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Low-gradient ‘severe’ aortic stenosis with preserved ejection fraction: new entity, or discrepant definitions?
Nikolaus Jander*
Department of Cardiology, Herz-Zentrum Bad Krozingen, Südring 15, 79188 Bad Krozingen, Germany
* Corresponding author. Tel: +49 7633 402 0; fax: +49 7633 402 4409. E-mail address: nikolaus.jander{at}herzzentrum.de
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Abstract
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Surgery of aortic valve stenosis (AS) is often dependent on
whether stenosis is considered severe, as defined by aortic
valve area (AVA) and/or mean pressure gradient (dPm) criteria
set forth by the American College of Cardiology/American Heart
Association and the European Society of Cardiology. Problems
arise in determining whether AS is severe in patients with normal
left-ventricular (LV) function who meet either an AVA criterion
or a dPm criterion but not the other, especially in patients
with low-gradient ‘severe’ AS (dPm
40 mmHg, AVA
< 1.0 cm
2). This article considers whether low-gradient ‘severe’
AS with preserved ejection fraction (EF) is a new entity or
merely an example of discrepant or inconsistent criteria for
defining severe AS.
Studies concerning the frequency of inconsistent grading of severe AS by AVA and dPm criteria were reviewed, with a focus on factors that may give rise to inconsistency. Inconsistent grading was found to be frequent and more frequent with AVA determined by echocardiography than by catheterisation. Inconsistent grading may be due to low flow despite normal EF (low-flow severe AS); however, many patients show inconsistent grading with normal flow (NF) (NF non-severe AS), possibly because of inconsistent AVA and dPm cut-off values. Small errors in measuring the LV outflow tract diameter via echocardiography may lead to an inaccurate diagnosis of low-gradient ‘severe’ AS.
Low-gradient ‘severe’ AS with preserved EF is not a new clinical entity; the term encompasses many patients with truly severe AS and low stroke volume and the attendant serious prognosis associated with severe AS. Low-gradient ‘severe’ AS is also found in patients with NF; the prognosis and indications for surgical therapy for these patients are not well defined, particularly, in the presence of non-specific symptoms. Differentiation by transthoracic echocardiography of low-flow severe AS from NF non-severe AS may be difficult and may be aided by transoesophageal echocardiography and functional testing with exercise.
Key Words: Aortic valve stenosis • Severity • Grading • Low-gradient • Echocardiography
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Introduction
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In the management of patients with aortic valve stenosis (AS),
symptoms attributable to AS (syncope, angina, dyspnoea) determine
which patients should undergo valve replacement. In addition
to the presence of symptoms, severity of AS plays a key role
in the decision to operate. Surgery may also be necessary in
case of non-specific symptoms, in the presence of heavy calcification
or rapid progression of stenosis.
1 Symptomatic patients with
comorbidities such as chronic obstructive pulmonary disease,
obesity, or hypertension may prove particularly difficult to
evaluate for AS surgery because of the non-specificity of the
symptom of dyspnoea. Therefore, evaluating the severity of AS
may be critical in deciding whether certain patients with symptoms
or with non-specific symptoms should be subjected to the risk
of valve replacement. Therefore, defining consistent cut-off
values for severe AS is more than an academic exercise.
According to the current guidelines for the management of patients with valvular heart disease, the grading of AS severity depends on values of aortic valve area (AVA) and mean pressure gradient (dPm) obtained from echocardiography and/or cardiac catheterisation (Table 1).2,3 To be useful, criteria for AS severity should be consistent across all patients with normal left-ventricular (LV) function.
However, problems arise when attempting to determine whether
there is severe AS present in patients with normal LV function
who meet either an AVA criterion or a dPm criterion for severe
AS, but not the other. This problem is illustrated by the case
of an 84-year-old woman with AS, chronic bronchitis, and hypertension
who was found by echocardiography to have normal LV function
with an LV ejection fraction (LVEF) of 62%, mild LV concentric
hypertrophy, and AS with an AVA of 0.9 cm
2 and a dPm of 28 mmHg.
Does this woman with normal LV function have severe AS? She
has severe AS according to the AVA criterion of <1.0 cm
2 but not according to the dPm criterion of either >40 mmHg
if the American College of Cardiology/American Heart Association
(ACC/AHA) criterion is used, or
50 mmHg if the European Society
of Cardiology criterion is used.
