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Spectrum of Calcific Aortic Valve Disease

2005; Lippincott Williams & Wilkins; Volume: 111; Issue: 24 Linguagem: Inglês

10.1161/circulationaha.104.486738

1524-4539

Rosario V. Freeman, Catherine M Otto,

Infective Endocarditis Diagnosis and Management

HomeCirculationVol. 111, No. 24Spectrum of Calcific Aortic Valve Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBSpectrum of Calcific Aortic Valve DiseasePathogenesis, Disease Progression, and Treatment Strategies Rosario V. Freeman, MD, MS and Catherine M. Otto, MD Rosario V. FreemanRosario V. Freeman From the Division of Cardiology, Department of Medicine, University of Washington School of Medicine, Seattle, Wash. and Catherine M. OttoCatherine M. Otto From the Division of Cardiology, Department of Medicine, University of Washington School of Medicine, Seattle, Wash. Originally published21 Jun 2005https://doi.org/10.1161/CIRCULATIONAHA.104.486738Circulation. 2005;111:3316–3326Calcific aortic valve disease is a slowly progressive disorder with a disease continuum that ranges from mild valve thickening without obstruction of blood flow, termed aortic sclerosis, to severe calcification with impaired leaflet motion, or aortic stenosis (Figure 1). In the past, this process was thought to be "degenerative" because of time-dependent wear-and-tear of the leaflets with passive calcium deposition. Now, there is compelling histopathologic and clinical data suggesting that calcific valve disease is an active disease process akin to atherosclerosis with lipoprotein deposition, chronic inflammation, and active leaflet calcification. The overlap in the clinical factors associated with calcific valve disease and atherosclerosis and the correlation between the severity of coronary artery and aortic valve calcification provide further support for a shared disease process. Download figureDownload PowerPointFigure 1. Gross specimen of minimally diseased aortic valve (left) and severely stenotic aortic valve (right). In the severely stenotic valve, there are prominent lipocalcific changes on aortic side of valve cusps (arrow), with sparing of commissures.Pathogenesis of Calcific Aortic Valve DiseaseAnatomy of Normal Aortic ValveThe normal aortic valve comprises 3 layers. The ventricularis, on the ventricular side of the leaflet, is composed of elastin-rich fibers that are aligned in a radial direction, perpendicular to the leaflet margin. The fibrosa, on the aortic side of the leaflet, comprises primarily fibroblasts and collagen fibers arranged circumferentially, parallel to the leaflet margin. The spongiosa is a layer of loose connective tissue at the base of the leaflet, between the fibrosa and ventricularis, composed of fibroblasts, mesenchymal cells, and a mucopolysaccharide-rich matrix. These layers work in concert to provide tensile strength and pliability for decades of repetitive motion.Early Lesion of Aortic SclerosisHistopathologic studies of aortic sclerosis show focal subendothelial plaquelike lesions on the aortic side of the leaflet that extend to the adjacent fibrosa layer. Similarities to atherosclerosis are present in these lesions, with prominent accumulation of "atherogenic" lipoproteins, including LDL and lipoprotein(a), evidence of LDL oxidation, an inflammatory cell infiltrate, and microscopic calcification (Figure 2).1–5Download figureDownload PowerPointFigure 2. Potential pathways depicting calcific aortic valve disease. T lymphocytes and macrophages infiltrate endothelium and release cytokines that act on valvular fibroblasts to promote cellular proliferation and extracellular matrix remodeling. A subset of valvular fibroblasts within fibrosa layer differentiate into myofibroblasts that possess characteristics of smooth muscle cells. LDL that is taken into the subendothelial layer is oxidatively modified and taken up by macrophages to become foam cells. ACE is colocalized with apolipoprotein B (ApoB) and facilitates conversion of angiotensin II (AngII), which acts on angiotensin 1 receptors (AT-1R), expressed on valvular myofibroblasts. A subset of valvular myofibroblasts differentiate into osteoblast phenotype that is capable of promoting calcium nodule and bone formation. IL indicates interleukin; TGF, transforming growth factor; and MMP, matrix metalloproteinases.Initiating FactorsThese early aortic lesions are likely initiated by endothelial disruption due to increased mechanical or decreased shear stress, similar to that seen in early atherosclerotic lesions. Mechanical stress of the aortic valve is highest on the aortic side of the leaflet in the flexion area, near the attachment to the aortic root. Shear stress across the endothelium of the noncoronary cusp is lower than the left and right coronary cusps because of the absence of diastolic coronary flow, which likely explains why the noncoronary cusp is often the first cusp affected. Further supporting the effects of leaflet stress as an instigating event is the discrepancy in average age at the time of presentation when tricuspid and bicuspid valves are compared, despite the identical histological appearance of lesions. Patients with bicuspid valves, which are subjected to