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Aortic valve sclerosis and pathogenesis of calcific aortic stenosis

Aortic valve sclerosis and pathogenesis of calcific aortic stenosis
Literature review current through: Jan 2024.
This topic last updated: Mar 07, 2022.

INTRODUCTION — Aortic valve thickening (sclerosis) without stenosis is common in older adults [1]. It is often detected either as a systolic murmur on physical examination or on echocardiography or computed tomography (CT) performed for some other reason. Aortic valve sclerosis is important clinically because it can progress to aortic stenosis and is associated with increased cardiovascular risk.

This topic will discuss the pathogenesis of aortic sclerosis and calcific aortic stenosis and the diagnosis, prevalence, clinical significance, and management of aortic sclerosis. The natural history, diagnosis, and management of aortic stenosis are discussed separately. (See "Natural history, epidemiology, and prognosis of aortic stenosis" and "Clinical manifestations and diagnosis of aortic stenosis in adults" and "Medical management of symptomatic aortic stenosis" and "Medical management of asymptomatic aortic stenosis in adults" and "Indications for valve replacement for high gradient aortic stenosis in adults".)

PREVALENCE — The prevalence of aortic valve sclerosis in adults increases with age, with rates <10 percent in most study populations with mean age less than 60 years [2]. As an example, in the Monica-KORA study of 935 European adults aged 35 to 84 years, the prevalence of aortic sclerosis increased across the age distribution from 7 percent in those ages 35 to 44 years to 65 percent in those ages 75 to 84 years [3]. Sclerosis of the aortic valve is found in around one quarter of individuals ≥65 years of age [1,4-6], although the rate may be higher in selected individuals of the same age such as those presenting to the emergency department with chest pain [7]. The prevalence is even higher with more advanced age: for example, 35 percent between 75 and 84 years of age and around 50 percent of those over age 80 [5,8].

Valvular sclerosis is more common in patients with hypertension and electrocardiographic evidence of left ventricular hypertrophy [9] and in those with end-stage kidney disease on maintenance dialysis. Among dialysis patients, aortic and mitral valve sclerosis have been noted in 55 to 69 percent and 40 to 60 percent, respectively [10,11]. However, when adjusted for other cardiovascular risk factors, moderate chronic kidney disease is not significantly associated with aortic valve calcification, although it is associated with mitral annular calcification [12]. (See "Valvular heart disease in patients with end-stage kidney disease", section on 'Valvular thickening' and "Valvular heart disease in patients with end-stage kidney disease", section on 'Valvular and annular calcification'.)

PATHOGENESIS OF CALCIFIC AORTIC VALVE DISEASE — The pathobiology of aortic sclerosis and early calcific aortic valve disease shares similarities with atherosclerosis involving lipid accumulation, inflammation, and calcification. Calcification predominates in more advanced stages of aortic stenosis driving valve stiffness and narrowing. The pathobiology of calcific aortic valve disease is an area of active research, and our understanding of the cellular and molecular mechanisms of disease is in flux [13-16].

It is useful to consider it in two stages: the early initiation phase associated with aortic sclerosis and the later propagation phase associated with more advanced aortic stenosis [17]. The early initiation phase is characterized by three primary processes: lipid accumulation, inflammation, and calcification [1,18,19], and demonstrates similarities to atherosclerosis. Indeed, the incidence of aortic stenosis is related to many of the same risk factors associated with atherosclerosis. By contrast, in the later stages of aortic stenosis (the propagation phase), clear differences with the pathology of atherosclerosis emerge, most notably the predominance of calcification within the leaflets as the key driver to progressive valve stiffness and narrowing.

Initiation phase — The early phase of the disease, observed in patients with aortic sclerosis, is characterized by the following pathological findings:

Focal areas of accumulation of apolipoproteins B, (a), and E, consistent with accumulation of low density lipoprotein (LDL) and lipoprotein(a), also referred to as Lp(a), with evidence of lipoprotein oxidation [18,20].

Inflammation as evidenced by macrophage and T lymphocyte infiltration on histology [21,22], inflammatory mediators such as interleukin-1-beta and transforming growth factor beta-1 [23,24], and increased 18F-fluorodeoxyglucose uptake on positron emission tomography (PET) scanning [25,26].

Local production of proteins that promote tissue calcification, suggesting that valve calcification is actively regulated rather than being an unregulated degenerative process [27-31]. Increased 18F-fluoride activity on PET is a marker of calcification activity [32].

