Download Low-Flow, Low-Gradient Aortic Stenosis With Preserved

Journal of the American College of Cardiology
© 2012 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Low-Flow, Low-Gradient
Aortic Stenosis With
Preserved Ejection Fraction
Still a Challenging Condition*
Helmut Baumgartner, MD
Muenster, Germany
Current practice of aortic stenosis assessment. Aortic
stenosis (AS) has become the most frequent valve disease
and has a very poor outcome when left untreated in
symptomatic patients. Because aortic valve replacement
can—in the best case—normalize survival, timely diagnosis
and correct quantification of AS are crucial (1). Current
practice guidelines recommend echocardiography as the
method of choice, whereas catheterization is only indicated
when echocardiography is non-diagnostic or discrepant
with clinical data (1,2). Nevertheless, echocardiography
remains markedly investigator-dependent in general daily
practice. Avoidance of basic sources of error such as velocity
underestimation by mal-alignment of Doppler beam and jet
or flow miscalculations requires special training and skills
that are frequently not present, considering the widespread
use of ultrasound. The primary hemodynamic parameters
recommended for assessment of AS severity are peak jet
See page 1259
velocity, mean gradient, and aortic valve area (AVA) calculated by the continuity equation (2). Although AVA being
less flow-dependent would theoretically be the best parameter, transvalvular velocity and gradient remain the morerobust and better reproducible measurements in daily practice. Because very small changes in AVA in the range
between 1.2 and 0.8 cm2 cause highly significant changes in
hemodynamic consequences from unremarkable to severe
flow obstruction, very accurate measurement techniques
would be required when characterizing stenosis severity
solely by AVA. However, such techniques are currently not
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Adult Congenital and Valvular Heart Disease Center, Department of
Cardiology and Angiology, University Hospital Muenster, Muenster, Germany. Dr.
Baumgartner has reported that he has no relationships relevant to the contents of this
paper to disclose.
Vol. 60, No. 14, 2012
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2011.12.053
available. Therefore, an integrated approach including AVA,
velocity/gradient, left ventricular (LV) function, flow status,
and clinical presentation is strongly recommended (1,2).
Although current guidelines define severe AS by a peak
velocity ⬎4 m/s, mean gradient ⬎40 mm Hg, and AVA
⬍1.0 cm2, many patients present with discrepant findings
with regard to these criteria (2). Most frequently patients
might have a small AVA (⬍1.0 cm2) but nevertheless lower
velocity (⬍4.0 m/s) and gradient (⬍30 to 40 mm Hg).
When measurement errors such as underestimation of left
ventricular outflow tract (LVOT) cross-section area, or
LVOT velocity that result in underestimation of flow and
eventually AVA are excluded and the patient is not of small
stature, “low flow conditions” due to poor LV function or
less commonly severe mitral regurgitation or mitral stenosis
must be considered (2). However, in this situation a small
AVA does not necessarily indicate severe AS. Left ventricular dysfunction of other cause might result in a severely
reduced AVA of a moderately diseased aortic valve, because
of insufficient energy to open the cusps resulting in “pseudosevere AS.” Although still controversial, dobutamine
response with either marked AVA increase or little AVA
change but gradient increase might help to separate pseudosevere from truly severe AS (3). Absence of contractile
reserve makes it impossible to distinguish between these
entities and predicts particularly poor long-term outcome
(4). Nevertheless, valve replacement might improve LV
function and outcome even in this subgroup and therefore
might be considered following current guidelines (IIb recommendation) (1,5).
