Clinical manifestations and diagnosis of low gradient severe aortic stenosis

INTRODUCTION — Degenerative valvular heart disease (VHD) is common and is the third most frequent cause of cardiac disease after hypertension and coronary artery disease in developed countries with aging populations. Among patients with at least moderate VHD in developed countries, aortic valve stenosis (AS) is most common, followed by mitral regurgitation then aortic regurgitation and finally mitral stenosis [1].

For appropriate diagnosis and management of AS, it is crucial to assess the severity of AS accurately as possible. However, the diagnosis and evaluation of AS is challenging due to a variety of pitfalls. These include discrepancies between severity of AS and patient symptoms, between transvalvular mean pressure gradient and aortic valve area, and between echocardiography and other imaging modalities. In addition, a number of confounding factors and technical issues affect the assessment of AS, including the presence of concurrent conditions such as uncontrolled hypertension, rapid atrial fibrillation, left ventricular dysfunction, and significant mitral regurgitation or stenosis, as well as the occurrence of measurement errors.

Issues relating to the clinical manifestations and diagnosis of low gradient AS will be reviewed here. Management and prognosis of low gradient severe AS, and the clinical presentation and management of classical high gradient severe AS are discussed separately. (See "Clinical manifestations and diagnosis of aortic stenosis in adults" and "Medical management of asymptomatic aortic stenosis in adults" and "Management and prognosis of low gradient aortic stenosis".)

DEFINITIONS AND CLASSIFICATION

High gradient severe AS — The 2020 American Heart Association/American College of Cardiology valvular heart disease guidelines identify severe aortic stenosis (AS) by the presence of an aortic transvalvular velocity ≥4 m/s and/or mean transvalvular pressure gradient ≥40 mmHg; the aortic valve area (AVA) is typically ≤1 cm² (with AVA indexed to body surface area ≤0.6 cm²/m²), although it may be larger with concurrent AS and aortic regurgitation (table 1) [2]; similar criteria are included in the 2021 European Society of Cardiology valve disease guidelines [3]. However, these high velocity and high pressure gradient criteria are valid only in the presence of a normal stroke volume. Only 50 percent of patients with severe AS will present with high-gradient AS.

Types of low flow and/or low gradient AS — Low flow (stroke volume indexed to body surface area ≤35 mL/m²) severe AS and low gradient (transvalvular mean pressure gradient ≤40 mmHg) severe AS are partially overlapping categories of AS:

●Low flow severe AS is identified by the presence of severe AS (AVA ≤1 cm² with AVA indexed to body surface area ≤0.6 cm²/m²) associated with a low flow defined as a stroke volume indexed to body surface area ≤35 mL/m². Since the transvalvular gradient depends on the flow per beat rather than the flow per minute, the stroke volume index is the most frequently used parameter to identify low flow [4]. A newer metric is the flow rate (the stroke volume divided by the systolic ejection time) with <200 mL/s considered a low flow rate [5]. However, it is uncertain whether flow rate has diagnostic or prognostic value over stroke volume index, so the stroke volume index remains the standard metric for low flow.

•Many patients with low flow AS also have a low transvalvular gradient (ie, low flow, low gradient [LFLG] AS), as described below.

•Some patients with very severe AS and low flow have a high transvalvular gradient (mean gradient >40 mmHg) and are thus more easily identified as having true AS.

●Low gradient severe AS is identified by the presence of severe AS (AVA ≤1 cm² with AVA indexed to body surface area ≤0.6 cm²/m²) associated with a transvalvular mean pressure gradient ≤40 mmHg (table 1).

•Many patients with low gradient AS also have low flow (ie, LFLG AS), as described below.

•Some patients with low gradient AS have normal flow (stroke volume index >35 mL/m²), ie, normal flow, low gradient (NFLG) AS.

●LFLG severe AS is identified by the presence of severe AS (AVA ≤1 cm² with AVA indexed to body surface area ≤0.6 cm²/m²) with both of the above conditions, that is, stroke volume indexed to surface area ≤35 mL/m² and mean pressure gradient ≤40 mmHg.

Categories of low gradient severe AS — Given the above framework, low gradient severe AS (mean pressure gradient ≤40 mmHg and AVA ≤1 cm² with AVA indexed to body surface area ≤0.6 cm²/m²) is classified into the following categories based upon flow (low or normal) and left ventricular (LV) systolic function (reduced or preserved) [6]. In the context of AS, reduced LV systolic function is commonly defined clinically as an LV ejection fraction (LVEF) <50 percent [2].

●Classical LFLG AS in which there is LFLG AS (stroke volume indexed to surface area ≤35 mL/m² and mean pressure gradient ≤40 mmHg) and reduced LVEF (LVEF <50 percent). The diagnostic evaluation of patients with findings consistent with this condition is discussed below. (See 'Approach to classical low flow, low gradient AS' below.)

●Paradoxical LFLG AS in which there is LFLG AS and preserved LVEF (LVEF ≥50 percent). The diagnostic evaluation of patients with findings consistent with this condition is discussed below. (See 'Approach to paradoxical low flow, low gradient AS' below.)

●NFLG AS in which there is low gradient AS but normal flow (stroke volume index >35 mL/m²) with generally preserved LVEF (LVEF ≥50 percent). The diagnostic evaluation of patients with findings consistent with this condition is discussed below. (See 'Approach to normal flow, low gradient AS' below.)

