JACC: CARDIOVASCULAR IMAGING VOL. 10, NO.

2, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 1936-878X/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jcmg.2017.01.002

Cardiac Imaging for Assessing

Low-Gradient Severe Aortic Stenosis
Marie-Annick Clavel, DVM, PHD,a Ian G. Burwash, MD,b Philippe Pibarot, DVM, PHDa

ABSTRACT

Up to 40% of patients with aortic stenosis (AS) harbor discordant Doppler-echocardiographic findings, the most common of
which is the presence of a small aortic valve area (#1.0 cm2) suggesting severe AS, but a low gradient (<40 mm Hg) suggesting
nonsevere AS. The purpose of this paper is to present the role of multimodality imaging in the diagnostic and therapeutic
management of this challenging entity referred to as low-gradient AS. Doppler-echocardiography is critical to determine the
subtype of low-gradient AS: that is, classical low-flow, paradoxical low-flow, or normal-flow. Patients with low-flow, low-
gradient AS generally have a worse prognosis compared with patients with high-gradient or with normal-flow, low-gradient AS.
Patients with low-gradient AS and evidence of severe AS benefit from aortic valve replacement (AVR). However, confirmation of
the presence of severe AS is particularly challenging in these patients and requires a multimodality imaging approach including
low-dose dobutamine stress echocardiography and aortic valve calcium scoring by multidetector computed tomography.
Transcatheter AVR using a transfemoral approach may be superior to surgical AVR in patients with low-flow, low-gradient AS.
Further studies are needed to confirm the best valve replacement procedure and prosthetic valve for each category of low-
gradient AS and to identify patients with low-gradient AS in whom AVR is likely to be futile. (J Am Coll Cardiol Img 2017;10:185–
202) © 2017 by the American College of Cardiology Foundation.

C alcific aortic stenosis (AS) is the most preva-

lent valvular heart disease in developed
countries and is responsible for approxi-
mately 85,000 valve replacement procedures and
suggesting nonsevere AS (Figure 1) (4–6). This discor-
dant grading pattern, often referred to as “low-
gradient AS,” raises challenges and uncertainties as
to the “actual” severity of the valve disease and the
15,000 deaths per year in North America. Currently, appropriate therapeutic decision making. The
surgical or transcatheter aortic valve replacement purpose of this paper is to provide a start-of-the-art
(AVR) remain the only effective treatments for severe review and some future perspectives on the
AS. The diagnosis and staging of AS are determined etiology, pathophysiology, diagnosis, and therapeutic
primarily on an assessment of the hemodynamic management of low-gradient AS. In particular, we
severity and left ventricular (LV) systolic function will underline the important role of multimodality
by Doppler echocardiography, and the presence of imaging for the characterization and management of
symptoms. Typically, AS is considered severe if the the different types of low-gradient AS, including clas-
patient has a mean transvalvular gradient $40 sical and paradoxical low-flow, low-gradient; and
mm Hg, a peak aortic jet velocity $4 m/s, an aortic normal-flow, low-gradient AS.
valve area (AVA) #1.0 cm 2, and an indexed
AVA #0.6 cm 2/m 2 (1–3). However, up to 40% of the CLASSIFICATION OF AS AND DIFFERENT TYPES OF
patients with AS harbor discordant Doppler- LOW-GRADIENT AS
echocardiographic findings, the most common of
which is the presence of a small AVA (#1.0 cm 2) sug- The American College of Cardiology/American Heart
gesting severe AS, but a low gradient (<40 mm Hg) Association and European Society of Cardiology/

From the aInstitut Universitaire de Cardiologie et de Pneumologie de Québec (Québec Heart and Lung Institute), Laval University,
Québec, Québec, Canada; and the bUniversity of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada. Dr. Pibarot
is the Canada Research Chair in Valvular Heart Diseases, Canadian Institutes of Health Research (CIHR), Ottawa, Ontario, Canada.
His research program is funded by research grant # FDN-143225 from CIHR. Dr. Pibarot has received a research grant from Edwards
Lifesciences and Medtronic for echocardiography core laboratory analyses in transcatheter heart valves. All other authors have
reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received November 28, 2016; revised manuscript received December 26, 2016, accepted January 5, 2017.
186 Clavel et al.
Cardiac Imaging for Assessing Low-Gradient AS
ABBREVIATIONS European Association for Cardio-Thoracic
Surgery guidelines have proposed similar
AND ACRONYMS
classification systems for the different stages
AS = aortic stenosis of AS according to the hemodynamic severity
AVA = aortic valve area of AS (mild, moderate, or severe), the state of
AVR = aortic valve
the LV systolic function (normal vs.
replacement depressed), the patient’s symptomatic status
HFrEF = heart failure with (asymptomatic vs. symptomatic), the flow
reduced left ventricular state (normal vs. low), and the level of the
ejection fraction
gradient (high vs. low) (Figure 1) (1,3). In pa-
LF-LG = low-flow,
tients with moderate AS, defined as a mean
low-gradient
gradient between 20 and 40 mm Hg and an
LVEF = left ventricular ejection
fraction
AVA between 1.0 and 1.5 cm 2 (“stage B” in
American College of Cardiology/American
Heart Association guidelines), there is currently no
indication for AVR unless the patient undergoes car-
diac surgery for another reason (e.g., coronary artery
bypass grafting). Patients with high-gradient (mean
gradient $40 mm Hg) AS have a Class I indication for
AVR if they have a depressed left ventricular ejection
fraction (LVEF) in the absence of symptoms (stage C2)
or if they are symptomatic (stage D1). In patients with
a low gradient (<40 mm Hg) but small AVA (#1.0
cm 2), several subtypes can be defined according to
the LVEF and flow status (Figure 1, Central
Illustration).
CLASSICAL LOW-FLOW, LOW-GRADIENT AS. The
classical low-flow, low-gradient (LF-LG) AS entity is
defined in the guidelines as a LVEF <50%, AVA #1.0
cm 2, and mean gradient <40 mm Hg (Figures 1 and 2).
This entity is found in about 5% to 10% of the AS
population, is more prevalent in men, and is very
often associated with coronary artery disease (7).
Patients with classical LF-LG AS generally have an
enlarged LV cavity with depressed LV systolic
function, and a substantial proportion also have
functional mitral regurgitation (Figure 2, Online
Videos 1 and 2). The depressed LVEF may be
caused by afterload mismatch related to the pres-
ence of severe AS and/or concomitant intrinsic dis-
ease of the myocardium, the most frequent being an
ischemic cardiomyopathy. The classical LF-LG AS
entity is identified as the stage D2 in the guidelines,
and there is a Class IIa recommendation for AVR in
patients with confirmed severe AS (Figure 1, Central
Illustration).
PARADOXICAL LF-LG AS. As opposed to patients
with classical LF-LG AS, those with paradoxical LF-LG
AS have a preserved LVEF. This entity is defined as an
LVEF $50%, the presence of a low flow (stroke vol-
ume index <35 ml/m 2), an AVA #1.0 cm 2, an indexed
AVA #0.6 cm 2/m 2, and a mean gradient <40 mm Hg
(Figures 1 and 3). The paradoxical LF-LG pattern is
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017
FEBRUARY 2017:185–202
observed in 5% to 15% of AS patients and is more
prevalent in women and elderly individuals. Typi-
cally, these patients have a small LV cavity with
pronounced LV concentric remodeling and a restric-
tive physiology, leading to a decrease in stroke vol-
ume despite a preserved LVEF (Figure 3, Online
Videos 3 and 4). Other factors may also lead to a low
flow state including significant mitral regurgitation,
mitral stenosis, tricuspid regurgitation, and atrial
fibrillation. The paradoxical LF-LG entity is identified
as stage D3 in the guidelines, and AVR is indicated
(Class IIa recommendation) if the patient is symp-
tomatic and has true severe stenosis (Figure 1, Central
Illustration). In essence, classical LF-LG AS represents
the heart failure with reduced left ventricular ejection
fraction (HFrEF) form of AS, whereas paradoxical LF-
LG AS represents the heart failure with preserved
LVEF form of AS (Figures 2 and 3).
NORMAL-FLOW, LOW-GRADIENT AS. Normal-flow,
low-gradient AS is defined as an LVEF $50%, a normal
flow state (stroke volume index $35 ml/m 2), an
AVA #1.0 cm2 , an indexed AVA #0.6 cm 2/m 2, and a
mean gradient <40 mm Hg (Figures 1 and 4) (8–10). It is
observed in up to 25% of AS patients and is thus the
most common subset of low-gradient AS. This entity
and recommendations for therapeutic management
are not addressed in the valve guidelines (1,3). How-
ever, recent studies suggest that approximately 50% of
these patients may have a severe stenosis and thus
may benefit from AVR when symptomatic (Figure 1).
The HAVEC (Heart Valve Clinic International database)
group proposed to label this entity as “stage D4” (10).
MODERATE AS WITH LOW LVEF. Patients with
concordant AVA (>1.0 cm2 ) and gradient (<40
mm Hg) findings have moderate AS, and in general,
conservative management with serial follow-up is
recommended (Figures 1 and 5, Central Illustration).
However, several studies have suggested that a
moderate AS may have a detrimental effect on out-
comes in patients with depressed LVEF, which raises
the prorogating hypothesis that AVR may be benefi-
cial in such patients (11,12). This hypothesis is
currently being tested in the TAVR UNLOAD (Trans-
catheter Aortic Valve Replacement to UNload the Left
ventricle in patients with ADvanced heart failure)
trial where patients with HFrEF and moderate AS
confirmed by resting and/or dobutamine stress
echocardiography are randomized to optimized heart
failure therapy alone versus optimized heart failure
therapy plus transcatheter AVR (NCT02661451) (13).
The moderate AS, low-LVEF entity could be labeled as
“stage B2” by analogy with stages C2 and D2 (Figures 1
and 5).
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017 Clavel et al. 187
FEBRUARY 2017:185–202 Cardiac Imaging for Assessing Low-Gradient AS

