Clinical manifestations and diagnosis of aortic stenosis in adults

INTRODUCTION — Aortic valve stenosis is the most common cause of left ventricular (LV) outflow obstruction in children and adults; less common causes are subvalvular or supravalvular disease (table 1). This topic will review the clinical features, diagnosis, and evaluation of valvular aortic stenosis (AS) [1].

The pathogenesis, epidemiology, natural history, medical therapy, and percutaneous and surgical valve interventions for AS are discussed separately. (See "Natural history, epidemiology, and prognosis of aortic stenosis" and "Medical management of asymptomatic aortic stenosis in adults" and "Indications for valve replacement for high gradient aortic stenosis in adults" and "Choice of prosthetic heart valve for surgical aortic or mitral valve replacement" and "Choice of intervention for severe calcific aortic stenosis" and "Percutaneous balloon aortic valvotomy for native aortic stenosis in adults".)

CLINICAL MANIFESTATIONS

Symptoms — The classic clinical manifestations of AS are heart failure (HF), syncope, and angina. However, these "classic" manifestations reflect end-stage disease. Now, with earlier diagnosis by echocardiography and prospective follow-up of patients, the following are the most common presenting symptoms (see early symptoms in (figure 1)):

●Dyspnea on exertion or decreased exercise tolerance

●Exertional dizziness (presyncope) or syncope

●Exertional angina

These three "early symptoms" are nonspecific. Care must be taken in attributing these symptoms to AS since most patients with these symptoms do not have AS. (See 'Differential diagnosis' below.)

The patient with AS typically is asymptomatic for a prolonged period despite the obstruction and increased pressure load on the LV. There is wide variability in the degree of outflow obstruction that causes symptoms, depending in part upon patient size and level of physical activity. As a result, there is no single value of maximum aortic transvalvular velocity, mean transvalvular gradient, or aortic valve area that identifies when symptoms will occur (table 2). In most patients with AS and normal LV systolic function, symptoms are uncommon until stenosis is severe (defined as a valve area ≤1.0 cm², an aortic velocity 4.0 m/s or higher, and/or a mean transvalvular gradient ≥40 mmHg). Conversely, many patients who meet this definition of severe AS are not symptomatic because this definition was chosen to have a high sensitivity (not specificity) for identification of patients who might benefit from relief of outflow obstruction.

In adults with moderate AS, care should be taken to avoid attributing symptoms caused by other disease processes (noncardiac or cardiac) to AS: dyspnea may be due to deconditioning or lung disease, ankle edema has many causes other than HF, and nonanginal chest or shoulder pain is not a symptom of AS.

However, when severe AS is present, even mild cardiac symptoms require prompt intervention because average survival without valve replacement is only two to three years, with a high risk of sudden death (figure 1) [2]. Care is required to identify the cause of cardiac symptoms in patients with AS with concurrent cardiac conditions such as coronary artery disease or cardiomyopathy. (See "Natural history, epidemiology, and prognosis of aortic stenosis", section on 'Prognosis of symptomatic AS' and "Indications for valve replacement for high gradient aortic stenosis in adults".)

Dyspnea and decreased exercise tolerance — The most common symptom of AS is dyspnea, usually with exertion. Two factors can contribute: diastolic dysfunction with an increase in LV filling pressures with exercise and an inability of the LV to increase the cardiac output during exercise.

Systolic LV dysfunction is uncommon, and overt HF is a late, often end-stage finding, usually in patients who have not received regular medical care. Once overt HF occurs, the patient may complain of shortness of breath, easy fatigability, debilitation, and other signs and symptoms of a low cardiac output state. Patients with severe low-gradient AS with either reduced LV ejection fraction (LVEF) or normal LVEF may present with HF, angina, and/or syncope [2,3].

Atrial fibrillation (AF) is common in adults with severe AS and may precipitate onset of symptoms. (See 'Arrhythmias' below.)

Dizziness and syncope — Syncope occurs as a presenting symptom in approximately 10 percent of patients with symptomatic severe AS (or approximately 3 percent of all patients with severe AS) [4]. There are several proposed explanations for exertional dizziness (presyncope) or syncope in patients with AS, both of which reflect decreased cerebral perfusion. (See "Syncope in adults: Epidemiology, pathogenesis, and etiologies".)

●Exercise-induced vasodilation in the presence of an obstruction with fixed cardiac output can result in hypotension.

●A transient bradyarrhythmia that can occur during or immediately after exertion.

●Abnormalities in the baroreceptor response with an ensuing failure to appropriately increase the blood pressure.

●An arrhythmia, such as AF; ventricular arrhythmias are uncommon.

Angina pectoris — Angina with effort is another symptom in patients with severe AS [5-7]. Approximately one-half of these patients have underlying coronary artery disease. Coronary artery disease is also seen in a minority of patients with severe AS without angina. (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Coronary artery disease'.)

Angina in patients with AS without significant obstructive coronary artery disease can cause myocardial ischemia by several mechanisms [8]:

●Increased total LV oxygen demand as a result of increased LV mass; oxygen consumption per gram of myocardium is normal.