The controversial new entity of “paradoxical low-flow,
low-gradient severe AS.” Since the group of Pibarot and
Dusmenil (6) published for the first time the new entity of
paradoxical low-flow, low-gradient (PLFLG) severe AS
despite preserved ejection fraction in 2007, assessment of
AS has become even more complicated. In this article,
Hachicha et al. (6) reported that patients with small AVA
and low gradient in the presence of preserved left ventricular
ejection fraction (LVEF) who were nevertheless found to
have low transvalvular flow (35% of 512 patients) might
indeed have severe AS and have a poor outcome if managed
medically. Although confirmed by others (7), this entity
remains controversial. Minners et al. (8) also reported, in a
series of 2,427 patients with AVA ⬍2.0 cm2 and preserved
LV function, that 30% of the patients had AVA ⬍1.0 cm2
but mean gradient ⬍40 mm Hg but suggested that this was
mainly caused by inconsistency of currently recommended
cutoffs for velocity/gradient and AVA. According to the
Gorlin equation in the presence of normal cardiac output,
an AVA of 1.0 cm2 yields indeed a mean gradient of only 26
mm Hg, and an AVA of ⱕ0.81 cm2 is required to reach
gradients of 40 mm Hg and greater (9). On the basis of such
findings, Jander (10) proposed to lower the AVA cutoff for
severe AS to 0.8 cm2 to make the criteria velocity/gradient
and AVA criteria consistent. Similarly, Zoghbi (11) re-
JACC Vol. 60, No. 14, 2012
October 2, 2012:1268–70
ported in an editorial that a review of 1,115 consecutive
patients with AS showed an appropriately corresponding
AVA cutoff close to 0.8 cm2 in patients with normal flow.
The position that low-gradient “severe” AS with preserved LVEF is mostly moderate AS that is just misclassified due to inconsistency of recommended criteria for AVA
and gradient seems to be supported by a recent study by
Jander et al. (12). In 1,525 patients included in the prospective SEAS (Simvastatin and Ezetimibe in Aortic Stenosis)
trial, the authors identified 184 with moderate AS and 435
with “low-gradient severe” AS (AVA ⬍1.0 cm2, mean
gradient ⱕ40 mm Hg). Outcome with regard to valverelated events, major cardiovascular events, or cardiac death
did not differ between these 2 groups. However, the series of
Hachicha and others (6,7) differed markedly from the
patient population of Jander (12). While the SEAS trial
followed asymptomatic low-risk patients with mild or moderate AS to study the effect of lipid lowering on the
progression of AS, the other studies included symptomatic
patients with older age and more comorbidities. In particular, most were hypertensive and had LV hypertrophy,
whereas normal wall thickness relative to LV size was
present in SEAS. Thus, in the study by Jander, measurement errors, small body size, and inconsistency of guideline
criteria are more likely to be a frequent reason for a low
gradient in the presence of a small AVA. In any case, this
study highlights that an uncritical, too-liberal use of “lowgradient severe AS“ might lead to surgical procedures in
patients who will not benefit. The study also demonstrates
once more the limitations of the continuity equation. The
use of the LVOT diameter with assumption of a circular
LVOT area frequently leads to an underestimation of this
area with consequent underestimation of the transvalvular
flow and thus the AVA. We have previously reported that
this error might lead to an underestimation of the AVA by,
on average, 0.2 cm2 (13). Stroke volumes calculated by
volumetric approach were indeed approximately 20% higher
than those calculated by Doppler in the study by Jander,
indicating that the percentage of low-flow conditions was
probably overestimated and that AVAs might frequently
have been underestimated.
New data to support the entity of PLFLG severe AS. In
this issue of the Journal, Clavel et al. (14) sought to further
elucidate the discrepancies between previous studies and to
confirm the concept of PLFLG severe AS. In this study,
187 patients with PLFLG severe AS were retrospectively
matched according to the gradient with 187 patients with
moderate AS and according to the AVA with 187 patients
with high-gradient severe AS. After adjustment for age, sex,
symptoms, coronary artery disease, diabetes, type of treatment, and LVEF, patients with PLFLG severe AS had a
1.88-fold increase in overall mortality and a 2.87-fold
increase in cardiovascular mortality compared with moderate AS, and aortic valve replacement was significantly
associated with improved survival (hazard ratio [HR]: 0.50).
The authors conclude that the finding of a low gradient
Baumgartner
Low-Gradient AS With Preserved EF
1269
cannot exclude the presence of severe AS in patients with
small AVA and preserved LVEF, that a more comprehensive diagnostic evaluation should be used to corroborate the
stenosis severity, and that aortic valve replacement might
improve outcome after confirmation of PLFLG severe AS.
This important study definitely adds to our current
knowledge of this challenging subgroup of AS patients.