F I G U R E 1 Classification and Characterization of the Different Types of AS According to AVA, Gradient, LVEF, and Flow

The classification of types of AS, including only the categories associated with symptoms and/or depressed LVEF. It does not include stage C1 (i.e., patients with high-
gradient AS, no symptoms, and preserved LVEF). Question mark indicates stage labels or indications for AVR that are proposed by the authors but are not included in
the guidelines and will need to be further tested and validated. AS ¼ aortic stenosis; AVA ¼ aortic valve area; AVAi ¼ indexed aortic valve area; AVR ¼ aortic valve
replacement; LVEF ¼ left ventricular ejection fraction; MG ¼ mean gradient; RCT ¼ randomized controlled trial; SVi ¼ stroke volume index.

TECHNICAL REASONS LEADING TO
LOW-GRADIENT AS
The first step when confronted with a patient with a
discordant AVA (small) and gradient (low) situation is
to ascertain the accuracy of the
echocardiographic measurements of stroke volume,
AVA, and gradient. Measurement errors may lead to
the erroneous conclusion that the patient has a low-
gradient AS entity, and can result in either an un-
derestimation of severe AS or an overestimation of
moderate AS.
TECHNICAL ISSUES UNDERESTIMATING AS SEVERITY.
Accurate measurement of velocity and gradients
by Doppler-echocardiography requires
alignment of the continuous-wave Doppler beam with
the direction of the aortic flow jet. If not, this may
result in an underestimation of the gradient, an
overestimation of the AVA, and an underestimation
of AS severity. Apical windows are usually the most
intensively interrogated for aortic jet velocity mea-
surements using continuous-wave Doppler; however,
the apical window reveals the maximum velocity in
only 40% of patients, whereas the maximum velocity
is obtained from the right parasternal window in up to
50% of patients (14). A multiwindow interrogation
that includes not only the apical window, but also the
right parasternal and suprasternal windows, is thus
Doppler- essential to obtain an accurate measure of the veloc-
ity and gradient.
TECHNICAL ISSUES OVERESTIMATING AS SEVERITY. The
most common technical pitfall that may lead to an
erroneous diagnosis of low-flow state and over-
estimation of AS severity is an underestimation of the
left ventricular outflow tract (LVOT) diameter mea-
surement. The effective AVA is determined by the
continuity equation method, where the numerator is
optimal the stroke volume measured at the LVOT and the
denominator is the time-velocity integral (TVI) of the
aortic transvalvular flow:
LVOT area  LVOT TVI
AVA ¼
Aortic valve TVI
Given that the LVOT diameter is squared in the
continuity equation, a small error in this measure-
ment may result in an important error in the
188 Clavel et al. JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017

Cardiac Imaging for Assessing Low-Gradient AS FEBRUARY 2017:185–202

C E NT R AL IL L U STR AT IO N Algorithm for the Management of Low-Gradient AS

Clavel, M.-A. et al. J Am Coll Cardiol Img. 2017;10(2):185–202.

