Natural history, epidemiology, and prognosis of aortic stenosis

INTRODUCTION — Aortic valve stenosis (aortic stenosis [AS]) is the most common cause of left ventricular outflow obstruction in children and adults; less common causes are subvalvular or supravalvular disease (table 1).

The epidemiology and natural history of AS will be reviewed here. The clinical features, diagnosis, evaluation, medical therapy, percutaneous aortic valvotomy, and valve replacement (transcatheter aortic valve implantation and surgical aortic valve replacement) for AS are discussed separately. (See "Clinical manifestations and diagnosis of aortic stenosis in adults" and "Medical management of asymptomatic aortic stenosis in adults" and "Indications for valve replacement for high gradient aortic stenosis in adults".)

DEFINITIONS — Aortic valve sclerosis is defined as aortic valve thickening, usually with at least mild calcification, without a significant pressure gradient (defined as an aortic jet velocity <2 m/s). AS is present when the antegrade velocity across an abnormal valve is at least 2 m/s. The clinical stages of AS are defined by symptoms, valve anatomy, valve hemodynamics, and left ventricular function (table 2). (See "Aortic valve sclerosis and pathogenesis of calcific aortic stenosis" and "Clinical manifestations and diagnosis of aortic stenosis in adults" and "Echocardiographic evaluation of the aortic valve".)

Severe AS is defined as with a maximum aortic transvalvular velocity ≥4 m/s, typically with an aortic valve area ≤1 cm² (table 3). Very severe AS is said to be present when the Doppler aortic jet velocity is ≥5 m/s (table 3). (See "Aortic valve area in aortic stenosis in adults", section on 'Critical valve area and severity'.)

The term "symptomatic AS" refers to AS that is causing cardiac symptoms. End-stage symptoms include heart failure, anginal chest discomfort, and syncope. However, the most common symptoms in patients who are followed prospectively are decreased exercise tolerance and/or cardiac dyspnea on exertion, both early symptoms of heart failure. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Symptoms'.)

ETIOLOGY OF AORTIC STENOSIS — There are three primary causes of valvular AS:

●A congenitally abnormal valve, often with superimposed calcification (unicuspid or bicuspid). (See "Clinical manifestations and diagnosis of bicuspid aortic valve in adults" and "Valvar aortic stenosis in children".)

●Calcific disease of a trileaflet valve.

●Rheumatic valve disease − Rheumatic valve disease is characterized by fusion of the commissures between the leaflets, with a small central orifice. Histologic studies show typical changes due to rheumatic disease. The rheumatic process typically involves the mitral valve as well; as a result, most patients with rheumatic AS also have mitral stenosis and/or mitral regurgitation. (See "Acute rheumatic fever: Epidemiology and pathogenesis" and "Acute rheumatic fever: Clinical manifestations and diagnosis".)

Rare causes include metabolic diseases (eg, Fabry's disease), systemic lupus erythematosus, and alkaptonuria. Calcific AS presents at a younger age and progresses more rapidly in patients with Paget disease or end-stage kidney disease. Disturbances of mineral metabolism may contribute to calcific aortic valve disease. (See "Valvular heart disease in patients with end-stage kidney disease", section on 'Valvular stenosis' and "Clinical manifestations and diagnosis of Paget disease of bone".)

EPIDEMIOLOGY — The relative frequency of the causes of AS varies geographically. Worldwide, rheumatic valve disease is most common and mitral valve involvement invariably accompanies rheumatic aortic valve disease. In North America and Europe, aortic valve disease is primarily due to calcific disease of a native trileaflet valve or a congenitally bicuspid valve.

The prevalence of AS increases with age, as demonstrated by a prospective population-based study of 3273 participants, including 164 subjects with AS. The prevalence of AS varied from 0.2 percent at ages 50 to 59 years to 1.3 percent at ages 60 to 69, 3.9 percent at ages 70 to 79 years, and 9.8 percent at ages 80 to 89 years [1]. Compared with the general population, mortality was not significantly increased in the asymptomatic AS group (hazard ratio [HR] 1.28), nor in those who received aortic valve replacement (HR 0.93).