Production and activity of angiotensin converting enzyme [33,34].

Upregulation of adhesion molecules and alterations in matrix metalloproteinase activity [35,36].

Role of mechanical stress — Mechanical stress causing endothelial damage is thought to be the precipitating event in the development of aortic sclerosis leading to inflammatory cell infiltration and lipid deposition analogous to that seen in early atherosclerosis [5]. This is perhaps best illustrated by the bicuspid aortic valve, which is associated with increased mechanical stresses in the valve leaflets and the almost invariable development of accelerated valve calcification and stenosis, although these patients may also have a genetic predisposition to tissue calcification [37]. Similarly, it has been speculated that hypertension and the increased stiffness of the aortic root that occurs with ageing may also cause abnormally high mechanical stresses in the valve, in part explaining the association of these two factors with aortic stenosis [38].

In a cohort study of 5.4 million patients in the United Kingdom with no known cardiovascular disease at baseline, systolic blood pressure was continuously related to the risk of aortic stenosis, with each 20 mmHg increment in systolic blood pressure associated with a 41 percent higher risk of aortic stenosis (hazard ratio 1.41, 95% CI 1.38-1.45). These findings support the concept that mechanical stress is related to development of calcific aortic valve disease [39].

The association between blood pressure and incidence aortic stenosis was further explored in a Mendelian randomization study. In this study of over 300,000 patients with genetic and blood pressure data, each genetically associated 20 mmHg increment in systolic blood pressure was associated with an increased risk of aortic stenosis (odds ratio [OR] 3.26, 95% CI 1.50-7.10), supporting the causality of hypertension in development of calcific valve disease [40].

Relation to atherosclerosis — The incidence of aortic sclerosis and stenosis is associated with many of the traditional risk factors for atherosclerosis, supporting pathological similarities between the early stages of these diseases. These include smoking, hypertension, hyperlipidemia, elevated Lp(a) levels, diabetes, and metabolic syndrome [3,5,9,41-48].

The following echocardiographic studies illustrate the range of associations between the incidence of aortic valve sclerosis, aortic stenosis, and atherosclerotic risk factors:

A report from the Cardiovascular Health Study (CHS) evaluated 5176 patients ≥65 years of age: 26 percent had aortic valve sclerosis with visually apparent leaflet thickening and/or calcification, and 2 percent had aortic stenosis [5]. Multivariate analysis found significant correlations of aortic valve disease with age, male sex, Lp(a), LDL cholesterol, hypertension, and smoking.

In the Framingham Heart Study offspring cohort (n = 2683, mean age 61 years), 8 percent had at least one calcified valve, 5 percent had aortic sclerosis, and 1 percent had aortic stenosis [46]. The threshold for diagnosis of aortic sclerosis was higher in this study than in the CHS study, and the population was younger, which could explain at least in part the lower rate of aortic sclerosis. Valvular calcification was associated with age, hypertension, and diabetes.

Similar findings have been noted when aortic valve calcification was assessed by CT:

In the Multi-Ethnic Study of Atherosclerosis (MESA) study (n = 6780, mean age 63 years), the prevalence of aortic valve calcification was higher among those with metabolic syndrome (12 percent in women, 22 percent in men) or diabetes (17 percent in women, 24 percent in men) compared with those with neither risk factor (8 percent in women, 14 percent in men) [47]. Metabolic syndrome and diabetes also were associated with a larger number of new cases of aortic valve calcification (OR 1.67, 95% CI 1.21-2.31 for metabolic syndrome and OR 2.06, 95% CI 1.39-3.06 for diabetes) [49].

In contrast to the CHS study, in a MESA cohort of 5801 non-statin using participants, LDL cholesterol (LDL-C) levels were associated with the presence of aortic valve calcification only in participants younger than 65 years, although the total cholesterol to high density lipoprotein ratio was associated with a slight increase in risk for calcific disease across all ages [50]. There was a significant association between Lp(a) and the degree of aortic valve calcification across a sample of 4678 participants [51]. An Lp(a) >30 mg/dL was significantly associated with aortic valve calcification in White subjects (relative risk [RR] 1.56, 95% CI 1.24-1.96) and was borderline significant in Black participants (RR 1.55, 95% CI 0.98-2.44; p = 0.059). In Hispanic and Chinese participants, no significant associations were observed. An interaction test identified a significant effect of race/ethnicity on the association between Lp(a) and aortic valve calcification.