higher mechanical stress, tend to present 2 decades younger than those with tricuspid valves.6,7 Nearly all patients with bicuspid valves develop significant outflow obstruction over time, whereas only a relatively small proportion of patients with a trileaflet valve progress to severe aortic stenosis.LipoproteinsWithin each valve leaflet, focal, extracellular lipid accumulation is seen in several small areas in the subendothelial region, with displacement of the elastic lamina and extension into the adjacent fibrosa (Figure 3).1 Apolipoproteins B, (a), and E are present in the vicinity of these lipid-rich areas, which implies that the lipids were derived from plasma lipoproteins.3 Oxidatively modified LDLs, associated with proinflammatory and growth-stimulatory properties, have been identified and are subsequently taken up by macrophages to become foam cells analogous to atherosclerotic lesions.4Download figureDownload PowerPointFigure 3. Examples of histological findings in early and late lesions of calcific aortic valve disease. Early lesion (left) demonstrates accumulation of cells and extracellular lipid and matrix in a subendothelial location on aortic side of leaflet, with displacement of normal subendothelial elastic lamina (arrow). In the late lesion (right), there is more prominent accumulation of lipid, cells, and extracellular matrix. Elastic lamina is displaced and fragmented (arrow). In both examples, the disease process extends into adjacent fibrosa. (Verhoeff-van Gieson stain, original magnification ×100).InflammationInflammatory cells are the predominant cell type in early aortic valve lesions, with T lymphocytes2,5 and macrophages identified.1 Monocytes infiltrate the endothelial layer via adhesion molecules and differentiate into macrophages.8 Activated T lymphocytes within the subendothelium and fibrosa release cytokines, such as transforming growth factor-β1,9 and interleukin-1β, a proinflammatory cytokine associated with increased local production of matrix metalloproteins,10 all of which contribute to extracellular matrix formation, remodeling, and local calcification. Tenascin C, which has been involved in growth promotion, stimulation of bone formation, and mineralization, is present in calcified aortic leaflets and is both coexpressed and overexpressed with matrix metalloproteinases.11,12Extracellular Matrix and ACEACE has been identified in aortic sclerotic lesions.13 Although there is evidence that some ACE may be produced locally, the majority was extracellular and colocalized with apolipoprotein B, a component of retained LDL particles, which suggests that the ACE may be "carried" into the lesion via LDL cholesterol particles. Additionally, angiotensin II, which has been associated with promotion of monocyte infiltration and enhancement of the uptake of modified LDL within atherosclerotic lesions, has been detected in early aortic sclerotic lesions, which implies that the ACE identified was active enzymatically.13In the diseased aortic valve, a subset of the normal valve fibroblasts within the fibrosa layer differentiate into myofibroblasts, which possess smooth muscle cell characteristics, with expression of α-actin, vimentin, and desmin.1,14 In advanced aortic stenotic valve specimens, angiotensin type-1 receptors have been detected on a subset of the myofibroblasts that express α-actin, which again suggests that the ACE detected is active enzymatically.13 Further investigations will be required to better define the potential role for the renin-angiotensin system and causative pathways in the pathogenesis of calcific aortic valve disease.Leaflet Calcification and End-Stage LesionsActive calcification is prominent early in the disease process and is a major factor in the leaflet stiffness of severe stenosis.15 With aortic sclerosis, microscopic areas of calcification colocalize in areas of lipoprotein accumulation and inflammatory cell infiltration. Oxidized LDL stimulates valvular fibroblasts to release matrix vesicles, a nidus for early calcification. It has been shown that macrophages express osteopontin, a protein needed in bone formation, with the degree of mRNA expression of osteopontin corresponding to the degree and location of valvular calcification.16,17 A subset of valvular myofibroblasts are an osteoblast phenotype and have been associated with development of calcific nodules.18,19 An increased rate of calcific nodule formation by these myofibroblasts has been shown in vitro by exposure to oxidized lipids and transforming growth factor-β1.19As the disease progresses, active bone formation is seen. In an evaluation of 347 human aortic valves removed for aortic valve replacement, the majority (83%) had evidence of dystrophic calcification, and up to 13% contained lamellar or endochondral bone tissue with hematopoietic marrow and evidence of remodeling.20 Within the specimens that contained bone tissue, there was expression of factors that promote osteogenesis, including bone morphogenic protein-2 and -4.20,21The importance of tissue calcification in the disease process is highlighted by the observation that subsets of patients with altered mineral metabolism have a higher prevalence of calcific aortic valve