1. Art and Diseño

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 65, NO. 5, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.10.067
Systemic Vascular Load in
Calcific Degenerative Aortic Valve Stenosis
Insight From Percutaneous Valve Replacement
Raquel Yotti, MD, PHD,* Javier Bermejo, MD, PHD,* Enrique Gutiérrez-Ibañes, MD,* Candelas Pérez del Villar, MD,*
Teresa Mombiela, MD,* Jaime Elízaga, MD, PHD,* Yolanda Benito, DCS, DVM,* Ana González-Mansilla, MD, PHD,*
Alicia Barrio, DCS, MBIOL,* Daniel Rodríguez-Pérez, PHD,y Pablo Martínez-Legazpi, MENG, PHD,z
Francisco Fernández-Avilés, MD, PHD*
ABSTRACT
BACKGROUND Systemic arterial load impacts the symptomatic status and outcome of patients with calcific degenerative aortic stenosis (AS). However, assessing vascular properties is challenging because the arterial tree’s behavior
could be influenced by the valvular obstruction.
OBJECTIVES This study sought to characterize the interaction between valvular and vascular functions in patients with
AS by using transcatheter aortic valve replacement (TAVR) as a clinical model of isolated intervention.
METHODS Aortic pressure and flow were measured simultaneously using high-fidelity sensors in 23 patients (mean
79 7 years of age) before and after TAVR. Blood pressure and clinical response were registered at 6-month follow-up.
RESULTS Systolic and pulse arterial pressures, as well as indices of vascular function (vascular resistance, aortic input
impedance, compliance, and arterial elastance), were significantly modified by TAVR, exhibiting stiffer vascular behavior
post-intervention (all, p < 0.05). Peak left ventricular pressure decreased after TAVR (186 36 mm Hg vs. 162 23
mm Hg, respectively; p ¼ 0.003) but remained at >140 mm Hg in 70% of patients. Wave intensity analysis showed
abnormally low forward and backward compression waves at baseline, increasing significantly after TAVR. Stroke volume
decreased (21 19%; p < 0.001) and correlated with continuous and pulsatile indices of arterial load. In the 48 h
following TAVR, a hypertensive response was observed in 12 patients (52%), and after 6-month follow-up, 5 patients
required further intensification of discharge antihypertensive therapy.
CONCLUSIONS Vascular function in calcific degenerative AS is conditioned by the upstream valvular obstruction that
dampens forward and backward compression waves in the arterial tree. An increase in vascular load after TAVR limits the
procedure’s acute afterload relief. (J Am Coll Cardiol 2015;65:423–33) © 2015 by the American College of Cardiology
Foundation.
C
alcific degenerative aortic valve stenosis
the symptomatic status and outcome of these pa-
(AS)
Western
tients (1–3). In AS, left ventricular (LV) afterload is
countries. For a given degree of valve
abnormally high because concentric remodeling and
obstruction, systemic arterial properties may impact
hypertrophy are insufficient to compensate for the
has
become
endemic
in
From the *Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria
Gregorio Marañón, and Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain; yDepartment of Mathematical
Physics and Fluids, Facultad de Ciencias, Universidad Nacional de Educación a Distancia, Madrid, Spain; and the zMechanical and
Aerospace Engineering Department, University of California San Diego, San Diego, California. This study was supported by
Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain, grants PIS09/02602, PIS012/02878, RD12/0042,
CM12/00273 (to Dr. Perez del Villar), and CM11/00221 (to Dr. Mombiela). Drs. Mombiela, González-Mansilla, and del Villar were
partially supported by grants from the Fundación para Investigación Biomédica Gregorio Marañón, Spain. Dr. Martínez-Legazpi
was supported by U.S. National Institutes of Health grant 1R21 HL108268-01. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose. This work was presented in part at the Scientific Sessions of the
American Heart Association, 2012, Los Angeles, California, November 4 to 7; abstract A15474.
Manuscript received August 5, 2014; revised manuscript received October 13, 2014, accepted October 21, 2014.