●Reduced coronary flow reserve related to myocardial and vascular factors.

●Elevated LV diastolic pressure contributes to a reduction in the perfusion pressure gradient, especially in the subendocardial myocardium.

●Reduced diastolic coronary perfusion time during tachycardia.

An additional factor that may contribute to angina was identified by a study of intracoronary pressures and flow velocities [9]. Coronary diastolic suction fell (rather than rose) with increasing heart rate in patients with severe AS. Appropriate increase in coronary diastolic suction with increasing heart rate was restored immediately after transcatheter aortic valve implantation.

Physical examination — The physical examination often provides the first clue to the presence of AS. The physical examination correlates with the severity of AS, though no combination of physical findings has both a high sensitivity and high specificity for excluding severe AS, particularly in asymptomatic patients [10]. (See "Auscultation of cardiac murmurs in adults" and "Auscultation of heart sounds".)

A review of clinical studies evaluated the published evidence on the precision and accuracy of the clinical examination for abnormal systolic murmurs; most studies used cardiology examiners [11]. The three findings most useful for diagnosis of significant AS are:

●A low volume and slow-rising carotid pulse

●A loud mid- to late-peaking systolic murmur in the right intercostal space

●A single second heart sound

On the other hand, patients with severe AS may have a soft murmur and may have an apparently normal carotid upstroke due to concurrent vascular disease [10]. The most useful findings for ruling out significant AS are the absence of any systolic murmur and normal physiologic splitting of the second heart sound [10-12]. When AS cannot be excluded on physical exam in a patient with possible symptoms due to AS, echocardiography is recommended. (See 'Diagnostic echocardiography' below.)

Carotid pulse — The quality of the arterial pulse in AS reflects the obstruction to blood flow into the peripheral arterial circulation. The arterial pulse has been described as "parvus and tardus," (ie, it is low volume and slow rising). This is best appreciated in the carotid artery where the pulse is reduced in amplitude and delayed in occurrence. However, the amplitude of the carotid upstroke may be preserved in older patients with AS due to vascular changes. The delay can be appreciated by simultaneous palpation of the apex (point of maximum impulse) and the carotid artery. There may also be an associated carotid artery thrill or coarse vibration ("shuddering") due to the marked turbulence of blood flow across the stenotic valve. (See "Examination of the arterial pulse".)

Precordial palpation — The cardiac impulse at the apex is sustained and is initially normal in location (see "Examination of the precordial pulsation"). Some patients have a palpable fourth heart sound (S4) due to vigorous left atrial contraction into the noncompliant ventricle. In addition, a systolic thrill may be felt at the base of the heart (right intercostal space) or at the sternal notch, especially during full expiration with the patient leaning forward.

Cardiac auscultation — Stenosis of the aortic leaflets is associated with reduced mobility and delayed closure. This leads to the following constellation of heart sounds (see "Auscultation of cardiac murmurs in adults" and "Auscultation of heart sounds"):

●The second heart sound (S2) is soft and single since the aortic component of the second heart sound (A2), which is due to aortic valve closure, is delayed and tends to occur simultaneously with the pulmonic component of the second heart sound (P2), which is due to pulmonic valve closure. The S2 may become paradoxically split when the stenosis is severe and associated with LV dysfunction (movie 1). With increasingly severe, fixed AS, the A2 closing sound may disappear. The presence of a normal split S2 is the most reliable finding to exclude severe AS in adults.

●The first heart sound (S1) is usually normal. However, an aortic ejection click, which is more commonly heard with a congenital bicuspid valve, may be heard after S1 early in AS when the leaflets are stiff but still somewhat compliant and mobile (movie 2 and movie 3).

●Vigorous left atrial contraction against a stiff, noncompliant ventricle can produce an S4.

●The murmur associated with AS is described as a systolic "ejection" murmur. It is typically heard best at the base of the heart in the "aortic" area (right intercostal space) where it has a harsh quality (movie 2 and movie 4). The murmur is transmitted well and equally to the carotid arteries. Diminished intensity in one carotid artery may indicate the presence of a stenosis in that vessel. (See "Auscultation of cardiac murmurs in adults", section on 'Valvular aortic stenosis'.)

The murmur generally begins after S1 and ends before S2. The intensity of the murmur reflects the amount and velocity of blood flow across the valve and the turbulence produced by the stenosis. A loud murmur (grade 4 or greater) has a high specificity for severe AS. However, most patients with severe stenosis have a grade 3 murmur, and many have only a grade 1 or 2 murmur. In patients with low flow low gradient AS, the murmur may be soft and almost inaudible. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Symptoms and signs'.)

The timing of the murmur also correlates with the severity of the stenosis, similar to the timing of the carotid pulse. An early-peaking murmur is typical for mild to moderate AS, while a late-peaking murmur is consistent with severe AS. However, evaluation of the timing of the murmur is not reproducible among examiners and is therefore of limited clinical utility.