disease and more rapid disease progression.22,23 Anecdotally, it has been observed that in patients with osteoporosis or increased bone demineralization, the prevalence of any valvular calcification is higher, possibly related to increased body mineral turnover or ectopic calcification; however, this hypothesis has been examined in only a few published studies, with inconsistent results.24,25 Whether this association represents a true causal relationship or is just an incidental association due to the high prevalence of both disorders in the elderly is not evident at this point.Genetic factors may be important in the development of valve leaflet calcification. In a recent case-control study of 100 patients with aortic stenosis matched for age, gender, and coronary artery disease compared with those without aortic stenosis, there was a significant difference in vitamin D receptor genotypes.26 In addition, other genetic polymorphisms of interleukin-10, connective tissue growth factor, and chemokine receptor-5 appear to influence the degree of valvular calcification.27 Other studies of apolipoprotein polymorphisms provide further support for a possible genetic component to valvular calcification and stenosis.28,29In addition to native aortic valves, calcific changes in bioprosthetic valves are a prominent feature of primary valve failure; however, the prevalence of calcification and bioprosthetic valve failure appears to decrease with age in contrast to native valves. In a study of 196 patients receiving a bioprosthetic aortic valve, 18 of 20 cases of primary valve failure occurred in those <65 years old.30 Similarly, in another study of 653 patients who underwent aortic valve replacement, younger age was the only predictor of valve failure and need for reoperation.31,32 This paradox suggests that the calcific process of bioprosthetic valves is different from the process observed in native valves.32Relationship Between Tissue Changes and Clinical DiseaseThe histological changes seen in aortic sclerosis with lipoprotein accumulation, cellular infiltration, and extracellular matrix formation result in macroscopic, progressive valve thickening. As these changes progress, increasing calcification corresponds to leaflet immobility and the outflow obstruction characteristic of end-stage aortic stenosis (Figure 4). Download figureDownload PowerPointFigure 4. Echocardiographic images of aortic sclerosis (A, B) and severe aortic stenosis (C, D). Continuous wave Doppler signal from both subjects was taken from an apical window. 2D image of sclerotic aortic valve (A) shows focal leaflet thickening with mild leaflet restriction of noncoronary cusp during systole. Overall jet velocity is minimally increased at 2.4 m/s. In contrast, aortic cusps of the severely stenotic valve are thickened and calcified, with severely restricted leaflet motion during systole (C). This corresponds to jet velocity of 4.7 m/s (D).Aortic SclerosisDiagnosis and EpidemiologyAortic sclerosis is common, present in ≈25% of people 65 to 74 years of age and in 48% of people older than 84 years.33–35 It is defined echocardiographically by focal areas of valve thickening, typically located in the leaflet center with commissural sparing and normal leaflet mobility. Diffuse leaflet thickening is not characteristic of aortic sclerosis; instead, it suggests normal aging changes, a different valvular pathology, or an imaging artifact. With aortic sclerosis, valvular hemodynamics are within normal limits, with an antegrade velocity across the valve 2000 patients with aortic sclerosis were studied. In this cohort, 16% developed aortic stenosis, with mild stenosis developing in 10.5% (jet velocity 2 to 3 m/s), moderate stenosis in 3% (jet velocity 3 to 4 m/s), and severe stenosis in 2.5% (jet velocity >4 m/s). The average time interval from a diagnosis of aortic sclerosis to progression to severe aortic stenosis was 8 years.51 Similar findings were seen in a smaller study of 400 subjects with aortic sclerosis,52 in which 5% of patients developed moderate aortic stenosis and 2.5% of patients developed severe aortic stenosis. Although only a small percentage of patients with aortic sclerosis progress to aortic stenosis, this proportion still represents a substantial number of patients overall, and it is likely that the number of those who progress to severe valve obstruction would increase in parallel with a longer follow-up duration. Given the adverse morbidity and mortality event rates in patients with aortic sclerosis and the significant portion who do subsequently develop aortic stenosis, these data highlight the need for close clinical follow-up and serial evaluation of patients once aortic sclerosis is identified.51Calcific Aortic StenosisEpidemiologyThe prevalence of calcific aortic stenosis increases with age, being present in 2% to 4% of adults over age 65 years.34,35 Aortic stenosis is the most common acquired valvular disorder found in developed countries. Within the United States, there are ≈50 000 aortic valve replacements performed for severe aortic stenosis annually.Diagnostic EvaluationThe standard diagnostic evaluation of aortic stenosis includes assessment of leaflet anatomy and the extent