- Email: [email protected]
The Functional Significance of Paradoxical Low-Gradient Aortic Valve Stenosis
JACC: CARDIOVASCULAR IMAGING
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
-, NO. -, 2016
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcmg.2016.03.018
The Functional Significance of Paradoxical Low Gradient Aortic Valve Stenosis Hemodynamic Findings During Cardiopulmonary Exercise Testing Candelas Pérez del Villar, MD, PHD, Raquel Yotti, MD, PHD, María Ángeles Espinosa, MD, PHD, Enrique Gutiérrez-Ibañes, MD, PHD, Alicia Barrio, DCS, MBIOL, María José Lorenzo, BSN, Pedro Luis Sánchez Fernández, MD, PHD, Yolanda Benito, DCS, DVM, Raquel Prieto, MD, PHD, Esther Pérez David, MD, PHD, Pablo Martínez-Legazpi, MENG, PHD, Francisco Fernández-Avilés, MD, PHD, Javier Bermejo, MD, PHD
ABSTRACT OBJECTIVES The goal of this study was to determine the functional impact of paradoxical low-gradient aortic stenosis (PLGAS) and clarify whether the relevance of the valvular obstruction is related to baseline flow. BACKGROUND Establishing the significance of PLGAS is particularly challenging. METHODS Twenty symptomatic patients (77 6 years of age; 17 female subjects) with PLGAS (mean gradient 28 6 mm Hg; aortic valve area 0.8 0.1 cm2; ejection fraction 66 7%) underwent cardiopulmonary exercise testing combined with right-heart catheterization and Doppler echocardiographic measurements. RESULTS Aortic valve area increased by 84 23% (p < 0.001) and, in 70% of subjects, it reached values >1.0 cm2 at peak exercise. Stroke volume index and blood pressure increased by 83 56% and 26 16%, respectively (both p < 0.0001). Peak oxygen consumption inversely correlated with the rate of increase in pulmonary capillary wedge pressure (PCWP) (PCWP slope: R ¼ –0.61; p ¼ 0.004). In turn, the PCWP slope was determined by changes in the valvular and vascular load but not by the rest of the indices of aortic stenosis. The functional impact of PLGAS was also not related to baseline flow. Agreement between Doppler echocardiography and the Fick technique was good up to intermediate workload. CONCLUSIONS In symptomatic patients with PLGAS, the capacity to dynamically reduce vascular and valvular loads determines the effect of exercise on PCWP, which, in turn, conditions the functional status. A critically fixed valvular obstruction may not be the main mechanism of functional impairment in a large proportion of patients with PLGAS. Exercise echocardiography is suitable to study the dynamics of PLGAS. (J Am Coll Cardiol Img 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.
A
lmost one-third of patients with aortic steno-
and <0.6 cm 2/m2 of body surface area), but their pres-
sis (AS) and normal left ventricular (LV) ejec-
sure gradients are below cutoff values considered to
tion fraction are considered to have severe
identify severity. This condition is designated para-
AS based on aortic valve area (AVA) (<1 cm 2
doxical low gradient aortic stenosis (PLGAS) (1).
From the Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, and Facultad de Medicina, Universidad Complutense de Madrid, Spain. This study was supported by grants PIS09/02602, PIS012/02878, and RD12/0042 (Red de Investigación Cardiovascular), FI11/00700 (Dr. Espinosa), and CM12/00273 (Dr. Pérez del Villar) from the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain, and by the EU– European Regional Development Fund. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received September 28, 2015; revised manuscript received February 29, 2016, accepted March 3, 2016.
2
Pérez del Villar et al.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
ABBREVIATIONS
Although
to
systolic arterial pressure >50 mm Hg), chronic
AND ACRONYMS
further distinguish low-flow PLGAS from
obstructive pulmonary disease, uncontrolled hyper-
normal-flow PLGAS (2), whether these 2
tension (cuff systolic blood pressure [SBP] or diastolic
forms have a different functional impact has
blood pressure >150 and 90 mm Hg, respectively),
not been addressed.
and inability to exercise on a cycle ergometer. The
AS = aortic stenosis AVA = aortic valve area LV = left ventricular MG = mean transvalvular pressure gradient
PCWP = pulmonary capillary wedge pressure
it
has
been
recommended
Only symptomatic patients with hemody-
study group consisted of mostly elderly female pa-
namically severe AS benefit from valve
tients (Table 1). Seventeen patients were taking anti-
replacement. Current guidelines therefore
hypertensive drugs.
recommend intervening in PLGAS when
STUDY PROTOCOL. Five to 7 days before the exercise
“clinical, hemodynamic and anatomic data
PLGAS = paradoxical low gradient aortic stenosis
SAC = systemic arterial
test, patients underwent clinical and echocardio-
support valve obstruction is the most likely
graphic enrollment examinations to ensure blood
cause of symptoms” (2). However, deter-
pressure control and to re-evaluate aortic valve
mining the clinical significance of PLGAS is
compliance
SACI = systemic arterial
sometimes difficult because of associated
compliance index
comorbidity (3). In addition, establishing the
SBP = systolic blood pressure
hemodynamic significance of PLGAS is chal-
SV = stroke volume
lenging. First, it is unclear which severity
Body surface area, m2
SVI = stroke volume index
criterion best accounts for the degree of
Body mass index, kg/m2
29 4
SvO2 = mixed venous
valvular obstruction. Second, Doppler echo-
Systolic cuff blood pressure, mm Hg
137 11
oxygen saturation
cardiography has limitations for measuring
Diastolic cuff blood pressure, mm Hg
68 13
SVRI = systemic vascular
AVA (4). We hypothesized that a compre-
Echocardiographic data
resistance index
hensive assessment of exercise hemody-
T A B L E 1 Clinical and Echocardiographic Data at Enrollment
Age, yrs
77 6
Female
17 (85)
Aortic valve mean pressure gradient, mm Hg
1.7 0.2
27 5
Aortic valve area, cm2
0.75 0.10
Aortic valve area index, cm2/m2
0.46 0.08
LV end-diastolic diameter, mm
43 4
in symptomatic patients with PLGAS. Symptomatic
LV end-systolic diameter, mm
29 3
patients with classical “high-gradient” severe AS
LV septal thickness, mm
12 2
exhibit a characteristic hemodynamic response to
LV posterior wall thickness, mm
exercise (5–10). Therefore, identifying this distinctive
LV end-diastolic volume, ml
VO2 = oxygen uptake
namic
variables
could
be
useful
for
understanding the mechanisms of exercise limitation
hemodynamic profile in PLGAS would favor a true hemodynamic significance. The present study was designed to assess the
11 1 62 12
LV end-systolic volume, ml
21 8
Ejection fraction, %
66 7
LV mass index, g/m2
94 26
E-wave, m/s
functional impact of PLGAS in symptomatic patients
0.72 0.30
E/A ratio
0.94 0.62
by characterizing their valvular and vascular response
e’, cm/s
4.4 1.3
to exercise by using Doppler echocardiography and
E/e’
16.3 5.8
right-heart cardiac catheterization. In addition, our goal was to analyze whether patients with low-flow PLGAS exhibit a singular hemodynamic response suggestive of a more severe disease than patients with normal-flow PLGAS.
Isovolumic relaxation time, ms II
19 (95)
III
1 (5)
Cardiovascular risk factors Hypertension
METHODS POPULATION. The
study
protocol
was
approved by the local institutional review board, and all subjects provided written informed consent. We studied 20 consecutive patients in sinus rhythm with
17 (85)
Diabetes
4 (20)
Dyslipidemia
15 (75)
Smoking
STUDY
83 19
NYHA functional class
0 (0)
Cardiovascular drugs ACE inhibitors
10 (50)
ARBs
4 (20)
Diuretics
8 (40)
Beta-blockers
8 (40)
exertional dyspnea (New York Heart Association
Aldosterone receptor antagonists
functional class higher than class I), AVA <1 cm2
Calcium antagonists
8 (40)
(indexed AVA <0.6 cm 2/m 2), mean transvalvular
Statins
15 (75)
pressure gradient <40 mm Hg, and ejection fraction >50%. Exclusion criteria were as follows: known or suspected ischemic heart disease, moderate or severe mitral valve disease or aortic regurgitation, pulmonary hypertension (baseline estimated pulmonary
1 (5)
Values are mean SD or n (%). ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; e0 ¼ early mitral annulus velocity; E ¼ early diastolic transmitral Doppler velocity; E/A ¼ ratio of the early to late transmitral filling Doppler velocities; LV ¼ left ventricular; NYHA ¼ New York Heart Association.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
Functional Significance of Low Gradient AS
stenosis severity (Table 1). Antihypertensive treatment was not withheld the day of the stress test.
n ¼ 60). Blood samples were obtained at rest, peak exercise, and recovery for SvO 2 calibration and B-type
Through the internal jugular vein, a Swan-Ganz
natriuretic peptide quantitation. Radial blood pres-
catheter was placed in the main pulmonary artery to
sure was monitored by using an indwelling arterial
continuously register pressures and mixed venous
catheter. Arterial saturation was measured by pulse
oxygen saturation (SvO 2) (Vigileo II monitor, Edwards
oximetry. Pressure readings and electrocardiography
Lifesciences, Irvine, California). Data were fed to a
signals were stored at 1,000 Hz.
computer every 2 s. Pulmonary capillary wedge
Patients were studied at rest and then underwent a
pressure (PCWP) was measured by transient catheter
symptom-limited bicycle-exercise test at 30 lateral
balloon inflation at baseline, peak exercise, and early
decubitus in a dedicated ergometer (Easystress, Eco-
recovery. After verification of a small and constant
gito Medical sprl, Liege, Belgium). Workload was
transvenous
initiated at 25 W and increased by 25 W every 3 min.
pressure
gradient,
we
interpolated
PCWP along the exercise period by using the linear
Expired gas CO 2 and O 2 content was continuously
regression equation between diastolic pulmonary
analyzed (Oxycon Delta, Jaeger, Würzburg, Ger-
pressure and PCWP data points (Pearson correlation
many). A hypertensive response was defined as a
[R] ¼ 0.91; intraclass correlation coefficient [Ric] ¼
radial SBP >210 mm Hg and 190 mm Hg for male
0.90
subjects
between
measured
and
estimated
values,
and
female
subjects,
respectively
(11).
F I G U R E 1 Synchronized Measurements of a Representative Patient
(A) Heart rate (black) and systemic arterial pressure (red, pink, and white) measurements. (B) Pulmonary pressures. (C) Mixed venous saturation (SvO2) (blue) and stroke volume (SV) (green). (D) Cardiac output (yellow). (E) Gas exchange (red and blue). Instantaneous workload is overlaid in grey and the instant of peak oxygen uptake (VO2) is depicted by the arrowhead. PCWP ¼ pulmonary capillary wedge pressure; VCO2 ¼ carbon dioxide production.
3
Pérez del Villar et al.
