Low-Gradient Aortic Stenosis; the Diagnostic Dilemma.

Low-gradient (LG) aortic valve stenosis (AS) constitutes a significant subset among patients with severe aortic stenosis. This entity represents one of the most challenging heart conditions when it comes to diagnosis and management, mainly because of the discrepancy between the small aortic valve area (≤1.0 cm2) that is considered a severe AS, and low mean transvalvular pressure gradient (<40 mmHg), which is one of the criteria for nonsevere AS. LG AS is divided according to transvalvular aortic flow rate into normal-flow LG AS and low-flow LG (LFLG) AS; the latter category can be divided further according to left ventricular ejection fraction (LVEF) into classical LFLG AS if LVEF is depressed or paradoxical LFLG AS if LVEF is preserved. The primary diagnostic challenge in patients with LG AS is to confirm that AS is truly severe and not pseudosevere, which is assessed mainly by either dobutamine stress echocardiography or multidetector computed tomography. The management of symptomatic true severe LG AS is mainly by aortic valve replacement (AVR), whether surgical or transcatheter approach. Patients with LG severe AS have a generally worse prognosis and higher mortality compared with patients with high-gradient severe AS. Despite the survival benefit of AVR in patients with true severe LG AS, these patients have higher surgical risk post-AVR compared with high-gradient AS patients. Early recognition and correct diagnosis of a patient with LG AS is crucial to improve their mortality and morbidity. Copyright:

INTRODUCTION

Aortic valve stenosis (AS) is the third most common cardiovascular disease after coronary artery disease and systemic arterial hypertension (HTN), and it is the most frequent degenerative valvular heart disease in developed countries.[1] AS is usually caused by thickening and calcification of the valve leaflets causing restricted valve opening during systole.[2] Worldwide, rheumatic valve disease is the most common cause of AS. In North America and Europe, AS is primarily due to a calcific disease of a native tri-leaflet valve or a congenitally bicuspid valve. The prevalence of AS increases with age, and it affects around 10% of patients aged 80–89 years.[3] Management of AS depends on the symptoms and its severity which is mainly assessed by echocardiography. However, accurate assessment of AS severity is not easy and can be challenging due to several reasons, which include difficulties in obtaining a precise transvalvular pressure gradient by echocardiography and calculating the aortic valve area (AVA).

As defined in the latest European society of cardiology (ESC) and American college of cardiology (ACC)/American Heart Association (AHA) guidelines, severe AS is referred to AS with a mean transvalvular pressure gradient ≥40 mmHg, peak aortic jet velocity ≥4 m/s, and AVA ≤1.0 cm2 (or indexed AVA ≤0.6 cm2/m2).[45] However, almost half patients with severe AS have small AVA (≤1.0 cm2), but the transvalvular mean pressure gradient is <40 mmHg, this category of AS is referred to as “low-gradient (LG) severe AS”.[6]

Patients with LG severe aortic stenosis have a generally worse prognosis and higher mortality compared with patients with high-gradient severe AS. The management of symptomatic true severe LG AS is mainly by aortic valve replacement (AVR), whether surgical or transcatheter. Despite the survival benefit of AVR in patients with true severe LG AS, these patients have higher surgical risk post-AVR compared with patients with high-gradient AS. According to one study, the 10-year survival was reduced in patients with severe low-flow LG (LFLG) AS (32 ± 9%) compared with those with severe normal flow high gradient (66 ± 4%; P = 0.0002).[7] In addition, the 1-year mortality rate postsurgical AVR of LFLG AS is almost three times that of high-gradient AS (13% vs. 4%).[8] Underestimation of AS severity in these patients may delay the proper management and results in a worse prognosis.

