-
Low-Gradient, Low-Flow Severer
AnSa
HR: 0.29; 95% CI: 0.18 to 0.46) and was not observed for LG/LF
aortic stenosis (adjusted HR: 0.75; 95% CI: 0.14 to 4.05).
CONCLUSIONS In this study, the outcome of severe LG/LF aortic
stenosis with preserved EF was similar to that of mild-
lower7). Be-urfaceopplerstroke
J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D
I O L O G Y V O L . 6 5 , N O . 1 , 2 0 1 5
2 0 1 5 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L
O G Y F O U N DA T I O N I S S N 0 7 3 5 - 1 0 9 7 / $ 3 6 . 0
0
P U B L I S H E D B Y E L S E V I E R I N C . h t t p : / / d x
. d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 4 . 0 9 . 0 8
0A variable proportion of patients with aorticstenosis and
preserved (>50%) left ventricu-lar ejection fraction (EF) that
are classiedas severe by echocardiography (aortic valve
area[AVA]
-
with pejorative outcome has been questioned by a
severe fand incMoreovneeds topotentia
The bexperienphy labLille) beysis areLG/LF anical maaortic
saortic sAVR in
METHO
STUDY
age dia
ABBR EV I A T I ON S
AND ACRONYMS
AVA = aortic valve area
AVR = aortic valve
replacement
CAD = coronary artery dis
EF = ejection fraction
HG = high-gradient
LG/LF = low-gradient/
low-ow
LG/NF = low-gradient/
normal-ow
MDG = mean Doppler grad
SV = stroke volume
Tribouilloy et
Low-Gradien
56enosis with preserved EF truly represents aorm of aortic
stenosis with poor prognosisreased risk of death when treated
medically.er, the impact of AVR in LG/LF aortic stenosisbe better
dened to avoid unnecessary andlly dangerous procedures.asis for the
present study is the consecutivece with aortic stenosis at the
echocardiogra-
oratories of 2-F tertiary centers (Amiens andtween 2000 and
2012. The aims of this anal-3-fold: 1) to establish the relation
betweenortic stenosis and outcome, regardless of cli-nagement; 2)
to compare the outcomes of LGtenosis, HG aortic stenosis, and
moderatetenosis; and 3) to understand the impact ofthese subsets of
patients.subanalysis of the SEAS (Simvastatin and Ezetimibein
Aortic Stenosis) trial (14) and by a recent single-center European
cohort study (15). Consistently,magnetic resonance data in LG
aortic stenosis showlarger AVAs, less hypertrophy, and similar
focalbrosis compared with HG aortic stenosis (16). Theserecent
results raise doubts about whether LG/LFaortic stvolume (SV) index,
despite a normal EF (par-adoxical low-ow) (8,9). Patients with
low-gradient/low-ow (LG/LF) aortic stenosishave been reported to
have small ventricularcavities (3,8), severe concentric
hypertrophy(3,8), increased afterload (10,11),
restrictivephysiology (8), subtle systolic dysfunction(12), and
increased subendocardial myocar-dial brosis (13). These features
have beeninterpreted as markers of a more advanceddisease, leading
to poor prognosis underconservative therapy. Survival analyses
oflimited patient numbers suggest that LG/LFaortic stenosis is
associated with greater mor-tality risk than high-gradient (HG)
severe
aortic stenosis (35,7,8), and that surgery might bebenecial in
this subset of patients. Therefore, guide-lines recommend (class
IIa recommendation) aorticvalve replacement (AVR) in symptomatic
patientswith LG/LF aortic stenosis when documentedvalvular
obstruction is the most probable cause ofsymptoms (2).
The view that LG/LF aortic stenosis with preservedEF represents
a more advanced form of the disease
SEE PAGE 67
ease
ient
al.
t, Low-Flow Severe Aortic Stenosis With Normal EFDS
DESIGN. Consecutive patients $18 years ofgnosed with mild or
more than mild aorticstenosis (aortic valve calcication with
reductionin systolic movements and AVA
-
ouilloy et al.
h Normal EF
57of linear measurements and indexed for bodysurface
area.CLINICAL DECISION AND FOLLOW-UP. After initialmedical
management, treatment was either conser-vative or surgical, as
deemed appropriate by thepatients personal physician. The majority
of pa-tients were followed by clinical consultation
andechocardiography in the outpatient clinics of the 2tertiary
centers. Others were followed in publichospitals or private
practices by referring cardiolo-gists working with the tertiary
centers. Informationon follow-up was retrospectively obtained by
directpatient interview or by repeated follow-up lettersand
questionnaires. Median follow-up with medicalmanagement was 22.8
months (range: 7 to 53 months).Median overall follow-up was 39.0
months (range:11 to 69 months). The endpoint of the study
wasoverall survival after diagnosis starting at
baselineechocardiography; the endpoint was analyzed undermedical
management, and under medical and surgicalmanagement.STATISTICAL
ANALYSIS. Continuous variables wereexpressed as mean 1 SD or
medians and inter-quartile ranges, and categorical variables
weresummarized as numbers and frequency percentages.The
relationship between baseline continuousbaseline variables and the
4 groups was exploredusing 1-way analysis of variance (for
normallydistributed variables) or Kruskal-Wallis tests
(fornon-normally distributed variables). Pearsons chi-square
statistic or Fishers exact test were used toexamine the association
between the 4 groups andbaseline categorical variables. The
signicance be-tween mild-to-moderate aortic stenosis
(referentgroup) and the other groups was examined if therewas a
signicant difference across categories. Indi-vidual differences
were compared with Mann-Whitney U tests (with Bonferroni correction
formultiple comparisons) and Tukey tests for normallydistributed
data.