Nevertheless, there remains a number of unresolved issues,
and the authors are wise by being rather careful with their
conclusions.
This retrospective analysis matched groups only by hemodynamic criteria. The PLFLG patients were significantly
older and had higher prevalence of female sex, coronary
artery disease, hypertension, and small LV cavities. Although adjustment for the aforementioned risk factors was
performed, relevant differences in their severity—particular
in the extent of hypertensive disease— cannot be excluded;
and important risk factors such as pulmonary, renal, or
peripheral arterial disease that have impact not only on
outcome but also on the decision for surgery were not
included. Thus, there remains some concern with regard to
confounding factors. It could still be that PLFLG patients—and, there again, those who did not undergo surgery—were just sicker with regard to comorbidities, compared with the other groups. Although surgery was
associated with improved survival in this group, the HR was
only 0.50 compared with 0.18 for high-gradient AS, indicating a smaller effect of surgery on survival. One explanation could be that these patients had too-advanced disease
or that they had more severe comorbidities uninfluenced by
valve replacement or even increasing operative risk. Finally,
it could be that only a subgroup of patients within the
PLFLG patients indeed had severe stenosis and thus benefit
from surgery. What is even more concerning when interpreting these results is that the HR of 0.50 in PLFLG AS
is close to that of 0.44 in moderate AS. Although the latter
just did not reach statistical significance (p ⫽ 0.09), the
former just reached significance (p ⫽ 0.04). Although the
numbers are close, the authors would probably not conclude
(even if both were significant) to operate on moderate AS.
For these reasons the results have to be interpreted with
caution and must be considered hypothesis-generating
rather than providing evidence.
It is also important to recognize that patients with
PLFLG AS in this study seem to be typically elderly
(predominantly women) with hypertension. Hypertension
might indeed be a key player in this context. Left ventricular
hypertrophy and increased fibrosis as they were reported in
another recent study (15) might be due to or at least be
heavily affected by long-lasting hypertension rather than
presenting more advanced stage of AS. The extent of
hypertensive disease might have influenced the presence of
symptoms as well as the observed outcome of these patients.
Overall, the study might conclude that the PLFLG severe
AS exists but cannot entirely solve the difficulty in selecting
those in this group who indeed have severe AS and
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Baumgartner
Low-Gradient AS With Preserved EF
eventually benefit from valve replacement. In this context, it
must be kept in mind that it remains totally unknown how
many patients in such a population might have pseudosevere
AS (see preceding text). Whether dobutamine echocardiography can also be helpful in this setting remains to be
shown. That we are dealing with small, stiff ventricles with
normal ejection fraction—in contrast to LFLG AS with
poor LVEF—makes that at least questionable.
How to deal currently with “PLFLG severe AS.” The
subset of AS patients who present with a small AVA but
low gradient despite preserved LVEF remains definitely
challenging. Although such patients might indeed have
severe AS, other reasons for this combination such as
underestimation of transaortic flow by Doppler echocardiography, inconsistency of grading criteria, and small body
size must be carefully excluded. This might require—in
addition to more detailed echocardiographic measurements—additional diagnostic tools such as magnetic resonance imaging and catheterization. Because such patients
are typically elderly with hypertension and other comorbidities, the evaluation remains difficult even after confirmation
of hemodynamic data. Left ventricular hypertrophy and
fibrosis as well as symptoms or elevation of neurohormones
might also be due to hypertensive heart disease and not help
to re-assure severe AS. Furthermore, it remains unclear how
to exclude pseudosevere AS, and the severity of valve
calcification might currently be the only clue in this context
(16). Thus, PLFLG AS is associated with poor outcome in
patients with the characteristics of the presented study
population. How to select those patients who definitely have
severe AS and who are most likely to benefit from surgery,
however, still needs to be better defined.
Reprint requests and correspondence: Prof. Helmut Baumgartner, Adult Congenital and Valvular Heart Disease Center, Department of Cardiology and Angiology, University Hospital
Muenster, Albert-Schweitzer-Campus 1, 46149 Muenster, Germany. E-mail: [email protected].
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Key Words: aortic stenosis y aortic valve replacement y
Doppler-echocardiography.