TERMINOLOGY

High-gradient severe aortic valve stenosis

As defined in the 2020 AHA/ACC valvular heart disease guidelines and the 2021 ESC valve disease guidelines, severe AS is referred to AS with an AVA of ≤1.0 cm2 (or AVA indexed to body surface area ≤0.6 cm2/m2), and a peak aortic jet velocity ≥4 m/s and/or a mean transvalvular pressure gradient ≥40 mmHg [Table 1, Figure 1].[45]

Table 1

Characteristics of severe AS subtypes

Severe AS category	Mean transvalvular pressure gradient (mmHg)	Transvalvular velocity (m/s)	AVA (cm2)	SVI (mL/m2)	LVEF
High gradient severe AS	≥40	≥4	≤1	>35	Variable
Classical LFLG AS	<40	<4	≤1	≤35	<50%
Paradoxical LFLG AS	<40	<4	≤1	≤35	≥50%
NFLG AS	<40	<4	≤1	>35	≥50%

AS: Aortic valve stenosis, LVEF: Left ventricular ejection fraction, AVA: Aortic valve area, SVI: Stroke volume index, LFLG: Low-flow low-gradient, NFLG: Normal-flow low-gradient

Figure 1

Classification of severe aortic stenosis

Low-flow severe aortic valve stenosis

AS with AVA of ≤1.0 cm2 and low stroke volume indexed to body surface area (SVI) ≤35 mL/m2 or flow rate (the stroke volume divided by the systolic ejection time) <200 mL/s.[45]

Low-gradient severe aortic valve stenosis

AS with AVA of ≤1.0 cm2 and mean transvalvular pressure gradient <40 mmHg. LG severe AS is further classified into one of the following 3 subtypes:

Classical LFLG AS: Defined as LG severe AS with decreased SVI to surface area (SVI ≤35 mL/m2), in the presence of reduced left ventricular ejection fraction (LVEF <50%)

Paradoxical LFLG AS: Defined as LG severe AS with decreased SVI to body surface area (SVI ≤35 mL/m2) in the presence of preserved LVEF (≥50%)

Normal-flow LG (NFLG) AS: Defined as LG severe AS with normal SVI to body surface area (SVI >35 mL/m2), or flow rate ≥200 mL/s. Usually, LVEF is preserved in this category.[45]

Pseudosevere aortic valve stenosis

Referred to as nonsevere (mild-moderate) AS with underestimated resting AVA because of incomplete valve opening due to low stroke volume and reduced valve opening forces. Patients with LG AS in any of the above three categories (classical LFLG, paradoxical LFLG AS, or NFLG AS) may have true severe or pseudosevere AS. Around one-third of patients with LFLG AS, whether classical or paradoxical, have pseudosevere AS.[9]

EPIDEMIOLOGY

The prevalence of AS increases significantly with age. According to one study, the prevalence of AS varied from 0.2% at ages 50 to 59 years to 9.8% at ages 80–89 years.[3] Up to 50% of patients with severe AS have a LG severe AS.[6] The prevalence of classical LFLG AS is approximately 5%–10% of patients with severe AS.[10] Around 25%–35% of patients with severe AS and preserved LVEF have paradoxical LFLG AS. NFLG AS represents around 15%–40% of severe AS cases.[6]

LG AS patients are generally older and tend to have a higher prevalence of comorbidities compared with high-gradient AS patients. In one study, the mean age was 71.5 ± 9.7 years in the LFLG AS group versus 68.7 ± 10.8 years in the normal flow high-gradient AS group (P = 0.01). The prevalence of diabetes, chronic obstructive pulmonary disease, previous coronary disease, peripheral vascular disease, atrial fibrillation, and pulmonary HTN were significantly higher in the LFLG AS patients (P < 0.01).[8]

Paradoxical LFLG AS and diastolic heart failure (HF with preserved LVEF) have similar pathophysiological and clinical characteristics. Both diseases are frequently associated with older age, female sex, and systemic HTN. Impaired diastolic and systolic longitudinal functions result in the reduction in stroke volume in both entities.[6]