True severe versus pseudosevere AS — Patients with low gradient AS in any of the above three categories (classical LFLG, paradoxical LFLG AS, or NFLG AS) may have true severe or pseudosevere AS.

In patients with true severe AS, the primary lesion is severe AS. In patients with LFLG true severe AS, the low gradient is caused by a low stroke volume. When true severe AS is accompanied by LV systolic dysfunction, the LV dysfunction may be secondary to AS or caused by a concurrent condition [4]. Since valve replacement is likely to be beneficial in patients with true severe AS, patients with this condition should undergo evaluation to assess indications and risks of valve replacement.

In patients with pseudosevere AS, a low transvalvular pressure gradient is caused by the combination of mild to moderate AS and low stroke volume. The low stroke volume can occur in the context of reduced LVEF or preserved LVEF. The low stroke volume reduces the valve opening forces, resulting in limited opening of a valve that is not severely diseased. The resting calculated AVA may be misinterpreted as suggesting severe stenosis because of limited opening as well as valve area equation limitations when applied to low flow rate conditions. Unlike patients with true severe AS, patients with pseudosevere AS are unlikely to benefit from valve replacement and face considerable risk of operative death.

PREVALENCE — Although data are limited, it has been estimated that up to one-half of patients with a small aortic valve area (ie, <1 cm²) have low gradient aortic stenosis (AS; mean transvalvular gradient <40 mmHg) [6].

Based upon retrospective data, classical low flow, low gradient (LFLG), low LVEF, severe AS represents approximately 5 to 10 percent of the severe AS population [4]. The prevalence of paradoxical LFLG, preserved LVEF, severe AS is more controversial with rates ranging from 5 to 25 percent of the severe AS population, depending upon the population studied (eg, asymptomatic versus symptomatic [7,8]) and the technique used to define AS severity (echocardiogram versus catheter versus magnetic resonance imaging) [9-11]. Normal flow, low gradient AS is common, constituting approximately 15 to 40 percent of severe AS cases.

Limited prospective data are available on the prevalence of LFLG AS. Among 971 patients with severe AS included in the prospective PARTNER trial, the following rates of low flow AS were identified [12]:

●Low flow (LV stroke volume index ≤35 mL/m²) was found in 55 percent (530 patients)

●Low flow and low LVEF (<50 percent) in 23 percent (225 patients)

●Low flow, low LVEF, and low aortic valve gradient (<40 mmHg) (ie, classical LFLG AS) in 15 percent (147 patients)

CAUSES AND PATHOPHYSIOLOGY — One or more of the following factors may cause low gradient aortic stenosis (AS): low stroke volume (with or without left ventricular [LV] systolic dysfunction), excess arterial afterload, and discrepant aortic valve area (AVA) and gradient thresholds used in guidelines.

Since the aortic transvalvular gradient depends upon the severity of aortic valve stenosis and the flow rate, a low flow rate (stroke volume divided by systolic ejection period) is frequently associated with a low transvalvular gradient. A low stroke volume may be caused by either LV systolic dysfunction with depressed LV ejection fraction (LVEF <50 percent as in classical low flow, low gradient [LFLG] AS) or small ventricular volumes with preserved LVEF ≥50 percent as in paradoxical LFLG AS. Among patients with LFLG AS, low flow may result in incomplete valve opening and thus overestimation of AS (ie, a lower AVA than present with a higher stroke volume). (See 'True severe versus pseudosevere AS' above.)

In patients with classical LFLG AS, impaired LV function may be caused primarily by AS itself, causing chronic pressure overload, can be secondary to other conditions (eg, concurrent coronary artery disease or severe mitral regurgitation) or most commonly is caused by the combined effect of the aortic valve lesion and concurrent conditions.

In patients with paradoxical LFLG AS, several causes may contribute to a low stroke volume despite a preserved LVEF. In patients with this disorder, low stroke volume is commonly associated with concentric LV remodeling or hypertrophy with a small LV cavity, impaired LV diastolic filling, and impaired LV longitudinal systolic function despite preserved LVEF [13]. This state is uncommonly preceded by a high gradient state [14]. Elevated arterial afterload caused by severe, uncontrolled, long-standing hypertension also contributes to the development of paradoxical LFLG AS [11,15,16]. Additional conditions that may contribute to low stroke volume in patients with preserved LVEF include atrial fibrillation, significant mitral regurgitation, mitral stenosis, tricuspid regurgitation, and right ventricular dysfunction [6].

Studies have identified transthyretin cardiac amyloidosis (ATTR-CA) in about 10 to 15 percent of patients with severe AS [17,18]. Patients with severe AS and ATTR-CA have paradoxical LFLG AS (with LVEF only mildly reduced) and have a worse prognosis than those with AS alone, but both groups of patients are likely to benefit from transcatheter aortic valve implantation [19]. (See "Management and prognosis of low gradient aortic stenosis", section on 'Management'.)