The murmur may also radiate to the apex of the heart, where it may have a different quality (musical due to high frequency vibrations) and may be louder, suggesting that the patient also has mitral regurgitation. This is known as the Gallavardin phenomenon. Another finding that has led to the misperception of two murmurs with different etiologies is that the murmur is often softer or even inaudible in the chest area between the apex and base.

Unfortunately, cardiac auscultation poorly predicts the presence or severity of aortic stenosis [13,14]. The potential role of point-of-care ultrasound in improving diagnostic accuracy is being studied [15].

AS is often associated with a small degree of aortic regurgitation since the stiff, calcified, and rigid aortic valve leaflets may not coapt normally (movie 5). In this setting, a soft diastolic murmur of aortic regurgitation may be heard. (See "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults".)

DIAGNOSIS AND EVALUATION

When to suspect aortic stenosis — AS is usually diagnosed when physical examination (including a typical systolic ejection murmur) suggests AS or when AS is detected on a point-of-care ultrasound exam or on a diagnostic echocardiogram performed for other indications [2]. Symptoms such as dyspnea and decreased exercise tolerance, dizziness, syncope, and angina pectoris may or may not be present in patients with severe AS.

Initial approach to diagnosis and evaluation — Echocardiography is the primary test for diagnosis and evaluation of AS; some patients may be initially studied by a point-of-care ultrasound when available, while others are referred directly for diagnostic echocardiography.

An electrogram and a chest radiograph are not required for diagnosis of AS but are commonly obtained in the evaluation of patients presenting with cardiac symptoms or findings.

Cardiac catheterization for hemodynamic measurements to assess the severity of AS is rarely needed except during interventional procedures to treat AS.

Point-of-care ultrasound — With the increasing availability of point-of-care ultrasound, primary care providers may choose to incorporate limited imaging to detect aortic valve disease when symptoms or signs suggestive of AS are present, particularly in patients over age 65 years. Key findings on parasternal long-axis images include increased brightness/thickness of the aortic valve leaflets and reduced leaflet motion. LV hypertrophy is also a marker of AS. When point-of-care ultrasound is used, the provider should have a low threshold for proceeding to a diagnostic echocardiography study. Images showing thin aortic leaflets with normal systolic excursion, a normal aortic root, and normal LV wall thickness and systolic function suggest absence of significant AS. If AS is clinically suspected and AS is not excluded by identification of these normal findings, a complete diagnostic echocardiographic study is indicated [13,15].

Diagnostic echocardiography — A transthoracic echocardiogram (TTE) is indicated to diagnose and evaluate AS in patients with signs or symptoms of AS. The echocardiographic exam in patients with AS includes evaluation of valve anatomy and structure, valve hemodynamics, hemodynamic consequences (LV size and function and pulmonary artery pressure), and concomitant aortic regurgitation and other valve disease. (See "Echocardiographic evaluation of the aortic valve" and "Transesophageal echocardiography in the evaluation of aortic valve disease".)

In patients with AS, the aortic leaflets are generally thickened and calcified with reduced systolic motion and a small aortic orifice during systole (movie 6A-D and movie 7). By contrast, in children or young adults with congenital AS, systolic motion of the leaflet bases ("doming") is seen despite a restricted orifice at the leaflet tips (see "Valvar aortic stenosis in children"). Patients with concurrent aortic valve disease and primary LV systolic dysfunction may have reduced leaflet excursion, even when AS is not severe. The approach to distinguishing severe AS from mild-moderate AS with LV dysfunction is discussed in detail elsewhere. (See "Echocardiographic evaluation of the aortic valve", section on 'Valvular aortic stenosis' and "Aortic valve area in aortic stenosis in adults".)

When a bicuspid aortic valve is present, systolic images show the two leaflets (and two commissures) of the open valve. A bicuspid valve may appear trileaflet on diastolic images if a raphe is present. In patients with bicuspid aortic valve, the risk of associated aortic root involvement may be related to the specific bicuspid valve phenotype (congenital fusion of the right and left versus the right and noncoronary cusps) (movie 8A-C). (See "Clinical manifestations and diagnosis of bicuspid aortic valve in adults".)

Doppler echocardiography permits measurement of transaortic velocity and calculation of the left ventricular-aortic gradient and the valve area (image 1 and image 2 and movie 9), which are the standard parameters used for evaluation of stenosis severity (table 3 and table 2). Concurrent aortic regurgitation is present in over 80 percent of patients with AS but is usually mild. (See "Aortic valve area in aortic stenosis in adults", section on 'Echocardiography'.)

The LV chamber is usually normal in size with normal systolic function. However, the LV wall is concentrically or uniformly hypertrophied (movie 6A and movie 6D), and LV longitudinal strain is reduced [16].

Mitral regurgitation is also common due to mitral annular calcification and leaflet thickening. The severity of mitral regurgitation is usually mild to moderate and may be exacerbated by the high systolic LV pressure resulting from the outflow obstruction. Echocardiography also allows evaluation of pulmonary hypertension.