A subsequent study demonstrated that Lp(a) levels >30 mg/dL were associated with increased calcification activity (18F-sodium fluoride on PET), faster disease progression on CT and echocardiography, and increased risk of aortic valve replacement [52].

Relation to mineral metabolism — Disturbances of mineral metabolism may also contribute to the development of aortic valve sclerosis and mitral annular calcification, as suggested by the following observations. In the Cardiovascular Health Study community-based cohort of older adults, each 0.5 mg/dL higher serum phosphate concentration was associated with 17, 12, and 12 percent higher adjusted prevalences of aortic sclerosis, mitral annular calcification, and aortic annular calcification, respectively [53]. Other markers of mineral metabolism, including serum calcium, parathyroid hormone (PTH), and 25 hydroxyvitamin D concentrations, were not associated with either aortic or mitral calcification. Similarly, among participants with chronic kidney disease in MESA, each 1 mg/dL increase in serum phosphate within the normal range (2.5 to 4.5 mg/dL) was associated with 25 and 62 percent higher prevalences of aortic and mitral valve calcification, respectively, after adjustment for traditional risk factors for atherosclerosis, parathyroid hormone, and 1,25 dihydroxyvitamin D levels [54]. However, there are no data to indicate that appropriate calcium supplementation in adults with osteoporosis or osteopenia increases the risk of aortic valve leaflet calcification. (See 'Concurrent use of calcium supplements' below.)

Genetic factors — Genetic factors contribute to the risk of aortic sclerosis and aortic stenosis [55-65]. Genetic contributions to calcific aortic valve disease were suggested by studies of community-based populations including the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (this amalgamated participants in the Framingham Heart Study [FHS], MESA, and the Age, Gene/Environment Susceptibility-Reykjavik Study [AGES-RS]) [62,63]:

A genome-wide association study in 6942 CHARGE participants identified a single-nucleotide polymorphism located in an intron of the Lp(a) gene (rs10455872) that was significantly associated with the presence of aortic valve calcification (OR per allele, 2.05) [62]. The association was confirmed in three additional cohorts of diverse ancestry. The same polymorphism was associated with circulating Lp(a) levels, and with the development of aortic stenosis.

A Mendelian randomization study found an association between the weighted genetic risk score (GRS, a measure of the genetic predisposition to elevations in plasma lipids) for LDL-C and aortic valve calcium in 6942 participants in the CHARGE consortium [63]. The LDL-C GRS was also associated with incident aortic stenosis identified by national register in the Malmo Diet and Cancer Study (MDCS) population-based cohort.

Other risk factors for calcific aortic valve disease include specific polymorphisms in the genes for apolipoprotein E, interleukin-10, the vitamin D receptor, and angiotensin-converting enzyme [58-61]. Patients with familial hypercholesterolemia are at risk for developing severe premature calcific valvular aortic stenosis as well as supravalvular aortic stenosis and premature atherosclerosis [66]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

Mutations in the signaling and transcriptional regulator NOTCH1 are associated with a variety of aortic valve anomalies (such as bicuspid aortic valve with or without thoracic aortic aneurysm) and with severe aortic valve calcification in human pedigrees in a nonsyndromic autosomal dominant pattern [55,56]. NOTCH1 transcripts are abundant in the developing aortic valve in mice and may promote valve calcification by diminishing the activity of Runx2, an important transcriptional regulator of the fate of osteoblast cells. This observation is consistent with the suggestion that aortic valve calcification is an active process mediated by the differentiation of valvular cells into osteoblast-like cells [29,55].

A familial aggregation of calcific aortic stenosis with apparent autosomal dominant inheritance was noted in a report from western France [57]. This aggregation could not be explained by hypercholesterolemia or chronic kidney disease, but a specific genetic abnormality has not yet been identified. A subsequent transcriptome-wide association study in 1009 cases and 1017 ethnically matched controls revealed palmdelphin (PALMD) on chromosome 1p21.2 as significantly associated with calcific aortic valve stenosis. This was replicated in 1391 cases and 352,195 controls from the UK Biobank and also in a large-scale eQTL mapping study of aortic valve tissue where increased disease severity was associated with decreased valve PALMD mRNA expression [67]. The exact function of PALMD in the valve is not known but may have a role in valve interstitial cell differentiation.