For analysis of outcomes under medical manage-ment, data were
censored at the time of cardiac sur-gery (if performed). The entire
follow-up was used toanalyze outcomes under conservative and
surgicaltreatments. The effect of surgery on outcome wasanalyzed as
a time-dependent covariate using theentire follow-up (18). Survival
rates 1 SE of the 4groups were estimated according to the
Kaplan-Meiermethod and compared with 2-sided log-rank
tests.Multivariable analyses of all-cause mortality were
J A C C V O L . 6 5 , N O . 1 , 2 0 1 5
J A N U A R Y 6 / 1 3 , 2 0 1 5 : 5 5 6 6performed using Cox
proportional hazards models.The risk of death in the 3 severe
aortic stenosis groups(LG/LF aortic stenosis, LG/NF aortic
stenosis, and HGaortic stenosis) was estimated versus the
referentgroup. We did not use model-building techniques,and entered
covariates were considered of potentialprognostic impact on an
epidemiological basis in themodels. These covariates were age, sex,
body surfacearea, the comorbidity index, symptoms at baseline,CAD,
history of atrial brillation, and EF. The pro-portional hazards
assumption was conrmed usingstatistics and graphs on the basis of
Schoenfeldresiduals. All p values were results of 2-tailed
tests.Data were analyzed with SPSS version 13.0 (SPSS Inc.,Chicago,
Illinois) and STATA (version 12, StataCorpLP, College Station,
Texas). The authors had fullaccess to the data and take
responsibility for itsintegrity. All authors read and agreed to
this paper aswritten.
RESULTS
BASELINE CHARACTERISTICS. The baseline de-mographic and clinical
characteristics of the 809 pa-tients with aortic stenosis are
displayed in Table 1.Patients with LG aortic stenosis were older
than thosewith mild-to-moderate aortic stenosis, were moreoften
women, and had lower body surface areas(Table 1). The proportion of
patients with New YorkHeart Association functional class III or IV
symptomsat baseline was comparable between LG/LF aorticstenosis and
moderate aortic stenosis. The comor-bidity index was higher in
LF/LG aortic stenosispatients compared with mild-to-moderate
aorticstenosis patients, and lower in HG aortic stenosispatients
(Table 1).
Baseline echocardiography data are summarizedin Table 2.
Compared with mild-to-moderate aorticstenosis, patients with LG/LF
aortic stenosis hadhigher MDG and peak aortic velocity, and
smallerSV, and less cardiac output. Left ventricular masswas
comparable between LG/LF aortic stenosisand mild-to-moderate aortic
stenosis (Table 2). HGaortic stenosis was associated with a
signicantlygreater degree of ventricular hypertrophy than
mild-to-moderate aortic stenosis (Table 2).
Outcome under medica l management . In 588 pa-tients (73%),
management was solely medical. Eightyseven percent of LG/LF aortic
stenosis patients pre-senting with symptoms at baseline were
treatedmedically. Overall, crude 4-year mortality with med-ical
management was similar for the 4 study groups:28 3% for
mild-to-moderate aortic stenosis, 34 8%for LG/LF aortic stenosis,
29 7% for LG/NF aortic
Trib
Low-Gradient, Low-Flow Severe Aortic Stenosis Witstenosis, and
31 5% for HG aortic stenosis(Figure 1A).
On multivariable analysis (Table 3, Figure 2A),comparedwith the
reference category (mild-to-moderate
-
TABLE 1 Baseline De h
L
Demographics, baseline
Age, yrs 5
Male *
Body surface area, m .8
Systolic blood pressu 0
NYHA functional clas 9
NYHA functional clas
I 5
II 3
III 8
IV 1
Medical history and ris
Hypertension 0
Smoking 4
Dyslipidemia 6
Diabetes mellitus 0
Coronary artery dise 2
History of atrial bri 2
Charlson comorbidity 0
Values are median (interqu
AS aortic stenosis; HG
Tribouilloy et
Low-Gradien
58mographic and Clinical Characteristics of the 4 Groups of
Patients Wit
All Patients(N 809)
Moderate AS(n 420)
, data and symptoms
77.4 (69.383.5) 76.9 (67.483.2) 78.