TTE typically is adequate for evaluation of AS and generally provides a broader selection of acoustic windows for measurement of aortic valve gradients than transesophageal echocardiography (TEE). However, TEE may be helpful in selected cases as it provides better images of aortic valve anatomy, providing better definition of the number of valve leaflets and degree of leaflet opening, and is more accurate for diagnosis of a sub- or supra-aortic membrane. TEE 3D imaging can also enable measurement of valve area, particularly for congenital AS.

Assessment of disease stages — AS is a progressive disease with sequential stages defined according to valve anatomy, valve hemodynamics, hemodynamic consequences of AS, and symptoms (table 3) [2]:

●Stage A includes asymptomatic patients with a maximum transvalvular aortic velocity (V_max) <2 m/s who are at risk for AS. This includes patients with bicuspid aortic valve (or other congenital aortic valve anomaly) or aortic sclerosis or other risk factors for aortic valve disease. (See "Aortic valve sclerosis and pathogenesis of calcific aortic stenosis".)

●Stage B is defined as progressive AS with mildly to moderately calcified valve leaflets, mildly to moderately reduced valve leaflet mobility, and mild or moderate AS. Patients with Stage B AS have a murmur on exam but no symptoms. Mild AS is identified by an aortic V_max 2.0 to 2.9 m/s or a mean transvalvular pressure gradient <20 mmHg. Moderate AS is identified by an aortic V_max 3.0 to 3.9 m/s or a mean transvalvular pressure gradient of 20 to 39 mmHg.

●Stage C AS is defined as severe valve obstruction in a patient with no symptoms. Severe AS is defined as severe leaflet calcification/thickening with reduced leaflet motion and an aortic velocity ≥4 m/s; aortic valve area often is ≤1.0 cm² (or aortic valve area indexed to body surface area is ≤0.6 cm²/m²), but no specific valve area is required for diagnosis of severe AS.

•In stage C1, LV ejection fraction (LVEF) is normal

•In stage C2, LVEF is <50 percent

●In stage D, patients have symptomatic severe AS.

•In stage D1, patients have severe high-gradient AS. Aortic V_max is ≥4 m/s or mean transvalvular pressure gradient is ≥40 mmHg. Aortic valve area is typically ≤1.0 cm² (or aortic valve area indexed to body surface area is ≤0.6 cm²/m²) but may be larger with mixed AS/aortic regurgitation.

•In stage D2, patients have symptomatic severe low flow, low gradient (LFLG) AS with reduced LVEF (LVEF <50 percent). Aortic valve area is ≤1.0 cm² with resting aortic V_max <4 m/s or mean pressure gradient <40 mmHg. Low-dose dobutamine stress echocardiography shows an aortic valve area ≤1.0 cm² with aortic V_max ≥4 m/s. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Low-dose dobutamine stress echocardiogram'.)

•In stage D3, patients have symptomatic severe low-gradient AS with normal LVEF (LVEF ≥50 percent; also known as paradoxical low-gradient severe AS). Aortic valve area is ≤1.0 cm² (or aortic valve area indexed to body surface area is ≤0.6 cm²/m²) with aortic V_max <4 m/s or mean transvalvular pressure gradient <40 mmHg. There is a small LV chamber with low stroke volume (stroke volume index <35 mL/m²).

Body size should be considered in assessing valve area in smaller patients because a small valve area may be normal for body size in smaller individuals. However, indexing by body surface area is not recommended in overweight or obese adults. The most reliable measure of AS severity is aortic velocity (or gradient) alone when LV systolic function is normal. Valve area measurements are generally important only in patients with a low forward stroke volume due to a low ejection fraction or a small LV chamber size. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Diagnosis and evaluation'.)

Other initial tests

Electrocardiogram — An electrocardiogram (ECG) is not indicated for diagnosis for AS but is generally performed as a component of the initial evaluation. The main value of the ECG in this setting is for detection of concomitant conditions such as atrial fibrillation and coronary disease, although similar repolarization abnormalities are caused by LV hypertrophy and ischemia. (See 'Arrhythmias' below.)

Chest radiograph — A chest radiograph is not generally required when evaluating AS but may be obtained in some patients who present with HF to assess for pulmonary edema and also in some patients who present with dyspnea to exclude other causes for shortness of breath. The lateral view of a chest radiograph may reveal calcification of the aortic valve in patients with calcific AS.

Role of serial evaluation — Asymptomatic patients with AS with normal LV function should be evaluated serially by history (to assess for development of symptoms including change in exercise tolerance), physical examination, and echocardiography to assess for evidence of progression. If exercise tolerance is uncertain, exercise testing is recommended. (See 'Asymptomatic sedentary patients' below.)

The frequency of recommended evaluation varies with the severity of disease [2,17]:

●For patients with mild AS and no significant calcification, evaluation is recommended every two to three years. If there is mild AS and significant calcification, some experts recommend yearly evaluation.

●For patients with moderate AS, evaluation should be performed every one to two years (the shorter interval applies when there is significant calcification).