Propagation phase — The risk factors associated with disease progression in the later stages of aortic stenosis are somewhat different from those governing its incidence. Indeed, the two strongest predictors of disease progression appear to be the severity of aortic stenosis and markers of valve calcification. This suggests pathological differences between the initiation and propagation phases with calcification dominating in the latter and driving progressive valve narrowing [1,18]. The accumulation of valve calcification appears related to the action of osteoblast-like cells and a range of pro-calcific mediators commonly associated with skeletal bone formation. Indeed, a histopathological study of 256 end-stage-excised calcified aortic valves demonstrated widespread evidence of active cartilage and bone formation, with 83 percent of valves showing regions of heterotopic ossification [30]. A PET imaging study in 121 adults with a range of calcific aortic valve severity demonstrated inflammation in early disease. However in patients with moderate and severe aortic stenosis, calcification activity was the dominant observed process [32,68] and closely predicted future disease progression [69,70]. Similarly, assessments of valvular calcium burden provided by both echocardiography and CT also offer powerful prediction of disease progression and clinical events in aortic stenosis [71].

CLINICAL MANIFESTATIONS — Aortic sclerosis is an asymptomatic condition that is generally detected either as a systolic ejection murmur on physical examination or as an incidental finding on echocardiography or CT. Aortic sclerosis, in the absence of stenosis, may be associated with a midsystolic ejection murmur, which is usually best heard over the right second interspace. In general, the murmur is brief and not very loud. Importantly, many patients with aortic sclerosis have no murmur on physical examination.

A normal carotid pulse and normal S2 suggest the absence of aortic stenosis (figure 1). (See "Auscultation of cardiac murmurs in adults".)

However, the physical examination is neither sensitive nor specific for excluding aortic valve obstruction. Thus, echocardiography should be performed to distinguish aortic sclerosis from aortic stenosis and other cardiac abnormalities that might account for the murmur when present.

DIAGNOSIS — Aortic sclerosis should be suspected when a systolic murmur is heard on auscultation but is also frequently detected as an incidental finding on transthoracic echocardiography or as aortic valve calcification or thickening on CT.

Aortic sclerosis is defined on echocardiography as irregular aortic leaflet thickening and focal increased echogenicity without impairment of leaflet excursion and with peak Doppler velocities across the valve <2 m/s. On CT, aortic sclerosis can be defined by the presence of leaflet thickening or the presence of calcific deposits within the aortic valve leaflets.

Aortic valve sclerosis is defined by the following features on echocardiography [1,4,5,72]:

Irregular leaflet thickening and focal increased echogenicity (calcification) are the hallmarks of the condition. Focal areas of thickening are typically seen on the aortic side of the valve in the center of the valve cusp, rather than at the leaflet edges, often initially involving the noncoronary cusp.

Leaflet excursion is not impaired and the commissures are not fused. Peak continuous wave Doppler flow velocities across the valve are normal or only minimally elevated (<2 m/sec).

Mitral annular calcification frequently accompanies aortic valve sclerosis [73,74]. (See "Echocardiographic evaluation of the mitral valve", section on 'Mitral annular calcification' and "Clinical manifestations and diagnosis of mitral annular calcification".)

Reduction in leaflet mobility, increases in leaflet calcification, and increases in aortic transvalvular Doppler flow velocities are signs of progression from aortic sclerosis to aortic stenosis (table 1). (See 'Progression to aortic stenosis' below.)

DIFFERENTIAL DIAGNOSIS — Aortic sclerosis should be differentiated from other causes of a systolic murmur, including the following conditions based on clinical signs (figure 1), electrocardiogram, and echocardiogram. As noted above, aortic sclerosis may or may not be associated with a midsystolic ejection murmur. However, differentiation of murmurs of these various conditions on physical examination is challenging and even experts cannot reliably distinguish these conditions by exam alone. Echocardiography is recommended when valve disease is suspected [75,76], including in asymptomatic adults with a grade 3 or louder murmur and in adults with potential cardiac symptoms and any cardiac murmur. (See "Auscultation of cardiac murmurs in adults".)

Aortic stenosis is associated with a midsystolic ejection murmur that radiates into the neck and over both carotid arteries (table 2). Aortic stenosis is associated with evidence of flow obstruction in addition to valve thickening on echocardiography. (See "Clinical manifestations and diagnosis of aortic stenosis in adults".)

