessary (see chapter 49) (Figures 17 and 18).
Patients with aortic insufficiency due to aortic aneurysm are usually on the 6th to 7th decade of life, unless they have Marfan syndrome or other congenital lesions, in which case they are usually in their 3rd or 4th decades (18). In older individuals, dilatation of the aorta is most often idiopathic or related to systemic hypertension (see chapter 49). As age increases, there is worsening of the disease with increased risk to develop aortic insufficiency.
Echocardiography is indicated to confirm the presence and severity of aortic insufficiency and assess aortic root size and morphology (19). It can also measure degree of left ventricular hypertrophy and systolic function. When echocardiography is inconclusive, cardiac catheterization with aortic root angiography is indicated for assessment of severity of regurgitation, ventricular function, and aortic root diameter. Aortic root dilatation of more than 5 cm is generally an indication for surgery, with or without valve regurgitation. A lower level of dilatation at 4.5 cm or an increase faster than 0.5cm/year may also be an indication for surgery if the patient’s left ventricle is also dilated or is there abnormal systolic function.
The standard surgical treatment for severe aortic insufficiency was valve replacement with or without aortic tube graft to repair the aneurysm (Bentall procedure). Currently, selected patients can be candidates for aortic valve repair. The ability to perform valve repair depends on the degree of cusp prolapse and restriction. Repair involves root annuloplasty and valve augmentation procedures in addition to graft aneurysm repair (Figures 20-21) (20). Intraoperative evaluation with transesophageal echocardiography plays an important role in electing the type of surgical procedure in assessing the diameter and morphology of the aortic root
The pathology of the aortic valve does not show specific signs of clinical regurgitation, other than mild rolling of the free edges (Figure 19). The non-coronary aortic sinus is most commonly affected by dilatation of the sinotubular junction, followed by the right sinus and the left sinus (21). With associated aortic root disease, the aorta usually shows medial degeneration, with or without dissection. The surgical pathologist usually receives an intact valve or portion of leaflet (Figure 22) (if valve-sparing procedures are performed) and a portion of aortic wall. Cases in which the valve insufficiency is resolved by aortic aneurysm repair alone, no valve tissue will be submitted.
Aortic valve prolapse
Aortic insufficiency without aortic root or ascending aortic dilatation and without evience of endocarditis or post-inflammatory disease is uncommon. In some centers there is a relatively high rate of aortic valve prolapse without apparent aortic root disease (22). Pathologic changes are non-specific (Figure 22) and are indistinguishable from aortic insufficiency due to aortic aneurysm. Aortic tissue is not received with the aortic valve specimen, as is typical in cases of aneurysm repair with concomitant aortic valve replacement.
Miscellaneous acquired aortic valve disease
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 (23). The pathogenesis of cardiovascular ochronosis is unclear, but is probably related to the extensive extracellular deposits of ochronotic pigment, homogentisic acid (Figure 24). Accumulation of this pigment can lead to an inflammatory reaction and to progressive valve dysfunction (24).
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 (25) and rarely with diffuse aortic calcification (“porcelain aorta”) (26) Echocardiographically there is a unique and consistent pattern of thickening of the aortic and mitral valves involving the aortic-mitral curtain. (27). Most reported cases of aortic stenosis after radiation are case reports (28)
Carcinoid valve disease is caused by serotonin [5-hydroxytryptamine (5-HT)]-mediated injury. Generally right-sided valves are involved, and only rarely does aortic and mitral disease occur. By similar pathogenetic mechanisms, methysergide-associated valvular disease results from stimulation of myofibroblast growth, mediated by the serotonin agonist effect,, causing characteristic “onlay” lesions thickening the valves. (29-31). Onlay lesions (or “stuck-on plaques” also occur after exposure to phentermine and fenfluoramine (Fen-phen); however, symptomatic disease is rarely, and there is mild regurgitation of predominantly aortic and mitral valves. The histologic of the valves show proliferation of myofibroblastic cells with myxoid stroma. Small vascular channels and slight lymphocytic infiltrate, without destruction of the underlying valve structure. (32)
1. Burke AP, Kolodgie FD, Virmani R. Fetuin-A, valve calcification, and diabetes: what do we understand? Circulation 2007;115:2464-7.
2. Kaden JJ, Reinohl JO, Blesch B, et al. Systemic and local levels of fetuin-A in calcific aortic valve stenosis. Int J Mol Med 2007;20:193-7.
3. Rosenhek R, Binder T, Porenta G, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343:611-7.
4. Lund O, Pilegaard HK, Magnussen K, Knudsen MA, Nielsen TT, Albrechtsen OK. Long-term prosthesis-related and sudden cardiac-related complications after valve replacement for aortic stenosis. Ann Thorac Surg 1990;50:396-406.