●For patients with asymptomatic severe AS, clinical evaluation should be performed every 6 to 12 months or sooner if symptoms develop or if there is a change in physical exam suggestive of worsening AS.

Additional testing based on clinical presentation — Additional testing is performed in selected patients based upon clinical presentation.

Patients with nondiagnostic noninvasive evaluation — Cardiac catheterization is rarely needed for diagnosis of AS but might be considered in selected patients when noninvasive data (including TTE, TEE, and coronary computed tomography [CT] calcium scores) are nondiagnostic or if there is a discrepancy between the clinical evaluation and noninvasive testing [2]. (See "Hemodynamics of valvular disorders as measured by cardiac catheterization", section on 'Aortic stenosis'.)

There is some risk of cerebral embolization associated with crossing the aortic valve in patients with severe calcific AS, so this approach should be undertaken only when needed [18,19]. For example, cardiac catheterization may be helpful when severe AS is suspected but the aortic valve gradient cannot be adequately determined by echocardiography. (See "Stroke after cardiac catheterization".)

Patients with a concurrent indication for coronary angiography — Coronary angiography is recommended in patients with apparently mild to moderate AS who have one or more of the general indications for coronary angiography such as progressive angina, objective evidence of ischemia, or either asymptomatic or symptomatic LV dysfunction. Noninvasive stress imaging tests have low sensitivity and specificity for ischemia when AS is present.

Asymptomatic sedentary patients — Exercise testing is suggested in selected patients with asymptomatic severe AS (maximum aortic valve velocity of ≥4.0 m/s or mean aortic valve pressure gradient ≥40 mmHg) who are sedentary to confirm asymptomatic status. Such evaluation is particularly helpful when a patient's level of physical activity is unclear or low. Standard maximum treadmill exercise (without echocardiography) is adequate, with key diagnostic parameters being exercise capacity (compared with age- and sex-matched individuals without cardiac disease), symptoms with exercise, and the blood pressure response to exercise. Patients with severe AS who develop typical symptoms of AS (eg, exertional dyspnea) during exercise testing should be considered symptomatic even if the clinical history is uncertain [2]. Exercise testing should not be performed in patients with symptomatic severe AS.

The use of low-dose dobutamine stress testing in patients with severe LFLG AS with reduced ejection fraction is discussed separately. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Low-dose dobutamine stress echocardiogram'.)

Patients with equivocal symptoms — For patients with equivocal symptoms (ie, symptoms that may or may not be caused by AS) and severe AS, natriuretic peptide (eg, plasma B-type natriuretic peptide [BNP] or N-terminal pro-BNP [NT-proBNP]) levels may be helpful; an elevated BNP or NT-proBNP level suggests that symptoms may be due to AS or other causes of high cardiac filling pressures.

Among patients with severe AS, BNP and NT-proBNP concentrations are higher in symptomatic than in asymptomatic patients [20,21] and fall after aortic valve replacement [22]. Higher BNP values are independently predictive of reduced symptom-free survival [23] and overall survival [24].

In a prospective study of 1953 patients with at least moderate AS with mean 3.8-year follow-up, a BNP ratio (measured BNP/maximal normal BNP value specific to age and sex) >1 was defined as BNP clinical activation [24]. BNP clinical activation independently predicted excess long-term mortality in the population as a whole (adjusted hazard ratio [HR] 1.91, 95% CI 1.55-2.35) as well as in asymptomatic patients with normal LVEF (adjusted HR 2.35, 95% CI 1.57-3.56). Aortic valve replacement was associated with similar improvement in survival in patients with BNP ratio of <2 (HR 0.68, 95% CI 0.52-0.89) or BNP ratio of ≥2 (HR 0.56, 95% CI 0.47-0.66).

In a multicenter registry of 3815 patients with severe AS, in the 387 patients who did not meet criteria for aortic valve replacement (asymptomatic, normal LV function, AS not very severe) higher BNP levels were associated with greater cumulative five-year adverse cardiovascular events (aortic valve-related death or HF hospitalization). In contrast, patients with severe AS and a BNP level <100 pg/mL had an event rate of only 2.1 percent per year [25].

Patients with low gradient aortic stenosis — Additional evaluation is indicated in patients with low gradient AS. The approach (which may include low-dose dobutamine stress echocardiography and/or multidetector CT [MDCT]) varies depending upon whether there is classical LFLG AS, paradoxical LFLG AS, or normal flow, low gradient AS, as discussed in detail separately. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis".)

Low-dose dobutamine stress echocardiogram — Among patients with low gradient AS, low-dose dobutamine stress TTE is performed to differentiate true severe AS (with a fixed small valve area) from pseudosevere AS (with a functionally small valve area due to reduced driving forces). Low-dose dobutamine stress test may also be helpful in symptomatic patients with findings consistent with paradoxical LFLG AS, although data are limited. In addition, the test provides information on LV contractile reserve, which is helpful for prognostic purposes in contemplating possible surgical aortic valve replacement or transcatheter aortic valve implantation (TAVI). (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis", section on 'Low-dose dobutamine stress echocardiogram'.)