PATHOPHYSIOLOGY

The pressure gradient across the aortic valve depends on two main factors: (1) AVA – the smaller AVA, the higher the pressure gradient and (2) the flow rate across AV; the lower flow, the lower the pressure gradient. Low flow rate is usually caused by low stroke volume, which is the result of either LV systolic dysfunction with depressed LV ejection fraction (LVEF <50%) as in classical LFLG AS or small ventricular volumes with preserved LVEF (≥50%) as in paradoxical LFLG AS.[610]

The depressed left ventricular (LV) systolic function in classical LFLG AS can be mainly caused by the chronic pressure overload of the AS itself. Or it may be caused by concurrent conditions, like coronary artery disease, severe mitral regurgitation, or more likely the result of combined effects of AS and concurrent conditions.[10]

Low stroke volume in paradoxical LFLG AS is secondary to the concentric LV hypertrophy that results in a small LV cavity and impaired LV diastolic filling. Uncontrolled, long-standing HTN that results in elevated arterial afterload and LV hypertrophy also contributes to the development of paradoxical LFLG. Other factors that may play a role in the development of low stroke volume in paradoxical LFLG AS include atrial fibrillation, mitral regurgitation or stenosis, tricuspid regurgitation, and right ventricular dysfunction.[6] Around 15% of patients with paradoxical LFLG AS have wild-type transthyretin (ATTR) cardiac amyloidosis, which may result in LV hypertrophy with a small LV cavity.[11]

There are some potential explanations for the finding of normal flow with a LG in patients with NFLG severe AS. First, there is discordance in guidelines’ cut points of AVA and mean gradient that defines severe AS. Hemodynamically, the AVA cut-point value of 1.0 cm2, which defines severe AS, corresponds to a mean gradient of 30–35 mmHg rather than 40 mmHg, which is the cut point for severe AS in most guidelines. Thus, following these cut points will result in the detection of high number of patients with NFLG AS. The second is that the increased blood pressure (BP) and decreased aortic compliance may result in a substantial decrease in pressure gradient across AV and lead to an NFLG in a patient with severe AS.[6]

CLINICAL FEATURES AND PRESENTATION

The clinical manifestations of LG aortic stenosis are generally similar to those of high-gradient AS. Patients with severe LG AS may or may not have symptoms. Symptoms include dyspnea on exertion, angina, dizziness, or syncope. However, these symptoms are nonspecific, and most patients with these symptoms do not have AS. Thus, careful clinical assessment is crucial before attributing these symptoms to AS. On physical examination, signs of severe AS include pulsus parvus et tardus, which refers to a slow rising weak pulse, decreased intensity of the second heart sound, paradoxical splitting of S2, and a late peaking systolic ejection murmur radiating to the carotid arteries. In patients with LFLG severe AS, the murmur may be soft and less impressive.

INVESTIGATIONS

Transthoracic echocardiogram

Transthoracic echocardiography (TTE) is the cornerstone investigation in AS diagnosis and assessment of its severity. It allows measurement the valve area, transvalvular velocity, and mean gradient. TTE also helps in the evaluation of LV size and function and rules out other valvular diseases. In most patients with high-gradient AS, TTE alone is enough to diagnose AS and assess its severity. However, in a patient with LG AS, additional investigations are required to confirm the diagnosis and get an accurate assessment of its severity.

Technical challenges of echocardiography

Measurement of AVA and pressure gradient by TTE is not easy and may be quite challenging in many patients, and checking the accuracy of these measurements is crucial before reaching the diagnosis of LG AS. To get an accurate measurement of peak jet velocity and mean pressure gradient across AV, the continuous-wave Doppler beam should be parallel to the direction of aortic flow; otherwise, the peak of velocity and pressure gradients will be underestimated, which may be interpreted falsely as LG AS. Thus, it is of great importance to take multi-window views and to align the Doppler beam with the direction of the aortic flow jet to avoid false assumptions. Another point is that AVA is calculated mainly by the continuity equation method, where AVA is directly proportional to the squared left ventricular outflow tract (LVOT) diameter. Hence, any little error in measurement of LVOT may result in significant error in AVA assessment and stroke volume calculation. Thus, the initial step done when echocardiographic measurements showed small AVA with a LG is to rule out measurement errors.[6]