4
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
A hypotensive response was defined as the inability
DATA ANALYSIS. A multidimensional data matrix
to increase SBP $20 mm Hg. A comprehensive ultra-
was generated for each patient that stored synchro-
sound examination was performed at rest using 2.0-
nized invasive and noninvasive signals with a tem-
to 4.0-MHz transducers on a Vivid 7 or Vivid 9 system
poral resolution of 5 s (custom-built registration and
(GE Healthcare, Little Chalfont, United Kingdom).
interpolation
Doppler tracings of transvalvular and LV outflow tract
Natick, Massachusetts]) (Figure 1). Continuous cardiac
velocities were acquired at the end of each stage,
output and stroke volume index (SVI) were calculated
peak stress, and recovery.
during exercise by using the Fick method from base-
algorithms;
MATLAB
[MathWorks,
line hemoglobin concentration and instantaneous values of arterial saturation, SvO 2, and oxygen uptake (VO 2) (12). Thermodilution cardiac output at baseline and early recovery was measured to check the Fick
T A B L E 2 Hemodynamic Changes Induced by Exercise
method. AVA was calculated from the ratio between
Baseline
50% of DVO2
Peak VO2
VO2, ml/kg/min
2.9 0.9
7.3 2.3*
10.4 4.2*
VCO2, ml/kg/min
2.9 0.9
6.1 1.4*
10.5 3.1*
Doppler time velocity integral. The systemic vascular
Heart rate, beats/min
76 13
101 20*
110 19*
resistance index (SVRI) was estimated as the ratio
SvO2, %
70 15
52 18*
46 18*
between mean radial pressure and cardiac index.
Cardiac index, l/min/m2
2.7 0.9
4.0 1.4*
5.6 2.5*
Total systemic arterial compliance index (SACI) was
Stroke volume index, ml/m2
33 11
43 15*
59 25*
Doppler-derived stroke volume index, ml/m2
36 8
38 11
40 12*
Systolic ejection period, ms
328 43
301 40*
305 54*
Mean systolic transvalvular flow rate, ml/s
165 52
231 67*
316 106*
Systolic blood pressure, mm Hg
159 19
190 21*
199 24*
Mean blood pressure, mm Hg
105 13
125 11*
128 13*
valvular pressure gradient (MG), systolic ejection
73 11
84 10*
86 12*
period, LV outflow tract diameter, and Doppler-
Systemic arterial hemodynamics
Diastolic blood pressure, mm Hg
3,424 1311 2,743 895* 2,128 818*
Systemic vascular resistance index, dyn$s/cm5/m2
0.39 0.13
Systemic arterial compliance index, ml/m2/mm Hg
0.42 0.17
0.53 0.22*
Fick-derived stroke volume (SV) and the aortic valve
estimated as the ratio between SVI and pulse pressure. Pulmonary vascular resistance index was calculated as follows: (mean pulmonary artery pressure – PCWP)/cardiac index. Doppler-derived
SVI
(SVIDoppler),
mean
trans-
derived AVA were measured as recommended (4). The LV outflow tract diameter was assumed constant during exercise (8,9,13). Baseline LV volumes and
Pulmonary hemodynamics
ejection fraction were measured using the biplane
Systolic pulmonary artery pressure, mm Hg
30 13
53 17*
60 21*
Mean pulmonary artery pressure, mm Hg
21 9
38 13*
41 14*
Diastolic pulmonary artery pressure, mm Hg
13 7
26 11*
30 12*
Estimated pulmonary capillary wedge pressure, mm Hg
12 6
23 9
26 10*
Transpulmonary gradient, mm Hg
10 6
14 7*
15 8*
24
36
46
Pulmonary vascular resistance index, dyn$s/cm5/m2
723 512
876 554*
751 493
Pulmonary arterial compliance index, ml/m2/mm Hg
2.55 1.71
2.11 1.76
2.64 2.57
Transpulmonary venous pressure gradient, mm Hg
Simpson’s method. Values of systolic longitudinal strain and strain rate were obtained from apical 4chamber views at baseline and peak stress using speckle-tracking (EchoPAC version 112, GE Medical Systems,
Waukesha,
Wisconsin).
Valvuloarterial
impedance was calculated as follows: ðSBP þ MGÞ=SVI. Mean systolic flow rate was computed as SV/ejection period. The following composite variables were estimated by the linear mixed effects fitting from the instan-
Aortic valve stenosis 3.4 0.4
Peak transvalvular velocity, m/s Mean transvalvular pressure gradient, mm Hg
25 6
3.7 0.5* 31 9*
4.0 0.6* 35 14*
taneous exercise data obtained for each patient. Valve
compliance,
designating
the
capacity
of
1.23 0.42*
increasing AVA, was obtained as the slope of the AVA
0.43 0.15
0.55 0.18* 0.78 0.39*
versus flow rate relationship (cm 2 per ml/s) (14). The
Aortic valve area, Doppler-derived, cm
0.74 0.12
0.81 0.16* 0.85 0.20*
Aortic valve velocity ratio (dimensionless)
0.25 0.05 0.27 0.05
0.71 0.18 0.89 0.21*
Aortic valve area, cm2 Aortic valve area index, cm2/m2 2
Valvuloarterial impedance, mm Hg/ml/m2
6.2 2.3
5.8 2.2
0.28 0.07 4.5 1.6*
Strain analysis Peak systolic longitudinal strain, % Peak systolic longitudinal strain rate, /s Peak early diastolic longitudinal strain, /s
–16.9 3.7
—
–0.9 0.2
—
1.0 0.4
–18.3 4.9 –1.1 0.3* 1.6 0.7*
SVI versus VO 2 (ml/m2 per ml/kg/min). This slope has shown to be flat in classical “high-gradient” severe AS (5–9). The PCWP slope was obtained as the PCWP versus VO2 relationship (mm Hg per ml/kg/min). The SVRI slope and the SACI slope, respectively,
Biomarkers B-type natriuretic peptide, pg/ml
SVI slope, defined as the capacity to increase SV during exercise, was calculated as the linear slope of
107 111
—
123 20*
Values are mean SD. *p < 0.05 versus baseline (Dunnet contrast). VO2 ¼ oxygen consumption; VCO2 ¼ carbon dioxide production; SvO2 ¼ mixed venous oxygen saturation.
account for the capacity of the systemic arterial tree to lower its resistance and increase compliance during exercise; they were measured as the linear SVRI versus VO 2 (dyn$s/cm 5/m 2 per ml/kg/min) and
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
Functional Significance of Low Gradient AS
SACI versus VO 2 (ml/m 2/mm Hg per ml/kg/min)
unchanged (0.75 0.10 vs. 0.74 0.12 cm 2; p ¼ 0.69).
relationships.
At rest, mean SVRI was abnormally high (2,056 701
STATISTICAL ANALYSIS. Measurements obtained at
dyn$s/cm 5/m 2), and SACI was low (0.4 0.1 ml/m 2/
baseline, at 50% of the increase from baseline to peak
mm Hg) (Table 2). Low-flow (SVI <35 ml/m 2) was
VO 2 (50% – D VO 2), and at peak VO 2 were compared by
present in 10 patients.
using linear mixed effects models accounting for
AGREEMENT BETWEEN INVASIVE AND NONINVASIVE
repeated measures followed by Dunnett contrasts
INDICES. Good agreement was observed between
(R version 3.2, R Foundation for Statistical Com-
Fick and thermodilution methods for measuring SVI
puting, Vienna, Austria). We obtained the aforemen-
(R ic ¼ 0.86) (Figure 2). At rest, good agreement was
tioned composite slope variables from mixed effects
observed between Fick- and Doppler-derived mea-
models of the within-subject relationship of the
surements of SVI and AVA (R ¼ 0.82 and R ic ¼ 0.79 for
hemodynamic parameters during exercise (fixed þ
SVI, respectively; R ¼ 0.80 and R ic¼ 0.76 for AVA). At
random effects). Univariate and multivariate linear
peak VO 2, both methods were still highly correlated
regression models were used to assess the predictors
(R ¼ 0.81 and 0.89 for SVI and AVA), but their
of the PCWP slope during exercise. Variables in
agreement was lower (R ic ¼ 0.32 and 0.44 for SVI and
multivariate models were selected by backward
AVA). At 50%- DVO2 , agreement was acceptable for
elimination based on Akaike information criterion.
SVI and AVA (R ic ¼ 0.72 and 0.67).
The Pearson correlation (R) and intraclass correlation
VALVULAR AND HEMODYNAMIC CHANGES. Indices
(R ic) coefficients were used to assess concordance.
of AS changed with exercise: AVA increased by 84
Values of p < 0.05 were considered significant.
23% (p < 0.0001) (Figure 3). Mean valve compliance was 0.003 0.001 cm 2 per ml/s, but there was high
RESULTS
individual variability (range 0.000 to 0.005 cm2 per BASELINE HEMODYNAMICS. After instrumentation,
ml/s of increase in flow). This outcome led to AVA
17 patients (85%) had a radial SBP >150 mm Hg.
values at peak exercise >1.0 cm2 in 70% of subjects.
Although this finding led to a MG slightly lower
No patient had a flat or hypotensive blood pressure
than at enrollment (25 6 vs. 27 5 mm Hg;
response, whereas 9 (45%) experienced a hyperten-
¼
0.001),
Doppler-derived
AVA
sive response. SBP increased 40 23 mm Hg from
remained
F I G U R E 2 Agreement Between Methods Used to Measure SVI
25
0
10
20
30
40
50
Average Thermodilution & Fick (ml/m2)
Baseline
Recovery
50
C
Ric = 0.79
25
0
20
30
40
Average Fick & Doppler (ml/m2)
Baseline
50
50
D
Ric = 0.72
Fick - Doppler (ml/m2)
Ric = 0.86
Fick - Doppler (ml/m2)
50
B
Fick - Doppler (ml/m2)
A Thermodilution - Fick (ml/m2)
p
25
0
30
40
50
Average Fick & Doppler (ml/m2)
50% of Δ VO2
60
50
Ric = 0.32
25
0
40
60
Peak VO2
(A) Fick versus thermodilution measurements obtained at baseline (pink) and during recovery (green). (B–D) Fick-derived versus Doppler echocardiography measurements (B) obtained at baseline, (C) 50% of the increase in VO2, and (D) peak VO2. Black dotted lines show the bias and 1.96 $ SD agreement limits between techniques. SVI ¼ stroke volume index; VO2 ¼ oxygen uptake.