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ABBREVIATIONS
additive effects of valvular obstruction and
AND ACRONYMS
vascular load (4). Thus, vascular stiffness
may be a source of LV systolic and diastolic
AS = aortic stenosis
dysfunctions
BCW = backward compression
wave
C = compliance
Ea = systemic arterial elastance
FCW = forward compression
wave
in
patients
with
moderate
degrees of valve obstruction (3). This mecha-
T A B L E 1 Baseline Clinical and Demographic Data (N ¼ 23)
79 7
Age, yrs
Female
11 (47)
Body surface area, m2
1.68 0.15
NYHA functional class III or IV
9 (39)
nism helps explain abnormally high mor-
Logistic EuroSCORE
10 7
bidity and mortality rates in patients with
Coronary heart disease
10 (43)
AS for whom classical obstruction indices
Chronic kidney disease
7 (30)
fail to predict outcomes (2).
Mitral regurgitation (grade > mild)
7 (30)
Cardiovascular risk factors
SVI = stroke volume index
SEE PAGE 434
TAVR = transcatheter aortic
valve replacement
WIA = wave intensity analysis
Hypertension
Characterizing intrinsic properties of the
arterial tree remains particularly challenging
in AS because of the difficulties of uncou-
Z = impedance
Zc = characteristic impedance
17 (74)
Diabetes
11 (48)
Dyslipidemia
12 (52)
Smoking
4 (17)
Taking cardiovascular treatment
pling valvular and vascular functions in vivo
ACEIs/ARBs
17 (74)
(5). Acute and chronic interventions on either
Diuretics
17 (73)
compartment cause reciprocal changes in the other.
For instance, changes in vascular resistance caused
by vasodilators (6,7) and exercise (8) induce significant modifications in valve hemodynamics. Likewise,
Beta-blockers
9 (39)
Aldosterone receptor antagonists
4 (17)
Calcium antagonists
2 (9)
Nitrates
1 (4)
Statins
14 (61)
valve interventions may acutely impact arterial
Values are mean SD or n (%).
function (9).
Although attempts have been made to quantify
vascular load in AS noninvasively (2,4), a rigorous
quantification
of
arterial
hemodynamics
ACEIs ¼ angiotensin-converting enzyme inhibitors; ARBs ¼ angiotensin receptor
blockers; EuroSCORE ¼ European System for Cardiac Operative Risk Evaluation;
NYHA ¼ New York Heart Association.
entails
simultaneous measurements of central aortic pressure and flow (10). Use of this invasive approach in a
small number of subjects has suggested that steady
and pulsatile loads are increased in symptomatic
degenerative calcific AS, particularly during exercise
(8). However, measurements of vascular load might
be conditioned by upstream valvular obstruction.
This study was designed to characterize the interaction between valvular and vascular function in
patients with calcific degenerative AS. We hypothesized that transcatheter aortic valve replacement
<40 mm Hg) was present in 9 patients and concomitant low-flow (stroke volume [SV] index of <35 ml/m 2)
in 3 patients. Sixteen patients (74%) had a preprocedural diagnosis of hypertension requiring pharmacotherapy. Antihypertensive agents were withheld
12 h before the procedure. After TAVR, patients were
initially kept on their pre-procedural antihypertensive
therapy.
The
local
Institutional
Review
Board
approved the study protocol and all subjects provided
written informed consent.
(TAVR) offers a useful clinical model of isolated
STUDY
valvular intervention to unmask underlying valvular-
were performed using the femoral approach under
vascular interactions of AS. Therefore, we analyzed
local anesthesia and conscious sedation with low
the acute changes induced by TAVR to understand
doses of midazolam (2 to 5 mg, intravenous) and
how valve obstruction impacts vascular function,
PROTOCOL
AND FOLLOW-UP. Procedures
fentanyl (2 m g/kg, intravenous); additional boluses
using state-of-the-art methods, including frequency
(1 mg and 50 m g, respectively) were used if necessary
domain and wave intensity analyses (WIA) of high-
to maintain patient comfort during the procedure.
fidelity data.