Patients with paradoxical LFLG AS usually have elevated valvuloarterial impedance (Zva), an expression of the total load the LV is facing (ie, the ventricular plus the arterial load) [20-22]. The valvuloarterial impedance is calculated using the following formula in which the stroke volume is indexed to body surface area and expressed in mmHg/mL/m²:

As noted above, normal flow, low gradient (NFLG) AS is a common cause of low gradient AS. One cause for this is that the guideline cut-point for AVA of 1 cm² to detect severe AS is a sensitive marker for mortality associated with severe AS but corresponds to a mean gradient of 30 to 35 mmHg (rather than 40 mmHg) in the presence of normal flow [6,9,23]. Thus, application of the guideline criteria for severe AS will lead to detection of numerous cases of NFLG AS. Another potential cause of NFLG AS is arterial afterload caused by reduced aortic compliance and associated systolic hypertension [6].

CLINICAL MANIFESTATIONS — The clinical manifestations of low gradient aortic stenosis (LG AS) are the same as for calcific AS generally. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Clinical manifestations'.)

Clinical characteristics — Patients with LG AS are typically older adults and frequently have multiple comorbidities such as hypertension, dyslipidemia, coronary artery disease, peripheral vascular disease, and diabetes mellitus [11,24].

Symptoms and signs — Patients with severe LG AS may or may not have symptoms [25]. Symptoms and signs of LG severe AS are the same as those for high gradient severe AS.

Symptoms typical for AS include dyspnea on exertion or decreased exercise tolerance, exertional angina, and dizziness (presyncope) or syncope. The classic symptoms of AS (heart failure, syncope, and angina) reflect advanced disease. Since these symptoms are nonspecific, care must be taken in attributing these symptoms to AS, since most patients with these symptoms do not have AS. When angina is present, it may be caused by AS or by concurrent coronary artery disease. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Symptoms'.)

On physical examination, signs of severe AS include a slow rate of rise in the carotid pulse, a mid to late peaking systolic ejection murmur radiating to the right carotid artery or right clavicle, and reduced intensity of the second heart sound. It should be noted that with severe LFLG AS, the murmur may be soft and unimpressive. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Physical examination'.)

Initial tests — An electrocardiogram is not required to diagnose AS but it is commonly performed to detect concomitant conditions such as atrial fibrillation and coronary artery disease (including prior myocardial infarction). Atrial fibrillation occurs commonly in patients with low flow, LG AS (in approximately 20 to 50 percent [15]). Other common findings include evidence of left ventricular hypertrophy and repolarization abnormalities caused by left ventricular hypertrophy or ischemia. Left bundle branch block is found in some patients, particularly those with dilated left ventricle and reduced left ventricular ejection fraction.

A chest radiograph is not generally required to diagnose AS. However, a chest radiograph may be obtained in some patients with dyspnea to assess for signs of heart failure and other potential causes of shortness of breath. In patients with AS, the chest radiograph may be normal or may show nonspecific signs such as increased heart size, pleural effusion, interstitial or alveolar edema consistent with pulmonary edema due to heart failure. Calcification in the region of the aortic valve may be detected on the lateral view.

DIAGNOSIS AND EVALUATION

Initial approach to diagnosis — We suggest the following approach to diagnosis and evaluation of low flow, low gradient AS (LFLG AS).

When and how to diagnose AS — The initial steps involve identification and evaluation of AS, which is discussed in greater detail separately. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Diagnosis and evaluation'.)

●When to suspect AS – 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. Symptoms such as dyspnea, angina or presyncope may or may not be present.

●Transthoracic echocardiography (TTE) is the primary test for diagnosis and evaluation of AS; it enables confirmation of the presence of stenosis, assessment of its severity (by estimated valve area, transvalvular velocity and transvalvular mean gradient), and evaluation of left ventricular (LV) and right ventricular size and function. In nearly all patients with high-gradient AS, TTE alone is sufficient to diagnose AS and assess its severity. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Initial approach to diagnosis and evaluation'.)

When to suspect low gradient AS — Low gradient (LG) severe AS is suspected when the echocardiogram reveals an aortic valve area (AVA) ≤1 cm² (with AVA indexed to body surface area ≤0.6 cm²/m²) associated with a transvalvular mean pressure gradient ≤40 mmHg (table 1). When these findings are identified, the first step is to confirm that all measurements are accurate.

●If the AVA, transvalvular mean pressure gradient, and flow are verified to be consistent with LFLG severe AS (AVA indexed to body surface area ≤0.6 cm²/m², transvalvular mean pressure gradient ≤40 mmHg, and stroke volume index <35 mL/m²), the next step is to determine whether the LV ejection fraction (LVEF) is <50 or ≥50 percent, as this will determine the course of further evaluation.

•An LVEF <50 percent suggests classical LFLG AS. Further diagnostic evaluation is discussed below. (See 'Approach to classical low flow, low gradient AS' below.)

•An LVEF >50 percent suggests paradoxical LFLG AS. Further diagnostic evaluation is discussed below. (See 'Approach to paradoxical low flow, low gradient AS' below.)

●If the AVA is ≤1 cm² (for individuals with small BSA, use AVA indexed to body surface area ≤0.6 cm²/m²), the transvalvular mean pressure gradient is ≤40 mmHg, but stroke volume index is >35 mL/m², findings are consistent with normal flow, low gradient (NFLG) AS. Further diagnostic evaluation is discussed below. (See 'Approach to normal flow, low gradient AS' below.)