The relative prevalence of trileaflet versus congenitally abnormal valves varies according to age as illustrated by a series of 932 adults who underwent surgery for isolated AS [2]. Patients with mitral valve replacement or mitral stenosis were excluded to ensure exclusion of rheumatic valve disease. Also excluded were patients with a previous aortic valvotomy, indicating severe valve obstruction due to congenital disease.

An anatomically abnormal valve was present in 54 percent: 49 percent had a bicuspid valve and 4 percent had a unicuspid valve, but the frequency varied importantly with age:

●Among the 7 percent of patients who underwent surgery at ≤50 years of age, approximately two-thirds had a bicuspid valve and one-third had a unicuspid valve. (See "Clinical manifestations and diagnosis of bicuspid aortic valve in adults", section on 'Valve disease'.)

●Among the 40 percent of patients who underwent surgery between the ages of 50 and 70, approximately two-thirds had a bicuspid valve and one-third a tricuspid valve; only rare patients had a unicuspid valve.

●Among the remaining patients over age 70, approximately 60 percent had a tricuspid valve and 40 percent had a bicuspid valve. (See "Valvular heart disease in older adults", section on 'Aortic stenosis'.)

PROGRESSION OF AORTIC STENOSIS

Hemodynamics — Serial hemodynamic examinations in patients with AS over years have revealed significant, though initially clinically silent, progression in most but not all patients. This progression is manifested by a reduction in the aortic valve area and an increase in the transvalvular systolic pressure gradient.

In individuals with normal aortic valves, the effective area of valve opening equals the cross-sectional area of the left ventricular outflow tract, which is approximately 3 to 4 cm² in adults. As aortic leaflet thickening and calcification develop, the antegrade velocity remains normal and there is a minimal valve gradient until the orifice area reaches less than half of normal. (See "Aortic valve area in aortic stenosis in adults".)

When AS becomes hemodynamically significant, it results in an increased impedance or resistance to left ventricular ejection. The stenotic process is gradual in onset and progression, resulting in adaptive changes in the left ventricle. The increased systolic pressure in the ventricular chamber leads to concentric hypertrophy as a compensatory adaptive mechanism to maintain normal wall stress. With a compensated ventricle, the ejection fraction, the cardiac output, and the left ventricular end-diastolic volume remain normal for a prolonged period. (See "Hemodynamics of valvular disorders as measured by cardiac catheterization".)

However, as stenosis severity and hypertrophy continue to progress, the left ventricle becomes less compliant and left ventricular end-diastolic pressure tends to increase. Abnormal diastolic function contributes to symptom onset and may persist after relief of stenosis due to persistent hypertrophy and/or interstitial fibrosis. Another contributing factor to the reduction in ventricular function is incoordinate contraction, resulting from regional wall motion abnormalities, fibrosis, or subendocardial ischemia [3].

Symptoms — The natural history of AS begins with a prolonged asymptomatic period. In general, symptoms in patients with AS and normal left ventricular systolic function rarely occur until the stenosis is severe (valve area is <1 cm², the jet velocity is over 4 m/s, and/or the mean transvalvular gradient exceeds 40 mmHg) (table 2). Many patients do not develop symptoms until critical (very severe) valve obstruction is present, while some patients become symptomatic when the stenosis is less severe, particularly if there is coexisting aortic regurgitation. Thus, serial hemodynamic measurements alone do not identify the time of symptom onset. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Symptoms'.)

Many, if not most, patients with AS develop symptoms before the onset of left ventricular systolic dysfunction. However, in some patients, there is a reduction in systolic myocardial function and a decrease in the ability of the left ventricle to develop pressure and shorten against a load before the onset of symptoms. At this point, the left ventricle is transitioning to failure, resulting in reductions in stroke volume and cardiac output, and eventually signs and symptoms of overt heart failure.