Computed tomography — MDCT is a key component of the evaluation in patients with low gradient AS, as discussed separately. (See "Clinical manifestations and diagnosis of low gradient severe aortic stenosis".)

The role of CT for TAVI is discussed separately. (See "Imaging for transcatheter aortic valve implantation".)

Emerging and investigational approaches — Cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) are not used for routine clinical assessment of AS but are emerging approaches for studying this condition.

Cardiovascular magnetic resonance — CMR is not used routinely for clinical evaluation of AS, and its availability is limited but may be an emerging approach as it enables evaluation of several features of AS. CMR provides accurate measurements of the size and shape of the aortic sinuses and ascending aorta, as well as 4D flow patterns, particularly in patients with AS due to bicuspid aortic valve disease. CMR also may show myocardial fibrosis and increased extracellular myocardial volumes, although the role of these findings in clinical decision-making has not yet been defined [26].

The anatomic aortic valve area can be measured from CMR short-axis views of the valve [27,28]. In addition, CMR velocity-encoded imaging can accurately measure the antegrade velocity through the stenotic valve without angle dependence, an advantage compared with echocardiography [29].

Some studies have found that the presence of late gadolinium enhancement (LGE) by CMR is an independent predictor of mortality in patients with severe AS [30-33]. As an example, in a CMR study of 143 patients with moderate or severe AS followed for a mean of two years, midwall fibrosis (HR 5.35, 95% CI 1.16-24.56) and LVEF (HR 0.96, 95% CI 0.94-0.99) were independent predictors of mortality. The potential prognostic value of CMR detection of myocardial fibrosis is discussed separately. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Late gadolinium enhancement'.)

Potential future applications of CMR include assessment of the amount of fibrosis and lipid infiltration in the valve leaflets [34].

Positron emission tomography — The role of PET-CT in clinical management of patients with AS has not been defined, but this is a promising research approach. Anatomic imaging with CT can be combined with physiologic information derived from PET imaging to visualize both calcification and inflammation. Uptake of ¹⁸F-NaF measures active mineralization which correlates with stenosis severity [35,36].

COMPLICATIONS

Heart failure — Most patients with AS have LV hypertrophy with normal systolic function. However, some studies suggest that alterations in ventricular function are present as evidenced by reduced global longitudinal strain [37,38]. Diastolic dysfunction, secondary to hypertrophy and fibrosis, is common and often persists after valve replacement. These patients may present with HF with preserved ejection fraction. A subset of patients presents with LV systolic dysfunction due to the high afterload imposed by the stenotic valve (eg, afterload mismatch) resulting in a low ejection fraction and symptoms of HF with reduced ejection fraction. Ventricular dysfunction due to valve obstruction improves rapidly after valve replacement.

Pulmonary hypertension — The pulmonary artery pressure may be increased in AS because of the chronic elevation in LV diastolic filling pressure. A severe elevation in pulmonary artery pressure (systolic pressure >50 mmHg) occurs in approximately 15 percent of patients [39]. In some cases, pulmonary hypertension is due to coexisting lung disease rather than to the effects of aortic valve obstruction. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

Sudden cardiac death — Symptomatic severe AS is associated with a high risk of sudden cardiac death. In patients with severe AS but no reported symptoms, the annual incidence of sudden death is approximately 1 percent [40,41]. In adults with symptoms due to severe AS, the annual incidence of sudden death has been reported to range from 8 to 34 percent in observational studies [42]. However, in a small (n = 145) randomized clinical trial of early aortic valve replacement for asymptomatic severe AS, death from any cause occurred in five patients in the early-surgery group (7 percent) and in 15 patients in the conservative-care group (21 percent) (hazard ratio 0.33, 95% CI 0.12-0.90). In the conservative-care group, the cumulative incidence of sudden death was 4 percent at four years and 14 percent at eight years [43]. However, many of these patients had very severe AS and thus were candidates for aortic valve replacement even if asymptomatic.

The mechanism of sudden death has not been established. A potential cause is activation of ventricular baroreceptors resulting in paradoxical bradycardia, decreased contractility, and hypotension (Bezold-Jarisch reflex). Another possible cause is ventricular tachyarrhythmias, although an association between ventricular arrhythmia and sudden death in patients with AS has not been established.

The risk of sudden death is reduced by valve replacement, so prompt valve replacement is generally recommended for symptomatic AS. Valve replacement is not recommended in asymptomatic adults with severe AS and normal LV systolic function, although a small randomized, controlled trial from Japan suggested that early aortic valve replacement might be beneficial in patients with a low surgical risk [40]. (See "Indications for valve replacement for high gradient aortic stenosis in adults".)

Arrhythmias — Intraventricular or atrioventricular conduction abnormalities are uncommon and, when present, may be due to severe hypertrophy, extension of calcium from the valve and valve ring into the interventricular septum, or concomitant heart disease.