Additional evaluation based upon type of low gradient AS — Further evaluation is based upon the type of low gradient AS and can be difficult. We suggest referral to clinicians and centers with experience and expertise with diagnosis and management of patients with low gradient severe AS.

Approach to classical low flow, low gradient AS — For patients with all three criteria suggestive of classical LFLG severe AS (AVA ≤1 cm², with AVA indexed to body surface area [BSA] ≤0.6 cm²/m²), transvalvular mean pressure gradient ≤40 mmHg (or V_max <4 m/s, plus LVEF <50 percent), we recommend the following evaluation to differentiate true severe from pseudo-severe AS.

●The first step is to confirm that all measurements and calculations for AVA (including indexed AVA), mean transvalvular gradient, and LVEF are accurate.

●Low-dose dobutamine stress echocardiography is the initial test to differentiate true severe from pseudosevere AS in patients with classical LFLG AS.

•If dobutamine stress transthoracic echocardiography (TTE) shows an AVA ≤1 cm² (with AVA indexed to BSA ≤0.6 cm²/m²) with transvalvular mean gradient ≥40 mmHg (or Vmax ≥4 m/s), then the presence of classical LFLG severe AS is confirmed.

•If dobutamine stress TTE shows an AVA >1 cm² (or AVA indexed to BSA >0.6 cm²/m²) with transvalvular mean gradient <40 mmHg, then the diagnosis of pseudosevere AS is confirmed.

•If dobutamine stress TTE shows modest or no flow reserve with persistent discordance between the AVA and mean gradient (ie, with stress, AVA remains ≤1.0 cm² (with AVA indexed to BSA ≤0.6 cm²/m²) and transvalvular mean gradient remains <40 mmHg), additional evaluation is needed.

-We suggest assessment of the aortic valve with multidetector computed tomography (MDCT). (See 'Multidetector computed tomography' below.)

-If there is at least a 15 percent increase in mean transvalvular flow rate (stroke volume/LV ejection time) with dobutamine stress compared with rest, we suggest also calculating the projected AVA at normal flow rate [6]. (See 'Projected aortic valve area' below.)

-The MDCT and/or projected AVA at normal flow rate is interpreted as follows:

•If the MDCT aortic valve calcium score is >1200 AU (women) or >2000 (men) and/or the projected AVA is <1 cm², the patient is diagnosed with true severe AS.

•If neither the MDCT nor projected AVA criterion for true severe AS is met, the patient is diagnosed with pseudosevere AS.

Approach to paradoxical low flow, low gradient AS — For patients with all four of the criteria suggestive of paradoxical LFLG severe AS (AVA ≤1 cm² [with AVA indexed to BSA ≤0.6 cm²/m²], transvalvular mean pressure gradient ≤40 mmHg, with a stroke volume index <35 mL/m² and LVEF ≥50 percent) [20], we recommend the following evaluation:

●The first step is to confirm that all measurements and calculations for AVA, mean gradient, and LVEF are accurate.

●The next step is to assess for presence of symptoms attributable to severe AS:

•If symptoms attributable to severe AS are lacking, we recommend follow-up to monitor for disease progression, early detection of symptom onset, and treatment of cardiovascular risk factors and comorbidities. (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Serial evaluation'.)

•If symptoms are equivocal, we suggest exercise stress echocardiography to ascertain symptom status.

•If symptoms attributable to severe AS are present, we recommend further evaluation as below to assess for presence of hypertension and distinguish true severe from pseudosevere AS [6].

●The next step is to check the systemic blood pressure (BP):

•If systolic BP is ≥135 mmHg, antihypertensive therapy should be optimized. After systolic BP is controlled to <135 mmHg, an echocardiogram should be repeated to reassess AVA, transvalvular mean pressure gradient, and stroke volume index. With optimized BP control, these parameters may or may not change, so some patients will continue to meet criteria for LFLG AS, some may meet criteria for NFLG AS, and some may not have criteria for either.

•If the systolic BP is <135 mmHg, (table 1) the cause of low flow should be assessed. A major cause is a small LV cavity with concentric LV hypertrophy associated with a restrictive mitral inflow pattern, elevated LV filling pressures, and dilated left atrium. Other contributing conditions include atrial fibrillation, mitral regurgitation, mitral stenosis, right ventricular dysfunction, and tricuspid regurgitation.

Studies suggest that 10 to 20 percent of patients with paradoxical LFLG AS have wild-type transthyretin (ATTR) cardiac amyloidosis [26-28], which can caused marked LV hypertrophy with a small LV cavity and a restrictive filling pattern. This entity is important to recognize and identify, as it may significantly affect the prognosis and outcome of patients with paradoxical LF after TAVR [29,30]. Moreover, it becomes crucial to diagnose wild-type ATTR amyloidosis given the availability of specific treatment. (See "Cardiac amyloidosis: Treatment and prognosis", section on 'Disease-specific therapy for ATTR amyloidosis'.)

-If a cause of low flow cannot be identified, we recommend excluding measurement errors in the stroke volume index and aortic valve parameters.

-If a cause of low flow is identified, a diagnosis of paradoxical LFLG severe AS is likely.

•For patients with likely paradoxical LFLG severe AS, we suggest the following evaluation to distinguish true severe from pseudo-severe AS:

-We suggest MDCT aortic valve calcium scoring:

If the MDCT aortic valve calcium score is >1200 AU (women) or >2000 (men), the patient is diagnosed with true severe AS.