This figure presents a 4-step algorithm for the diagnostic and therapeutic management of low-gradient AS. AVC ¼ aortic valve calcification; AVCd ¼ aortic valve
calcification density; AVR ¼ aortic valve replacement; CMR ¼ cardiac magnetic resonance; MDCT ¼ multidetector computed tomography; RCT ¼ randomized
controlled trial; TEE ¼ transesophageal echocardiography; TTE ¼ transthoracic echocardiography; other abbreviations as in Figures 1 to 3.
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017
FEBRUARY 2017:185–202
calculation of the stroke volume and AVA. Hence, an
underestimation of the LVOT diameter may lead to
the false conclusion that the patient has low-flow,
low-gradient severe AS when, in fact, the patient
has normal-flow and/or moderate AS.
The LVOT dimension that is measured with stan-
dard 2-dimensional (2D) echocardiography is the
anteroposterior diameter at peak systole and the
stroke volume is calculated by assuming that the
LVOT cross-section is circular (Figure 6). However,
the LVOT is a dynamic 3-dimensional (3D) structure
that is often elliptically shaped, with the ante-
roposterior dimension representing the smaller minor
axis diameter, as compared with the generally larger
sagittal diameter. Hence, 2D echocardiography may
underestimate the LVOT area compared with 3D im-
aging modalities such as 3D echocardiography, mul-
tidetector computed tomography (MDCT), or cardiac
magnetic resonance (CMR) (15–19). Some studies
suggest that the underestimation of the LVOT area by
2D echocardiography using the circular assumption
may be more important if the LVOT diameter is
measured 5 to 10 mm below the aortic annulus
compared with at the aortic annulus (20).
To overcome the potential underestimation of the
LVOT diameter and thus stroke volume and AVA by 2D
echocardiography, the use of a hybrid approach has
been suggested, where the LVOT area is measured by
MDCT or 3D echocardiography (Figure 6) and the LVOT
and aortic flow velocities are measured by Doppler
echocardiography (18,19). This hybrid approach is
interesting and may help to ascertain the accuracy of
flow and AVA measurements. However, it is subject to
significant pitfalls. First, MDCT has been shown to
overestimate the LVOT area compared with CMR im-
aging or direct anatomic measurement at the time of
surgery (21,22). Hence, the use of MDCT may result in
an overestimation of “actual” effective AVA. Second,
the AVA cut-point value generally used to define se-
vere AS, 1.0 cm 2, has been established and validated by
outcome studies in which AVA was measured by
standard Doppler-echocardiography (1,3). This cut-
point cannot be directly extrapolated to the hybrid
methods that systematically measure larger AVAs
compared with Doppler-echocardiography. A recent
study reported that AVA calculated by a hybrid
approach (MDCT-Doppler) was not superior to AVA
determined by standard Doppler-echocardiography
to predict transvalvular gradients or patient out-
comes. Moreover, the best discriminative cut-point
of the hybrid AVA to predict mortality in patients
with AS under medical treatment was larger (i.e.,
1.2 cm2 ) versus the Doppler-echocardiographic AVA
(1.0 cm2) (19).
Clavel et al. 189
Cardiac Imaging for Assessing Low-Gradient AS
To optimize the accuracy of the measures of stroke
volume and AVA, one may consider the following
steps (Central Illustration):
Step 1. The clearest on-axis image of the LVOT
providing the largest LVOT diameter should be used
(Figure 6). The 2009 European Association of Echo-
cardiography/American Society of Echocardiography
guidelines suggest measuring the diameter and ve-
locity 5 to 10 mm below the aortic annulus (2). How-
ever, recent studies suggest measuring the LVOT
diameter inner-edge-to-inner-edge from the base of
the right coronary cusp anteriorly to the commissure
posteriorly, as originally described by Skjaerpe et al.
(20,23) (Figure 6).
Step 2. The measures of LVOT diameter and stroke
volume should be corroborated with other methods.
LVOT diameter generally relates to body surface area,
and 90% of patients have an LVOT diameter within
2 mm of predicted for their body surface area using
the following formula (24):
LVOTdiameter ¼ ð5:7  body surface areaÞ þ 12:1
If the measured diameter is more than 2 mm
smaller or larger than the predicted value, one
should suspect a technical error and reassess the
2D-echocardiographic LVOT measurement and/or
corroborate it with 3D imaging modalities (Figure 6).
It should be noted that patients with a bicuspid
valve may have an LVOT diameter larger than that
predicted by this formula (24). Moreover, in obese
patients, the formula may overestimate the actual
LVOT diameter.
Another approach to corroborate the LVOT diam-
eter measurement in a patient with low-gradient AS
with a small AVA is to calculate the Doppler velocity
index (i.e., the ratio of the LVOT to aortic flow time-
velocity integrals) (25,26). If the index is <0.25, the
results are consistent with AVA and indirectly
corroborate the validity of the LVOT measurement
(Figure 3). If the index is >0.25 and thus suggestive of
nonsevere AS, one should suspect an error in the
LVOT diameter measurement.
Several 2D or 3D-echocardiographic methods can
be used to corroborate the stroke volume measure-
ment (Central Illustration). The ASE guidelines do not
recommend using the standard Teichholz method to
measure LV volumes and LVEF (27). However, a
modified Teichholz method may be considered as a
first approach to rapidly corroborate the LVOT stroke
volume (Figures 3 and 4). The LV end-diastolic
diameter should be measured apical to the septal
bulge to obtain the largest diameter and avoid
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Cardiac Imaging for Assessing Low-Gradient AS FEBRUARY 2017:185–202

F I G U R E 2 Case of Classical Low-Flow, Low-Gradient AS With True-Severe Stenosis

An 83-year-old man with New York Heart Association functional class III dyspnea. LVEF was markedly depressed at rest but improved substantially with dobutamine stress
echocardiography (DSE) (A) (Online Videos 1 and 2). There was a significant increase in stroke volume (SV) and mean transvalvular flow rate (Qmean ¼ SV/LV ejection time),
but the increase in stroke volume was not sufficient to completely normalize flow, and the AVA/gradient discordance at rest persisted at DSE (B). The AVA projected at a
normal flow rate (250 ml/s) was thus calculated to confirm stenosis severity (C). First, the valve compliance (VC) is calculated by dividing the absolute increase in AVA by
the increase in Qmean during DSE: VC ¼ DAVA/DQmean. In this case, VC is equal to 0.015 cm2/100 ml/s. Then the projected AVA is calculated with the formula: projected
AVA ¼ rest AVA þ VC  (250  Rest Qmean). The projected AVA is equal to 0.82 cm2 in this patient, thus confirming the presence of true-severe AS. The patient underwent
transcatheter AVR. Dob ¼ dobutamine; MG ¼ mean gradient; Qmean ¼ mean transvalvular flow rate; SV ¼ stroke volume; other abbreviations as in Figure 1.