Observational studies

Overview — Studies of patients undergoing serial cardiac catheterization have identified subgroups of patients with AS with distinctly different progression rates [4-10]. Serial echocardiography studies have provided data similar to that obtained in cardiac catheterization studies, although the time intervals between follow-up have been shorter and these studies are less prone to selection bias [1,11-19]. The average rate of progression has been similar in numerous studies, but the rate of progression varies widely among individual patients:

●The average rate of increase in the mean systolic pressure gradient was 3 to 7 mmHg per year, but some patients showed an increase of as much as 15 to 19 mmHg per year.

●Valve area declined at an average rate of 0.1 cm² per year, but some patients had little or no progression and others progressed more rapidly.

●Aortic jet velocity increased by an average of 0.3 m/s per year, but this is also variable. (See 'Medical University of Vienna' below.)

Patients with mild disease (ie, aortic jet velocity less than 3.0 m/s) are unlikely to develop symptoms due to AS over the ensuing five years [11]. A substantial number of patients with severe AS are not yet symptomatic, but most such patients have low event-free survival rates (56 to 63 percent at two years and 25 to 33 percent at four to five years) [13,20].

Data from observational studies of patients with asymptomatic AS suggest that peak aortic velocity and/or rate of progression of peak aortic velocity is associated with risk of death or aortic valve replacement. Studies at three different sites illustrate the range of predictive factors and rates of progression:

University of Washington — The importance of hemodynamic factors was demonstrated in a prospective study of 123 patients with AS in whom yearly echocardiography and exercise testing were performed for a mean of 2.5 years [11]. Entry criteria included an aortic jet velocity ≥2.5 m/s and the absence of symptoms due to AS. The end point was defined as death or aortic valve surgery.

●Event-free survival at one, three, and five years was 93, 62, and 26 percent, respectively (figure 1).

●The aortic jet velocity increased by 0.32±0.34 m/s per year, the mean gradient by 7±7 mmHg per year, and the aortic valve area decreased by 0.12±0.19 cm² per year. Multivariate predictors of outcome were jet velocity at baseline, the rate of change of aortic jet velocity, and functional status score. Factors such as age, sex, or cause of AS were not predictive of outcome.

●The likelihood of remaining alive and free of valve surgery at two years varied inversely with disease severity as estimated from the baseline aortic jet velocity: The respective values were 84, 66, and 21 percent when the baseline aortic jet velocity was <3, 3 to 4, and >4 m/s, respectively (figure 2). These values defined patients with mild, moderate, and severe AS (table 3).

Medical University of Vienna — A prospective study evaluated 126 asymptomatic patients with severe AS, defined as an aortic jet velocity ≥4 m/s, who were followed for a mean of 22 months [13].

●Event-free survival (with end point defined as death or aortic valve replacement for symptoms) was 67 percent at one year, 56 percent at two years, and 33 percent at four years.

●Only the extent of aortic valve calcification was an independent predictor of outcome. Patients with no or mild valvular calcification, compared with those with moderate or severe calcification, had significantly higher rates of event-free survival at one and four years (92 versus 60 percent and 75 versus 20 percent, respectively) (figure 3).

●Not surprisingly, patients who had events had a higher rate of progression of stenosis. Among patients with moderate to severe calcification with increase in aortic jet velocity of ≥0.3 m/s within one year, the cardiac event rate was 79 percent.

Investigators at this institution also prospectively followed a series of 116 asymptomatic patients with very severe AS, defined by a peak aortic jet velocity of ≥5 m/s [21].

●Event-free survival (with the end points of death or indication for aortic valve replacement including symptoms, left ventricular systolic dysfunction, or rapid hemodynamic progression) was 64, 36, 25, 12, and 3 percent at one, two, three, four, and six years.

●Peak aortic valve velocity, but not aortic valve area, was an independent predictor of event-free survival. Patients with a peak aortic valve velocity ≥5.5 m/s had event-free survivals of 44, 25, 11, and 4 percent at one, two, three, and four years compared with 76, 43, 33, and 17 percent for patients with peak aortic velocities between 5 and 5.5 m/s.