If the MDCT aortic valve calcium score is ≤1200 (women) or ≤2000 (men), the patient is diagnosed with pseudosevere AS.

-As an alternative to MDCT, if there is no evidence of restrictive LV physiology, we recommend low-dose dobutamine stress echocardiography [31]. (See 'Low-dose dobutamine stress echocardiogram' below.)

Approach to normal flow, low gradient AS — For patients with all three criteria for normal flow, low gradient (NFLG) AS, including normal flow (stroke volume index >35 mL/m²), low gradient (mean gradient <40 mmHg), and preserved LVEF (LVEF ≥50 percent), we recommend the following evaluation:

●The first step is to confirm that all measurements and calculations for AVA, mean gradient, and LVEF are accurate. Some patients with NFLG AS, particularly those who are asymptomatic and have small body surface area, likely have only moderate AS. Indexing AVA for BSA can help in recognition of these.

●The next step is to assess whether the patient has symptoms attributable to severe AS:

•If symptoms attributable to severe AS are lacking, we recommend follow-up to monitor for disease progression, early detection of symptom onset, and treatment of cardiovascular risk factors and comorbidities. (See "Medical management of asymptomatic aortic stenosis in adults", section on 'Serial evaluation'.)

•If symptoms are present, we recommend proceeding with the evaluation below, including assessment of the effect of hypertension and testing to distinguish true severe from pseudosevere AS is recommended.

●For patients with symptomatic NFLG AS, the potential impact of hypertension should be assessed. If systolic BP is ≥130 mmHg, antihypertensive therapy should be optimized. After systolic BP is controlled to <130 mmHg, an echocardiogram should be repeated to reassess AVA, transvalvular mean pressure gradient, stroke volume index, and symptom status.

●For patients with symptomatic NFLG AS, we also recommend MDCT aortic valve calcium scoring to differentiate true severe AS from pseudosevere AS:

•If the MDCT aortic valve calcium score is >1200 AU (women) or >2000 (men), the patient is diagnosed with true severe AS.

•If the MDCT aortic valve calcium score is ≤1200 AU (women) or ≤2000 (men), the patient is diagnosed with moderate or pseudosevere AS.

As noted above, the finding of NFLG AS in part reflects tension between threshold values to sensitively detect AS (AVA ≤1 cm², which corresponds to a mean aortic valve gradient >30 mmHg) and a threshold value to specifically detect AS (mean aortic valve gradient >40 mmHg) [6]. (See 'Causes and pathophysiology' above.)

Diagnostic tests — Most patients with low gradient severe AS are identified by TTE. For patients with low flow states (without contraindications such as restrictive physiology), low-dose dobutamine echocardiography test is helpful in distinguishing true stenosis from pseudostenosis, and to identify those with and without contractile reserve. MDCT is the test of choice in patients with indeterminate results on low-dose dobutamine echocardiography and for patients who are not candidates for dobutamine testing either because there is normal flow across the aortic valve at rest or due to a contraindication (such as presence of restrictive physiology). If the preceding work-up is inconclusive, dobutamine stress catheterization is an option, though it entails risks and limitations.

Key tests — In patients with LFLG severe AS or NFLG severe AS, the standard gradient criteria for AS are not applicable. After resting echocardiography is performed, additional testing (such as low-dose dobutamine stress echocardiography, MDCT, and projected AVA) is needed to distinguish true severe from pseudosevere AS. (See 'Causes and pathophysiology' above and 'Additional evaluation based upon type of low gradient AS' above.)

Resting transthoracic echocardiogram — A TTE is the key test for diagnosis and evaluation of AS. Echocardiographic features of AS are discussed separately. (See "Echocardiographic evaluation of the aortic valve", section on 'Valvular aortic stenosis' and "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Diagnostic echocardiography'.)

Low-dose dobutamine stress echocardiogram — A 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). In addition, the test provides information on LV contractile reserve, which is helpful for prognostic purposes in contemplating possible surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI).

●Low-dose dobutamine stress test is indicated to distinguish true AS from pseudosevere AS in the following clinical setting: patients with findings consistent with classical LFLG AS, namely AVA ≤1 cm² (or AVA indexed to body surface area ≤0.6 cm²/m²), resting transvalvular mean pressure gradient ≤40 mmHg (or V_max <4 m/s), plus LVEF <50 percent.

●Low-dose dobutamine stress test may also be helpful in the following setting, but there are limited data: symptomatic patients with findings consistent with paradoxical LFLG AS, namely AVA ≤1 cm² (or AVA indexed to body surface area ≤0.6 cm²/m²), resting transvalvular mean pressure gradient ≤40 mmHg (or V_max <4 m/s), plus LVEF ≥50 percent.

Low-dose dobutamine stress TTE is recommended in the above clinical settings unless there is an absolute contraindication (eg, severe arrhythmias). (See "Overview of stress echocardiography", section on 'Safety of dobutamine administration'.)

After obtaining baseline echocardiographic recordings in the resting state (to confirm presence of the above resting parameters), echocardiography is repeated while administering dobutamine starting at 5 mcg/kg/min that is gradually increased by increments of 5 mcg/kg/min every three to five minutes up to a maximum dose of 20 mcg/kg/min, trying not to increase the baseline heart rate by more than 10 to 15 beats, with the peak heart rate usually 100 to 110 beats/minute. (See "Overview of stress echocardiography", section on 'Dobutamine stress echocardiography'.)