428 (53.0) 249 (59.3) 242 1.90 0.23 1.94 0.22 1re, mm Hg 140.0
(125.0150.0) 140.0 (125.0150.0) 140.
s IIIIV symptoms 128 (15.8) 59 (14.0)
s
360 (44.5) 196 (46.7) 2
321 (39.7) 165 (39.3) 2
99 (12.2) 46 (11.0)
29 (3.6) 13 (3.1)
k factors
583 (72.1) 316 (75.2) 4
225 (27.8) 126 (30.0) 1
343 (42.4) 186 (44.3) 1
243 (30.0) 138 (32.9) 2
ase 265 (32.8) 126 (30.0) 2
llation 266 (32.9) 146 (34.8) 2
index 2.0 (1.03.0) 2.0 (1.04.0) 2.
al.
t, Low-Flow Severe Aortic Stenosis With Normal EFaortic
stenosis), the 2 LG groups did not exhibit excessmortality risk
with medical treatment (adjusted hazardratio [HR]: 0.88; 95%
condence interval [CI]: 0.53 to1.48 for LG/LF aortic stenosis vs.
mild-to-moderateaortic stenosis, and adjusted HR: 1.06; 95% CI:
0.66to 1.71 for LG/NF aortic stenosis vs. mild-to-moderateaortic
stenosis). In contrast, HG aortic stenosis pa-tients were at higher
risk of death than those withmild-to-moderate aortic stenosis
(adjusted HR: 1.47;95% CI: 1.03 to 2.07). When only patients
withoutsymptoms at baseline were considered, the samemortality risk
pattern was observed: patients withmild-to-moderate aortic
stenosis, LG/LF aortic stenosis,and LG/NF aortic stenosis had
comparable risks ofdeath (adjusted HR: 0.89; 95% CI: 0.53 to 1.49
forLG/LF aortic stenosis vs. mild-to-moderate aorticstenosis, and
adjusted HR: 1.06; 95% CI: 0.66 to 1.70for LG/NF aortic stenosis
vs. mild-to-moderate aorticstenosis). HG aortic stenosis patients
were at signi-cantly higher risk of death than patients with
mild-to-moderate aortic stenosis (adjusted HR: 1.44; 95% CI:1.02 to
2.04). Among symptomatic patients, patientswith HG aortic stenosis
had excess mortality undermedical management compared with
mild-to-moderateaortic stenosis (adjusted HR: 1.58; 95% CI: 1.02
to2.48), whereas patients with LF/LG aortic stenosis and
artile range), n (%), or mean 1 SD. *p < 0.05 individual
category versus moderate AS. high-gradient; LF low-ow; LG
low-gradient; LV left ventricular; NF normal-Aortic Stenosis
Group
p ValueG/LF AS(n 57)
LG/NF AS(n 85)
HG AS(n 247)
(73.586.3)* 79.3 (73.983.9)* 76.9 (67.983.1) 0.009
(42.1) 33* (38.8) 122 (49.4) 0.001
6 0.21* 1.78 0.23 1.88 0.24
-
sp ValueAS247)
1 60.8)
-
FIGUREAl
l-cau
se M
orta
lity
(%)
Patients at rHG ASLG/NF AS
LG/LF AS
Mild tomoderate A
A
d-
(A) Med
AS ao
Tribouilloy et
Low-Gradien
601 Kaplan-Meier Mortality Curves of the 4 Groups of AS
Patients
0.4
0.3
0.2
0.1
0.00 10 20 30 40 50
Follow-up (Months)
348%315%297%283%
overall p value 0.72
BHG AS LG/NF AS Mil
al.
t, Low-Flow Severe Aortic Stenosis With Normal EFtotal study
population was important (adjusted HR:0.49; 95% CI: 0.35 to 0.68).
Figure 3 depicts theoverall benet of surgery in patients with
severeaortic stenosis. On multivariable analysis, there was
asignicant interaction between the aortic stenosisgroup
classication and the magnitude of survivalbenet after surgery (p
for interaction 0.022). Thebenet associated with AVR was conned to
the HGaortic stenosis group and was not signicant in theother
groups (Figure 4).
DISCUSSION
Our analysis of a large cohort of aortic stenosis pa-tients with
long-term follow-up puts into perspectivethe various ow-gradient
patterns with regard tonatural history and management.
Mild-to-moderateaortic stenosis, LG aortic stenosis, and HG aortic
ste-nosis display comparable long-term crude mortalitywith
conservative therapy, as well as with medicaland surgical
management. After taking age, comor-bidity, and other factors with
prognostic implica-tions into account, LG/LF aortic stenosis has a
rather
isk
S
PatiHG ALG/N
LG/L
Mildmo
24785 52 42 37 31 22
57 37 32 28 20 15
420 317
131 87
266 238 192 152
66 46 36
ical management. (B) Medical and surgical management.
rtic stenosis; HG high-gradient; LF low-ow; LG low-gradient; NF
0.4
0.3
0.2
0.1
0.00 10 20 30 40 50
Follow-up (Months)
All-c
ause
Mor
talit
y (%
)
357%
293%296%282%
overall p value 0.57
LG/LF ASto-moderate AS
J A C C V O L . 6 5 , N O . 1 , 2 0 1 5
J A N U A R Y 6 / 1 3 , 2 0 1 5 : 5 5 6 6benign outcome under
medical management, despitethe symptomatic status. The natural
history of LG/LFaortic stenosis appears similar to that of
moderateaortic stenosis (Central Illustration). In contrast,
re-gardless of management, HG aortic stenosis showsexcess mortality
compared with mild-to-moderateaortic stenosis. Finally, AVR is
associated with im-proved outcome in HG aortic stenosis, but itdoes
not signicantly affect mortality in LG aorticstenosis.