potential underestimation of the LV end-diastolic
volume by the Teichholz formula. The end-diastolic
volume is then multiplied by the LVEF measured
by biplane Simpson method to estimate the LVOT
stroke volume (28). The biplane Simpson method
generally underestimates stroke volume due to
frequent foreshortening of the LV cavity, and careful
consideration of image quality is required when
corroborating data using this technique. If image
quality is adequate, 3D echocardiography can be
used to estimate LV end-diastolic and -systolic vol-
umes and thus derive stroke volume (Figure 3,
Central Illustration). One of the advantages of 3D
echocardiography is that it does
geometrical assumptions (27). The 2D- or 3D-volu-
metric methods measure the “total” LV stroke
volume and should not be used to corroborate
LVOT stroke volume (i.e., forward stroke volume)
in presence of more than moderate mitral
regurgitation.
Step 3. Continuity equation AVA may be corroborated
by other methods such as planimetry of the anatomic
orifice using 2D or 3D transthoracic or trans-
esophageal echocardiography (29,30). An AVA <1.0
cm 2 on planimetry confirms the presence of severe
AS; however, an AVA slightly >1.0 cm 2 does not
definitively exclude severe AS, because the effective
orifice area is usually slightly smaller than the
anatomic AVA. As previously discussed, hybrid
(MDCT-Doppler) method may be used to corroborate
not rely on AS severity (18,19). However, a larger cut-point value
for AVA (<1.2 cm 2) should be used to define severe AS
to avoid an over-reclassification of severe AS to
moderate AS (19).
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017 Clavel et al. 191
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F I G U R E 3 Case of Paradoxical Low-Flow, Low-Gradient AS

An 82-year-old woman with New York Heart Association functional class III dyspnea and recent hospitalization for heart failure. This patient has a small LV cavity with
pronounced concentric remodeling, severe diastolic dysfunction, impaired global longitudinal strain (13%), and dilated left atrium (A) (Online Video 3). The valve
appears to be severely thickened and calcified with restricted opening (Online Video 4). The stroke volume measured in the LV outflow tract is 53 ml (B and C), and this
patient has a low-flow state (stroke volume index <35 ml/m2). The LV end-diastolic diameter measured apical to the septal bulge (where the diameter is the largest)
was 42 mm. The total LV stroke volume estimated with modified Teichholz formula is 51 ml (LV end-diastolic volume by Teichholz: 79 ml  LVEF by Simpson: 65%),
which is consistent with the LVOT stroke volume. The total stroke volume measured by 3D echocardiography was 56 ml (not shown), also consistent with the LVOT
stroke volume. It is also important to perform multiwindow interrogation with continuous-wave Doppler (D and E). In this patient, a slightly higher velocity was
obtained at the right parasternal border window (E). In this patient, the AVA, AVAi, and DVI are in the severe range, but the mean gradient is low (26 mm Hg).
The presence of severe stenosis was corroborated by the presence of very high aortic valve calcium score at MDCT (see Figure 7, right panel). The patient underwent
transcatheter AVR. AVAi ¼ indexed aortic valve area; diam. ¼ diameter; DVI ¼ Doppler velocity index; LVEDV ¼ left ventricular end-diastolic volume; LVOT ¼ left
ventricular outflow tract; other abbreviations as in Figure 2.

PHYSIOLOGICAL REASONS LEADING TO nonetheless associated with a reduction in forces

LOW-GRADIENT AS
LOW-FLOW STATE. The presence of a low-flow state
is one of the most frequent causes of low-gradient AS.
Mean gradient and peak aortic jet velocity are highly
dependent on the magnitude of transvalvular flow,
and a small decrease in LVOT stroke volume and thus
transvalvular flow rate may result in an important
decrease in transvalvular gradient, a phenomenon
known as gradient “pseudo-normalization” (Figure 2).
Although AVA is much less flow-dependent than
gradient (31), a decrease in transvalvular flow is
applied to the valve cusps, a decrease in valve
opening and AVA, and a phenomenon known as
“pseudo-severe” AVA (Figure 5). Hence, in the pres-
ence of low flow, the gradient and peak aortic velocity
may underestimate AS severity, whereas AVA may
overestimate AS severity. A low-flow state is defined
in the guidelines as a stroke volume index <35 ml/m 2
(1,3). The clinical relevance and prognostic value of
the cut-point of 35 ml/m2 has been confirmed by
several studies and meta-analyses (4,32–37).
A low-flow state may be related to depressed LV
systolic function, a condition named “classical” low-
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F I G U R E 4 Case of Normal-Flow, Low-Gradient AS

A 65-year-old symptomatic (New York Heart Association functional class II) man with AVA-gradient discordance, preserved LVEF, and normal flow (A to C). Both AVA and
AVAi are small, but the gradient is 32 mm Hg (D and E). The stroke volume estimated by the modified Teichholz method is similar to that obtained in the LVOT (A to C).
This patient had an aortic valve calcium score (2,430 AU) suggesting the presence of severe AS. The patient underwent surgical AVR. Abbreviations as in Figures 2 and 3.

flow AS (Figures 1, 2, and 5). Alternatively, a low-flow
state may be present in patients with preserved LVEF,
a condition named “paradoxical” low-flow AS (Fig-
ures 1 and 3). This low-flow state is predominantly a
result of pronounced LV concentric remodeling with
advanced diastolic dysfunction, impaired LV filling,
and reduced longitudinal systolic function. Other
factors may contribute to reduce LV outflow in the
setting of preserved LVEF including atrial fibrillation,
mitral regurgitation, mitral stenosis, right ventricular
dysfunction, tricuspid regurgitation, and constrictive
pericarditis.
Whereas current guidelines use stroke volume in-
dex to define the presence of a low-flow state, mea-
sures that also account for the systolic ejection period
are physiologically more appropriate and may better
reflect the effect of flow on transvalvular gradient and
AVA (38,39). The mean transvalvular flow rate is
calculated by dividing stroke volume by the LV ejec-
tion time, and a value <200 ml/s is consistent with a
low-flow state. In fact, stroke volume index and mean
flow rate are complementary measures of LV outflow
in the sense that the former is likely more important
from the standpoint of prognosis, whereas the latter
is more relevant from the standpoint of diagnosis.
SMALL BODY SIZE. Body surface area is the main
physiological factor determining the magnitude of
stroke volume and cardiac output in a normal subject.
Given that a small body size is associated with a lower
transvalvular flow rate, it may lead to a discordant
small AVA and a low-gradient situation. Indeed, a
small AVA in a small patient may actually correspond
to moderate AS and be associated with a low gradient.
In patients of small body size, it is thus recommended
to calculate the indexed AVA, and a value >0.6 cm 2/m 2
would rule out the presence of severe AS. Indexation
of AVA for body surface area may, however, over-
estimate the severity of AS in obese individuals. Two
approaches may be considered to overcome this lim-
itation: 1) use a lower cutoff value of indexed AVA
(<0.5 cm2 /m 2) to define severe AS in patients with a
body mass index $30 kg/m 2, similar to what has been
proposed for defining prosthesis-patient mismatch
(40); or 2) use other types of indexation such as AVA
indexed to height (<0.45 cm2 /m) (41). Of note, similar
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017 Clavel et al. 193
FEBRUARY 2017:185–202 Cardiac Imaging for Assessing Low-Gradient AS

F I G U R E 5 Case of Classical Low-Flow, Low-Gradient AS With Pseudo-Severe Stenosis