Ventricular and supraventricular arrhythmias are also uncommon and, when present, are usually a reflection of underlying LV dysfunction.

Atrial fibrillation (AF) is uncommon in adults with mild to moderate AS (seen in 5 to 6 percent [44]) but is common in adults with severe AS (eg, 34 percent in a series of patients scheduled to undergo transcatheter aortic valve replacement [45]). Additional risk factors for AF in patients with AS include older age, LV hypertrophy, and LV systolic dysfunction [44,46]. In patients with mild to moderate AS, the incidence of new-onset AF is 1.2 percent per year and is highest when there is concurrent LV systolic dysfunction [44]. New-onset AF can precipitate symptom onset in adults with severe AS because the loss of atrial contraction and the rapid heart rate both limit diastolic filling of the small, stiff LV. (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Atrial fibrillation'.)

In the above cited series of patients with mild to moderate AS, longstanding AF compared with no AF at baseline was associated with a 4.1-fold higher risk of HF (CI 1.2-13.8) and a 4.8-fold higher risk of nonhemorrhagic stroke (CI 1.7-13.6) [44]. The onset of AF is not affected by statin therapy [46].

Endocarditis — Infective endocarditis (IE) can occur in patients with AS, particularly those with a congenitally bicuspid aortic valve. In a series of 2401 patients with congenital heart lesions who were followed prospectively, those with AS developed IE at a rate of 0.27 percent per year [47]. A higher peak gradient across the aortic valve was associated with a greater risk of IE. Although definitive data are lacking, clinical experience suggests that the risk of IE is lower in older patients with heavily calcified valves than in younger patients with less severe abnormalities.

The 2007 American Heart Association guidelines on IE revised prior recommendations for patients with acquired valvular disease, including those with AS [48]. As a result, antibiotic prophylaxis is no longer recommended when patients with AS undergo dental or other invasive procedures that produce significant bacteremia with organisms associated with endocarditis. However, antibiotic prophylaxis is recommended in certain high-risk groups (eg, patients with prior IE and patients with prosthetic heart valves). (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Endocarditis prophylaxis' and "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

Bleeding tendency — Patients with AS have an increased risk of bleeding, including chronic gastrointestinal bleeding that is often due to angiodysplasia (also known as arteriovenous malformation) and bleeding at skin and mucosal sites. The association between chronic gastrointestinal bleeding due to angiodysplasia and calcific AS has been termed Heyde syndrome [49]. In a series of 42 patients with severe AS who underwent aortic valve replacement, for example, nine had a history of skin or mucosal bleeding (causing manifestations such as epistaxis and ecchymoses), and four had a history of gastrointestinal bleeding [50]. (See "Angiodysplasia of the gastrointestinal tract", section on 'Aortic stenosis'.)

The increased risk of bleeding appears to be due to an acquired von Willebrand syndrome, which has been described in 67 to 92 percent of patients with severe AS [50]. This abnormality is thought to result from mechanical disruption of von Willebrand multimers during turbulent passage through the narrowed valve and from a von Willebrand factor interaction with platelets that triggers platelet clearance [50,51]. The severity of the von Willebrand factor abnormality is directly related to the severity of the AS, as measured by the mean transvalvular gradient [50,52,53]. The hemostatic abnormality is corrected after surgery but recurs within six months of valve replacement in two-thirds of patients, particularly in the presence of a mismatch between patient and prosthesis (an effective orifice area <0.8 cm²/m²). (See "Acquired von Willebrand syndrome" and "Pathophysiology of von Willebrand disease", section on 'Causes of reduced VWF in acquired VWS'.)

The most likely explanation for the association of AS with angiodysplasia is that patients with AS have an increased bleeding tendency, leading to the identification of angiodysplasia. This issue is discussed in detail separately. (See "Angiodysplasia of the gastrointestinal tract", section on 'Aortic stenosis'.)

Embolic events — Isolated case reports have described cerebral or systemic embolic events due to calcium emboli in patients with AS. This appears to be an infrequent complication. In a cohort study that included 515 patients with calcific AS, 300 with aortic valve calcification without stenosis, and 562 controls, the stroke rates were not different at two years (5, 8, and 5 percent, respectively) [54].

DIFFERENTIAL DIAGNOSIS

Other causes of symptoms — Symptoms of severe AS overlap symptoms of other causes of HF, angina, and syncope or presyncope. Therefore, other causes for these symptoms should be considered, such as cardiomyopathy as a cause of HF and coronary artery disease as a cause of angina. As noted above, in adults with moderate AS, care should be taken to avoid attributing symptoms caused by other disease processes to AS. Approaches to the diagnostic evaluation of suspected HF, chest pain, and syncope are discussed separately. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Determining the etiology and severity of heart failure or cardiomyopathy" and "Outpatient evaluation of the adult with chest pain" and "Approach to the patient with suspected angina pectoris" and "Syncope in adults: Clinical manifestations and initial diagnostic evaluation".)