The entity of paradoxical LG/LF aortic stenosisdespite preserved
EF was rst described in 2007 (3).LG/LF aortic stenosis is diagnosed
in patients pre-senting with an AVA of
-
ouilloy et al.
h Normal EF
61TABLE 3 Relative Risk of All-Cause Mortality in Patients
With
Severe Aortic Stenosis (LG/LF, LG/NF, and HG) Compared With
Moderate Aortic Stenosis
Multivariable Model HR (95% CI) p Value
All-Cause Mortality With Medical Management
Model 1
Moderate AS Referent
LG/LF AS 0.88 (0.531.47) 0.63
LG/NF AS 1.06 (0.671.70) 0.79
HG AS 1.41 (1.011.99) 0.04
Model 2
Moderate AS Referent
LG/LF AS 0.88 (0.531.48) 0.65
LG/NF AS 1.06 (0.661.71) 0.81
HG AS 1.47 (1.032.07) 0.032
All-Cause Mortality With Medical and Surgical Management*
Model 1
Moderate AS Referent
J A C C V O L . 6 5 , N O . 1 , 2 0 1 5
J A N U A R Y 6 / 1 3 , 2 0 1 5 : 5 5 6 6small cavity size,
impaired ventricular lling, and anincreased global hemodynamic load
(3,4,8,10). ForDumesnil et al. (8,21), LG/LF aortic stenosis
repre-sents the most advanced stage of aortic stenosis
withpreserved EF. Nevertheless, more advanced diseaseat
presentation does not necessarily imply a temporalrelationship, for
example, that HG aortic stenosisprogresses to LG/LF aortic
stenosis. Subsequently,severe LG aortic stenosis was frequently
observedamong patients with a preserved EF and NF (SVindex $35
ml/min) and was interpreted mainly inrelation to measurement errors
or inconsistencies inthe guidelines criteria (6,20). A new 4-group
classi-cation of aortic stenosis according to MDG and owcriteria
was proposed in 2010 (8).
The prognosis of LG/LF aortic stenosis is thesubject of an
ongoing debate. Several studies haveshown that patients with LG/LF
aortic stenosis havea pejorative survival compared with both
moderateaortic stenosis and HG aortic stenosis (35,7,22).Among 150
asymptomatic patients with severeaortic stenosis, LF/LG was
identied as independent
LG/LF AS 0.95 (0.591.52) 0.83
LG/NF AS 1.09 (0.711.66) 0.69
HG AS 1.69 (1.242.30) 0.001
Model 2
Moderate AS Referent
LG/LF AS 0.96 (0.581.53) 0.82
LG/NF AS 1.07 (0.691.65) 0.75
HG AS 1.74 (1.272.39) 0.001
Model 1 is adjusted for age and Charlson comorbidity index.
Model 2 is adjusted forage, gender, Charlson comorbidity index,
symptoms, coronary artery disease,history of atrial brillation,
left ventricular ejection fraction, and body surface area.*Analysis
of mortality with medical and surgical management also includes
surgeryas a time-dependent covariate.
CI condence interval; HR hazard ratio; other abbreviations as in
Table 1.determinant of reduced event-free survival (4).Clavel et
al. (5) used retrospective matching tocompare the outcomes of LG/LF
aortic stenosis,moderate aortic stenosis, and HG aortic stenosis,
andreported a 1.71-fold increase in the adjusted risk ofall-cause
death and a 2.09-fold increase in theadjusted risk of
cardiovascular death for LG/LFaortic stenosis compared with a
pooled population ofmoderate aortic stenosis and HG aortic
stenosis.Ozkan et al. (22) reported a 53% mortality rate
forsymptomatic LG aortic stenosis patients who weremanaged
medically, with similar outcomes for pa-tients with LG/LF aortic
stenosis and LG/NF aorticstenosis who were under medical therapy.
Inthis series, the outcome of LG aortic stenosissignicantly
improved with AVR (22). Finally, Eleidet al. (7) showed that the
LG/LF pattern signicantlyincreased the risk of death, whereas AVR
had amarkedly protective effect.