Another consideration is in patients with small body size; small AVA (≤1 cm2) may in fact represent a moderate AS. Thus, it is important to calculate the indexed AVA, and if a value is ≤ 0.6 cm2/m2, then AS is considered severe.[11]

Low-dose dobutamine stress echocardiography

Low-dose dobutamine stress echocardiography (DSE) is used to differentiate true severe from pseudosevere AS in patients with classical LFLG AS and selected patients with paradoxical LFLG AS. Low-dose DSE is also important to assess the presence of contractile reserve, which is referred to as at least 20% increase in LV stroke volume with DSE compared with rest.[8] Patients with LFLG AS and no contractile reserve (<20% increase in stroke volume with DSE) have a worse perioperative prognosis when undergoing AVR compared with patients with contractile reserve.[12]

The DSE protocol used in AS assessment differs from the one used for ischemia evaluation in two aspects; the target dose of dobutamine is 20 mg/kg/min, which lower than that used for ischemia evaluation, and the duration of each stage is longer to allow enough time for taking different measurements accurately. If AS is true severe, then DSE shows an increase in mean pressure gradient to ≥40 mmHg, and AVA remains AVA ≤1.0 cm2. On the other hand, DSE in pseudosevere AS shows a significant increase in AVA to >1 cm2 and the mean pressure gradient remains <40 mmHg. However, some patients with LFLG AS will still have a discrepancy between the AVA and mean gradient with DSE (peak stress gradient <40 mmHg with a peak stress AVA ≤1.0 cm2). In such a case, further investigation is required to confirm the severity.[6]

Projected aortic valve area

The projected AVA at normal flow rate is an estimation of how much the AVA would be at a normal transvalvular flow rate (250 ml/s). It can be used in patients with inconclusive DSE studies to differentiate true severe from pseudosevere AS in patients with classical LFLG AS. The projected AVA at a normal flow rate is calculated by using the following formula, where Q is the mean transvalvular flow rate = (stroke volume)/(LV ejection time):

Projected AVA = AVARest + ([AVADSE-AVARest]/[QDSE-QRest]) × (250-QRest).

If the projected AVA is ≤1.0 cm2, then the diagnosis of true-severe AS is confirmed. If the projected AVA is >1.0 cm2, then AS is considered pseudosevere. However, projected AVA can be reliably calculated only if the flow reserve, which is the increase in mean transvalvular flow rate (stroke volume/LV ejection time) with DSE compared with rest, is ≥15%. If the flow reserve is <15%, then projected AVA cannot be calculated, and DSE remains inconclusive.[1314]

Multidetector computed tomography

Multidetector computed tomography (MDCT) is used to assess the degree of aortic valve calcification in patients with AS. It helps to evaluate the stenosis severity in patients with LFLG AS who have inconclusive DSE or in patients with NFLG AS. This modality is independent of hemodynamics/flow state, and it is used in almost all patients. In addition, MDCT does not need contrast and thus can be used in patients with renal problems. As per the 2021 ESC guidelines, the diagnosis of true severe AS is likely if the MDCT aortic valve calcium score (in Agatston units): is >1200 AU in females or >2000 AU in males.[5]

Role of cardiac catheterization

Cardiac catheterization can be used to confirm AS severity when noninvasive investigations are inconclusive or if there is a discrepancy between the clinical assessment and the noninvasive methods regarding AS severity.[4] In patients with LG AS, cardiac catheterization at rest has similar limitations as the rest echocardiography. Using dobutamine stress during cardiac catheterization can help to differentiate true severe from pseudosevere AS. However, noninvasive investigations are usually preferred and better tolerated.[15]