80
Average Fick & Doppler (ml/m2)
5
Pérez del Villar et al.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
F I G U R E 3 Acute Changes in Valve Hemodynamics Induced by Exercise
A
B
C
70
2.5
500 60 2.0
400
300
200
50
Aortic Valve Area (cm2)
Mean Pressure Gradient (mm Hg)
Mean Systolic Transvalvular Flow Rate (ml/s)
6
40
1.5
1.0
30
20
0.5
100 10 Baseline
Low VO2 Peak VO2
Baseline
Phase
Low VO2
Peak VO2
Phase
Baseline
Low VO2
Peak VO2
Phase
Scatterplots and boxplots show the distributions of (A) mean systolic flow rate, (B) pressure gradient, and (C) aortic valve area. Values are shown at baseline, at the 50% increase from baseline to peak oxygen uptake (VO2) (low VO2), and at peak VO2. Boxplots show the median (black thick line), the 95% confidence interval for the median (waist), the 25 and 75% quartiles, and distribution limits without outliers (vertical lines).
baseline to peak VO 2, despite a significant decrease in
arterial compliance index (the SACI slope) and valve
SVRI and an increase in SACI (Figure 4, Table 2). SVI
compliance were powerful determinants of the PCWP
linearly increased an 83 56% during exercise,
slope (Table 3). No baseline hemodynamic index
following an average slope of 2.67 2.76 ml/m 2 per
predicted the PCWP response. Values of PCWP and
ml/kg/min increase in VO 2 (Figures 4 and 5). Again,
SVI at peak VO 2 inversely correlated (R ¼ –0.60;
there were huge individual variations in these slopes
p ¼ 0.005). The hemodynamic responses were not
(range –0.49 to 11.14 ml/m 2 per ml/kg/min).
significantly different between low-flow patients and
Pulmonary pressures and PVRI increased linearly
normal-flow patients (Table 4); they also did not
during exercise (Figure 4, Table 2). PCWP reached
correlate with baseline SVI when the latter was
>16 mm Hg at peak VO 2 in 16 (80%) patients. The
analyzed as a continuous variable.
increase in natriuretic peptide from baseline to peak exercise correlated with the increase in PCWP (R ¼ 0.67; p ¼ 0.009).
DISCUSSION The present study helps to clarify a number of issues
MECHANISMS OF FUNCTIONAL IMPAIRMENT. Exer-
regarding the significance of PLGAS. First, combined
cise capacity inversely correlated with the PCWP
Doppler- and Fick-derived measurements during ex-
slope: the steeper the PCWP increase during exercise,
ercise showed that the aortic valve has a relatively
the lower peak VO 2 values achieved (R ¼ –0.61;
large residual opening reserve. Second, baseline
p ¼ 0.004) (Figure 6). In turn, the capacity to increase
indices of LV valvular and vascular load did not
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
7
Functional Significance of Low Gradient AS
F I G U R E 4 Changes in Vascular Hemodynamics Induced by Exercise
A
B
C
D
125 40
50
4000
2000
PCWP (mm Hg)
75
SACI (ml/m2/mm Hg)
SVRI (dyn·s/cm5/m2)
SVI (ml/m2)
100
0.9
6000
0.6
0.3
Low VO2
Baseline
Peak VO2
Phase
Low VO2
Peak VO2
20
10
25
Baseline
30
Baseline
Phase
Low VO2
Peak VO2
Baseline
Phase
Low VO2
Peak VO2
Phase
Scatterplots and boxplots show the distributions of (A) SVI, (B) systemic vascular resistance index (SVRI), (C) systemic arterial compliance index (SACI), and (D) PCWP. Abbreviations as in Figures 1 and 2.
correlate with the degree of functional impairment or
gradient disease. Fourth, we identified important
exercise-induced hemodynamic transients. Third,
dynamic ventricular–vascular interactions that con-
symptomatic patients with PLGAS did not exhibit the
dition the impact of exercise on PCWP, which, in turn,
characteristic exercise response of patients with high-
correlates with the functional capacity of these
F I G U R E 5 Changes in SVI for All Patients
5
10 15
5
10 15 150 100 50
150 100
SVI (ml/m2)
50 150 100 50 150 100 50 5
10 15
5
10 15
5
10 15
VO2 (ml/kg/min) The individual response group is shown by the green line. The average response for the full sample is shown by the red dotted line. Abbreviations as in Figures 1 and 2.
Pérez del Villar et al.
8
JACC: CARDIOVASCULAR IMAGING, VOL.
F I G U R E 6 Correlation Between the PCWP Slope and Peak Oxygen Consumption
vascular function on pulmonary pressures. PCWP increased faster in patients who had a limited valve opening reserve and a lower capacity to lower SAC. In
C
addition, a faster rise in PCWP determined a lower PCWP (mm Hg)
A
functional capacity. The relationship we observed
30
between valve compliance and the rate of increase of
20
PCWP explains why valve compliance is a better
10
predictor of exertional symptoms than resting AVA (14). 5 10 15 VO2 (ml/kg/min)
15
interactions
between
valvular
and
also help to clarify why impaired outcome in AS is related to exercise responses such as limited valve opening
PCWP (mm Hg)
10
These
vascular dynamics, PCWP, and functional capacity
B Peak VO2 (ml/kg/min)
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
reserve
(16,17),
abnormal
arterial
hemodynamics (7,18), exercise-induced pulmonary
30
hypertension (19), high increments of natriuretic
20
peptides (20), and low peak VO 2 (21).
10
THE VASCULAR TREE IN PLGAS. In AS, LV afterload 5 10 15 VO2 (ml/kg/min)
depends on the additive effects of valvular obstruction and vascular load (1,6,7,22–25), and increased vascular load may contribute to the high morbidity and mortality rates sometimes observed in patients
5
with this condition (1,23). The values of vascular load observed at rest in the present study are similar to R = -0.61 p = 0.005
invasive measures previously reported in patients with low-gradient AS and higher than values obtained
0
2.5
5
7.5
in patients with high-gradient severe or moderate AS
PCWP/VO2 Slope (mm Hg/ml/kg/min)
(26). Beyond baseline characterization, our study emphasizes the importance of analyzing dynamic
(A) Inverse correlation between the PCWP versus VO2 slope and the peak VO2 for each
vascular reflexes in the evaluation of AS hemody-
patient. Inserts show extreme responses for (B) a patient with a steep slope (rapid PCWP
namics (24).
increase) who achieves a low peak VO2 and (C) a patient with a relatively flat slope (slow PCWP increase) who achieves a high peak VO2. Abbreviations as in Figure 1.
Current evidence supports that systemic hypertension can influence the evaluation of AS severity (18,25,27), frequently leading to AVA underestimation (18). For this reason, in hypertensive patients with
patients. Fifth, we were unable to find functional differences among patients with normal-flow PLGAS and low-flow PLGAS. FUNCTIONAL
SIGNIFICANCE
low-gradient AS, AS severity and functional status should always be evaluated after controlling blood pressure (2,28). Although achieving recommended blood pressure goals may be difficult in elderly pa-
OF
PLGAS. Valve
tients, our findings suggest that, even when blood
compliance allowed a relatively large effective area
pressure is not completely under control, exercise
opening at peak stress (14). By acutely lowering
may be useful to unmask a load-mediated underes-
afterload, the combined effects of enlarging area and
timation of AVA.
increasing SAC facilitate raising SV during exercise. Consequently, blood pressure can rise despite the fact
STRESS ECHOCARDIOGRAPHY IN PLGAS. Because
that systemic vascular resistance drops due to exer-
all indices of AS are, to a certain degree, flow
cise. Symptomatic patients with high-gradient severe
dependent, a baseline assessment of the obstruction
AS characteristically exhibit a different behavior. The
severity may be insufficient. On this basis, stress
SV of patients with severe high-gradient AS is typi-
echocardiography may be useful in particular groups
cally fixed, falling, or remaining constant when they
(6,8,9,16). However, an indiscriminate use of exercise
exercise, as consistently demonstrated by invasive
tests in patients with symptomatic AS is hazardous
(5–7,15) and noninvasive (9,13) studies.
and formally contraindicated. In accordance with
Importantly, to the best of our knowledge this is
previous studies (16), our findings suggest that the
the first study in patients with AS that demonstrates
technique is safe in patients with PLGAS under care-
the influence of dynamic changes of valvular and
ful monitoring. Furthermore, we demonstrated that
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
exercise echocardiography provides an objective assessment of functional capacity and identifies the
9
Functional Significance of Low Gradient AS
T A B L E 3 Determinants of the Rate of Rise of PCWP During Exercise
(PCWP Versus VO 2 Slope)
hemodynamic valvular and vascular changes related Univariate
to symptoms. By head-to-head validation, we found
R
p Value
Sex
–
0.33
Age
–0.03
0.87
that stress echocardiography was reliable up to intermediate workload. In addition, exercise-mediated valvular and vascular trends were highly linear (Figures 5 and 6), and most relevant hemodynamic
Aortic valve area
0.29
0.2
Mean pressure gradient
0.24
0.3
Further clinical studies should establish the definitive
Systemic vascular resistance index
–0.2
0.51
role of exercise echocardiography in patients with
Stroke volume index
0.1
0.67
PLGAS.
Diastolic pulmonary artery pressure
0.08
0.72
Systemic arterial compliance
0.8
0.73
CLINICAL DECISION-MAKING IN PLGAS. The indi-
BNP
–0.2
0.4
cation of valve replacement in symptomatic PLGAS is
E/A
–0.2
0.5
still an unsolved issue. As previously discussed,
E/e’
–0.05
0.84
some investigators have identified a high systemic
Peak systolic longitudinal strain
0.00
0.98
vascular load that greatly increases global LV after-
Peak systolic longitudinal strain rate
0.17
0.49
–0.17
0.48
PLGAS would account for an advanced form of AS
Peak early diastolic longitudinal strain Zva/VO2 slope
0.36
0.11
–0.47
0.08
(29,30) and worse prognosis (1,31). However, the
Valve compliance
–0.63
0.002
underestimation of SV by Doppler echocardiography
Mean G/VO2 slope
0.27
SBP/VO2 slope
0.35
0.12
may cause overestimation of AS. Our study supports
SVRI/VO2 slope
0.03
0.91
SACI/VO2 slope
–0.59
Doppler technique but of the limitations of baseline AVA to define severity. Our study showed that symptomatic PLGAS does not share the functional
–779
–0.5
0.009
–36
–0.41
0.03
0.25
(3) and the inconsistency of AS severity criteria (32) that PLGAS is not a consequence of errors of the
p Value
Dynamic indices
D BNP
with more structural and functional LV impairment
Standardized b
Baseline indices
changes were observed early (Figure 3, Table 2).
load and reduces SV in PLGAS (1). Consequently,
Multivariate
b
0.006
BNP ¼ B-type natriuretic peptide; PCWP ¼ pulmonary capillary wedge pressure; SACI ¼ systemic arterial compliance index; SBP ¼ systolic blood pressure; SVRI ¼ systemic vascular resistance index; Zva ¼ valvuloarterial impedance; other abbreviations as in Tables 1 and 2.
behavior of high-gradient AS. Although patients with PLGAS may be symptomatic due to exertional dyspnea, they frequently achieve large effective AVA values when required. Peak flow AVA values in this study were sometimes actually larger than effective areas of several prosthetic valves. Thus, the functional results of our study do not support a critical LV outflow obstruction at the time of presentation of PLGAS. With the limitations of small sample groups, we were unable to identify a clearly different hemodynamic behavior between patient groups with low-
dioxide resulting from an increase in heart rate (12). However, in our study, patients underwent submaximal exercise, with SV not reaching a plateau. Thus, a relatively large increase in Fick-derived SV during the second exercise phase resulted in relatively small changes in SvO 2 and heart rate despite large increases in VO 2. This finding is somewhat paradoxical, and we cannot exclude a certain degree of error in the estimation of reference SV at peak VO 2. However, we did our best to ensure maximal quality signals
flow PLGAS and normal-flow PLGAS. Furthermore, when analyzed as a continuous variable, baseline SVI values did not correlate with the PCWP slope or the
T A B L E 4 Differences in Hemodynamic Behavior Between the Low-Flow PLGAS
Group Versus the Normal-Flow PLGAS Group
degree of valve compliance during exercise. Thus, in pure hemodynamic terms, there seems to be no
N (%) of patients
SVI > 35 ml/m 2
SVI < 35 ml/m2
10 (50)
10 (50)
p Value
functional difference between normal-flow PLGAS
Valve compliance, cm2 per ml/s
0.003 0.002
0.004 0.001
0.2
and low-flow PLGAS.