This perspective was questioned by a report fromthe SEAS trial
that compared the long-term outcomeof 2 asymptomatic subsets of
aortic stenosis patients:184 patients with moderate aortic stenosis
and 435patients with LG severe aortic stenosis (14). Out-comes,
with regard to valve-related events, majorcardiovascular events, or
cardiac death during long-term follow-up, did not signicantly
differ betweenthe 2 groups (14). Both groups had better
prognosesthan patients with HG aortic stenosis. This report (14)was
criticized for analyzing a low-risk populationthat did not display
typical features of LG/LF aorticstenosis, and was considered awed
by measurementerrors, use of nonindexed AVA, and inconsistency
ofguideline criteria (21). Despite these arguments, webelieve that
these randomized trial data are notbiased by confounding factors,
such as poor func-tional status, symptoms and comorbidities,
whichplay a major role when discussing surgery for LG/LSsevere
aortic stenosis. Recently, in a cohort of pa-tients with severe
aortic stenosis and preserved EF,Maes et al. reported better
outcomes under medicalmanagement for patients with LG aortic
stenosiscompared with patients with HG stenosis, andobserved that
>80% of patients with LG aortic ste-nosis exhibited signicant
increases in MDG duringfollow-up (15).
Our results showed that the long-term outcomeof the LG/LF
pattern is similar to that of mild-to-moderate aortic stenosis,
regardless of the manage-ment type and symptomatic status;
therefore, LG/LF
Trib
Low-Gradient, Low-Flow Severe Aortic Stenosis Witaortic stenosis
does not represent a more advancedstage of the disease. This result
should be interpretedwith some important considerations kept in
mind.First, we separated LG aortic stenosis into LG/LF and
-
FIGURE 2 Adjusted Mortality Curves for the 4 Groups of AS
Patient
HG AS LG/NF AS
0.5
0.4
0.3
0.2
0.1
0.00 10 20 30 40 50
HG vs. Mild-to-moderate ASLG/NF vs. Mild-to-moderate ASLG/LF vs.
Mild-to-moderate AS
p = 0.032p = nsp = ns
Adju
sted
All-
caus
e M
orta
lity
(%)
Follow-up (Months)
A BMedical management
Adjusted for age, sex, body surface area, comorbidity, symptoms,
corona
management. (B) Medical and surgical management. Abbreviations
as in
Tribouilloy et al.
Low-Gradient, Low-Flow Severe Aortic Stenosis With Normal EF
62LG/NF aortic stenosis, included the indexed AVA todene severe
LG/LF aortic stenosis, calculated the
index SV according to guideline criteria (1,2), andin survival
analyses, we systematically took body
FIGURE 3 Comparison Between Adjusted Mortality Curves of
Patients With Severe AS With Surgical (AVR) Versus
Medical Management
0.0
0.2
0.4
0.6
0.8
0 10 20 30 40 50Follow-up (Months)
Adju
sted
All-
caus
e M
orta
lity
(%)
Adjusted HR 0.36 (0.24-0.55), p < 0.001
Aortic valve replacement
Medical therapy
Adjusted for age, sex, body surface area, comorbidity,
symptoms,
coronary artery disease, atrial brillation, and ejection
fraction.
AVR aortic valve replacement; HR hazard ratio;
otherabbreviations as in Figure 1.surface area into account.
Second, we aimed toinvestigate the natural history of LG/LF aortic
steno-
s
LG/LF ASMild-to-moderate AS
0 10 20 30 40 50
0.5
0.4
0.3
0.2
0.1
0.0
HG vs. Mild-to-moderate ASLG/NF vs. Mild-to-moderate ASLG/LF vs.
Mild-to-moderate AS
p = 0.001p = nsp = ns
Adju
sted
All-
caus
e M
orta
lity
(%)
Follow-up (Months)
Medical and surgical management
ry artery disease, atrial brillation, and ejection fraction. (A)
Medical
Figure 1.
J A C C V O L . 6 5 , N O . 1 , 2 0 1 5
J A N U A R Y 6 / 1 3 , 2 0 1 5 : 5 5 6 6sis by allowing a
medical management period of atleast 3 months after diagnosis (15).
In our opinion,this approach reduced surgery-related biases
byeliminating patients with severe aortic stenosis who,because of
severe symptoms, were operated onimmediately after diagnosis.
Third, older retrospec-tive series of LG/LF aortic stenosis did not
reportthe symptomatic status of the patients (3), whereasmore
recent series included either asymptomatic in-dividuals (4,14) or
patients with severe symptoms(22). Our study included the entire
symptomaticspectrum of aortic stenosis, and the similar outcomesfor
LG/LF aortic stenosis and mild-to-moderate aorticstenosis observed
in the overall population wereconrmed in the subgroup of patients
who wereasymptomatic at baseline. Fourth, in contrast toprevious
studies that used composite endpoints(4,14), our study focused on
all-cause death andanalyzed AVR with a time-dependent
methodology.We believe that AVR is not an appropriate endpoint
inthis type of analysis, because it is mainly the result ofthe
physicians assessment of the severity of thedisease. For all
survival analyses, we took into ac-count age and comorbidities that
signicantlyaffected outcome and played major roles in the de-cision
for surgery. Finally, aortic stenosis severitymight be
underestimated when the right parasternalwindow is not used for
recording the continuous
-
oem
B
ouilloy et al.