2,3 She might be considered
to represent an example of ‘low-gradient severe AS’
with normal AVA and preserved LVEF. This article summarises
studies that provide information about low-gradient severe AS
with preserved LVEF and considers whether this is indeed a new
clinical entity or merely an example of discrepant definitions
of severe AS.
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Inconsistent grading is frequent
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A study by Minners
et al.
4 at our institution demonstrated the
frequency with which inconsistency of AS severity grading criteria
may be encountered. In a retrospective review of our cardiology
department’s database, we identified 6152 records of consecutive
echocardiographic studies performed between 1994 and 2004 and
showing normal LV function and AVA
2.0 cm
2. From these, we
excluded studies showing dPm < 10 mmHg (
n = 1420), more than
mild mitral or aortic regurgitation (
n = 1019), peak flow velocity
<0.8 and >1.5 m/s in the LV outflow tract (LVOT) (
n =
125), an LVOT diameter of <15 mm (
n = 4), or incomplete data
(
n = 101), and evaluated the remaining 3483 records of echocardiographic
examinations performed in 2427 patients.
The AVA and dPm data from these echocardiographic studies are plotted in Figure 1. As shown, 30% of patients (those represented in the lower left quadrant of the plot) were diagnosed with severe AS based on the AVA and non-severe AS based on the dPm. Overall, an AVA of 1.0 cm2 correlated with a dPm of 22.8 mmHg on the fitted curve for the study population. Conversely, a dPm of 40 mmHg correlated with an in vivo AVA of 0.75 cm2, and a maximum flow velocity of 4.0 m/s correlated with an in vivo AVA of 0.82 cm2. In the framework of current guidelines, the percentage of patients diagnosed with severe AS was 40% based on dPm, 45% based on maximum flow velocity, and 69% based on AVA.
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Figure 1 Valve area and mean pressure gradient (dPm) with relationship to criteria for severe aortic stenosis. Quadrants are based on cut-off values for severe aortic stenosis as stated in current guidelines (American Heart Association/American College of Cardiology). The percentages correspond to patients per quadrant: 30% of patients are diagnosed with severe stenosis based on aortic valve area (AVA) and non-severe stenosis based on dPm.4 The curve signifies the fitted relationship between AVA and dPm (data from Minners et al.4 Eur Heart J 2007).
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This study demonstrated that inconsistent grading is frequent.
Two possible interpretations of these findings have been offered.
One is that there is a discrepancy in cut-off values, suggesting
that an AVA of 1.0 cm
2 usually does not relate to a dPm of 40
mmHg. The other is that there is low flow, which despite normal
LVEF, results in a lower dPm than expected, based on AVA.
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Inconsistent grading of severity may be due to ‘paradoxical’ low flow
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Hachicha
et al.
5 investigated the prevalence, potential mechanisms,
and clinical relevance of the phenomenon of severe AS diagnosed
on the basis of low AVA occurring in conjunction with a relatively
low gradient despite the presence of a preserved LVEF. In this
study, 512 consecutive patients with echocardiographically determined
low-gradient severe AS (AVA
0.6 cm
2/m
2) and normal LVEF (
50%)
were subdivided into a group with ‘normal flow (NF),’
having stroke volume (SV) index (SVI) >35 mL (
n = 331, 65%),
and one with ‘paradoxical low flow (PLF),’ having
an SVI
35 mL (
n = 181, 35%).
Compared with patients having NF, those with PLF were found to be older (73 ± 13 vs. 69 ± 14 years; P = 0.004); more likely female (51 vs. 39%; P < 0.05); to have a lower LV diastolic volume index (52 ± 12 vs. 59 ± 13 mL/m2; P < 0.001), LVEF (62 ± 8 vs. 68 ± 7%; P < 0.001), and dPm (32 ± 17 vs. 40 ± 15 mmHg; P < 0.001); as well as a higher systemic vascular resistance (1986 ± 677 vs. 1508 ± 380 mmHg x min/L; P < 0.001).