SV slope, ml/m2 per ml/kg/min
4.3 2.4
2.9 1.8
0.2
STUDY LIMITATIONS. During exercise, the agree-
ment of the Fick technique with Doppler echocardi-
PCWP slope, mm Hg per ml/kg/min SAC slope, ml/m2/mm Hg per ml/kg/min Peak AVA, cm2
3.1 3.8
2.0 1.3
0.4
0.028 0.028
0.023 0.025
0.7
1.3 0.5
1.1 0.3
0.3
ography was good up to intermediate workload, but some discrepancy was shown at peak exercise. Pre-
Values are mean SD.
vious studies have shown a SV plateauing with ex-
AVA ¼ aortic valve area; PLGAS ¼ paradoxical low gradient aortic stenosis; SV ¼ stroke volume; SVI ¼ stroke volume index; other abbreviations as in Table 3.
ercise and most of the subsequent rise in carbon
10
Pérez del Villar et al.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
and performed ad hoc thermodilution validation
vascular resistance. Their capacity to lower vascular
measurements. In addition, the correlations we
and valvular load affects the rate of their rise in
observed between VO 2 and simultaneous pulmonary
PCWP, which, in turn, is the major determinant of
pressures further support our findings. Moreover,
their functional status. As opposed to patients with
most relevant pulmonary and systemic hemodynamic
high-gradient AS, the exercise hemodynamic pattern
changes were observed at early phases, when there
suggests that the valvular obstruction may not be
was a good match between the Doppler and Fick
functionally significant in a relatively large propor-
methods.
tion of patients with PLGAS.
The inclusion of a matched group of patients with high-gradient AS would have reinforced our findings.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Despite
Raquel Yotti, Department of Cardiology, Hospital
careful
adjustment
of
antihypertensive
drugs, blood pressure was elevated immediately
General
before exercise in a number of patients. However, all
Esquerdo 46. 28007 Madrid, Spain. E-mail: raquel.
patients fulfilled criteria for LGAS at enrollment. High
[email protected].
Universitario
Gregorio
Marañón,
Dr.
blood pressure values probably were related to the catheterization procedure itself, underscoring the
PERSPECTIVES
clinical difficulties in defining an adequate blood pressure control with isolated cuff measurements. Importantly, exercise tests in our study were performed under careful invasive hemodynamic monitoring; thus, the results cannot be used to support the widespread use of exercise tests in severe AS. Because of the study’s complexity, we were unable to analyze the ventricular compartment comprehensively; however, albeit limited to single-plane acquisitions, LV strain measurements did not predict the PCWP slope. Finally, despite careful measurement of transvalvular Doppler velocities during exercise, a potential underestimation of aortic velocities could account for some degree of overestimation in the AVA.
COMPETENCY IN MEDICAL KNOWLEDGE: In elderly patients with PLGAS, the AVA is highly dynamic. In these patients, exercise induces an increase in AVA and a reduction in vascular load, which allows the SV to increase. This hemodynamic pattern is different from classical high-gradient severe AS. COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Unmasking the underlying hemodynamic mechanisms of functional impairment in PLGAS can be achieved by using stress echocardiography. TRANSLATIONAL OUTLOOK: Our study suggests that in patients with PLGAS, the hemodynamic response to exercise could add valuable information
CONCLUSIONS
to evaluate the indication of valve replacement, but
In these study patients with PLGAS, combined ultrasound and invasive hemodynamic techniques found that AVA was highly dynamic and flow dependent. Patients with PLGAS typically had increased blood
large-scale studies are needed. Previous mathematical simulation studies suggesting the interaction between valvular, vascular, and ventricular function are confirmed in the clinical setting.
pressure and SV during exercise despite a fall in
REFERENCES 1. 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;115:2856–64.
4. Baumgartner H, Hung J, Bermejo J, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 2009;22: 1–23.
2. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart
5. Bache RJ, Wang Y, Jorgensen CR. Hemodynamic effects of exercise in isolated valvular aortic stenosis. Circulation 1971;44:1003–13.
Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57–185. 3. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96.
6. Laskey WK, Kussmaul WG, Noordergraaf A. Valvular and systemic arterial hemodynamics in aortic valve stenosis. A model-based approach. Circulation 1995;92:1473–8. 7. Laskey WK, Kussmaul WG 3rd, Noordergraaf A. Systemic arterial response to exercise in patients
with aortic valve stenosis. Circulation 2009;119: 996–1004. 8. Burwash IG, Pearlman Miyake-Hull C, Healy NL, Otto dence of measures of aortic during exercise. J Am Coll 1342–50.
AS, Kraft CD, CM. Flow depenstenosis severity Cardiol 1994;24:
9. Bermejo J, Garcia-Fernandez MA, Torrecilla EG, et al. Effects of dobutamine on Doppler echocardiographic indexes of aortic stenosis. J Am Coll Cardiol 1996;28:1206–13. 10. Otto CM, Burwash IG, Legget ME, et al. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
predictors 2262–70.
of
outcome.
Functional Significance of Low Gradient AS
Circulation
1997;95:
asymptomatic valvular aortic stenosis. Eur J Echocardiogr 2008;9:338–43.
11. Schultz MG, Otahal P, Cleland VJ, Blizzard L, Marwick TH, Sharman JE. Exercise-induced hypertension, cardiovascular events, and mortality in
18. Eleid MF, Nishimura RA, Sorajja P, Borlaug BA.
patients undergoing exercise stress testing: a systematic review and meta-analysis. Am J Hypertens 2013;26:357–66. 12. Nakanishi N, Yoshioka T, Okano Y, Nishimura T. Continuous Fick cardiac output measurement during exercise by monitoring of mixed venous oxygen saturation and oxygen uptake. Chest 1993; 104:419–26. 13. Otto CM, Pearlman AS, Kraft CD, MiyakeHull CY, Burwash IG, Gardner CJ. Physiologic changes with maximal exercise in asymptomatic valvular aortic stenosis assessed by Doppler echocardiography. J Am Coll Cardiol 1992;20: 1160–7. 14. Das P, Rimington H, Smeeton N, Chambers J. Determinants of symptoms and exercise capacity in aortic stenosis: a comparison of resting haemodynamics and valve compliance during dobutamine stress. Eur Heart J 2003;24:1254–63. 15. Clyne CA, Arrighi JA, Maron BJ, Dilsizian V, Bonow RO, Cannon RO 3rd Systemic and left ventricular responses to exercise stress in asymptomatic patients with valvular aortic stenosis. Am J Cardiol 1991;68:1469–76. 16. Clavel MA, Ennezat PV, Marechaux S, et al. Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF. J Am Coll Cardiol Img 2013;6: 175–83. 17. Lancellotti P, Karsera D, Tumminello G, Lebois F, Pierard LA. Determinants of an abnormal response to exercise in patients with
Systemic hypertension in low-gradient severe aortic stenosis with preserved ejection fraction. Circulation 2013;128:1349–53. 19. Lancellotti P, Magne J, Donal E, et al. Determinants and prognostic significance of exercise pulmonary hypertension in asymptomatic severe aortic stenosis. Circulation 2012;126: 851–9. 20. Capoulade R, Magne J, Dulgheru R, et al. Prognostic value of plasma B-type natriuretic peptide levels after exercise in patients with severe asymptomatic aortic stenosis. Heart 2014; 100:1606–12. 21. Dhoble A, Enriquez-Sarano M, Kopecky SL, et al. Cardiopulmonary responses to exercise and its utility in patients with aortic stenosis. Am J Cardiol 2014;113:1711–6. 22. Briand M, Dumesnil JG, Kadem L, et al. Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment. J Am Coll Cardiol 2005;46: 291–8. 23. Hachicha Z, Dumesnil JG, Pibarot P. Usefulness of the valvuloarterial impedance to predict adverse outcome in asymptomatic aortic stenosis. J Am Coll Cardiol 2009;54:1003–11. 24. Yotti R, Bermejo J, Gutierrez-Ibanes E, et al. Systemic vascular load in calcific degenerative aortic valve stenosis: insight from percutaneous valve replacement. J Am Coll Cardiol 2015;65: 423–33. 25. Bermejo J. The effects of hypertension on aortic valve stenosis. Heart 2005;91:280–2.
26. Eleid MF, Nishimura RA, Borlaug BA, Sorajja P. Invasive measures of afterload in low gradient severe aortic stenosis with preserved ejection fraction. Circ Heart Fail 2013;6:703–10. 27. Little SH, Chan KL, Burwash IG. Impact of blood pressure on the Doppler echocardiographic assessment of severity of aortic stenosis. Heart 2007;93:848–55. 28. Lindman BR, Otto CM. Time to treat hypertension in patients with aortic stenosis. Circulation 2013;128:1281–3. 29. Dumesnil JG, Pibarot P, Carabello B. Paradoxical low flow and/or low gradient severe aortic stenosis despite preserved left ventricular ejection fraction: implications for diagnosis and treatment. Eur Heart J 2010;31:281–9. 30. Adda J, Mielot C, Giorgi R, et al. Low-flow, low-gradient severe aortic stenosis despite normal ejection fraction is associated with severe left ventricular dysfunction as assessed by speckle-tracking echocardiography: a multicenter study. Circ Cardiovasc Imaging 2012;5: 27–35. 31. Clavel MA, Dumesnil JG, Capoulade R, Mathieu P, Senechal M, Pibarot P. Outcome of patients with aortic stenosis, small valve area, and low-flow, low-gradient despite preserved left ventricular ejection fraction. J Am Coll Cardiol 2012;60:1259–67. 32. 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 2008;29: 1043–8.