Analysis of the low-dose dobutamine stress test begins with confirming the presence of contractile reserve, which is generally defined as a relative increase in stroke volume >20 percent of baseline stroke volume. If there is contractile reserve, the LVEF will usually augment 5 to 10 percent absolute points above the baseline LVEF. The indices of stenosis severity (aortic valve area and mean transvalvular gradient) are re-assessed with dobutamine stress.

●If the peak effective orifice area achieved during dobutamine stress remains lower than 1 cm² and the mean pressure gradient rises above 40 mmHg, true severe stenosis is identified. SAVR or TAVI is recommended for such patients.

●Conversely, if the AVA increases to more than 1 cm² and the mean gradient remains <40 mmHg, the AS is considered as pseudosevere and generally, medical therapy is appropriate.

●If dobutamine stress TTE shows modest or no flow reserve with persistent discordance between the AVA and mean gradient (ie, with stress, AVA remains ≤1 cm² or AVA indexed to body surface area ≤0.6 cm²/m² and transvalvular mean gradient remains <40 mmHg), additional evaluation is needed. (See 'Approach to classical low flow, low gradient AS' above.)

●If there is no contractile reserve (absence of increase of stroke volume more than 20 percent or absence of increase in LVEF from baseline with AVA remaining <1 cm² and mean gradient remaining <40 mmHg) it is a marker of poor prognosis with regard to operative and postoperative mortality but not a contraindication to AVR. In such cases, MDCT may be used to assess the severity of calcification since this is significantly correlated to hemodynamic AS severity.

The main limitation of stress dobutamine TTE for evaluation of the severity of low gradient AS is a variable increase in stroke volume in response to dobutamine. Standardization by indexing the increase in valve area to the transvalvular flow rate has been proposed [32]. In a series of 23 adults, this approach distinguished true stenosis from pseudostenosis, using surgical inspection as the reference standard, with an accuracy of 83 percent compared with an accuracy of 61 percent with other measures of stenosis severity. This approach requires more complex measurements and calculations and further validation is needed.

Multidetector computed tomography — For patients with classical LFLG AS with inconclusive low-dose dobutamine stress echocardiography results (ie, stress mean aortic gradient <40 mmHg and AVA <1 cm²), for patients with symptomatic paradoxical LFLG AS who are not candidates for low-dose dobutamine stress echocardiography (or have inconclusive dobutamine stress results), and for symptomatic patients with NFLG AS, we recommend MDCT as a means of assessing the severity of AS [2,6]. The severity of aortic valve calcification by MDCT is also predictive of risk of mortality [33].

The thresholds for aortic valve calcium score are ≥1200 AU in women and ≥2000 AU in men are used to identify true severe AS [6]. For patients with either small or large aortic annuli, "the aortic valve calcium density" (AVC_d, the AVA indexed by the cross-sectional area of the aortic annulus) is used to identify true-severe AS, using ≥300 AU/cm² for women and ≥500 AU/cm² for men.

Support for this approach comes from studies showing that aortic valve calcium score by CT is inversely correlated with AVA. This relationship was observed in studies using electron beam CT [34] and later studies in studies using MDCT [33,35,36]:

●In a study of 646 patients with AS (mean age 74), an aortic valve calcium score threshold of ≥1274 AU yielded a sensitivity of 86 percent and a specificity of 89 percent for severe AS in women; an aortic valve calcium score of ≥2065 AU yielded a sensitivity of 89 percent and a specificity of 80 percent for men [36]. For AVC_d, the best threshold for severe AS was ≥292 in women (sensitivity 92 percent and specificity of 81 percent) and ≥476 in men (sensitivity of 90 percent and specificity of 80 percent).

●In a series of 918 patients with AS (mean age of 77 years), CT aortic valve calcium scores accurately identified those with severe AS. Sex-specific cutoff values predicted aortic valve replacement and death after adjustment for age, sex, peak velocity, and aortic valve area (HR 3.90, 95% CI 2.19-6.78) [37].

One limitation of the MDCT approach for assessing severity of AS is that this approach is applicable only for calcific AS, and thus is likely not applicable for younger patients with bicuspid aortic valve [6].

A role for MDCT as a means of measuring the left ventricular outflow tract (LVOT) diameter for use together with Doppler echocardiography to estimate AVA has not been established. Such hybrid approach yields higher AVA estimates than use of echocardiography alone and has not been shown to enhance prediction of mortality [6,38,39].

Projected aortic valve area — Some experts recommend calculation of the projected aortic valve area at normal flow rate as a method to distinguish true severe from pseudosevere AS in patients with findings consistent with classical LFLG AS with modest flow reserve (at least a 15 percent increase in mean transvalvular flow rate [stroke volume/LV ejection time]) associated with persistently discordant AVA and mean gradient with low-dose dobutamine stress (ie, AVA remains <1 cm² and mean gradient remains <40 mmHg) [6]. Projected AVA may be used along with (or in place of) MDCT aortic valve calcium score in this patient population. The projected AVA is calculated as follows, in which Q is the mean transvalvular flow rate = (stroke volume) / (LV ejection time):

Additional tests — Additional tests such as transesophageal echocardiography (TEE) and cardiac catheterization are indicated in only selected patients in the diagnostic evaluation of low gradient AS.