A 73-year-old symptomatic (New York Heart Association functional class III) woman. In this patient, there is an improvement of LVEF and
complete normalization of flow rate with DSE. The peak stress mean gradient is <40 mm Hg and the AVA is >1.0 cm2, thus suggesting the
presence of pseudo-severe AS. The patient was managed conservatively with heart failure therapy. Abbreviations as in Figures 2 and 3.

limitations apply to the definition of low flow using hypertension (43,44). This may further increase LV
stroke volume indexed to body surface area. afterload (already augmented because of AS) and lead
An alternative in obese patients is to use stroke to a decrease in LV outflow, thus contributing to the
volume indexed to a 2.04 power of height to define development of a low-gradient AS pattern (43,45–47).
low flow (<22 ml/m 2.04 ) (42). The total LV afterload resulting from the addition of
the valvular and arterial loads may be estimated by
REDUCED ARTERIAL COMPLIANCE AND HYPERTENSION. the valvuloarterial impedance (Zva), which is calcu-
The vast majority of patients with calcific AS have lated by dividing the sum of the mean gradient and
reduced arterial compliance and systolic systolic blood pressure by the stroke volume index
194 Clavel et al. JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017

Cardiac Imaging for Assessing Low-Gradient AS FEBRUARY 2017:185–202

F I G U R E 6 Pitfalls in the Measurement of the LVOT Diameter

(A) MDCT image showing the elliptical shape of the LVOT with the anteroposterior diameter (green arrow) that is smaller than the sagittal
diameter (blue arrow). (B) Anatomic view of the aortic aspect of the aortic valve illustrating the optimal plane for 2-dimensional (2D)
echocardiographic measurement of the LVOT. The plane should bisect the right coronary cusp anteriorly and the commissure between the left
and noncoronary cusp posteriorly (green arrows). A plane bisecting a cusp posteriorly provides a truncated section of the LVOT and thus may
underestimate the LVOT diameter (red arrow). (C) The parasternal zoomed view providing the largest diameter of the LVOT should be used.
The LVOT diameter should preferably be measured at—or very close to—the aortic annulus (i.e., base of cusp/commissure) (green arrows)
rather than 5 to 10 mm below the annulus, as proposed in the European Association of Echocardiography/American Society of Echocardi-
ography guidelines (yellow arrows). (D) The LVOT area estimated by 2D echocardiography assuming a circular shape of the LVOT
underestimates the actual LVOT area (and thus the AVA) measured by 3D echocardiography by 16% in this case. Abbreviations as in
Figures 2 and 3.

(48). Typically, patients with LF-LG AS have abnor-
mally high valvuloarterial impedance (>4.5 mm Hg/
ml$m 2 ); if not, the low flow state is likely not related
to afterload excess, but is rather an intrinsic cardio-
myopathy such as ischemic disease.
Moreover, reduced arterial compliance leads to a
faster arterial wave reflection from the periphery. The
early reflection of the arterial wave at the end of
systole may dampen the transvalvular gradients, in-
dependent of transvalvular flow (49,50). This phe-
nomenon may, at least in part, explain the small AVA
and low gradient discordance observed in patients
with normal-flow, low-gradient AS (Figures 1 and 4)
(46,50). In patients with low-gradient AS
concomitant systolic hypertension, it is recom-
mended to reassess the echocardiographic
parameters of AS severity, as well as the symptomatic
status, after the normalization of blood pressure.
INCONSISTENCIES IN GUIDELINES CRITERIA
FOR SEVERE AS
The majority of patients with discordant grading at
echocardiography or catheterization actually have
normal flow (i.e., stroke volume index $35 ml/m 2)
(Figures 1 and 4) (5,6,8). Besides reduced arterial
compliance, another cause of normal-flow, low-
gradient AS is the inherent inconsistency, or
misalignment, of the AVA and gradient cut-points for
and the definition of severe AS in the valve guidelines (6).
Indeed, in a patient with a normal flow rate, an AVA
of 1.0 cm 2 does not correspond to a mean gradient of
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017
FEBRUARY 2017:185–202
40 mm Hg or a peak AS velocity of 4 m/s, but rather
corresponds to a mean gradient of 30 mm Hg and a
peak velocity of 3.5 m/s (5,8). To overcome this
pitfall, some investigators have suggested decreasing
the AVA cut-point for defining severe AS to 0.8 cm2.
However, patients with an AVA between 0.8 and 1.0
cm 2, but with a low gradient, are at increased risk of
mortality if treated medically and receive an impor-
tant survival benefit with AVR (5,35). Hence, the best
approach, for now, appears to be to maintain the
current cut-points: AVA #1.0 cm 2 as a sensitive
criteria and mean gradient $40 mm Hg as a specific
criteria. In symptomatic patients with discordant
grading and low-gradient AS, additional tests and
parameters should be used to confirm the stenosis
severity.
MANAGEMENT OF LOW-GRADIENT AS
Patients with LF-LG AS, especially those with classical
LF-LG, have worse outcomes following surgical or
transcatheter AVR compared with patients with high-
gradient AS (33,51–53). Nonetheless, several studies
and meta-analyses have reported that patients with
classical LF-LG; paradoxical LF-LG; or normal-flow,
low-gradient severe AS display a significant survival
benefit with AVR compared with conservative man-
agement (32,35,54–60). Hence, the crucial step to
determine the need for AVR in a symptomatic patient
with low-gradient AS is to confirm the presence of a
severe stenosis, which may be particularly chal-
lenging in the context of low-gradient AS (Central
Illustration). In these patients, there is frequently un-
certainty with respect to the “actual” severity of AS
given that some echocardiographic or catheterization
parameters (i.e., AVA, Doppler velocity index) suggest
a severe stenosis, whereas others (gradients and peak
velocity) suggest nonsevere AS.
CONFIRMATION OF AS SEVERITY TO DETERMINE
THE NEED FOR AVR. Among patients with small
AVA, low-gradient AS, 30% to 50% have nonsevere
AS; these patients should probably be treated
conservatively because they would not be expected
to receive a benefit from AVR (Figure 1) (7,11,50,61,62).
Stress echocardiography and/or MDCT may be used to
identify those patients with true-severe AS who
should be referred for valve replacement (Central
Illustration).
Low-dose dobutamine stress echocardiography. In
patients with classical LF-LG AS, it is difficult to
differentiate true-severe AS, which generally requires
AVR, from pseudo-severe AS, in which there is
incomplete opening of a valve that is only moderately
Clavel et al. 195
Cardiac Imaging for Assessing Low-Gradient AS
or mildly stenotic. Low-dose (up to 20 mg/kg/min)
dobutamine stress echocardiography (or dobutamine
stress cardiac catheterization) is useful to distinguish
true-severe from pseudo-severe stenosis in these
patients with a low LVEF (Figures 2 and 5) (63).
Various parameters have been proposed to define
true-severe AS (Table 1). However, the guidelines
suggest a peak stress mean gradient $40 mm Hg in
the presence of an AVA #1.0 cm 2 as the main criteria
to confirm the presence of severe AS in patients with
classical LF-LG AS (1,3).
The main limitation of this test is that the flow
response to dobutamine and thus the magnitude of
transvalvular flow rate at peak stress varies exten-
sively from one patient to the other. Most patients
normalize or even over-normalize their flow rate, and
if they have true-severe AS, they will generally
display a high gradient at peak stress. On the other
hand, many patients exhibit a significant increase in
flow with dobutamine; however, it is not sufficient to
reach the normal flow range, and a discordant small
AVA, low-gradient pattern persists at the end of the
dobutamine stress test (Figure 2, Online Videos 1 and
2). In these patients, it is useful to calculate the pro-
jected AVA at a normal flow rate using the method
presented in Figure 2. On the basis of the AVA-flow
behavior, this parameter projects what the AVA
would be at a standardized normal flow rate of 250
ml/s. This parameter, standardized for flow, has been
shown to better predict the actual hemodynamic
severity of the valve stenosis and the clinical outcome
of patients with classical or paradoxical LF-LG AS, as
compared with standard stress echocardiography
parameters (11,61,64). A projected AVA <1.0 cm 2
confirms the presence of true severe AS (Figure 2,
Table 1). It should be noted that many patients do not
have an increase in stroke volume with dobutamine
infusion, and indeed, may have a decrease in stroke
volume; however, transvalvular flow rate will almost
always increase because of a shortening of the ejec-
tion time. Importantly, a minimum 15%
(ideally $20%) increase in flow rate is required to
obtain a reliable estimate of the projected AVA (11). In
patients with no or minimal increase in flow rate,
dobutamine stress echocardiography remains incon-
clusive, and other tests such as aortic valve calcium
scoring may be used to corroborate AS severity as
described in the following section (Figure 7).
Although the vast majority of patients with low
LVEF and low gradient (i.e. classical LF-LG) have a
low-flow state at rest, some may nonetheless have a
normal mean transvalvular flow rate (>200 ml/s) (39).
These patients generally have enlarged LV cavities
with moderately depressed LVEF and no or minimal
196 Clavel et al. JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017