KEY WORDS aortic valve stenosis, hemodynamics, vascular function
11
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
-, NO. -, 2016
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcmg.2016.03.018
The Functional Significance of Paradoxical Low Gradient Aortic Valve Stenosis Hemodynamic Findings During Cardiopulmonary Exercise Testing Candelas Pérez del Villar, MD, PHD, Raquel Yotti, MD, PHD, María Ángeles Espinosa, MD, PHD, Enrique Gutiérrez-Ibañes, MD, PHD, Alicia Barrio, DCS, MBIOL, María José Lorenzo, BSN, Pedro Luis Sánchez Fernández, MD, PHD, Yolanda Benito, DCS, DVM, Raquel Prieto, MD, PHD, Esther Pérez David, MD, PHD, Pablo Martínez-Legazpi, MENG, PHD, Francisco Fernández-Avilés, MD, PHD, Javier Bermejo, MD, PHD
ABSTRACT OBJECTIVES The goal of this study was to determine the functional impact of paradoxical low-gradient aortic stenosis (PLGAS) and clarify whether the relevance of the valvular obstruction is related to baseline flow. BACKGROUND Establishing the significance of PLGAS is particularly challenging. METHODS Twenty symptomatic patients (77 6 years of age; 17 female subjects) with PLGAS (mean gradient 28 6 mm Hg; aortic valve area 0.8 0.1 cm2; ejection fraction 66 7%) underwent cardiopulmonary exercise testing combined with right-heart catheterization and Doppler echocardiographic measurements. RESULTS Aortic valve area increased by 84 23% (p < 0.001) and, in 70% of subjects, it reached values >1.0 cm2 at peak exercise. Stroke volume index and blood pressure increased by 83 56% and 26 16%, respectively (both p < 0.0001). Peak oxygen consumption inversely correlated with the rate of increase in pulmonary capillary wedge pressure (PCWP) (PCWP slope: R ¼ –0.61; p ¼ 0.004). In turn, the PCWP slope was determined by changes in the valvular and vascular load but not by the rest of the indices of aortic stenosis. The functional impact of PLGAS was also not related to baseline flow. Agreement between Doppler echocardiography and the Fick technique was good up to intermediate workload. CONCLUSIONS In symptomatic patients with PLGAS, the capacity to dynamically reduce vascular and valvular loads determines the effect of exercise on PCWP, which, in turn, conditions the functional status. A critically fixed valvular obstruction may not be the main mechanism of functional impairment in a large proportion of patients with PLGAS. Exercise echocardiography is suitable to study the dynamics of PLGAS. (J Am Coll Cardiol Img 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.
A
lmost one-third of patients with aortic steno-
and <0.6 cm 2/m2 of body surface area), but their pres-
sis (AS) and normal left ventricular (LV) ejec-
sure gradients are below cutoff values considered to
tion fraction are considered to have severe
identify severity. This condition is designated para-
AS based on aortic valve area (AVA) (<1 cm 2
doxical low gradient aortic stenosis (PLGAS) (1).
From the Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, and Facultad de Medicina, Universidad Complutense de Madrid, Spain. This study was supported by grants PIS09/02602, PIS012/02878, and RD12/0042 (Red de Investigación Cardiovascular), FI11/00700 (Dr. Espinosa), and CM12/00273 (Dr. Pérez del Villar) from the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain, and by the EU– European Regional Development Fund. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received September 28, 2015; revised manuscript received February 29, 2016, accepted March 3, 2016.
2
Pérez del Villar et al.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
ABBREVIATIONS
Although
to
systolic arterial pressure >50 mm Hg), chronic
AND ACRONYMS
further distinguish low-flow PLGAS from
obstructive pulmonary disease, uncontrolled hyper-
normal-flow PLGAS (2), whether these 2
tension (cuff systolic blood pressure [SBP] or diastolic
forms have a different functional impact has
blood pressure >150 and 90 mm Hg, respectively),
not been addressed.
and inability to exercise on a cycle ergometer. The
AS = aortic stenosis AVA = aortic valve area LV = left ventricular MG = mean transvalvular pressure gradient
PCWP = pulmonary capillary wedge pressure
it
has
been
recommended
Only symptomatic patients with hemody-
study group consisted of mostly elderly female pa-
namically severe AS benefit from valve
tients (Table 1). Seventeen patients were taking anti-
replacement. Current guidelines therefore
hypertensive drugs.
recommend intervening in PLGAS when
STUDY PROTOCOL. Five to 7 days before the exercise
“clinical, hemodynamic and anatomic data
PLGAS = paradoxical low gradient aortic stenosis
SAC = systemic arterial
test, patients underwent clinical and echocardio-
support valve obstruction is the most likely
graphic enrollment examinations to ensure blood
cause of symptoms” (2). However, deter-
pressure control and to re-evaluate aortic valve
mining the clinical significance of PLGAS is
compliance
SACI = systemic arterial
sometimes difficult because of associated
compliance index
comorbidity (3). In addition, establishing the
SBP = systolic blood pressure
hemodynamic significance of PLGAS is chal-
SV = stroke volume
lenging. First, it is unclear which severity
Body surface area, m2
SVI = stroke volume index
criterion best accounts for the degree of
Body mass index, kg/m2
29 4
SvO2 = mixed venous
valvular obstruction. Second, Doppler echo-
Systolic cuff blood pressure, mm Hg
137 11
oxygen saturation
cardiography has limitations for measuring
Diastolic cuff blood pressure, mm Hg
68 13
SVRI = systemic vascular
AVA (4). We hypothesized that a compre-
Echocardiographic data
resistance index
hensive assessment of exercise hemody-
T A B L E 1 Clinical and Echocardiographic Data at Enrollment
Age, yrs
77 6
Female
17 (85)
Aortic valve mean pressure gradient, mm Hg
1.7 0.2
27 5
Aortic valve area, cm2
0.75 0.10
Aortic valve area index, cm2/m2
0.46 0.08
LV end-diastolic diameter, mm
43 4
in symptomatic patients with PLGAS. Symptomatic
LV end-systolic diameter, mm
29 3
patients with classical “high-gradient” severe AS
LV septal thickness, mm
12 2
exhibit a characteristic hemodynamic response to
LV posterior wall thickness, mm
exercise (5–10). Therefore, identifying this distinctive
LV end-diastolic volume, ml
VO2 = oxygen uptake
namic
variables
could
be
useful
for
understanding the mechanisms of exercise limitation
hemodynamic profile in PLGAS would favor a true hemodynamic significance. The present study was designed to assess the
11 1 62 12
LV end-systolic volume, ml
21 8
Ejection fraction, %
66 7
LV mass index, g/m2
94 26
E-wave, m/s
functional impact of PLGAS in symptomatic patients
0.72 0.30
E/A ratio
0.94 0.62
by characterizing their valvular and vascular response
e’, cm/s
4.4 1.3
to exercise by using Doppler echocardiography and
E/e’
16.3 5.8
right-heart cardiac catheterization. In addition, our goal was to analyze whether patients with low-flow PLGAS exhibit a singular hemodynamic response suggestive of a more severe disease than patients with normal-flow PLGAS.
Isovolumic relaxation time, ms II
19 (95)
III
1 (5)
Cardiovascular risk factors Hypertension
METHODS POPULATION. The
study
protocol
was
approved by the local institutional review board, and all subjects provided written informed consent. We studied 20 consecutive patients in sinus rhythm with
17 (85)
Diabetes
4 (20)
Dyslipidemia
15 (75)
Smoking
STUDY
83 19
NYHA functional class
0 (0)
Cardiovascular drugs ACE inhibitors
10 (50)
ARBs
4 (20)
Diuretics
8 (40)
Beta-blockers
8 (40)
exertional dyspnea (New York Heart Association
Aldosterone receptor antagonists
functional class higher than class I), AVA <1 cm2
Calcium antagonists
8 (40)
(indexed AVA <0.6 cm 2/m 2), mean transvalvular
Statins
15 (75)
pressure gradient <40 mm Hg, and ejection fraction >50%. Exclusion criteria were as follows: known or suspected ischemic heart disease, moderate or severe mitral valve disease or aortic regurgitation, pulmonary hypertension (baseline estimated pulmonary
1 (5)
Values are mean SD or n (%). ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; e0 ¼ early mitral annulus velocity; E ¼ early diastolic transmitral Doppler velocity; E/A ¼ ratio of the early to late transmitral filling Doppler velocities; LV ¼ left ventricular; NYHA ¼ New York Heart Association.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
Functional Significance of Low Gradient AS
stenosis severity (Table 1). Antihypertensive treatment was not withheld the day of the stress test.
n ¼ 60). Blood samples were obtained at rest, peak exercise, and recovery for SvO 2 calibration and B-type
Through the internal jugular vein, a Swan-Ganz
natriuretic peptide quantitation. Radial blood pres-
catheter was placed in the main pulmonary artery to
sure was monitored by using an indwelling arterial
continuously register pressures and mixed venous
catheter. Arterial saturation was measured by pulse
oxygen saturation (SvO 2) (Vigileo II monitor, Edwards
oximetry. Pressure readings and electrocardiography
Lifesciences, Irvine, California). Data were fed to a
signals were stored at 1,000 Hz.
computer every 2 s. Pulmonary capillary wedge
Patients were studied at rest and then underwent a
pressure (PCWP) was measured by transient catheter
symptom-limited bicycle-exercise test at 30 lateral
balloon inflation at baseline, peak exercise, and early
decubitus in a dedicated ergometer (Easystress, Eco-
recovery. After verification of a small and constant
gito Medical sprl, Liege, Belgium). Workload was
transvenous
initiated at 25 W and increased by 25 W every 3 min.
pressure
gradient,
we
interpolated
PCWP along the exercise period by using the linear
Expired gas CO 2 and O 2 content was continuously
regression equation between diastolic pulmonary
analyzed (Oxycon Delta, Jaeger, Würzburg, Ger-
pressure and PCWP data points (Pearson correlation
many). A hypertensive response was defined as a
[R] ¼ 0.91; intraclass correlation coefficient [Ric] ¼
radial SBP >210 mm Hg and 190 mm Hg for male
0.90
subjects
between
measured
and
estimated
values,
and
female
subjects,
respectively
(11).
F I G U R E 1 Synchronized Measurements of a Representative Patient
(A) Heart rate (black) and systemic arterial pressure (red, pink, and white) measurements. (B) Pulmonary pressures. (C) Mixed venous saturation (SvO2) (blue) and stroke volume (SV) (green). (D) Cardiac output (yellow). (E) Gas exchange (red and blue). Instantaneous workload is overlaid in grey and the instant of peak oxygen uptake (VO2) is depicted by the arrowhead. PCWP ¼ pulmonary capillary wedge pressure; VCO2 ¼ carbon dioxide production.
3
Pérez del Villar et al.