h Normal EF
63FIGURE 4 Comparison Between Adjusted Mortality Curves of
Each
Medical Management
0.6
0.8
ality
(%)
Adjusted HR 0.66 (0.36-1.22), p = 0.19
Aortic valve replac
A
J A C C V O L . 6 5 , N O . 1 , 2 0 1 5
J A N U A R Y 6 / 1 3 , 2 0 1 5 : 5 5 6 6Doppler ow across the
aortic valve. On the otherhand, underestimation of the diameter of
the leftventricular outow tract might lead to an over-estimation of
the severity of the disease (20). In ourstudy, we systemically
performed careful measure-ments of the outow tract diameter in
zoomed para-sternal views and multiple acoustic windows
forcontinuous-wave Doppler, including the right para-sternal
window. Nevertheless, despite rigorousechocardiographic evaluation
and use of currentlyaccepted denitions for LG/LF severe aortic
stenosis,inherent errors in measurement might have led tosome
misclassication of mild-to-moderate aorticstenosis into LG/LF
severe aortic stenosis.
0.0
0.2
0.4
0.0
0.2
0.4
0.6
0.8
0 10 20 30 40 50
0 10 20 30 40 50
Adju
sted
All-
caus
e M
ort
Follow-up (Months)
Follow-up (Months)
Adju
sted
All-
caus
e M
orta
lity
(%)
Adjusted HR 0.55 (0.16-1.89), p = 0.34
C D
Adjusted for age, sex, body surface area, comorbidity, symptoms,
corona
AS. (B) LG/LF AS. (C) LG/NF AS. (D) HG AS. Abbreviations as in
Figuresf the 4 Groups of AS Patients With Surgical (AVR) Versus
0.6
0.8
talit
y (%
)
Adjusted HR 0.75 (0.14-4.05), p = 0.74
ent Medical therapy
Trib
Low-Gradient, Low-Flow Severe Aortic Stenosis WitOur survival
data were in accordance with recentanatomical and morphological
data (16,23,24). In apopulation of patients with severe aortic
stenosis andpreserved EFs, magnetic resonance imaging showedlarger
AVAs, a lower degree of ventricular hypertro-phy, and similar focal
brosis in the LG/LF subgroupcompared with the HG aortic stenosis
subgroup (15).Moreover, compared with HG aortic stenosis, theaortic
valves of patients with LG/LF aortic stenosishad lower weights (23)
and showed less severe calci-cation (24).
With regard to surgery, previous series (5,7,14)suggested that
LG/LF aortic stenosis has a pejorativeprognosis when treated
conservatively, and that AVR
0.0
0.2
0.4
0.0
0.2
0.4
0.6
0.8
0 10 20 30 40 50
0 10 20 30 40 50
Follow-up (Months)
Follow-up (Months)
Adju
sted
All-
caus
e M
orta
lity
(%)
Adju
sted
All-
caus
e M
or
Adjusted HR 0.29 (0.18-0.46), p < 0.001
ry artery disease, atrial brillation, and ejection fraction.
(A)Moderate
1 and 3.
-
ren
Tribouilloy et
Low-Gradien
64CENTRAL ILLUSTRATION Long-Term Outcome of Low-GHigh-Gradient
Aortic Stenosis Under Medical Managem
al.
t, Low-Flow Severe Aortic Stenosis With Normal EFsignicantly
improves the outcome. In our series,although AVR was associated
overall with markedmortality reduction in the population with
severeaortic stenosis, we did not observe any signicantbenecial
effect in the subset with LG/LF aorticstenosis.STRENGTHS AND
LIMITATIONS. Our study had theinherent limitations of retrospective
analyses. How-ever, cardiologists with expertise in valvular
diseaseperformed diagnosis and follow-up, and surgicaldecisions
were made by the heart team with theapproval of the patients
physicians, in accordancewith current practice guidelines. The
specic in-dications for surgery during follow-up were notcollected
in our database. Our study was not aprevalence study, because
patients were recruitedat the echocardiography laboratory, and we
excludedpatients who were operated on during the rst3 months after
diagnosis. We acknowledge that the
Under medical management, the outcome for low-gradient/low-ow
ao
moderate aortic stenosis and poorer compared with high-gradient
aortiadient Aortic Stenosis, Moderate Aortic Stenosis, andt
J A C C V O L . 6 5 , N O . 1 , 2 0 1 5
J A N U A R Y 6 / 1 3 , 2 0 1 5 : 5 5 6 6relatively small number
of patients with LF/LG aorticstenosis represented a limitation, and
that the rela-tionship between surgery and outcome in the
LGsubgroups should be interpreted with caution. Themultivariable
model that investigated the effect ofsurgery in LG/LF aortic
stenosis might be overtted,and the result should be viewed as
exploratory.Further studies with larger numbers of LG/LF
aorticstenosis patients are needed to denitively establishthe
impact of surgery in LG/LF aortic stenosis.Censoring the patients
who were initially managedconservatively at the time of surgery did
not accountfor the benet and/or risk of waiting. Despite
system-atic adjustment for CAD in multivariable analyses,CAD
severity and revascularization status might in-crease the
heterogeneity of the population and affectoutcomes. Finally, this
study did not use hemody-namic parameters, which might have allowed
moreprecise classication of the ow-gradient patterns.
rtic stenosis with preserved ejection fraction is similar to
that of
c stenosis.