Supravalvular aortic stenosis is associated with a midsystolic ejection murmur. Echocardiography is helpful in identifying the location of obstruction above the aortic valve. (See "Valvar aortic stenosis in children".)

Subvalvular aortic stenosis is associated with a midsystolic ejection murmur. Echocardiography is helpful in identifying the location and structure of the subaortic lesion. (See "Subvalvar aortic stenosis (subaortic stenosis)".)

Mitral regurgitation (MR) is generally associated with a holosystolic murmur. Echocardiographic findings include mitral valve apparatus abnormalities consistent with primary or secondary MR as well as Doppler findings that aid in identifying and quantifying the MR jet. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation".)

Hypertrophic cardiomyopathy with dynamic outflow obstruction causes a midsystolic ejection murmur that increases upon standing from a squatting position. Echocardiographic findings include unexplained left ventricular hypertrophy, systolic anterior motion of the mitral valve, as well as Doppler evidence of left ventricular outflow obstruction. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Echocardiography'.)

Ventricular septal defects (VSDs) typically cause a holosystolic murmur if right ventricular pressure is lower than left ventricular pressure throughout systole. An echocardiogram is a sensitive means of detecting most VSDs. (See "Clinical manifestations and diagnosis of ventricular septal defect in adults".)

An innocent midsystolic flow murmur is commonly thought to originate from vibrations in the pulmonary trunk. When an innocent murmur is present, an echocardiogram reveals no underlying cardiac lesion. (See "Auscultation of cardiac murmurs in adults", section on 'Innocent midsystolic murmurs'.)

CLINICAL SIGNIFICANCE OF AORTIC SCLEROSIS — Aortic valve sclerosis can progress to aortic stenosis and is a marker for increased cardiovascular risk.

Progression to aortic stenosis — As aortic valve leaflet thickening and calcification progress, the increased valve stiffness results in obstruction at the valve level and transition from aortic sclerosis to stenosis [4]. Prospective clinical studies suggest that this progression occurs in approximately one of eight patients, with progression from sclerosis to severe stenosis occurring in 1 out of 64 patients [74,77]. In a meta-analysis of 22 studies, the rate of progression from aortic sclerosis to aortic stenosis was 1.8 to 1.9 percent per year [2]. These low conversion rates put into question the rationale of strategies aimed at treating aortic sclerosis in order to prevent the development of aortic stenosis. (See "Natural history, epidemiology, and prognosis of aortic stenosis".)

Unlike atherosclerosis, in which clinical events are due to plaque rupture and thrombosis, obstruction in calcific aortic stenosis is due to the bulk of the lesion rather than plaque instability. It is likely that the disease process is accelerated by abnormal shear or mechanical stress on the leaflet. This could explain why symptomatic calcification in patients with bicuspid aortic valves occurs about 10 years earlier than in patients with trileaflet valves. In most patients, a bicuspid aortic valve functions normally for many years. A subset of patients develop significant regurgitation, but most are asymptomatic until superimposed calcification results in obstruction to flow later in life. (See "Clinical manifestations and diagnosis of bicuspid aortic valve in adults".)

The likelihood of progression was assessed in a review of 2131 patients with aortic valve thickening detected on echocardiography: aortic stenosis developed in 338 (16 percent) after seven years [74]. The stenosis was mild to moderate in 84 percent and severe in 16 percent. Only mitral annular calcification, a pathologic process similar to aortic valve sclerosis, was significantly associated with progression in multivariable analysis. As described in the next section, both aortic valve sclerosis and mitral annular calcification may also be predictors of cardiovascular events and mortality. A similar rate of progression to aortic stenosis was observed in the Cardiovascular Health Study cohort in which 9 percent of subjects with aortic sclerosis progressed to aortic stenosis in five years [78].

Factors associated with progressive aortic valve calcification were identified in 5880 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) [79]. The incidence rate of aortic valve calcium was 1.7 percent per year. Risk factors for incident aortic valve calcium included older age, male sex, a higher body mass index, current smoking, and the use of lipid-lowering and antihypertensive medications. The risk of aortic valve calcium progression was associated with male sex and, consistent with other studies, the severity of baseline calcification.

Predictor of cardiovascular events and mortality — Aortic sclerosis is consistently associated with an increased risk of cardiovascular events [2].