4
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
A hypotensive response was defined as the inability
DATA ANALYSIS. A multidimensional data matrix
to increase SBP $20 mm Hg. A comprehensive ultra-
was generated for each patient that stored synchro-
sound examination was performed at rest using 2.0-
nized invasive and noninvasive signals with a tem-
to 4.0-MHz transducers on a Vivid 7 or Vivid 9 system
poral resolution of 5 s (custom-built registration and
(GE Healthcare, Little Chalfont, United Kingdom).
interpolation
Doppler tracings of transvalvular and LV outflow tract
Natick, Massachusetts]) (Figure 1). Continuous cardiac
velocities were acquired at the end of each stage,
output and stroke volume index (SVI) were calculated
peak stress, and recovery.
during exercise by using the Fick method from base-
algorithms;
MATLAB
[MathWorks,
line hemoglobin concentration and instantaneous values of arterial saturation, SvO 2, and oxygen uptake (VO 2) (12). Thermodilution cardiac output at baseline and early recovery was measured to check the Fick
T A B L E 2 Hemodynamic Changes Induced by Exercise
method. AVA was calculated from the ratio between
Baseline
50% of DVO2
Peak VO2
VO2, ml/kg/min
2.9 0.9
7.3 2.3*
10.4 4.2*
VCO2, ml/kg/min
2.9 0.9
6.1 1.4*
10.5 3.1*
Doppler time velocity integral. The systemic vascular
Heart rate, beats/min
76 13
101 20*
110 19*
resistance index (SVRI) was estimated as the ratio
SvO2, %
70 15
52 18*
46 18*
between mean radial pressure and cardiac index.
Cardiac index, l/min/m2
2.7 0.9
4.0 1.4*
5.6 2.5*
Total systemic arterial compliance index (SACI) was
Stroke volume index, ml/m2
33 11
43 15*
59 25*
Doppler-derived stroke volume index, ml/m2
36 8
38 11
40 12*
Systolic ejection period, ms
328 43
301 40*
305 54*
Mean systolic transvalvular flow rate, ml/s
165 52
231 67*
316 106*
Systolic blood pressure, mm Hg
159 19
190 21*
199 24*
Mean blood pressure, mm Hg
105 13
125 11*
128 13*
valvular pressure gradient (MG), systolic ejection
73 11
84 10*
86 12*
period, LV outflow tract diameter, and Doppler-
Systemic arterial hemodynamics
Diastolic blood pressure, mm Hg
3,424 1311 2,743 895* 2,128 818*
Systemic vascular resistance index, dyn$s/cm5/m2
0.39 0.13
Systemic arterial compliance index, ml/m2/mm Hg
0.42 0.17
0.53 0.22*
Fick-derived stroke volume (SV) and the aortic valve
estimated as the ratio between SVI and pulse pressure. Pulmonary vascular resistance index was calculated as follows: (mean pulmonary artery pressure – PCWP)/cardiac index. Doppler-derived
SVI
(SVIDoppler),
mean
trans-
derived AVA were measured as recommended (4). The LV outflow tract diameter was assumed constant during exercise (8,9,13). Baseline LV volumes and
Pulmonary hemodynamics
ejection fraction were measured using the biplane
Systolic pulmonary artery pressure, mm Hg
30 13
53 17*
60 21*
Mean pulmonary artery pressure, mm Hg
21 9
38 13*
41 14*
Diastolic pulmonary artery pressure, mm Hg
13 7
26 11*
30 12*
Estimated pulmonary capillary wedge pressure, mm Hg
12 6
23 9
26 10*
Transpulmonary gradient, mm Hg
10 6
14 7*
15 8*
24
36
46
Pulmonary vascular resistance index, dyn$s/cm5/m2
723 512
876 554*
751 493
Pulmonary arterial compliance index, ml/m2/mm Hg
2.55 1.71
2.11 1.76
2.64 2.57
Transpulmonary venous pressure gradient, mm Hg
Simpson’s method. Values of systolic longitudinal strain and strain rate were obtained from apical 4chamber views at baseline and peak stress using speckle-tracking (EchoPAC version 112, GE Medical Systems,
Waukesha,
Wisconsin).
Valvuloarterial
impedance was calculated as follows: ðSBP þ MGÞ=SVI. Mean systolic flow rate was computed as SV/ejection period. The following composite variables were estimated by the linear mixed effects fitting from the instan-
Aortic valve stenosis 3.4 0.4
Peak transvalvular velocity, m/s Mean transvalvular pressure gradient, mm Hg
25 6
3.7 0.5* 31 9*
4.0 0.6* 35 14*
taneous exercise data obtained for each patient. Valve
compliance,
designating
the
capacity
of
1.23 0.42*
increasing AVA, was obtained as the slope of the AVA
0.43 0.15
0.55 0.18* 0.78 0.39*
versus flow rate relationship (cm 2 per ml/s) (14). The
Aortic valve area, Doppler-derived, cm
0.74 0.12
0.81 0.16* 0.85 0.20*
Aortic valve velocity ratio (dimensionless)
0.25 0.05 0.27 0.05
0.71 0.18 0.89 0.21*
Aortic valve area, cm2 Aortic valve area index, cm2/m2 2
Valvuloarterial impedance, mm Hg/ml/m2
6.2 2.3
5.8 2.2
0.28 0.07 4.5 1.6*
Strain analysis Peak systolic longitudinal strain, % Peak systolic longitudinal strain rate, /s Peak early diastolic longitudinal strain, /s
–16.9 3.7
—
–0.9 0.2
—
1.0 0.4
–18.3 4.9 –1.1 0.3* 1.6 0.7*
SVI versus VO 2 (ml/m2 per ml/kg/min). This slope has shown to be flat in classical “high-gradient” severe AS (5–9). The PCWP slope was obtained as the PCWP versus VO2 relationship (mm Hg per ml/kg/min). The SVRI slope and the SACI slope, respectively,
Biomarkers B-type natriuretic peptide, pg/ml
SVI slope, defined as the capacity to increase SV during exercise, was calculated as the linear slope of
107 111
—
123 20*
Values are mean SD. *p < 0.05 versus baseline (Dunnet contrast). VO2 ¼ oxygen consumption; VCO2 ¼ carbon dioxide production; SvO2 ¼ mixed venous oxygen saturation.
account for the capacity of the systemic arterial tree to lower its resistance and increase compliance during exercise; they were measured as the linear SVRI versus VO 2 (dyn$s/cm 5/m 2 per ml/kg/min) and
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
Functional Significance of Low Gradient AS
SACI versus VO 2 (ml/m 2/mm Hg per ml/kg/min)
unchanged (0.75 0.10 vs. 0.74 0.12 cm 2; p ¼ 0.69).
relationships.
At rest, mean SVRI was abnormally high (2,056 701
STATISTICAL ANALYSIS. Measurements obtained at
dyn$s/cm 5/m 2), and SACI was low (0.4 0.1 ml/m 2/
baseline, at 50% of the increase from baseline to peak
mm Hg) (Table 2). Low-flow (SVI <35 ml/m 2) was
VO 2 (50% – D VO 2), and at peak VO 2 were compared by
present in 10 patients.
using linear mixed effects models accounting for
AGREEMENT BETWEEN INVASIVE AND NONINVASIVE
repeated measures followed by Dunnett contrasts
INDICES. Good agreement was observed between
(R version 3.2, R Foundation for Statistical Com-
Fick and thermodilution methods for measuring SVI
puting, Vienna, Austria). We obtained the aforemen-
(R ic ¼ 0.86) (Figure 2). At rest, good agreement was
tioned composite slope variables from mixed effects
observed between Fick- and Doppler-derived mea-
models of the within-subject relationship of the
surements of SVI and AVA (R ¼ 0.82 and R ic ¼ 0.79 for
hemodynamic parameters during exercise (fixed þ
SVI, respectively; R ¼ 0.80 and R ic¼ 0.76 for AVA). At
random effects). Univariate and multivariate linear
peak VO 2, both methods were still highly correlated
regression models were used to assess the predictors
(R ¼ 0.81 and 0.89 for SVI and AVA), but their
of the PCWP slope during exercise. Variables in
agreement was lower (R ic ¼ 0.32 and 0.44 for SVI and
multivariate models were selected by backward
AVA). At 50%- DVO2 , agreement was acceptable for
elimination based on Akaike information criterion.
SVI and AVA (R ic ¼ 0.72 and 0.67).
The Pearson correlation (R) and intraclass correlation
VALVULAR AND HEMODYNAMIC CHANGES. Indices
(R ic) coefficients were used to assess concordance.
of AS changed with exercise: AVA increased by 84
Values of p < 0.05 were considered significant.
23% (p < 0.0001) (Figure 3). Mean valve compliance was 0.003 0.001 cm 2 per ml/s, but there was high
RESULTS
individual variability (range 0.000 to 0.005 cm2 per BASELINE HEMODYNAMICS. After instrumentation,
ml/s of increase in flow). This outcome led to AVA
17 patients (85%) had a radial SBP >150 mm Hg.
values at peak exercise >1.0 cm2 in 70% of subjects.
Although this finding led to a MG slightly lower
No patient had a flat or hypotensive blood pressure
than at enrollment (25 6 vs. 27 5 mm Hg;
response, whereas 9 (45%) experienced a hyperten-
¼
0.001),
Doppler-derived
AVA
sive response. SBP increased 40 23 mm Hg from
remained
F I G U R E 2 Agreement Between Methods Used to Measure SVI
25
0
10
20
30
40
50
Average Thermodilution & Fick (ml/m2)
Baseline
Recovery
50
C
Ric = 0.79
25
0
20
30
40
Average Fick & Doppler (ml/m2)
Baseline
50
50
D
Ric = 0.72
Fick - Doppler (ml/m2)
Ric = 0.86
Fick - Doppler (ml/m2)
50
B
Fick - Doppler (ml/m2)
A Thermodilution - Fick (ml/m2)
p
25
0
30
40
50
Average Fick & Doppler (ml/m2)
50% of Δ VO2
60
50
Ric = 0.32
25
0
40
60
Peak VO2
(A) Fick versus thermodilution measurements obtained at baseline (pink) and during recovery (green). (B–D) Fick-derived versus Doppler echocardiography measurements (B) obtained at baseline, (C) 50% of the increase in VO2, and (D) peak VO2. Black dotted lines show the bias and 1.96 $ SD agreement limits between techniques. SVI ¼ stroke volume index; VO2 ¼ oxygen uptake.
