European Heart Journal Supplements (2008) 10 (Supplement E), E11–E15
doi:10.1093/eurheartj/sun016
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
KEYWORDS
Aortic valve stenosis;
Severity;
Grading;
Low-gradient;
Echocardiography
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 cm2). 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.
Introduction
In the management of patients with aortic valve stenosis
(AS), symptoms attributable to AS (syncope, angina, dyspnoea) determine which patients should undergo valve
* Corresponding author. Tel: þ49 7633 402 0; fax: þ49 7633 402 4409.
E-mail address: [email protected]
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 nonspecific 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
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.
For permissions please email: [email protected].
E12
N. Jander
Table 1 Guideline criteria for severe aortic stenosis
Aortic valve area (AVA)
Aortic mean pressure gradient (dPm)
Maximum aortic jet velocity
ACC/AHA2
ESC3
,1.0 cm2; ,0.6 cm2/m2 of body surface area
.40 mmHg
.4 m/s
,1.0 cm2; ,0.6 cm2/m2 of body surface area
50 mmHg
ACC/AHA, American College of Cardiology/American Heart Association; ESC, European Society of Cardiology.
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 nonspecific 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 leftventricular (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 cm2 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 cm2 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.
Inconsistent grading is frequent
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 cm2. From these, we
excluded studies showing dPm , 10 mmHg (n ¼ 1420),
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).
more than mild mitral or aortic regurgitation (n ¼
1019), peak flow velocity ,0.8 and .1.5 m/s in the LV
outflow tract (LVOT) (n ¼ 125), an LVOT diameter of
,15 mm (n ¼ 4), or incomplete data (n ¼ 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 nonsevere 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.
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 cm2 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.
Low-gradient severe AS with preserved EF
E13
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’.
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.
Inconsistent grading of severity may be
due to ‘paradoxical’ low flow
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 lowgradient severe AS (AVA 0.6 cm2/m2) and normal LVEF
(50%) were subdivided into a group with ‘normal flow
(NF),’ having stroke volume (SV) index (SVI) .35 mL
(n ¼ 331, 65%), and one with ‘paradoxical low flow
(PLF),’ having an SVI 35 mL (n ¼ 181, 35%).
Compared with patients having NF, those with PLF were
found to be older (73 + 13 vs. 69 + 14 years; P ¼ 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 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 ¼ 0.006;
P-value adjusted for age and gender ¼ 0.045); both
groups showed reduced survival with medical therapy
compared with surgery (Figure 2).
Before inferring from these results that every patient
with an AVA , 1.0 cm2 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
Inaccurate measurements may contribute
to inconsistent severity grading
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
Inconsistent grading also occurs with data
from catheterisation
Inconsistent grading of the severity of AS may occur using
data obtained from catheterisation as well as from echocardiography. Carabello11 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).
Inconsistent grading also occurs with
normal flow
As shown by the Carabello calculation,11 patients may
have severe AS according to an AVA criterion, but not a
E14
N. Jander
Clinical summary
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.
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 ¼ [cardiac output/(systolic ejection period heart rate)]/
p
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.
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 cm2/m2 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.
Inconsistent grading is more frequent with
echocardiography vs. catheterisation
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
Clinical implications
In patients with dPm 40 mmHg, AVA , 1.0 cm2, 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 added12 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
Conclusions
Low-gradient ‘severe’ AS (AVA , 1.0 cm2, 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
Low-gradient severe AS with preserved EF
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.
E15
4.
5.
Acknowledgements
6.
Assistance in manuscript preparation was provided by Rete Biomedical Communications Corp. (Ridgewood, NJ, USA).
7.
Conflict of interest: Dr N.J. reports receiving lecture fees from
Merck Sharp & Dohme.
8.
9.
Funding
The symposium and theses proceedings were supported by an
educational grant from Merck/Schering-Plough.
10.
References
11.
1. Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M,
Maurer G, Baumgartner H. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343:611–617.
2. Bonow RO, Carabello BA, Kanu C, de LA Jr, Faxon DP, Freed MD,
Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA,
Otto CM, Shah PM, Shanewise JS. ACC/AHA 2006 guidelines for the
management of patients with valvular heart disease: a report of
the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (writing committee to revise the
1998 Guidelines for the Management of Patients With Valvular
Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic
Surgeons. Circulation 2006;114:e84–e231.
3. Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G,
Flachskampf F, Hall R, Iung B, Kasprzak J, Nataf P, Tornos P,
Torracca L, Wenink A. Guidelines on the management of valvular
12.
13.
14.
15.
16.
heart disease: The Task Force on the Management of Valvular Heart
Disease of the European Society of Cardiology. Eur Heart J 2007;28:
230–268.
Minners J, Allgeier M, Gohlke-Baerwolf C, Kienzle RP, Neumann FJ,
Jander N. Inconsistencies of echocardiographic criteria for the
grading of aortic valve stenosis. Eur Heart J Advance Access published December 22, 2007.
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.
de Simone SG, Devereux RB, Celentano A, Roman MJ. Left ventricular
chamber and wall mechanics in the presence of concentric geometry.
J Hypertens 1999;17:1001–1006.
Weyman AE, Scherrer-Crosbie M. Aortic stenosis: physics and physiology–what do the numbers really mean? Rev Cardiovasc Med 2005;
6:23–32.
Gorlin R, Gorlin SG. Hydraulic formula for calculation of the area of
the stenotic mitral valve, other cardiac valves, and central circulatory shunts. Am Heart J 1951;4:1–29.
Doddamani S, Bello R, Friedman MA, Banerjee A, Bowers JH Jr, Kim B,
Vennalaqanti RR, Ostfeld RJ, Gordon GM, Malhotra D, Spevack DM.
Demonstration of left ventricular outflow tract eccentricity by real
time 3D echocardiography: implications for the determination of
aortic valve area. Echocardiography 2007;24:860–866.
Burgstahler C, Kunze M, Loffler C, Gawaz MP, Hombach V, Merkle N.
Assessment of left ventricular outflow tract geometry in non-stenotic
and stenotic aortic valves by cardiovascular magnetic resonance.
J Cardiovasc Magn Reson 2006;8:825–829.
Carabello BA. Clinical practice. Aortic stenosis. N Engl J Med 2002;
346:677–682.
Naqvi TZ, Siegel RJ. Aortic stenosis: the role of transesophageal
echocardiography. Echocardiography 1999;16:677–688.
Amato MC, Moffa PJ, Werner KE, Ramires JA. Treatment decision in
asymptomatic aortic valve stenosis: role of exercise testing. Heart
2001;86:381–386.
Lancellotti P, Lebois F, Simon M, Tombeux C, Chauvel C, Pierard LA.
Prognostic importance of quantitative exercise Doppler echocardiography in asymptomatic valvular aortic stenosis. Circulation 2005;
112(Suppl. 9):I377–I382.
Das P, Rimington H, Chambers J. Exercise testing to stratify risk in
aortic stenosis. Eur Heart J 2005;26:1309–1313.
Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL,
Kraft CD, Miyake-Hull CY, Schwaegler RH. Prospective study of asymptomatic valvular aortic stenosis: clinical, echocardiographic,
and exercise predictors of outcome. Circulation 1997;95:
2262–2270.