of valvular calcification by echocardiography. The severity of aortic stenosis can be measured accurately and reliably on the basis of antegrade velocity, mean pressure gradient, and continuity equation valve area. Because symptom onset does not correspond to a single value in all patients, there are no absolute breakpoints that define severity in adults; however, general guidelines are presented in Table 2. Beyond this information, echocardiography provides an assessment of left ventricular hypertrophy, diastolic dysfunction, and regional and global systolic function with calculation of ejection fraction. Other associated abnormalities also are evaluated, including aortic dilation, coexisting mitral valve disease, and pulmonary hypertension. Serial echocardiography in patients with aortic stenosis provides valuable interval information, with the timing of examination determined by the stenosis severity and any changes in physical examination or clinical status. Current clinical guidelines suggest that echocardiography is appropriate annually in patients with severe asymptomatic stenosis, every 2 years in those with moderate aortic stenosis, and every 5 years in patients with mild aortic stenosis.53 Cardiac catheterization for measurement of the transvalvular gradient is reserved for the rare patient in whom echocardiography is nondiagnostic or when clinical and echocardiographic data are discrepant. Coronary angiography is usually needed before valve surgery to determine whether concurrent coronary artery bypass surgery is needed. TABLE 2. Guidelines for Grading Severity of Calcific Aortic Valve DiseaseAntegrade Jet Velocity, m/sAortic Valve Area, cm2Aortic sclerosis<2.5NormalMild aortic stenosis2.5– 1.5Moderate aortic stenosis3.0– 4.0 4.0 m/s) (A) and those with mild to moderate aortic stenosis (jet velocity 2.5 to 4.0 m/s) (B), extent of valvular calcification significantly affected event-free survival, with events defined either as death or valve replacement necessitated by symptom onset. P=0.0001. Reproduced with permission from (A) Rosenhek et al77 (The New England Journal of Medicine; Copyright 2000 Massachusetts Medical Society; all rights reserved) and (B) Rosenhek et al78 (The European Heart Journal; Copyright 2004 The European Society of Cardiology; permission from Elsevier).Aortic valve disease progression to symptom onset warranting aortic valve replacement can occur even in the absence of hemodynamically severe valvular obstruction at baseline. In a study of patients with mild or moderate aortic stenosis (jet velocity between 2.5 and 4 m/s), the likelihood of surviving without need for valve replacement was 95% at 1 year and 60% at 5 years. Peak jet velocity was an independent predictor of outcome, along with the severity of valve calcification and coexistent coronary artery disease. Importantly, in this population of aortic stenosis patients with relatively milder hemodynamic severity, 19% of the total cohort developed symptoms during the follow-up time period, with the extent of valvular calcification again a significant factor associated with either death or symptom onset that necessitated valve replacement (Figure 5B).78 This again reinforces the need for close clinical monitoring in any patient with asymptomatic aortic stenosis, regardless of severity at initial diagnosis.Symptom Onset in Adults With Aortic StenosisAlthough the cardinal symptoms of severe aortic stenosis are angina, congestive heart failure, and syncope, clinicians should also monitor for more subtle symptoms, such as a decrease in exercise tolerance or exertional dyspnea.72 Symptomatic patients with severe stenosis have a dismal prognosis if valve replacement is delayed. In one study of symptomatic patients who refused surgery, average survival was only 2 years, with a 5-year survival rate <20%.71 In another study, only 40% of patients with symptomatic, severe aortic stenosis survived 2 years, and only 12% remained event free after 5 years of follow-up.70 In contrast, symptomatic patients who undergo aortic valve replacement have an age-corrected postoperative survival that is nearly normalized.80 Therefore, current guidelines advocate surgical referral for aortic valve replacement once cardiac symptoms are present.53If symptom determination is equivocal, stress testing can be a helpful adjunct to delineate exercise tolerance and possible symptoms. Stress testing can be performed safely when monitored by an experienced physician76 but should be ended promptly if the patient experiences symptoms or if there is a decrease or minimal increase (<20 mm Hg) in blood pressure. During stress testing of an otherwise asymptomatic individual with severe aortic stenosis, provocation of symptoms, a limited exercise tolerance, or a blunted blood pressure response to exercise should prompt consideration of surgical referral. In patients with mild aortic stenosis with provocation of symptoms, other causes should be evaluated, such as myocardial ischemia from coronary artery disease.The most common symptom of aortic stenosis is exertional dyspnea or decreased exercise tolerance due to the inability of the heart to adequately increase stroke volume to meet increased metabolic dem