In patients with uncontrolled HTN and LG severe AS with preserved ejection fraction (EF), nitroprusside administration during cardiac catheterization decreases the afterload which allows better assessment of AS severity. One study that included 41 patients with LG severe AS and preserved EF, using nitroprusside during cardiac catheterization increased AVA significantly and allowed reclassification of around 25% of patients from severe to moderate AS.[16]

DIAGNOSTIC APPROACH TO LOW-GRADIENT AORTIC VALVE STENOSIS

Approach to classical low-flow low-gradient aortic valve stenosis

The diagnosis of classical LFLG severe AS is suggested if the initial TTE examination shows the following three criteria; AVA ≤1 cm2, transvalvular mean pressure gradient <40 mmHg (or Vmax <4 m/s), and LVEF <50% [Figure 2]. Before proceeding with further evaluation, it is very important to exclude any measurement or calculation error.

Figure 2

Diagnostic approach to classical low-flow low-gradient AS

The next recommended step after TTE is low-dose DSE which helps to differentiate true severe from pseudosevere AS and assess the LV flow reserve. There are three possibilities with DSE: (1) transvalvular mean gradient increases to ≥40 mmHg with AVA remains ≤1.0 cm2. In this case, the diagnosis of classical LFLG severe AS is confirmed. (2) Transvalvular mean gradient remains <40 mmHg but AVA increases to >1 cm2. In this case, AS is considered pseudosevere. (3) DSE still shows a discrepancy between the AVA and mean gradient (AVA ≤1.0 cm2 and mean gradient remains <40 mmHg). In such a case, the projected AVA at a normal flow rate can be calculated. The projected AVA is an estimation of how much the AVA would be at a normal transvalvular flow rate (250 ml/s). It is calculated by using the following formula, where Q is the mean transvalvular flow rate (stroke volume)/(LV ejection time):

Projected AVA = AVARest + ([AVADSE-AVARest]/[QDSE-QRest]) × (250-QRest).

If the projected AVA is ≤1.0 cm2, then the diagnosis of true-severe AS is confirmed. If the projected AVA is >1.0 cm2, then AS is considered pseudosevere. However, projected AVA can be reliably calculated only if the flow reserve (increase in mean transvalvular flow rate (stroke volume/LV ejection time) with DSE compared with rest) is ≥15%. If the flow reserve is <15%, then projected AVA cannot be calculated, and DSE remains inconclusive. In such a case, further evaluation with MDCT is recommended to quantify the degree of aortic valve calcification and assess the severity of AS. The diagnosis of true severe AS is confirmed if the MDCT aortic valve calcium score is >1200 AU in females or >2000 in males. If the aortic valve calcium score is ≤1200 AU in females or ≤2000 in males, then AS is pseudosevere.[61417]