This was illustrated by a meta-analysis of 22 studies that reported that subjects with aortic sclerosis had a 68 percent increased risk of coronary events, 27 percent increased risk of stroke, 69 percent increased risk of cardiovascular mortality, and 36 percent increased risk of all-cause mortality compared with subjects without this condition [2].

The mechanisms responsible for the association between aortic valve sclerosis and cardiovascular events and mortality are not fully understood [1,80]. The valve lesion itself is not likely to be important, since hemodynamics are normal or near normal and the time to increased risk is short compared with the possible rate of progression to aortic stenosis (see 'Pathogenesis of calcific aortic valve disease' above). A more probable explanation is that, given the common risk factors (see 'Relation to atherosclerosis' above), aortic valve sclerosis is a marker for underlying atherosclerosis [7,80]. An analysis of the SCOTHEART trial, in which CT was performed in outpatients with chest pain, found that patients with aortic or mitral valve calcification had higher coronary calcium scores and more obstructive coronary artery disease. It also again confirmed the association between both aortic valve and mitral annular calcification and adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). However, these associations were lost when coronary CT calcium scores or obstructive coronary artery disease were considered in the model. This would suggest the association between aortic sclerosis and atherothrombotic events is noncausal and instead mediated by associated atheroma [81]. This suggests that the finding of aortic sclerosis or mitral annular calcification on echocardiography is a marker of increased risk of coronary disease. However, data are lacking on whether this finding should prompt further diagnostic evaluation or a change in cardiovascular preventive therapies.

Embolic risk — Although calcific microemboli have been observed in patients with calcific aortic valve disease, these appear to be rarely associated with clinical events [82]. No significant increase in stroke risk was found in studies comparing patients with aortic stenosis or aortic sclerosis with matched controls [4,83,84].

MANAGEMENT — Patients with aortic sclerosis should receive follow-up for progression to aortic stenosis and full assessment of their cardiovascular risk profile with lifestyle and risk factor modification as appropriate [85].

Follow-up — Aortic valve sclerosis is a major type of Stage A (meaning "at risk of") valvular aortic stenosis (along with bicuspid aortic valve) (table 1). Since aortic sclerosis often progresses to aortic stenosis, clinical follow-up by the primary care provider is recommended with periodic (at least annual) evaluation for changes in cardiac symptoms or signs. Follow-up echocardiography is appropriate to evaluate any new cardiac symptoms, such as dyspnea on exertion, or changes in physical examination findings, such as an increase in the loudness of the murmur, a single second heart sound, or a decrease in carotid upstroke. In addition, we favor repeating an echocardiogram every five years in adults with aortic sclerosis, as symptoms do not develop until late in the disease process and may not be appreciated by the patient and changes in physical examination findings may be subtle.

Risk factor modification — A prudent approach is to consider aortic valve sclerosis to be a marker of increased cardiovascular risk [1,42]. Thus, all patients with aortic sclerosis should undergo a careful history and physical examination with assessment of conventional cardiac risk factors, including hypertension, smoking, diabetes, and hyperlipidemia. Risk factor reduction should be instituted based upon accepted guidelines. In addition, further diagnostic evaluation may be needed in patients with clinical signs or symptoms of cardiovascular disease. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of primary prevention of cardiovascular disease".)

Aside from their beneficial effects with respect to atherosclerosis, there are no controlled trials to confirm whether aggressive control of blood pressure or other non-lipid risk factors for coronary heart disease will reduce the progression of aortic valve sclerosis or stenosis. Although histologic evidence of lipid infiltration is seen early in the disease process and small retrospective studies were promising, there is no convincing evidence of benefit from lipid lowering therapy in adults with calcific aortic valve disease. In two prospective randomized trials of statin (hydroxymethylglutaryl CoA [HMG CoA] reductase inhibitor) versus placebo in adults with mild to moderate calcific aortic stenosis, no difference was found in the rate of hemodynamic progression [86,87]. In addition, the larger, prospective, randomized SEAS trial in adults with mild to moderate aortic stenosis found no benefit of aggressive lipid lowering therapy on a combined cardiovascular endpoint [88]. Ongoing randomized controlled trials are assessing whether drugs targeting calcium metabolism more directly may be more effective in slowing aortic stenosis progression. There is also interest in modifying lipoprotein(a) levels as a novel treatment strategy. (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Hypercholesterolemia and statin therapy'.)