Noncardiac causes of symptoms — Symptoms of dyspnea on exertion may be due to noncardiac causes in adults with AS, and it can be challenging to distinguish the cause of symptoms in many patients. Pulmonary disease is common in AS patients; standard pulmonary function tests are recommended when this is a concern. Cardiopulmonary exercise testing can also provide objective evidence of whether exertional limitation is due to cardiac or pulmonary disease. (See "Cardiopulmonary exercise testing in cardiovascular disease", section on 'Clinical applications'.)

In a patient with AS with new onset symptoms, it is mandatory to consider other causes for these symptoms, particularly when symptoms seem out of proportion to the severity of outflow obstruction. Complete history, physical examination, and laboratory testing are recommended to evaluate for other prevalent conditions (eg, anemia, cancer, and depression). However, when a thorough evaluation does not show any other significant comorbid conditions to account for symptoms, it is likely that symptoms are due to AS, and the patient should be considered for aortic valve replacement.

Other causes of LV outflow obstruction — The differential diagnosis of valvular AS includes other causes of systolic ejection murmur with or without LV outflow obstruction, including aortic sclerosis without significant stenosis and subvalvular AS (due to a fixed lesion or due to dynamic obstruction as seen in hypertrophic cardiomyopathy) and supravalvular AS (table 1). The physical examination provides some clues in distinguishing valvular AS from other causes of LV outflow tract obstruction (table 1) with the diagnosis of AS confirmed by echocardiogram (table 3).

Subvalvular disease — Subvalvular AS can result from a variety of fixed lesions. These include a thin membrane (the most common lesion), thick fibromuscular ridge, diffuse tunnel-like obstruction, abnormal mitral valve attachments, and occasionally, accessory endocardial cushion tissue. (See "Subvalvar aortic stenosis (subaortic stenosis)".)

Subvalvular AS also may have a dynamic component such as that seen in hypertrophic cardiomyopathy. In some cases, dynamic outflow obstruction and valvular AS are concurrent lesions. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction".)

Supravalvular disease — There are at least two anatomic forms of supravalvular AS. The majority of patients (60 to 75 percent) have an hourglass deformity, consisting of a discrete constriction of a thickened ascending aorta at the superior aspect of the sinuses of Valsalva (the "hourglass deformity") (image 3). More diffuse narrowing for a variable distance along the ascending aorta is seen in the remaining patients. (See "Valvar aortic stenosis in children".)

There is a high frequency of supravalvular AS in patients with Williams syndrome, which is due to a mutation in the elastin gene. Supravalvular AS is also common in patients with homozygous familial hypercholesterolemia and occurs infrequently in heterozygotes [55,56]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

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 AND RECOMMENDATIONS

●Clinical manifestations (see 'Clinical manifestations' above)

•Symptoms – The patient with AS is generally asymptomatic for a prolonged period. There is wide variability in the degree of outflow obstruction that causes symptoms, depending in part upon patient size and level of physical activity. As a result, there are no hemodynamic values that identify when symptoms will occur (table 2). (See 'Symptoms' above.)

The classic symptoms of aortic stenosis (AS) are heart failure, angina, and syncope. However, the most common symptoms in patients who are followed prospectively are often nonspecific (eg, decreased exercise tolerance, dyspnea on exertion, and dizziness), so care must be taken in attributing these symptoms to AS. Prompt attention is required when even mild symptoms develop in a patient with severe AS given the poor prognosis with medical management (figure 1). (See 'Symptoms' above and 'Sudden cardiac death' above.)

•Signs – Typical signs of AS are a low volume and slow-rising carotid pulse, a mid- to late-peaking systolic murmur in the right intercostal space (movie 2 and movie 4), and a single second heart sound. Although the physical examination may suggest the presence and severity of AS, no single finding or combination of findings on physical examination has both high sensitivity and high specificity for excluding severe AS, particularly in asymptomatic patients. (See 'Physical examination' above.)

●Diagnosis – AS is usually diagnosed when physical examination (including a typical systolic ejection murmur) suggests AS or when AS is detected on an echocardiogram performed for other indications. Echocardiography is the primary test in diagnosis and evaluation of AS. (See 'Diagnosis and evaluation' above.)

When AS severity is uncertain, additional testing may include exercise stress testing, computed tomography for quantitation of valve calcification, transesophageal echocardiography for better visualization of valve anatomy, or serum markers such as B-type natriuretic peptide levels. Cardiac catheterization rarely is needed for diagnosis.

●Differential diagnosis – The differential diagnosis of exertional dyspnea in an older adult is broad, mandating echocardiography if a murmur is present. The differential diagnosis of systolic ejection murmur includes other causes of left ventricular outflow obstruction, including aortic sclerosis without significant stenosis and subvalvular AS (due to a fixed lesion or due to dynamic obstruction as seen in hypertrophic cardiomyopathy) and supravalvular AS. (See 'Differential diagnosis' above.)

●Evaluation of AS stages – The stages of AS are defined according to valve anatomy, valve hemodynamics, hemodynamic consequences of AS, and symptoms (table 3). (See 'Assessment of disease stages' above.)

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