-
isthvssrteneistsamdcao
S
u, D8y
m Coll Cardiol 2012;59:
JG, Capoulade R, et al.h aortic stenosis, small, low-gradient
despiter ejection fraction. J Am967.
Gohlke-Baerwolf C, et al.aortic valve stenosis byodynamic
studies innormal left ventricular:14638.
chelena HI, et al. Flow-re aortic stenosis with pre-clinical
characteristics andculation 2013;128:17819.
P,grdd9
G.osrd
11. Lancellotti P, Donal E, Magne J, et al. Impact ofglobal left
ventricular afterload on left ventricularfunction in asymptomatic
severe aortic stenosis: atwo-dimensional speckle-tracking study.
Eur JEchocardiogr 2010;11:53743.
12. Adda J, Mielot C, Giorgi R, et al. Low-ow,low-gradient
severe aortic stenosis despite normalejection fraction is
associated with severe leftventricular dysfunction as assessed by
speckle-tracking echocardiography: a multicenter study.Circ
Cardiovasc Img 2012;5:2735.
13. Herrmann S, Strk S, Niemann M, et al. Low-gradient aortic
valve stenosis myocardial brosisand its inuence on function and
outcome. J AmColl Cardiol 2011;58:40212.
14. Jander N, Minners J, Holme I, et al. Outcome
S
I e of
/ EF is
o tic
I tom-
F fol-
n ions,
t p.
eded
ere
aortic stenosis with preserved EF and whether the natural
history
and approach to management vary for patients on the basis of
specic ow-gradient patterns associated with valvular aortic
stenosis.
ouilloy et al.
Lo h Normal EF
65intense debate about the indication for AVR in pa-tients with
LG/LF aortic stenosis with preserved EF,the natural history and the
impact of AVR in LG/LFaortic stenosis deserve future, carefully
designed,large, prospective studies.
RE F E RENCE S
1. Bonow RO, Carabello BA, Chatterjee K, et al.ACC/AHA 2006
guidelines for the managementof patients with valvular heart
disease: a reportof the American College of
Cardiology/AmericanHeart Association Task Force on Practice
Guide-lines (Writing Committee to Revise the 1998guidelines for the
management of patients withvalvular heart disease) developed in
collabora-tion with the Society of Cardiovascular
Anes-thesiologists endorsed by the Society forCardiovascular
Angiography and the Society ofThoracic Surgeons. J Am Coll Cardiol
2006;48:e1148.
2. Joint Task Force on the Management ofValvular Heart Disease
of the European Soci-ety of Cardiology (ESC); European
Associationfor Cardio-Thoracic Surgery (EACTS),Vahanian A, Aleri O,
Andreotti F, et al.Guidelines on the management of valvularheart
disease (version 2012). Eur Heart J2012;33:245196.
3. Hachicha Z, Dumesnil JG, Bogaty P, et al.Paradoxical low-ow,
low-gradient severeaortic stenosis despite preserved
ejectionfraction is associated with higher afterload and
grading classication. J A23543.
5. Clavel MA, DumesnilOutcome of patients witvalve area, and
low-owpreserved left ventriculaColl Cardiol 2012;60:125
6. Minners J, Allgeier M,Inconsistent grading ofcurrent
guidelines: haempatients with apparentlyfunction. Heart 2010;96
7. Eleid MF, Sorajja P, Migradient patterns in seveserved
ejection fraction:predictors of survival. Cir
8. Dumesnil JG, Pibarotcal low ow and/or lowstenosis despite
preservefraction: implications forEur Heart J 2010;31:281
9. Pibarot P, Dumesnil Jlow-gradient aortic stenthe puzzle. J Am
Coll Careduced survival. Circulation 2007;115:285664.
4. Lancellotti P, Magne J, Donal E, et al. Clinicaloutcome in
asymptomatic severe aortic stenosis:insights from the new proposed
aortic stenosis
10. Cramariuc D, Ciof G,ow aortic stenosis in
asymvalvular-arterial impedancfrom the SEAS Substudy.
J2009;2:3909.Carabello B. Paradoxi-adient severe aorticleft
ventricular ejectioniagnosis and treatment..
Paradoxical low-ow,is adding new pieces toiol 2011;58:4135.
of patients with low-gradient severe aortic ste-nosis and
preserved ejection fraction. Circulation2011;123:88795.
15. Maes F, Boulif J, Pierard S, et al. Natural his-tory of
paradoxical low gradient severe aorticstenosis. Circ Cardiovasc Img
2014;7:71422.
16. Barone-Rochette G, Pirard S, Seldrum S, et al.Aortic valve
area, stroke volume, left ventricularmay be helpful in difcult
cases. Because of theinterpret, because these patients are elderly,
andhave CAD, atrial brillation, and important comor-bidities.