Concurrent use of calcium supplements — For adults with aortic valve leaflet calcification with indications for calcium supplementation, we continue calcium supplements. As noted above, disturbances of mineral metabolism may contribute to the development of aortic valve sclerosis and mitral annular calcification. However, there are no data to indicate that appropriate calcium supplementation in adults with osteoporosis or osteopenia increases the risk of aortic valve leaflet calcification. (See 'Relation to mineral metabolism' above and "Calcium and vitamin D supplementation in osteoporosis".)

Therapies that are not indicated

Antithrombotic therapy — As noted in the 2012 American College of Chest Physicians guidelines, antithrombotic therapy does not have a role in management of calcific aortic valve disease [89]. Embolic events are not significantly associated with aortic valve sclerosis. No treatment has been established for prevention of calcific microemboli. (See 'Embolic risk' above.)

Patients with calcific aortic valve disease who have had an ischemic stroke or transient ischemic attack (TIA) with no other identifiable source should be managed according to standard guidelines for secondary prevention of noncardioembolic stroke or TIA. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Summary and recommendations'.)

Endocarditis prophylaxis — Endocarditis prophylaxis is not recommended in patients with aortic valve sclerosis [76]. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

SUMMARY AND RECOMMENDATIONS

Aortic sclerosis is an asymptomatic condition that is generally detected either as a systolic ejection murmur on physical examination or as an incidental finding on echocardiography or computed tomography. (See 'Clinical manifestations' above.)

The prevalence of aortic sclerosis increases with age from less than 10 percent in middle-aged adults to ≥25 percent in adults ≥65 years old. (See 'Prevalence' above.)

The pathobiology of aortic sclerosis and early calcific aortic valve disease (the initiation phase) shares similarities with atherosclerosis involving lipid accumulation, inflammation, and calcification. The incidence of aortic sclerosis has been correlated with clinical risk factors for atherosclerosis, including smoking, hypertension, hyperlipidemia, and diabetes. The factors driving aortic stenosis progression in the propagation phase appear different, with calcification predominating. (See 'Pathogenesis of calcific aortic valve disease' above.)

Genetic factors, including some linked to dyslipidemia, contribute to the risk of aortic valve calcification and development of calcific aortic stenosis. (See 'Genetic factors' above.)

Aortic sclerosis is defined as irregular aortic leaflet thickening and focal increased echogenicity without impairment of leaflet excursion and with peak Doppler velocities across the valve <2 m/s. (See 'Diagnosis' above.)

Since aortic sclerosis can progress to aortic stenosis, clinical follow-up is recommended with periodic (eg, at yearly or greater intervals) evaluation for changes in cardiac symptoms or signs. Follow-up echocardiography is appropriate to evaluate any new cardiac symptoms, such as dyspnea on exertion, or changes in physical examination findings, such as an increase in the loudness of the murmur, a single second heart sound, or a decrease in carotid upstroke. In addition, we favor repeating an echocardiogram every five years in adults with aortic sclerosis. (See 'Follow-up' above.)

Patients with aortic valve sclerosis (including those with and without known cardiovascular disease) have an increased frequency of cardiovascular events and mortality. This may be explained by the association between aortic valve sclerosis and coronary and carotid atherosclerosis rather than representing a direct causal effect. (See 'Predictor of cardiovascular events and mortality' above.)

All patients with aortic sclerosis should undergo a careful history and physical examination with assessment of conventional cardiac risk factors, including hypertension, smoking, diabetes, and hyperlipidemia. Risk factor reduction should be instituted based upon accepted guidelines. In addition, further diagnostic evaluation may be needed in patients with clinical signs or symptoms of cardiovascular disease. (See 'Risk factor modification' above and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of primary prevention of cardiovascular disease".)

There is no convincing evidence of benefit from lipid lowering therapy in adults with calcific aortic valve disease separate from established cardiovascular indications for such therapy. (See 'Risk factor modification' above.)

There are no data to indicate that appropriate calcium supplementation in adults with osteoporosis or osteopenia increases the risk of aortic valve leaflet calcification. Because of this, we do not discontinue calcium supplements in adults with aortic valve calcification. (See 'Concurrent use of calcium supplements' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David S Siscovick, MD, who contributed to earlier versions of this topic review.

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Topic 8123 Version 29.0

References

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