Cardiac Imaging for Assessing Low-Gradient AS FEBRUARY 2017:185–202

T A B L E 1 Multimodality Imaging for Identification of Low Flow and Confirmation of Stenosis Severity in Low-Gradient AS

Imaging Modality Imaging Parameter and Criteria Advantages Limitations

Low Flow

Doppler-echocardiography Stroke volume index Good marker of LV pump function Does not account for the effect of ejection
<35 ml/m2* and prognosis duration on the gradient. May overestimate
the prevalence of low-flow state in
obese patients.
Mean transvalvular flow rate Better determinant of gradient Potentially inferior to stroke volume index to
<200 ml/s than stroke volume index predict prognosis.

Severe AS

Doppler-echocardiography Peak aortic jet velocity $4 m/s* Less subject to measurement error Highly flow-dependent. May underestimate
Mean gradient $40 mm Hg* than the AVA AS severity in low-flow states.
AVA <1.0 cm2* Less flow-dependent than the Subject to measurement error. May
Indexed AVA <0.6 cm2/m2* gradient or peak velocity overestimate AS severity in low-flow
(<0.5 cm2/m2 if BMI $30 kg/m2) states.
Doppler velocity index <0.25
Severe valve leaflet thickening and Reduced leaflet mobility may overestimate
calcification. Severely reduced AS severity in low-flow states.
leaflet mobility. Often difficult to assess by TTE; better
assessed by TEE.
Dobutamine-stress Peak aortic jet velocity $4 m/s Less subject to measurement error Highly flow-dependent. May underestimate
echocardiography Mean gradient $40 mm Hg* than the AVA AS severity if flow rate remains below
Mean gradient $30 mm Hg normal with dobutamine stress or
overestimate AS severity if supra-normal
response to dobutamine stress.
AVA<1.0 cm2* Less flow-dependent than the Subject to measurement error. May
AVA<1.2 cm2 gradient or peak velocity overestimate AS severity if flow rate
Doppler velocity index <0.25 remains below normal with dobutamine
Increase in AVA<0.3 cm2 stress
Projected AVA <1.0 cm2 Standardized for flow Subject to measurement error. Not
Indexed Projected AVA <0.55 cm2/m2 measurable if increase in flow rate <15%
with dobutamine stress.
MDCT Aortic valve calcium score Highly accurate and reproducible. Reflects anatomic rather than hemodynamic
>2,000 AU in men Independent of flow and severity. Does not take into account
>1,200 AU in women hemodynamics. Does not require valvular fibrosis and therefore may
Aortic valve calcium density administration of stress or underestimate AS severity.
>500 AU/cm2 in men contrast agent.
>300 AU/ cm2 in women

*Criteria and parameters recommended in the guidelines.

AS ¼ aortic stenosis; AVA ¼ aortic valve area; BMI ¼ body mass index; LV ¼ left ventricular; MDCT ¼ multidetector computed tomography; TEE ¼ transesophageal echocardiography; TTE ¼ transthoracic
echocardiography.