80
Average Fick & Doppler (ml/m2)
5
Pérez del Villar et al.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
F I G U R E 3 Acute Changes in Valve Hemodynamics Induced by Exercise
A
B
C
70
2.5
500 60 2.0
400
300
200
50
Aortic Valve Area (cm2)
Mean Pressure Gradient (mm Hg)
Mean Systolic Transvalvular Flow Rate (ml/s)
6
40
1.5
1.0
30
20
0.5
100 10 Baseline
Low VO2 Peak VO2
Baseline
Phase
Low VO2
Peak VO2
Phase
Baseline
Low VO2
Peak VO2
Phase
Scatterplots and boxplots show the distributions of (A) mean systolic flow rate, (B) pressure gradient, and (C) aortic valve area. Values are shown at baseline, at the 50% increase from baseline to peak oxygen uptake (VO2) (low VO2), and at peak VO2. Boxplots show the median (black thick line), the 95% confidence interval for the median (waist), the 25 and 75% quartiles, and distribution limits without outliers (vertical lines).
baseline to peak VO 2, despite a significant decrease in
arterial compliance index (the SACI slope) and valve
SVRI and an increase in SACI (Figure 4, Table 2). SVI
compliance were powerful determinants of the PCWP
linearly increased an 83 56% during exercise,
slope (Table 3). No baseline hemodynamic index
following an average slope of 2.67 2.76 ml/m 2 per
predicted the PCWP response. Values of PCWP and
ml/kg/min increase in VO 2 (Figures 4 and 5). Again,
SVI at peak VO 2 inversely correlated (R ¼ –0.60;
there were huge individual variations in these slopes
p ¼ 0.005). The hemodynamic responses were not
(range –0.49 to 11.14 ml/m 2 per ml/kg/min).
significantly different between low-flow patients and
Pulmonary pressures and PVRI increased linearly
normal-flow patients (Table 4); they also did not
during exercise (Figure 4, Table 2). PCWP reached
correlate with baseline SVI when the latter was
>16 mm Hg at peak VO 2 in 16 (80%) patients. The
analyzed as a continuous variable.
increase in natriuretic peptide from baseline to peak exercise correlated with the increase in PCWP (R ¼ 0.67; p ¼ 0.009).
DISCUSSION The present study helps to clarify a number of issues
MECHANISMS OF FUNCTIONAL IMPAIRMENT. Exer-
regarding the significance of PLGAS. First, combined
cise capacity inversely correlated with the PCWP
Doppler- and Fick-derived measurements during ex-
slope: the steeper the PCWP increase during exercise,
ercise showed that the aortic valve has a relatively
the lower peak VO 2 values achieved (R ¼ –0.61;
large residual opening reserve. Second, baseline
p ¼ 0.004) (Figure 6). In turn, the capacity to increase
indices of LV valvular and vascular load did not
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
7
Functional Significance of Low Gradient AS
F I G U R E 4 Changes in Vascular Hemodynamics Induced by Exercise
A
B
C
D
125 40
50
4000
2000
PCWP (mm Hg)
75
SACI (ml/m2/mm Hg)
SVRI (dyn·s/cm5/m2)
SVI (ml/m2)
100
0.9
6000
0.6
0.3
Low VO2
Baseline
Peak VO2
Phase
Low VO2
Peak VO2
20
10
25
Baseline
30
Baseline
Phase
Low VO2
Peak VO2
Baseline
Phase
Low VO2
Peak VO2
Phase
Scatterplots and boxplots show the distributions of (A) SVI, (B) systemic vascular resistance index (SVRI), (C) systemic arterial compliance index (SACI), and (D) PCWP. Abbreviations as in Figures 1 and 2.
correlate with the degree of functional impairment or
gradient disease. Fourth, we identified important
exercise-induced hemodynamic transients. Third,
dynamic ventricular–vascular interactions that con-
symptomatic patients with PLGAS did not exhibit the
dition the impact of exercise on PCWP, which, in turn,
characteristic exercise response of patients with high-
correlates with the functional capacity of these
F I G U R E 5 Changes in SVI for All Patients
5
10 15
5
10 15 150 100 50
150 100
SVI (ml/m2)
50 150 100 50 150 100 50 5
10 15
5
10 15
5
10 15
VO2 (ml/kg/min) The individual response group is shown by the green line. The average response for the full sample is shown by the red dotted line. Abbreviations as in Figures 1 and 2.
Pérez del Villar et al.
8
JACC: CARDIOVASCULAR IMAGING, VOL.
F I G U R E 6 Correlation Between the PCWP Slope and Peak Oxygen Consumption
vascular function on pulmonary pressures. PCWP increased faster in patients who had a limited valve opening reserve and a lower capacity to lower SAC. In
C
addition, a faster rise in PCWP determined a lower PCWP (mm Hg)
A
functional capacity. The relationship we observed
30
between valve compliance and the rate of increase of
20
PCWP explains why valve compliance is a better
10
predictor of exertional symptoms than resting AVA (14). 5 10 15 VO2 (ml/kg/min)
15
interactions
between
valvular
and
also help to clarify why impaired outcome in AS is related to exercise responses such as limited valve opening
PCWP (mm Hg)
10
These
vascular dynamics, PCWP, and functional capacity
B Peak VO2 (ml/kg/min)
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
reserve
(16,17),
abnormal
arterial
hemodynamics (7,18), exercise-induced pulmonary
30
hypertension (19), high increments of natriuretic
20
peptides (20), and low peak VO 2 (21).
10
THE VASCULAR TREE IN PLGAS. In AS, LV afterload 5 10 15 VO2 (ml/kg/min)
depends on the additive effects of valvular obstruction and vascular load (1,6,7,22–25), and increased vascular load may contribute to the high morbidity and mortality rates sometimes observed in patients
5
with this condition (1,23). The values of vascular load observed at rest in the present study are similar to R = -0.61 p = 0.005
invasive measures previously reported in patients with low-gradient AS and higher than values obtained
0
2.5
5
7.5
in patients with high-gradient severe or moderate AS
PCWP/VO2 Slope (mm Hg/ml/kg/min)
(26). Beyond baseline characterization, our study emphasizes the importance of analyzing dynamic
(A) Inverse correlation between the PCWP versus VO2 slope and the peak VO2 for each
vascular reflexes in the evaluation of AS hemody-
patient. Inserts show extreme responses for (B) a patient with a steep slope (rapid PCWP
namics (24).
increase) who achieves a low peak VO2 and (C) a patient with a relatively flat slope (slow PCWP increase) who achieves a high peak VO2. Abbreviations as in Figure 1.
Current evidence supports that systemic hypertension can influence the evaluation of AS severity (18,25,27), frequently leading to AVA underestimation (18). For this reason, in hypertensive patients with
patients. Fifth, we were unable to find functional differences among patients with normal-flow PLGAS and low-flow PLGAS. FUNCTIONAL
SIGNIFICANCE
low-gradient AS, AS severity and functional status should always be evaluated after controlling blood pressure (2,28). Although achieving recommended blood pressure goals may be difficult in elderly pa-
OF
PLGAS. Valve
tients, our findings suggest that, even when blood
compliance allowed a relatively large effective area
pressure is not completely under control, exercise
opening at peak stress (14). By acutely lowering
may be useful to unmask a load-mediated underes-
afterload, the combined effects of enlarging area and
timation of AVA.
increasing SAC facilitate raising SV during exercise. Consequently, blood pressure can rise despite the fact
STRESS ECHOCARDIOGRAPHY IN PLGAS. Because
that systemic vascular resistance drops due to exer-
all indices of AS are, to a certain degree, flow
cise. Symptomatic patients with high-gradient severe
dependent, a baseline assessment of the obstruction
AS characteristically exhibit a different behavior. The
severity may be insufficient. On this basis, stress
SV of patients with severe high-gradient AS is typi-
echocardiography may be useful in particular groups
cally fixed, falling, or remaining constant when they
(6,8,9,16). However, an indiscriminate use of exercise
exercise, as consistently demonstrated by invasive
tests in patients with symptomatic AS is hazardous
(5–7,15) and noninvasive (9,13) studies.
and formally contraindicated. In accordance with
Importantly, to the best of our knowledge this is
previous studies (16), our findings suggest that the
the first study in patients with AS that demonstrates
technique is safe in patients with PLGAS under care-
the influence of dynamic changes of valvular and
ful monitoring. Furthermore, we demonstrated that
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
exercise echocardiography provides an objective assessment of functional capacity and identifies the
9
Functional Significance of Low Gradient AS
T A B L E 3 Determinants of the Rate of Rise of PCWP During Exercise
(PCWP Versus VO 2 Slope)
hemodynamic valvular and vascular changes related Univariate
to symptoms. By head-to-head validation, we found
R
p Value
Sex
–
0.33
Age
–0.03
0.87
that stress echocardiography was reliable up to intermediate workload. In addition, exercise-mediated valvular and vascular trends were highly linear (Figures 5 and 6), and most relevant hemodynamic
Aortic valve area
0.29
0.2
Mean pressure gradient
0.24
0.3
Further clinical studies should establish the definitive
Systemic vascular resistance index
–0.2
0.51
role of exercise echocardiography in patients with
Stroke volume index
0.1
0.67
PLGAS.
Diastolic pulmonary artery pressure
0.08
0.72
Systemic arterial compliance
0.8
0.73
CLINICAL DECISION-MAKING IN PLGAS. The indi-
BNP
–0.2
0.4
cation of valve replacement in symptomatic PLGAS is
E/A
–0.2
0.5
still an unsolved issue. As previously discussed,
E/e’
–0.05
0.84
some investigators have identified a high systemic
Peak systolic longitudinal strain
0.00
0.98
vascular load that greatly increases global LV after-
Peak systolic longitudinal strain rate
0.17
0.49
–0.17
0.48
PLGAS would account for an advanced form of AS
Peak early diastolic longitudinal strain Zva/VO2 slope
0.36
0.11
–0.47
0.08
(29,30) and worse prognosis (1,31). However, the
Valve compliance
–0.63
0.002
underestimation of SV by Doppler echocardiography
Mean G/VO2 slope
0.27
SBP/VO2 slope
0.35
0.12
may cause overestimation of AS. Our study supports
SVRI/VO2 slope
0.03
0.91
SACI/VO2 slope
–0.59
Doppler technique but of the limitations of baseline AVA to define severity. Our study showed that symptomatic PLGAS does not share the functional
–779
–0.5
0.009
–36
–0.41
0.03
0.25
(3) and the inconsistency of AS severity criteria (32) that PLGAS is not a consequence of errors of the
p Value
Dynamic indices
D BNP
with more structural and functional LV impairment
Standardized b
Baseline indices
changes were observed early (Figure 3, Table 2).
load and reduces SV in PLGAS (1). Consequently,
Multivariate
b
0.006
BNP ¼ B-type natriuretic peptide; PCWP ¼ pulmonary capillary wedge pressure; SACI ¼ systemic arterial compliance index; SBP ¼ systolic blood pressure; SVRI ¼ systemic vascular resistance index; Zva ¼ valvuloarterial impedance; other abbreviations as in Tables 1 and 2.
behavior of high-gradient AS. Although patients with PLGAS may be symptomatic due to exertional dyspnea, they frequently achieve large effective AVA values when required. Peak flow AVA values in this study were sometimes actually larger than effective areas of several prosthetic valves. Thus, the functional results of our study do not support a critical LV outflow obstruction at the time of presentation of PLGAS. With the limitations of small sample groups, we were unable to identify a clearly different hemodynamic behavior between patient groups with low-
dioxide resulting from an increase in heart rate (12). However, in our study, patients underwent submaximal exercise, with SV not reaching a plateau. Thus, a relatively large increase in Fick-derived SV during the second exercise phase resulted in relatively small changes in SvO 2 and heart rate despite large increases in VO 2. This finding is somewhat paradoxical, and we cannot exclude a certain degree of error in the estimation of reference SV at peak VO 2. However, we did our best to ensure maximal quality signals
flow PLGAS and normal-flow PLGAS. Furthermore, when analyzed as a continuous variable, baseline SVI values did not correlate with the PCWP slope or the
T A B L E 4 Differences in Hemodynamic Behavior Between the Low-Flow PLGAS
Group Versus the Normal-Flow PLGAS Group
degree of valve compliance during exercise. Thus, in pure hemodynamic terms, there seems to be no
N (%) of patients
SVI > 35 ml/m 2
SVI < 35 ml/m2
10 (50)
10 (50)
p Value
functional difference between normal-flow PLGAS
Valve compliance, cm2 per ml/s
0.003 0.002
0.004 0.001
0.2
and low-flow PLGAS.