●All but seven patients had moderate to severe aortic valve calcification. Valve calcification was not associated with event-free survival.

Mayo Clinic — A large retrospective study included 622 patients with severe, asymptomatic AS (peak aortic jet velocity ≥4 m/s and mean aortic valve area 0.9 cm²) [20].

●The probability of remaining free of cardiac death or aortic valve replacement was 80, 63, and 25 percent at one, two, and five years; the rate of remaining free of cardiac symptoms while unoperated was 82, 67, and 33 percent at the same time points.

●Patients with peak aortic jet velocity ≥4.5 m/s had increased event rates (relative risk 1.34 for symptoms and 1.48 for valve replacement or death).

●The rate of sudden death while still asymptomatic and without surgery was less than 1 percent per year.

A major limitation of this study is that among the 352 patients who underwent surgery, 131 (37 percent) were referred for surgery by their physician while they were still asymptomatic, which is not the treatment strategy recommended by current guidelines.

Risk factors for progression — The rate of progression of the stenotic lesion and the time to onset of symptoms varies significantly among patients. Whether patients at high risk for rapid progression can be successfully identified remains controversial [12]. Several prospective series have attempted to identify risk factors for progression in asymptomatic patients (with symptomatic patients being treated surgically) [11,13,14,20,22-26]. Among the factors that may be important are:

●Aortic jet velocity and valve area

●Degree of valve calcification

●Older age

●Male sex

●Cause of AS

●Hypercholesterolemia

●Renal insufficiency

●Hypercalcemia

●Smoking

●Metabolic syndrome

●Diabetes mellitus

Other valve characteristics that may have prognostic value include the energy loss index and the rate of change in aortic valve area during a cardiac cycle [27,28]. (See "Aortic valve area in aortic stenosis in adults".)

The potential roles of exercise testing and brain natriuretic peptide levels in risk stratifying patients with AS are discussed separately. (See "Indications for valve replacement for high gradient aortic stenosis in adults", section on 'Asymptomatic severe aortic stenosis'.)

Effect of cause of AS — Among patients with congenital or degenerative disease, progression to valve replacement occurs earliest with a unicuspid valve, later with a bicuspid valve, and latest with a tricuspid valve. These relationships were illustrated in a study of 932 adults who underwent surgery for isolated AS [2]. Patients with mitral valve replacement or mitral stenosis were excluded to ensure that patients with rheumatic valve disease were not included. Also excluded were patients with a previous aortic valvotomy, indicating severe valve obstruction due to congenital disease.

An anatomically abnormal valve was present in 54 percent: 49 percent had a bicuspid valve and 4 percent had a unicuspid valve, but the frequency varied importantly with age:

●Among the 7 percent of patients who underwent surgery at ≤50 years of age, approximately two-thirds had a bicuspid valve and one-third had a unicuspid valve. (See "Clinical manifestations and diagnosis of bicuspid aortic valve in adults", section on 'Valve disease'.)

●Among the 40 percent of patients who underwent surgery between the ages of 50 and 70, approximately two-thirds had a bicuspid valve and one-third a tricuspid valve; only rare patients had a unicuspid valve.

●Among the remaining patients over age 70, approximately 60 percent had a tricuspid valve and 40 percent had a bicuspid valve. (See "Valvular heart disease in older adults", section on 'Aortic stenosis'.)

PROGNOSIS OF SYMPTOMATIC AS — Patients with symptomatic severe AS who do not undergo valve replacement have a poor prognosis (figure 4) [29-34]. Mortality in patients with AS dramatically increases after the development of cardiac symptoms. This observation, along with improved survival rates following valve replacement, is the basis for the recommendation for prompt valve replacement in such patients (see "Indications for valve replacement for high gradient aortic stenosis in adults", section on 'Evidence'). Poor clinical outcomes in symptomatic AS patients were documented in early studies [9,29-31] and have continued to be observed in later series of medically treated patients [29,32-34]. In later series, some medically treated symptomatic patients underwent balloon aortic valvuloplasty for palliation, but their clinical outcomes were not substantially changed by this procedure, which has been shown not to improve prognosis in adults with severe AS (see "Percutaneous balloon aortic valvotomy for native aortic stenosis in adults", section on 'Evidence'). The high mortality rates observed in symptomatic patients who do not undergo valve replacement may be in part due to comorbidities that precluded surgery.