During 5 years of follow-up, patients in the PLF group had an overall reduced survival compared with those in the NF group (1 year, 87 ± 3 vs. 94 ± 1%; 2 years, 79 ± 4 vs. 90 ± 2%; 3 years, 76 ± 4 vs. 86 ± 3%; P = 0.006; P-value adjusted for age and gender = 0.045); both groups showed reduced survival with medical therapy compared with surgery (Figure 2).
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Figure 2 Survival in the patients with aortic stenosis (AVA 0.6 cm2/m2) according to normal flow (NF) and paradoxical low flow (PLF) with medical vs. surgical treatment.5 *P-value adjusted for age and gender. **P-value adjusted for age, gender, and valvulo-arterial impedance. Reproduced with permission from: Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation 2007;115:2856–2864. Copyright © 2007 Lippincott Williams & Wilkins.
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Before inferring from these results that every patient with
an AVA < 1.0 cm
2 and dPm
40 mmHg requires surgery, some
study limitations must be taken into account. This was a retrospective
study with small numbers of patients in the follow-up (
Figure 2);
no information was provided about clinical symptoms and the
decision to perform or reject surgery; and not all of the patients
in the study belonged to the group of inconsistently graded
patients, that is, with severe AS that could be diagnosed on
the basis of AVA but not dPm criteria. Conversely, even in the
low-flow group, there were many patients with dPm
40 mmHg;
these patients would in any case have been identified as having
severe AS by AHA/ACC criteria.
2 However, the most important
limitation of the study is the chosen definition of normal or
‘preserved’ LV function (LVEF
50%). As discussed
by the authors, an LVEF of 50% in these patients with concentric
remodelling reflects substantial reduction in intrinsic myocardial
shortening and cannot be considered normal.
6 Low flow in these
circumstances is neither unexpected nor ‘paradoxical’.
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Inaccurate measurements may contribute to inconsistent severity grading
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Caution is needed when making a diagnosis of low-flow severe
AS because of the nature of the measurements upon which the
diagnosis is made. AVA is calculated using the continuity equation.
7,8 The cross-sectional area of the LVOT is needed for this calculation
and is obtained by measuring the diameter of the LVOT and calculating
the area using the square of half the diameter. SV, also required
for the continuity equation, is calculated using the product
of the velocity-time integral and the area of the LVOT for which
once again the diameter of the LVOT is required. Thus, if the
measurement of the diameter is too low, both the AVA and the
SV will be too small, misleadingly resulting in the diagnosis
of a severe low-flow AS. In addition, the shape of the LVOT
may be more eccentric than annular, leading to underestimation
of the LVOT area if the area is based on the shorter diameter,
which is usually the one measured.
9,10
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Inconsistent grading also occurs with data from catheterisation
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Inconsistent grading of the severity of AS may occur using data
obtained from catheterisation as well as from echocardiography.
Carabello
11 calculated the dPm for a range of AVA values in
patients with normal LV function according to a cardiac output
of 6 L/min, ejection period of 0.33 s, and heart rate of 80/min,
using the Gorlin formula for calculating AVA (
Figure 3).
According to these assumptions, some patients would be diagnosed
with ‘severe’ AS based on the AVA criterion but
not the dPm criterion. The fact that inconsistent grading can
also occur using data from catheterisation was confirmed in
a subgroup of our patients from the study by Minners
et al.
4 who underwent additional catheterisation (unpublished results).
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Figure 3 Calculated relation of aortic valve area to mean pressure gradient. Data for the curve were derived using the Gorlin formula: Aortic valve area = [cardiac output/(systolic ejection period x heart rate)]/44.3 mean gradient, in which the cardiac output was assumed to be 6 L/min, systolic ejection period 0.33 s, and heart rate 80 beats/min.10 Data from Carabello BA.11 N Engl J Med 2002.
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Inconsistent grading also occurs with normal flow
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As shown by the Carabello calculation,
11 patients may have severe
AS according to an AVA criterion, but not a dPm criterion, and
yet have NF.
11 This is confirmed by the study of Hachicha
et al.,
5 which showed that patients in the NF group (SVI > 35
mL) had a dPm of only 40 ± 15 mmHg, indicating that many
patients with NF also had inconsistent grading (AVA
0.6 cm
2/m
2 and dPm < 40 mmHg).