SV slope, ml/m2 per ml/kg/min
4.3 2.4
2.9 1.8
0.2
STUDY LIMITATIONS. During exercise, the agree-
ment of the Fick technique with Doppler echocardi-
PCWP slope, mm Hg per ml/kg/min SAC slope, ml/m2/mm Hg per ml/kg/min Peak AVA, cm2
3.1 3.8
2.0 1.3
0.4
0.028 0.028
0.023 0.025
0.7
1.3 0.5
1.1 0.3
0.3
ography was good up to intermediate workload, but some discrepancy was shown at peak exercise. Pre-
Values are mean SD.
vious studies have shown a SV plateauing with ex-
AVA ¼ aortic valve area; PLGAS ¼ paradoxical low gradient aortic stenosis; SV ¼ stroke volume; SVI ¼ stroke volume index; other abbreviations as in Table 3.
ercise and most of the subsequent rise in carbon
10
Pérez del Villar et al.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Functional Significance of Low Gradient AS
and performed ad hoc thermodilution validation
vascular resistance. Their capacity to lower vascular
measurements. In addition, the correlations we
and valvular load affects the rate of their rise in
observed between VO 2 and simultaneous pulmonary
PCWP, which, in turn, is the major determinant of
pressures further support our findings. Moreover,
their functional status. As opposed to patients with
most relevant pulmonary and systemic hemodynamic
high-gradient AS, the exercise hemodynamic pattern
changes were observed at early phases, when there
suggests that the valvular obstruction may not be
was a good match between the Doppler and Fick
functionally significant in a relatively large propor-
methods.
tion of patients with PLGAS.
The inclusion of a matched group of patients with high-gradient AS would have reinforced our findings.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Despite
Raquel Yotti, Department of Cardiology, Hospital
careful
adjustment
of
antihypertensive
drugs, blood pressure was elevated immediately
General
before exercise in a number of patients. However, all
Esquerdo 46. 28007 Madrid, Spain. E-mail: raquel.
patients fulfilled criteria for LGAS at enrollment. High
[email protected].
Universitario
Gregorio
Marañón,
Dr.
blood pressure values probably were related to the catheterization procedure itself, underscoring the
PERSPECTIVES
clinical difficulties in defining an adequate blood pressure control with isolated cuff measurements. Importantly, exercise tests in our study were performed under careful invasive hemodynamic monitoring; thus, the results cannot be used to support the widespread use of exercise tests in severe AS. Because of the study’s complexity, we were unable to analyze the ventricular compartment comprehensively; however, albeit limited to single-plane acquisitions, LV strain measurements did not predict the PCWP slope. Finally, despite careful measurement of transvalvular Doppler velocities during exercise, a potential underestimation of aortic velocities could account for some degree of overestimation in the AVA.
COMPETENCY IN MEDICAL KNOWLEDGE: In elderly patients with PLGAS, the AVA is highly dynamic. In these patients, exercise induces an increase in AVA and a reduction in vascular load, which allows the SV to increase. This hemodynamic pattern is different from classical high-gradient severe AS. COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Unmasking the underlying hemodynamic mechanisms of functional impairment in PLGAS can be achieved by using stress echocardiography. TRANSLATIONAL OUTLOOK: Our study suggests that in patients with PLGAS, the hemodynamic response to exercise could add valuable information
CONCLUSIONS
to evaluate the indication of valve replacement, but
In these study patients with PLGAS, combined ultrasound and invasive hemodynamic techniques found that AVA was highly dynamic and flow dependent. Patients with PLGAS typically had increased blood
large-scale studies are needed. Previous mathematical simulation studies suggesting the interaction between valvular, vascular, and ventricular function are confirmed in the clinical setting.
pressure and SV during exercise despite a fall in
REFERENCES 1. 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;115:2856–64.
4. Baumgartner H, Hung J, Bermejo J, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 2009;22: 1–23.
2. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart
5. Bache RJ, Wang Y, Jorgensen CR. Hemodynamic effects of exercise in isolated valvular aortic stenosis. Circulation 1971;44:1003–13.
Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57–185. 3. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96.
6. Laskey WK, Kussmaul WG, Noordergraaf A. Valvular and systemic arterial hemodynamics in aortic valve stenosis. A model-based approach. Circulation 1995;92:1473–8. 7. Laskey WK, Kussmaul WG 3rd, Noordergraaf A. Systemic arterial response to exercise in patients
with aortic valve stenosis. Circulation 2009;119: 996–1004. 8. Burwash IG, Pearlman Miyake-Hull C, Healy NL, Otto dence of measures of aortic during exercise. J Am Coll 1342–50.
AS, Kraft CD, CM. Flow depenstenosis severity Cardiol 1994;24:
9. Bermejo J, Garcia-Fernandez MA, Torrecilla EG, et al. Effects of dobutamine on Doppler echocardiographic indexes of aortic stenosis. J Am Coll Cardiol 1996;28:1206–13. 10. Otto CM, Burwash IG, Legget ME, et al. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Pérez del Villar et al.
- 2016:-–-
predictors 2262–70.
of
outcome.
Functional Significance of Low Gradient AS
Circulation
1997;95:
asymptomatic valvular aortic stenosis. Eur J Echocardiogr 2008;9:338–43.
11. Schultz MG, Otahal P, Cleland VJ, Blizzard L, Marwick TH, Sharman JE. Exercise-induced hypertension, cardiovascular events, and mortality in
18. Eleid MF, Nishimura RA, Sorajja P, Borlaug BA.
patients undergoing exercise stress testing: a systematic review and meta-analysis. Am J Hypertens 2013;26:357–66. 12. Nakanishi N, Yoshioka T, Okano Y, Nishimura T. Continuous Fick cardiac output measurement during exercise by monitoring of mixed venous oxygen saturation and oxygen uptake. Chest 1993; 104:419–26. 13. Otto CM, Pearlman AS, Kraft CD, MiyakeHull CY, Burwash IG, Gardner CJ. Physiologic changes with maximal exercise in asymptomatic valvular aortic stenosis assessed by Doppler echocardiography. J Am Coll Cardiol 1992;20: 1160–7. 14. Das P, Rimington H, Smeeton N, Chambers J. Determinants of symptoms and exercise capacity in aortic stenosis: a comparison of resting haemodynamics and valve compliance during dobutamine stress. Eur Heart J 2003;24:1254–63. 15. Clyne CA, Arrighi JA, Maron BJ, Dilsizian V, Bonow RO, Cannon RO 3rd Systemic and left ventricular responses to exercise stress in asymptomatic patients with valvular aortic stenosis. Am J Cardiol 1991;68:1469–76. 16. Clavel MA, Ennezat PV, Marechaux S, et al. Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF. J Am Coll Cardiol Img 2013;6: 175–83. 17. Lancellotti P, Karsera D, Tumminello G, Lebois F, Pierard LA. Determinants of an abnormal response to exercise in patients with
Systemic hypertension in low-gradient severe aortic stenosis with preserved ejection fraction. Circulation 2013;128:1349–53. 19. Lancellotti P, Magne J, Donal E, et al. Determinants and prognostic significance of exercise pulmonary hypertension in asymptomatic severe aortic stenosis. Circulation 2012;126: 851–9. 20. Capoulade R, Magne J, Dulgheru R, et al. Prognostic value of plasma B-type natriuretic peptide levels after exercise in patients with severe asymptomatic aortic stenosis. Heart 2014; 100:1606–12. 21. Dhoble A, Enriquez-Sarano M, Kopecky SL, et al. Cardiopulmonary responses to exercise and its utility in patients with aortic stenosis. Am J Cardiol 2014;113:1711–6. 22. Briand M, Dumesnil JG, Kadem L, et al. Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment. J Am Coll Cardiol 2005;46: 291–8. 23. Hachicha Z, Dumesnil JG, Pibarot P. Usefulness of the valvuloarterial impedance to predict adverse outcome in asymptomatic aortic stenosis. J Am Coll Cardiol 2009;54:1003–11. 24. Yotti R, Bermejo J, Gutierrez-Ibanes E, et al. Systemic vascular load in calcific degenerative aortic valve stenosis: insight from percutaneous valve replacement. J Am Coll Cardiol 2015;65: 423–33. 25. Bermejo J. The effects of hypertension on aortic valve stenosis. Heart 2005;91:280–2.
26. Eleid MF, Nishimura RA, Borlaug BA, Sorajja P. Invasive measures of afterload in low gradient severe aortic stenosis with preserved ejection fraction. Circ Heart Fail 2013;6:703–10. 27. Little SH, Chan KL, Burwash IG. Impact of blood pressure on the Doppler echocardiographic assessment of severity of aortic stenosis. Heart 2007;93:848–55. 28. Lindman BR, Otto CM. Time to treat hypertension in patients with aortic stenosis. Circulation 2013;128:1281–3. 29. Dumesnil JG, Pibarot P, Carabello B. Paradoxical low flow and/or low gradient severe aortic stenosis despite preserved left ventricular ejection fraction: implications for diagnosis and treatment. Eur Heart J 2010;31:281–9. 30. Adda J, Mielot C, Giorgi R, et al. Low-flow, low-gradient severe aortic stenosis despite normal ejection fraction is associated with severe left ventricular dysfunction as assessed by speckle-tracking echocardiography: a multicenter study. Circ Cardiovasc Imaging 2012;5: 27–35. 31. Clavel MA, Dumesnil JG, Capoulade R, Mathieu P, Senechal M, Pibarot P. Outcome of patients with aortic stenosis, small valve area, and low-flow, low-gradient despite preserved left ventricular ejection fraction. J Am Coll Cardiol 2012;60:1259–67. 32. 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 2008;29: 1043–8.
KEY WORDS aortic valve stenosis, hemodynamics, vascular function
11