5. Otto CM, Burwash IG, Legget ME, et al. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262-70.
6. Berland J, Cribier A, Savin T, Lefebvre E, Koning R, Letac B. Percutaneous balloon valvuloplasty in patients with severe aortic stenosis and low ejection fraction. Immediate results and 1-year follow-up. Circulation 1989;79:1189-96.
7. Davidson CJ, Harrison JK, Leithe ME, Kisslo KB, Bashore TM. Failure of balloon aortic valvuloplasty to result in sustained clinical improvement in patients with depressed left ventricular function. Am J Cardiol 1990;65:72-7.
8. Mohler ER, 3rd, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation 2001;103:1522-8.
9. Veinot JP. Pathology of inflammatory native valvular heart disease. Cardiovasc Pathol 2006;15:243-51.
10. Kaden JJ, Dempfle CE, Grobholz R, et al. Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. Cardiovasc Pathol 2005;14:80-7.
11. Leask RL, Jain N, Butany J. Endothelium and valvular diseases of the heart. Microsc Res Tech 2003;60:129-37.
12. Bergfeldt L. HLA-B27-associated cardiac disease. Ann Intern Med 1997;127:621-9.
13. Huffer LL, Furgerson JL. Aortic root dilatation with sinus of valsalva and coronary artery aneurysms associated with ankylosing spondylitis. Tex Heart Inst J 2006;33:70-3.
14. Lautermann D, Braun J. Ankylosing spondylitis–cardiac manifestations. Clin Exp Rheumatol 2002;20:S11-5.
15. O’Neill TW, Bresnihan B. The heart in ankylosing spondylitis. Ann Rheum Dis 1992;51:705-6.
16. David TE, Armstrong S, Ivanov J, Webb GD. Aortic valve sparing operations: an update. Ann Thorac Surg 1999;67:1840-2; discussion 1853-6.
17. Frater RW. Aortic valve insufficiency due to aortic dilatation: correction by sinus rim adjustment. Circulation 1986;74:I136-42.
18. David TE. Aortic valve-sparing operations for aortic root aneurysm. Semin Thorac Cardiovasc Surg 2001;13:291-6.
19. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84-231.
20. Boodhwani M, de Kerchove L, Glineur D, et al. Repair-oriented classification of aortic insufficiency: impact on surgical techniques and clinical outcomes. J Thorac Cardiovasc Surg 2009;137:286-94.
21. David TE, Feindel CM, Bos J. Repair of the aortic valve in patients with aortic insufficiency and aortic root aneurysm. J Thorac Cardiovasc Surg 1995;109:345-51; discussion 351-2.
22. El Khoury G, Vanoverschelde JL, Glineur D, et al. Repair of aortic valve prolapse: experience with 44 patients. Eur J Cardiothorac Surg 2004;26:628-33.
23. Ffolkes LV, Brull D, Krywawych S, Hayward M, Hughes SE. Aortic stenosis in cardiovascular ochronosis. J Clin Pathol 2007;60:92-3.
24. Butany JW, Naseemuddin A, Moshkowitz Y, Nair V. Ochronosis and aortic valve stenosis. J Card Surg 2006;21:182-4.
25. Chenu PC, Schroeder E, Buche M, Marchandise B. Bilateral coronary ostial stenosis and aortic valvular disease after radiotherapy. Eur Heart J 1994;15:1150-1.
26. Daitoku K, Fukui K, Ichinoseki I, Munakata M, Takahashi S, Fukuda I. Radiotherapy-induced aortic valve disease associated with porcelain aorta. Jpn J Thorac Cardiovasc Surg 2004;52:349-52.
27. Brand MD, Abadi CA, Aurigemma GP, Dauerman HL, Meyer TE. Radiation-associated valvular heart disease in Hodgkin’s disease is associated with characteristic thickening and fibrosis of the aortic-mitral curtain. J Heart Valve Dis 2001;10:681-5.
28. Adabag AS, Dykoski R, Ward H, Anand IS. Critical stenosis of aortic and mitral valves after mediastinal irradiation. Catheter Cardiovasc Interv 2004;63:247-50.
29. Hauck AJ, Edwards WD, Danielson GK, Mullany CJ, Bresnahan DR. Mitral and aortic valve disease associated with ergotamine therapy for migraine. Report of two cases and review of literature. Arch Pathol Lab Med 1990;114:62-4.
30. Hendrikx M, Van Dorpe J, Flameng W, Daenen W. Aortic and mitral valve disease induced by ergotamine therapy for migraine: a case report and review of the literature. J Heart Valve Dis 1996;5:235-7.
31. Xu J, Jian B, Chu R, et al. Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells. Am J Pathol 2002;161:2209-18.
32. Volmar KE, Hutchins GM. Aortic and mitral fenfluramine-phentermine valvulopathy in 64 patients treated with anorectic agents. Arch Pathol Lab Med 2001;125:1555-61.