5 These data demonstrate that in a substantial
group of patients with normal SV inconsistency of AS severity
grading will occur.
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Inconsistent grading is more frequent with echocardiography vs. catheterisation
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In general, the AVA calculated using Doppler-derived data is
smaller than that derived from catheterisation data,
7 mainly
because catheterisation provides an ‘anatomic’ AVA
whereas Doppler provides an ‘effective’ AVA. Anatomic
AVA, as measured by planimetry at autopsy and/or during cardiac
catheterisation, is usually larger than effective AVA derived
from Doppler echocardiography. The difference between anatomic
and effective AVA rests on the fact that streamlines continue
to converge for a short distance downstream of AS. Thus, inconsistent
grading may be more pronounced with echocardiography than with
catheterisation because smaller AVAs are calculated from echocardiography
(vs. catheterisation) data.
Guidelines for the grading of AS were initially based on data derived from invasive measurements reflecting anatomic AVA. Currently, Doppler echocardiographic measurements with lower (effective) AVAs usually provide the information for clinical decision-making. This may support the adjustment of the AVA cut-off value obtained by echocardiographic measurements for defining severe AS.4,7
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Clinical summary
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Data from the studies reviewed in this article show that:
- inconsistent grading of the severity of AS is frequent (30% in our study population);
- inconsistent grading is more frequent with echocardiography than with catheterisation;
- inconsistent grading can be due to low flow despite normal LVEF (low-flow severe AS);
- many patients show inconsistent grading with NF (NF non-severe AS). This may be due to inconsistent cut-off values: an AVA of 1.0 cm2 usually does not relate to a dPm of 40 mmHg even in patients with NF;
- calculation of AVA and SV with echocardiography is problematic, with small errors in measuring LVOT diameter potentially leading to an inaccurate diagnosis of low-gradient ‘severe’ AS.
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Clinical implications
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In patients with dPm
40 mmHg, AVA < 1.0 cm
2, and normal
LVEF determined by transthoracic echocardiography, every effort
should be made to distinguish patients with severe AS from those
with non-severe AS, and those with NF from those with low flow,
via echocardiography and other methods. When there is doubt,
the diameter of the LVOT should be re-checked on closer examination
because this measurement is critical for the calculation of
both AVA and SV. If the result is not definitive, a transoesophageal
echocardiographic (TEE) examination should be added
12 to assess
morphology and calcification of the aortic valve; planimetry
of the valve should be performed. The diameter of the LVOT should
be rechecked; if the result differs from the transthoracic echocardiographic
measure, the new value should be substituted into the continuity
equation. Thereby obtaining reliable anatomic and functional
AVA, definitive grading of the aortic stenosis is possible in
most cases. Additional testing may be required for some patients,
especially functional testing with exercise.
13–15
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Conclusions
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Low-gradient ‘severe’ AS (AVA < 1.0 cm
2, dPm
40 mmHg) with preserved LVEF is not a new clinical entity.
The term encompasses many patients with truly severe AS and
low SV with the serious prognosis associated with severe AS.
On the other hand, low-gradient ‘severe’ AS is found
in many patients with NF as a result of inconsistent cut-off
values for AVA and dPm; such disparities may support adjustment
of the AVA cut-off value, at least for echocardiographic measurements.
The prognosis of this latter group of patients is not well defined
and indications for surgery are less clear,
13,16 particularly
in the presence of non-specific symptoms. Although differentiation
of low-flow severe AS from NF non-severe AS may be crucial for
the management of an individual patient, differentiation by
transthoracic echocardiography may be difficult because of uncertainties
in determination of SV and, thereby, AVA. Using TEE may help
to differentiate these patients in part because this modality
enables a clear demonstration of morphology and performance
of planimetry of the anatomic AVA in most cases. Additional
testing may be required for some patients.
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Funding
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The symposium and theses proceedings were supported by an educational
grant from Merck/Schering-Plough.
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Acknowledgements
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Assistance in manuscript preparation was provided by Rete Biomedical
Communications Corp. (Ridgewood, NJ, USA).
Conflict of interest: Dr N.J. reports receiving lecture fees from Merck Sharp & Dohme.
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Abstract
Introduction