Transesophageal echocardiography — TEE has a limited role during the evaluation of patients with LFLG; it may be useful in patients with suboptimal acoustic windows in whom it is impossible to see the aortic valve and measure the LVOT diameter; in this situation, the anatomic AVA, as determined by planimetry, can be used. Of note, the anatomic area by two-dimensional TEE is generally slightly larger than the calculated valve area by TTE. In addition, in low flow states, the anatomic valve area on rest TEE generally cannot differentiate true stenosis from pseudostenosis.

For patients with suspected LFLG severe AS on TTE, one potential role for TEE is to more accurately assess the size and shape of an elliptical LVOT for use in estimating AVA [40]. However, the value of such an approach has not been validated.

The role of TEE in selected patients with LFLG who may be candidates for TAVI is discussed separately. (See "Imaging for transcatheter aortic valve implantation".)

Cardiac catheterization — As noted in the American College of Cardiology/American Heart Association guidelines, cardiac catheterization is indicated to evaluate patients with suspected significant AS when noninvasive tests are inconclusive or if there is a discrepancy between the clinical evaluation and the echocardiogram regarding severity of the valve lesions [2]. However, for patients with low gradient AS, rest cardiac catheterization is subject to similar limitations as rest echocardiography. For patients with LFLG AS, dobutamine stress catheterization is a potential means of differentiating true severe from pseudosevere AS but noninvasive methods are generally preferred [6].

There is some risk of cerebral embolization associated with crossing the aortic valve in patients with severe calcific AS, so this procedure should be undertaken only when needed [41,42]. (See "Stroke after cardiac catheterization".)

The separate issue of coronary angiography at the time of aortic valve replacement to identify patients who might also benefit from coronary artery bypass graft surgery is discussed elsewhere (figure 1). (See "Indications for valve replacement for high gradient aortic stenosis in adults", section on 'Concomitant coronary revascularization'.)

Investigational tests — The potential roles of natriuretic peptides and measures of longitudinal LV systolic function in diagnosis and evaluation of low gradient AS remain to be established.

Natriuretic peptides — A role for natriuretic peptide (eg, B-type natriuretic peptide [BNP] or N-terminal proBNP [NT-proBNP]) level testing in patients with LFLG AS has not been established. The ability of plasma BNP to separate patients with true stenosis from those with pseudostenosis was evaluated in the TOPAS study, which enrolled 69 symptomatic (81 percent New York Heart Association functional class II and III) patients with low flow (indexed aortic orifice area <0.6 cm²/m²) and low gradient (mean gradient ≤40 mmHg) AS with reduced LVEF (≤40 percent) [43]. After classification using dobutamine stress echocardiography, patients with true AS (29) compared with those with pseudostenosis (40) had significantly higher BNP levels (median, 743 versus 471 pg/mL), though there was overlap between the two groups. Further studies are needed to determine the value of natriuretic peptide testing in evaluation of LFLG AS, particularly since BNP may be elevated due to LV dysfunction with heart failure, even when AS is not severe.

One-year survival was significantly lower in those patients with a plasma BNP ≥550 pg/mL compared with those with <550 pg/mL (47 versus 97 percent) in the entire cohort and in the 29 patients who underwent surgery (53 versus 92 percent). These findings are consistent with previous studies showing that outcome depends upon the severity of LV dysfunction and heart failure. However, plasma BNP will rarely affect clinical decision-making because all of these patients benefit from aortic valve replacement, unless the surgical risk is prohibitive.

The use of plasma BNP to predict outcome from surgery and an overview of the use of plasma BNP as a tool for diagnosis and management of cardiovascular disease are discussed separately. (See "Natriuretic peptide measurement in heart failure" and "Management and prognosis of low gradient aortic stenosis", section on 'Natriuretic peptides'.)

Measures of longitudinal LV systolic function — Global longitudinal strain (GLS) imaging may have prognostic value in patients with classical or paradoxical LFLG AS, but its clinical role has not been established. GLS is an echocardiographic imaging technique that enables myocardial deformation analysis for precise and early detection of LV systolic dysfunction. GLS has been found to be a robust method of detecting subtle LV dysfunction associated with adverse clinical outcomes in various cardiac diseases. It has also been studied as a marker of adverse outcomes in patients with paradoxical LFLG AS. GLS in patients with paradoxical low flow AS is depressed compared with that in patients with normal flow AS [44]. Moreover, higher valvuloarterial impedance was a significant predictor of reduced GLS. (See "Tissue Doppler echocardiography", section on 'Assessment of global and regional left ventricular systolic function'.)

A multicenter study including 340 asymptomatic patients with severe AS and normal LVEF found that 9 percent had paradoxical LFLG AS. LFLG AS was associated with markedly reduced basal longitudinal systolic function as assessed by two-dimensional GLS [7]. This suggests that subclinical myocardial dysfunction is more prominent in paradoxical LFLG AS compared with normal flow low gradient AS and a potential value of GLS in diagnosing paradoxical LFLG AS.