mitral regurgitation, and are therefore able to
generate a normal stroke volume. In these patients,
the AVA at rest may actually be a good predictor of
the presence of true severe stenosis, and dobutamine
stress may not be required (Table 1) (39).
Dobutamine stress echocardiography (symptom-
atic patients) or exercise stress echocardiography
(patients with no or equivocal symptoms) may also be
useful to confirm the presence of severe AS in pa-
tients with paradoxical LF-LG or in those with
normal-flow, low-gradient AS (61). However, an
important proportion of patients with paradoxical LF-
LG AS have small thick left ventricles with restrictive
physiology, which may preclude a significant increase
in flow during dobutamine stress and can lead to side
effects (LVOT dynamic obstruction, hypotension,
etc.) (Figure 3, Online Videos 3 and 4). Hence,
assessment of the valve morphology by transthoracic
or transesophageal echocardiography
quantitation of aortic valve calcification by MDCT
may be the preferred approach to corroborate AS
severity in these patients (Figure 7). In patients with
normal-flow, low-gradient AS, the stroke volume is by
definition normal at rest, and the utility of stress
echocardiography is thus limited in these patients.
However, some of these patients may actually have a
low-flow state with a reduced mean transvalvular
flow rate as a result of prolongation of the ejection
time, and therefore may benefit from dobutamine
stress testing. On the other hand, some patients with
classical or paradoxical LF-LG may have a normal
mean flow rate (>200 ml/s) despite a reduced LVEF
and/or stroke volume index if their ejection time is
short. In such cases, the resting AVA measured under
normal flow rate conditions likely reflects the true
severity of AS, and DSE is not needed to confirm
stenosis severity (39). The documentation of mark-
and edly abnormal valve leaflet morphology/mobility and
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017
FEBRUARY 2017:185–202
F I G U R E 7 Quantitation of Aortic Valve Calcification by MDCT to Differentiate True Versus Pseudo-Severe Stenosis in Low-Gradient AS
Abbreviations as in Figures 1 to 3.
the presence of severe valve calcification at MDCT
might be considered to trigger AVR in symptomatic
patients with normal-flow, low-gradient AS (Figure 7).
However, further studies are needed to develop and
validate imaging markers of AS severity in patients
with low-gradient AS, and particularly those with
normal-flow and those with paradoxical low-flow AS.
Assessment of valve leaflet morphology by transthoracic
or transesophageal echocardiography. Transthoracic or
transesophageal 2D or 3D echocardiography can be
used to assess the degree of valve leaflet thickening
and calcification and can therefore corroborate the
“anatomic” severity of AS (Figure 3, Online Video 4).
The limitations of this method are: 1) it is subject to
interobserver and intraobserver variability; and 2) it
is semiquantitative with limited gradations (mild,
moderate, and severe calcification) (65). Hence, this
assessment may need to be confirmed by quantitative
methods such as MDCT (Figure 7). The presence of
reduced leaflet mobility at echocardiography is also a
criterion supporting the presence of severe AS.
However, this feature, as with AVA, may overestimate
severity in the presence of low flow (pseudo-severe
phenomenon due to incomplete opening of the
valve).
Clavel et al. 197
Cardiac Imaging for Assessing Low-Gradient AS
Quantitation of aortic valve calcification by MDCT. MDCT
is a highly accurate and reproducible method to
quantitate aortic valve calcification and it has the
advantage of being independent of hemodynamics/
flow and does not require the administration of any
stress or contrast agents. This method is thus appli-
cable to all patients with low-gradient AS. Aortic
valve calcium scoring by MDCT is useful to corrobo-
rate AS severity in patients with low-gradient AS
when dobutamine stress echocardiography is not
indicated, not feasible, or inconclusive. Hence, MDCT
is particularly helpful in patients with classical LF-LG
AS with no or minimal increase in flow with dobut-
amine stress; in patients with paradoxical LF-LG; and
in those patients with normal-flow, low-gradient AS
(Figures 2, 3, 4, and 7). For the quantitation of calci-
fication, a noncontrast MDCT scan during trained
end-inspiration breath-hold is performed, and the
radiation exposure for such an examination is <3
mSV. The amount of calcification in the region of the
aortic valve is quantitated using the modified Agat-
ston method, in which calcification is defined as 4
adjacent pixels with a density >130 Hounsfield units
(66). Importantly, MDCT assesses the “anatomic”
rather than the “hemodynamic” severity of AS.
198 Clavel et al.
Cardiac Imaging for Assessing Low-Gradient AS
Nonetheless, the aortic valve calcium score measured
by MDCT strongly correlates with hemodynamic
severity, the progression rate, and the clinical out-
comes of AS patients (19,50,67,68). It is important to
highlight that women reach the same hemodynamic
severity as men with less calcification, and therefore,
different cut-point values of valve calcification score
need to be applied to differentiate severe versus
nonsevere AS in men ($2,000 AU) compared with
women ($1,200 AU) (Table 1, Figure 7) (50,69). The
same approach should be applied when using cut-
point values for aortic valve calcium density (i.e.,
calcium score divided by aortic annulus area): $500
2
AU/cm in men versus $300 AU/cm in women.2
MDCT has important pitfalls that should be appre-
ciated. In particular, this method does not capture
valvular fibrosis, which also contributes to the hemo-
dynamic severity of the valve stenosis. This issue may,
at least in part, explain the discrepancy between men
and women with regard to the cut-point values for
aortic valve calcium score and density to identify se-
vere AS. Recent studies suggest that for a given degree
of hemodynamic severity, women have less valvular
calcification but more fibrosis compared with men (70).
Furthermore, younger patients with bicuspid valves
may have hemodynamically severe AS with no or little
valve calcification (71). However, these patients rarely
exhibit a low-gradient AS pattern.
Indication for AVR in low-gradient AS. In patients with
low-gradient AS who have symptoms and/or
LVEF <50%, it is essential to confirm the stenosis
severity (Central Illustration). AVR should be consid-
ered (Class IIa) in those patients with evidence of
true-severe AS on the basis of the assessment of the
aortic valve leaflet morphology/mobility by trans-
thoracic or transesophageal echocardiography,
confirmation of hemodynamic severity by dobut-
amine stress echocardiography, and/or quantitation
of aortic valve calcification by MDCT (Table 1). Pa-
tients with nonsevere AS on the basis of dobutamine
stress echocardiography or MDCT should a priori be
treated conservatively (Figures 5 and 6) (72). Howev-
er, nonsevere AS does not imply the absence of AS,
and most of these patients have moderate or
moderate-to-severe AS. Therefore, patients should
receive close clinical and echocardiographic surveil-
lance to evaluate for both disease progression and
progressive symptoms. In patients with a reduced
LVEF, guideline-based heart failure therapies should
be optimized (72). Although moderate AS may be well
tolerated in patients with preserved LV systolic
function, it may represent a severe hemodynamic
burden and have a detrimental effect on outcomes in
patients with a depressed LVEF (11,12). In the TOPAS
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FEBRUARY 2017:185–202
(Truly or Pseudo Severe Aortic Stenosis) study, the
cut-point for the projected AVA that best predicted
mortality in patients with classical LF-LG AS treated
medically was >1.2 cm 2, which is larger than the cut-
point traditionally used to define severe AS (11).
These findings raise the hypothesis that AVR might be
beneficial in patients with moderate AS and HFrEF
(Figures 1 and 6, Central Illustration). The TAVR UN-
LOAD trial may provide guidance in the management
of such patients (13).
INDIVIDUALIZED RISK STRATIFICATION TO SELECT
THE TYPE OF AVR. Once the indication for AVR is
established, the next step is to decide on the best type
and access for AVR in the individual patient (Central
Illustration). The choice between surgical versus
transcatheter AVR is essentially determined by the
predicted surgical risk that is assessed by combining