Measuring brain natriuretic peptide levels
TRANSLATIONAL OUTLOOK: Prospective studies are ne
to clarify the benet of surgery for patients with LG/LF
sevCONCLUSIONS
Across the spectrum of aortic stenosaortic stenosis does not
representthe disease, and has a more facompared with HG aortic
stenosidespite the management type andtus, the mortality risk of
LG/LF aosimilar to that of mild-to-moderaand did not appear to be
signicaAVR. According to current guidelincal decision in LG/LF
aortic stenoscussed only for symptomatic patienshould be made
cautiously on a cwhen there is evidence that symptodue to valve
stenosis (1,25) and afterseverity of the stenosis and
signicications. However, symptoms are
J A C C V O L . 6 5 , N O . 1 , 2 0 1 5
J A N U A R Y 6 / 1 3 , 2 0 1 5 : 5 5 6 6severity, LG/LFe nal
stage oforable outcome. In our series,ymptomatic sta-tic stenosis
wasaortic stenosis
tly improved bys (25), the surgi-should be dis-
. Such decisionsse-by-case basiss are most likelyocumenting
thent valvular cal-ften difcult to
REPRINT REQUE
Christophe TriboHospital AmiensRen Lannec,E-mail: tribouillo
PERSPECTIVE
COMPETENCY
management, LG
associated with
stenosis.
COMPETENCY
atic severe LG/L
lowed carefully a
and surgery musRieck AE, et al. Low-ptomatic patients:
e and systolic functionAm Coll Cardiol ImgTS AND CORRESPONDENCE:
Dr.illoy, INSERM, U-1088, Universityepartment of Cardiology,
Avenue0054 Amiens Cedex 1, [email protected].
N MEDICAL KNOWLEDGE: Irrespectiv
LF severe aortic stenosis with preserved
utcomes similar to those of moderate aor
N MEDICAL CARE: Patients with asymp
aortic stenosis with preserved EF must be
d closely for symptoms due to the valve les
be discussed when these symptoms develo
Trib
w-Gradient, Low-Flow Severe Aortic Stenosis Withypertrophy,
remodeling, and brosis in aorticstenosis assessed by cardiac
magnetic resonanceimaging: comparison between high and lowgradient
and normal and low ow aortic stenosis.Circ Cardiovasc Img
2013;6:100917.
-
17. Charlson ME, Pompei P, Ales KL, et al. A newmethod of
classifying prognostic comorbidity inlongitudinal studies:
development and validation.J Chronic Dis 1987;40:37383.
18. Venables WN, Ripley BD. Modern AppliedStatistics with
S-PLUS, 3rd ed. New York, NY:Springer-Verlag, 1999:3914.
19. Lauten J, Rost C, Breithardt OA, et al.Invasive hemodynamic
characteristics of lowgradient severe aortic stenosis despite
preservedejection fraction. J Am Coll Cardiol 2013;61:1799808.
20. Minners J, Allgeier M, Gohlke-Baerwolf C,et al.
Inconsistencies of echocardiographic criteriafor grading of aortic
valve stenosis. Eur Heart J2008;29:10438.
21. Dumesnil JG, Pibarot P. Low-ow, low-gradient severe aortic
stenosis in patients withnormal ejection fraction. Curr Opin
Cardiol 2013;28:52430.
22. Ozkan A, Hachamovitch R, Kapadia SR, et al.Impact of aortic
valve replacement on outcome ofsymptomatic patients with severe
aortic stenosiswith low gradient and preserved left
ventricularejection fraction. Circulation 2013;128:62231.
23. Clavel MA, Cote N, Mathieu P, et al. Paradox-ical low-ow,
low-gradient aortic stenosis despitepreserved left ventricular
ejection fraction: newinsights from weights of operatively excised
aorticvalves. Eur Heart J 2014;35:265562.
24. Clavel MA, Messika-Zeitoun D, Pibarot P, et al.The complex
nature of discordant severe calcied
aortic valve disease grading: new insights fromcombined Doppler
echocardiographic and com-puted tomographic study. J Am Coll
Cardiol 2013;62:232938.
25. Nishimura RA, Otto CM, Bonow RO, et al.American College of
Cardiology/American HeartAssociation Task Force on Practice
Guidelines.2014 AHA/ACC Guideline for the managementof patients
with valvular heart disease: areport of the American College of
Cardiology/American Heart Association Task Force onPractice
Guidelines. J Am Coll Cardiol 2014;63:e57185.
KEY WORDS aortic valve, cardiac surgicalprocedures, follow-up
studies, mortality
Tribouilloy et al. J A C C V O L . 6 5 , N O . 1 , 2 0 1 5
Low-Gradient, Low-Flow Severe Aortic Stenosis With Normal EF J A
N U A R Y 6 / 1 3 , 2 0 1 5 : 5 5 6 666
Low-Gradient, Low-Flow Severe Aortic Stenosis With Preserved
Left Ventricular Ejection FractionMethodsStudy
designEchocardiographyClinical decision and follow-upStatistical
analysis
ResultsBaseline characteristicsOutcome under medical
managementOutcome with medical and surgical management
Effect of surgery
DiscussionStrengths and limitations
ConclusionsReferences