Some other studies have assessed LV systolic function using the technically simpler approach of the mitral annular plane systolic excursion (MAPSE) or displacement (calculated as the mean of septal and lateral systolic mitral annular motion using M-mode echocardiography in an apical four chamber view). These studies suggest that MAPSE may also be helpful in distinguishing true stenosis from pseudostenosis [45]. In a population of patients with at least moderate AS and mean transvalvular pressure gradient <40 mmHg, all 20 patients with MAPSE <9 mm had severe AS and all 17 of those with displacements ≥9 mm had moderate AS. Moreover, MAPSE was inversely correlated with interstitial fibrosis on myocardial biopsy.

DIFFERENTIAL DIAGNOSIS — As noted above, when low gradient aortic stenosis (LG AS) is suspected based upon transthoracic echocardiogram results, the first step is to exclude measurement error due to technical issues such as inaccurate transvalvular or left ventricular outflow tract (LVOT) velocity measurement or inaccurate measurement of LVOT dimension. As an example, valve area may be underestimated using the continuity equation, if the LVOT diameter and thus LVOT flow is underestimated. Also, for patients with small body size, it is important to adjust AVA for body size (ie, identify severe AS using a threshold of AVA indexed to body surface area ≤0.6 cm²/m² instead of AVA ≤1 cm²); in small patients, an AVA slightly less than 1 cm² may represent moderate AS [46].

After findings consistent with LG AS are confirmed, other imaging modalities (chiefly low-dose dobutamine stress echocardiography and multidetector computed tomography) are used to distinguish true severe AS from pseudosevere AS. (See 'True severe versus pseudosevere AS' above and 'Additional evaluation based upon type of low gradient AS' above and 'Low-dose dobutamine stress echocardiogram' above and 'Multidetector computed tomography' above.)

The differential diagnosis of AS versus other causes of similar physical examination or echocardiography findings is discussed in detail separately. Briefly summarized, transthoracic echocardiography is the key modality for distinguishing AS from other causes of left ventricular outflow obstruction such as supravalvular AS, congenital subvalvular aortic stenosis, and obstructive hypertrophic cardiomyopathy. In addition, care should be taken to distinguish signal from mitral regurgitation from the jet of AS, since both are high velocity signals directed away from the LV apex. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Differential diagnosis'.)

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

●Low gradient severe aortic stenosis (AS; mean pressure gradient ≤40 mmHg and aortic valve area ≤1 cm² with aortic valve area (AVA) indexed to body surface area ≤0.6 cm²/m²) includes the following conditions (see 'Categories of low gradient severe AS' above):

•Classical low flow, low gradient (LFLG) AS in which there is LFLG AS (stroke volume indexed to surface area ≤35 mL/m² and mean pressure gradient ≤40 mmHg) and reduced left ventricular ejection fraction (LVEF; <50 percent).

•Paradoxical LFLG AS in which there is LFLG AS and preserved LVEF (LVEF ≥50 percent).

•Normal flow, low gradient (NFLG) AS in which there is low gradient AS but normal flow (stroke volume index >35 mL/m²) with generally preserved LVEF (LVEF ≥50 percent).

●As many as one-half of patients with severe AS may have low gradient AS. This includes approximately 5 to 10 percent with classical LFLG AS, 5 to 25 percent with paradoxical LFLG AS, and 15 to 40 percent with NFLG AS. (See 'Prevalence' above.)

●Patients with parameters consistent with low gradient severe AS in any of the above three categories (classical LFLG AS, paradoxical LFLG AS, or NFLG AS) may have true severe or pseudosevere AS. (See 'True severe versus pseudosevere AS' above.)

•Some patients with apparent low gradient severe AS, particularly those who are asymptomatic and have small body surface area, have only moderate AS. Indexing AVA for body surface area can aid in identification of these cases.

•Among patients who have parameters (including indexed AVA) consistent with low gradient severe AS, tests beyond resting echocardiography are required to distinguish true severe from pseudosevere AS. (See 'Key tests' above.)

●One or more of the following factors may cause low gradient AS: low stroke volume (with or without LV systolic dysfunction), excess arterial afterload, and discrepant AVA and gradient thresholds. (See 'Causes and pathophysiology' above.)

●The clinical manifestations of low gradient AS are the same as for calcific AS generally. Patients with severe LG may or may not have symptoms. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Clinical manifestations'.)

●The diagnostic evaluation for patients with LG AS varies with type (classical LFLG AS, paradoxical LFLG AS, or NFLG AS), although common principles apply (see 'Additional evaluation based upon type of low gradient AS' above):

•The first step for all types is to confirm the accuracy of AVA, mean valve gradient, and LVEF measurements.

•For patients with low gradient AS who may have indications for surgery (ie, those with LVEF <50 percent and/or symptoms attributable to severe AS), further evaluation is indicated to distinguish true stenosis from pseudostenosis.

-Low-dose dobutamine stress echocardiography is indicated in patients with LFLG AS (excluding patients with paradoxical LFLG AS with restrictive physiology or other patients with contraindications).

-Multidetector computed tomography is indicated in patients with LFLG AS with inconclusive low-dose dobutamine stress echocardiography results or contraindication to low-dose dobutamine testing. It is also indicated in symptomatic patients with NFLG AS.

ACKNOWLEDGMENTS

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

The UpToDate editorial staff acknowledges Catherine M Otto, MD, who contributed to earlier versions of this topic review.