the Society of Thoracic Surgeons risk estimate, pa-
tient’s frailty, major organ system dysfunction, and
procedure-specific impediments (1). Transcatheter
AVR is recommended in patients who are at prohibi-
tive surgical risk (Society of Thoracic Surgeons
score $10%) and a predicted post-TAVR survival >1
year. Transcatheter AVR is a reasonable alternative to
surgical AVR in patients at high (>8%) or intermedi-
ate (>4%) risk for surgical AVR. Besides the surgical
risk scores, it is also important to consider the type of
low-gradient AS to select the type of AVR (Central
Illustration).
Classical low-flow, low-gradient AS. Depressed LVEF is a
well-known and powerful risk factor for operative
mortality following surgical AVR. In contrast, there is
no or only a weak association between LVEF and
procedural outcomes following transcatheter AVR
(32,33,73). Nonrandomized studies have also sug-
gested that transcatheter AVR is associated with
better and faster recovery of LV systolic function and
better survival compared with surgical AVR (53,74).
Although randomized studies such as the PARTNER
(Placement of Aortic Transcatheter Valves) trial
showed no difference in outcome between trans-
catheter versus surgical AVR, patients with very low
LVEF as well as those with no flow reserve on
dobutamine stress were excluded (32,75). The
absence of flow reserve, defined as an increase in
LVOT stroke volume <20% during dobutamine stress
echocardiography or catheterization, is a strong pre-
dictor of high/extreme surgical risk for AVR in pa-
tients with classical LF-LG AS (55). However, a recent
study from a large, multicenter, international registry
revealed that patients with classical LF-LG AS have
excellent procedural and 1-year outcomes with
transcatheter AVR (76). Furthermore, the absence of
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017
FEBRUARY 2017:185–202
flow reserve had no effect on the 30-day or 1-year
mortality. Transcatheter AVR with transapical access
has been associated with more important myocardial
injury and less recovery of LVEF compared with
transfemoral or transaortic access and should prob-
ably be avoided in patients with classical LF-LG AS
(77). These findings in their entirety would suggest
that transcatheter AVR via a transfemoral approach
may be superior to surgical or transapical AVR in
patients with classical LF-LG AS, especially in those
patients with no flow reserve on dobutamine stress
(Central Illustration).
Coronary artery disease is highly prevalent among
patients with classical LF-LG AS, and the presence of
severe coronary artery disease (SYNTAX score >22) is
independently associated with reduced survival
following AVR (78). Furthermore, patients with sig-
nificant coronary artery disease and incomplete
revascularization have worse outcomes after AVR.
Therefore, revascularization strategies are an impor-
tant component of the management of patients with
classical LF-LG AS who are undergoing surgical or
transcatheter AVR.
Paradoxical LF-LG AS. Because of their particular clin-
ical, anatomic, and hemodynamic features (higher
prevalence of women, small LV cavity with restrictive
physiology, small aortic annulus, and so on), patients
with paradoxical LF-LG AS may be at higher surgical
risk compared with patients with high-gradient AS
(Figure 3) (52). Furthermore, they may be more prone
to develop prosthesis-patient mismatch following
surgical AVR, which may negatively affect their clin-
ical outcome (79). Compared with surgical AVR,
transcatheter AVR is associated with less frequent
and less severe prosthesis-patient mismatch, partic-
ularly in the subset of patients with a small aortic
annulus (80,81). On the other hand, transcatheter
AVR is associated with a higher prevalence of para-
valvular regurgitation compared with surgical AVR,
and even mild aortic regurgitation may be potentially
detrimental in patients with paradoxical LF-LG AS.
The post hoc analysis of the PARTNER 1A trial none-
theless suggests that transcatheter AVR may be su-
perior to surgical AVR in these patients (32). Further
studies are needed to confirm which treatment mo-
dality is best in these patients.
Normal-flow, low-gradient AS. In contrast to patients
with classical or paradoxical LF-LG AS, those with
normal-flow, low-gradient AS do not appear to be at
increased surgical risk. Hence, the strategy for these
patients should be to select surgical or transcatheter
AVR depending on the comorbidities and expected
surgical risk as recommended for patients with high-
gradient AS (Central Illustration). However, there is
Clavel et al. 199
Cardiac Imaging for Assessing Low-Gradient AS
no specific recommendation for patients with normal-
flow, low-gradient AS in the guidelines, and further
studies are needed to determine the best timing and
type of AVR for these patients.
Futility of AVR. Although the vast majority of symp-
tomatic patients with low-gradient severe AS benefit
from AVR in terms of longevity and quality of life,
unfortunately, some have poor clinical and functional
outcomes despite successful intervention (82). An
important research priority in this field is to develop
and validate imaging and blood biomarkers to predict
treatment futility, that is, identify patients who are
unlikely to benefit from AVR. Multimodality imaging
may be helpful in this regard. Very low baseline mean
gradient (<20 mm Hg), moderate/severe mitral
regurgitation, severe right ventricular dysfunction,
and severe tricuspid regurgitation are among the
imaging factors that have been associated with an
increased risk of poor outcome and lack of functional
improvement following AVR in patients with low-
gradient AS (73,83–87). Quantitation of myocardial
fibrosis by CMR is also a very promising approach to
identify patients with low-gradient AS who may
potentially have irreversible myocardial impairment
and thus a low likelihood to benefit from AVR (88).
Further studies are needed to determine which CMR
methods, parameters, and cut-point values should be
applied to identify the presence of extensive irre-
versible fibrosis that would potentially compromise
the utility of AVR. An approach on the basis of
multiple complementary blood biomarkers of car-
diovascular stress may be helpful to predict treatment
futility in low-gradient AS (89). Pending further
studies, the presence of these emerging biomarkers of
higher risk of treatment futility should not be used at
this time to preclude the consideration of AVR in low-
gradient AS patients with evidence of severe AS.
Indeed, such patients often have an even worse
prognosis with conservative management.
CONCLUSIONS
Low-gradient AS is found in up to 40% of AS pa-
tients with a small AVA. Multimodality imaging is
essential for optimal diagnosis, risk stratification,
and therapeutic management of this entity. Doppler-
echocardiography is critical to determine the type of
low-gradient AS: classical low-flow, paradoxical low-
flow, or normal-flow AS (Central Illustration). Hybrid
methods fusing MDCT and Doppler imaging may be
used to corroborate the measurement of flow and
AVA, but larger cut-point values of stroke volume
index and AVA should be applied to define a low-
flow state and severe AS, respectively. Patients
200 Clavel et al. JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 2, 2017

Cardiac Imaging for Assessing Low-Gradient AS FEBRUARY 2017:185–202

with LF-LG AS generally have a worse prognosis
compared with patients with high-gradient or with
normal-flow, low-gradient AS. Patients with low-
gradient AS and evidence of severe AS benefit from
AVR; however, confirmation of the presence of
severe AS is challenging in these patients and
requires a multimodality imaging approach
including dobutamine stress echocardiography and
aortic valve calcium scoring by MDCT. Transcatheter
AVR using a transfemoral approach may be superior
to surgical AVR in patients with LF-LG AS. Further
studies are needed to confirm the best type of AVR
for each category of low-gradient AS and to identify
patients with low-gradient AS in whom AVR is likely
to be futile.
ADDRESS FOR CORRESPONDENCE: Dr. Philippe
Pibarot, Institut Universitaire de Cardiologie et de
Pneumologie de Québec (Quebec Heart and Lung
Institute), 2725 Chemin Sainte-Foy, #A-2075, Québec,
Québec, Canada, G1V 4G5. E-mail: philippe.pibarot@
med.ulaval.ca.

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KEY WORDS aortic stenosis, computed
tomography, echocardiography, low flow,
low-gradient
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