Approach to paradoxical low-flow low-gradient aortic valve stenosis

The diagnosis of paradoxical LFLG severe AS is suggested if the initial TTE examination shows the following 4 criteria; AVA ≤1 cm2, transvalvular mean pressure gradient <40 mmHg (or Vmax <4 m/s), LVEF ≥50%, and SVI ≤35 mL/m2 [Figure 3]. Measurements and calculations should be re-assessed to exclude any possible errors. In paradoxical LF-LG severe AS, LV hypertrophy and/or sigmoid septum can result in LV outlet (LVOT) narrowing leading to measurement errors and underestimation of AS severity. Thus, it is important to consider the effect of LVOT morphology when assessing the severity of AS in a patient with paradoxical LFLG AS.[18] Next step in evaluating patients with paradoxical LFLG AS depends mainly on the presence of symptoms related to AS. If the patient does not have symptoms attributable to AS, then regular monitoring for AS progression and development of symptoms is recommended. If symptoms are not certain, then exercise stress echocardiography, if not contraindicated, may be considered to confirm if symptoms are related to AS or not.[9] If the patient has symptoms related to AS, then further evaluation is recommended to assess for HTN, investigate the causes of low flow state, and distinguish true severe from pseudosevere AS. To get accurate measurements, BP should be controlled (systolic BP <140) during the echocardiographic assessment. If BP is not controlled, then TTE should be repeated when BP is controlled. If echocardiographic measurements after BP optimization still meet the 4 criteria for paradoxical LFLG AS, then the next step is to look for the cause and etiology of the low flow state (SVI ≤35). The primary etiology is concentric LV hypertrophy with a small LV cavity and diastolic dysfunction. Other causes that may play a role include mitral regurgitation, mitral stenosis, atrial fibrillation, tricuspid regurgitation, and right ventricular dysfunction. In case no cause of the low flow state could be found, then it is recommended to go back and re-check the measurements and confirm the calculations. If a cause is found, then the next step is to differentiate true severe from pseudosevere paradoxical LFLG AS which is done mainly by MDCT.[6] In some patients with paradoxical LFLG AS, DSE can be used, if not contraindicated as in restrictive LV pattern, to confirm the severity.[9] The same MDCT and DSE cut points mentioned previously for classical LFLG AS are used for paradoxical LFLG AS.

Figure 3

Diagnostic approach to paradoxical low-flow low-gradient AS

In addition, calculating the valvuloarterial impedance (Zva), which reflects the global load the LV is facing that results from both valvular and vascular loads, may be useful in distinguishing the severity of paradoxical LFLG AS.[19] Zva value of >5.0 mmHg/mL.m2 is an indicator of severe AS.[20] The valvuloarterial impedance is calculated using the following formula:

Zva = (mean transvalvular aortic pressure gradient + systolic arterial BP)/(indexed stroke volume).

Approach to normal-flow low-gradient aortic valve stenosis

The diagnosis of NFLG severe AS is suggested if the initial TTE examination shows the following four criteria; AVA ≤1 cm2, transvalvular mean pressure gradient <40 mmHg (or Vmax <4 m/s), LVEF ≥50%, and SVI >35 mL/m2. AS in the previous categories of LG AS, the first step in evaluation is to rule out any measurement or calculation errors with special attention that measurements should be taken while BP is controlled (systolic BP <140). The next step is to make sure that AS is not pseudosevere by MDCT. The diagnosis of true severe NFLG AS is confirmed if the MDCT aortic valve calcium score is >1200 AU in females or >2000 in males. If MDCT aortic valve calcium score is ≤1200 AU in females or ≤2000 in males, then AS is pseudosevere.[6]

PROGNOSIS

Among patients with severe AS, those with classical LFLG severe AS hold the worst prognosis with 2-year survival rate of 40%–60% with conservative management. Paradoxical LFLG AS has worse prognosis than high-gradient AS and NFLG AS but better than classical LFLG AS.[6] Among patients undergoing AVR, both classical and paradoxical LFLG AS have higher surgical risk compared with high-gradient AS. However, survival improves significantly in both categories with AVR compared with conservative management.[2122] The prognosis of NFLG severe AS is similar to that of high-gradient severe AS. On the other hand, patients with LG pseudosevere AS have an outcome similar to that of patients without AS.[23]

CONCLUSION

LG AS is common among patients with severe AS and represents a challenging diagnosis because of the discrepancy between AVA and transvalvular pressure gradient. LG AS is divided into three categories: classical LFLG AS, paradoxical LFLG AS, and NFLG AS.

The main aim in evaluating patients with LG AS is to confirm the severity of AS and exclude pseudosevere AS, which is assessed mainly by either DSE, which is the preferred method in classical LFLG AS, or MDCT, which is the preferred method in a patient with paradoxical LFLG AS and NFLG AS.

The management of symptomatic true severe LG AS is mainly by AVR, whether surgical or transcatheter. Patients with LG severe AS have a generally worse prognosis and higher mortality compared with patients with high-gradient severe AS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.