The following examples demonstrate the high mortality rate associated with severe symptomatic AS:

●A review of studies performed between 1913 and 1970 found that mean survival after onset of heart failure ranged from 0.5 to 2.8 years, after onset of syncope ranged from 0.8 to 3.8 years, and after onset of angina ranged from 2 to 4.7 years [9]. Studies performed during 1967 to 1982 reported two-year actuarial mortality rates of 24 to 69 percent in patients with New York Heart Association functional class III to IV symptoms.

●In the PARTNER trial, 179 patients with AS with heart failure symptoms were assigned to the standard therapy arm [33]. The majority of these patients received balloon aortic valvuloplasty (64 percent during the first 30 days and 20 percent later). The mortality rate at one year was 51 percent in this group.

●In an observational study of symptomatic AS patients not eligible for a transcatheter aortic valve implantation trial, 274 patients received medical treatment (including balloon aortic valvuloplasty in 65 percent) [34]. Mortality was 32 percent during median follow-up of one year. Thus, valvotomy alone is not an effective management strategy. (See "Percutaneous balloon aortic valvotomy for native aortic stenosis in adults".)

Pulmonary hypertension — Pulmonary hypertension (pulmonary artery pressure >30 mmHg) commonly occurs in symptomatic patients with AS and is associated with a more severe clinical picture as well as a poor prognosis after aortic valve replacement. (See "Estimating the risk of valvular procedures".)

The prevalence of pulmonary hypertension was illustrated in a study of 388 symptomatic patients with isolated AS who underwent cardiac catheterization; pulmonary hypertension was absent in 35 percent, mild to moderate pulmonary hypertension (defined as pulmonary artery systolic pressure 31 to 50 mmHg) was present in 50 percent, and severe pulmonary hypertension in 15 percent [35]. The only factors associated with severe pulmonary hypertension were overt heart failure and elevated left ventricular diastolic pressure; neither the aortic valve area nor the left ventricular ejection fraction was related to the pulmonary artery pressure. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Aortic stenosis (The Basics)")

SUMMARY

●There are three primary causes of valvular aortic stenosis (AS):

•A congenitally abnormal valve (bicuspid or, rarely, unicuspid), often with superimposed calcification. (See "Clinical manifestations and diagnosis of bicuspid aortic valve in adults".)

•Calcific disease of a trileaflet valve.

•Rheumatic valve disease.

●The natural history of AS begins with a prolonged asymptomatic period. In general, symptoms in patients with AS and normal left ventricular systolic function rarely occur until the stenosis is severe (valve area is <1 cm², the jet velocity is over 4 m/s, and/or the mean transvalvular gradient exceeds 40 mmHg) (table 2). Serial hemodynamic measurements alone do not predict the time of symptom onset. (See 'Symptoms' above.)

●Hemodynamic progression of AS is variable. The aortic valve area declines at an average rate of 0.1 cm² per year but some patients have little or no progression and others progress more rapidly. (See 'Observational studies' above.)

●Data from observational studies of patients with asymptomatic AS suggest that higher peak aortic velocity and/or rate of progression of peak aortic velocity is associated with increased risk of the combined end point of death or aortic valve replacement. (See 'Observational studies' above.)

●AS develops at a younger age in patients with bicuspid aortic valve as compared with those with tricuspid aortic valve but there is substantial overlap in age ranges. (See 'Effect of cause of AS' above.)

●Mortality in patients with AS dramatically increases after the development of cardiac symptoms (figure 4). (See 'Prognosis of symptomatic AS' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William H Gaasch, MD (deceased), who contributed to an earlier version of this topic review.