Special care was taken to ensure a constant level of
sedation during pre- and post-procedural measure-
METHODS
ments. A pacing wire and a thermodilution SwanGanz catheter were placed in the RV and in the main
STUDY POPULATION. We studied 23 consecutive
pulmonary artery, respectively. The self-expanding
patients with severe symptomatic calcific degenera-
valve (Corevalve, Medtronic, Inc., Minneapolis, Min-
tive AS undergoing TAVR (Table 1). Patients were
nesota) transfemoral implantation procedure (11) was
either in sinus rhythm or permanent right ventricular
successful in all patients. Mild residual AR was pres-
(RV) pacing (n ¼ 3). No patient had significant
ent in 10 patients (grade 1 in 9 patients and grade
aortic regurgitation (AR), and 7 patients had an ejec-
2 in 1 patient). Aortic and LV pressures were simul-
tion fraction of #45%. Low-gradient AS (mean:
taneously recorded before and after TAVR, using
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Systemic Vascular Load in Aortic Stenosis
fluid-filled catheters. Aortic valve areas were calcu-
Beats were selected for analysis if peak ascending
lated using the Gorlin formula.
aortic pressure exhibited variation of <10 mm Hg over
High-fidelity pressure and flow velocity were
the interval examined and the flow velocity wave-
recorded simultaneously at the ascending aorta by
form was stable and periodic (8). For each hemody-
using a 0.014-inch-diameter wire (Combowire, Vol-
namic run, 13 beats (range: 5 to 19 beats) underwent
cano Corp., San Diego, California) under stable he-
digital low-pass (50-Hz) filtering and ensemble aver-
modynamic conditions (<10% variation in mean
aging (Figure 1) (8,13). The aortic input impedance
blood pressure [BP] during $10 min before and $30
spectrum was derived using Fourier decomposition of
min after TAVR). To minimize artifacts within the
the pressure and velocity signals up to 10 Hz (10).
region of pressure recovery, the wire was introduced
Respective pressure and flow moduli at each har-
though a 6-F multipurpose guiding catheter placed in
monic were used to derive the impedance (Z) moduli.
the ascending aorta w5 cm above the aortic annulus
Characteristic impedance (Zc) was calculated as the
(Central
micro-
average of Z moduli above 4 Hz, excluding outlier
manometry sensors located at the wire’s tip were
values of >3 times the median. Because this method
advanced approximately 1 cm out of the guiding
is highly sensitive to signal noise, we additionally
Illustration).
The
Doppler
and
catheter before data recording. After TAVR, the
calculated Z c from wave speed, the latter measured in
pressure-velocity wire was reinserted, matching the
the time domain from the early P–Q linear relation-
tip’s position fluoroscopically stored in the baseline
ship, as used for measuring wave velocity (Online
study. The pressure signal was balanced against the
Appendix). Correlation and agreement for both
fluid-filled guiding catheter. Signals were recorded
methods for measuring Z c were r ¼ 0.67 and r ic ¼ 0.59,
for at least 1 minute during sinus rhythm and then
respectively (pooled before and after TAVR data). The
during RV pacing at 20 beats/min above intrinsic
augmentation index was computed as the difference
baseline heart rate in all patients before and after
between the maximum and minimum values of Z
TAVR. In patients with permanent RV pacing or those
components >3 Hz. We calculated the distance to the
who were developing new-onset complete atrioven-
reflecting site by the quarter-wavelength relationship
tricular or left branch bundle block (n ¼ 9), we used
(14), as well as by WIA (r ¼ 0.51 and r ic ¼ 0.40 between
pacing signals before and after TAVR. High-fidelity
methods [Online Appendix]). Arterial compliance (C)
pressure, flow velocity, and electrocardiogram sig-
was calculated using the pulse pressure method (15),
nals were digitally stored at 200 Hz.
exponential decay, and diastolic area methods (10)
Comprehensive Doppler electrocardiogram exami-
(r > 0.92 and r ic $ 0.90, among all methods). We
nations were performed immediately before and <24 h
calculated effective arterial elastance as: 1) the ratio
after TAVR, using broadband 2.0- to 4.0-MHz ma-
between end systolic pressure (obtained from the
trix and volumetric transducers on a Vivid-7 or a
fluid-filled LV pressure catheter) and SV (Ea); and
Vivid-9 system (General Electric Healthcare, Little
2) the ratio between systemic vascular resistance
Chalfont, United Kingdom). Cuff BP was monitored
and the cardiac period (E aR; r ¼ 0.95 and r ic ¼ 0.67
hourly during the first 48 h and then every 8 h until
between methods) (16,17).
discharge. Hypertensive response after TAVR was
WIA is a well-established method used to assess
defined (12) in the presence of 1 of the following:
arterial hemodynamics (18); its foundations define
1) sustained (>48-h) systolic pressure >140 mm Hg
pressure and velocity waveforms as the summation
or diastolic pressure >90 mm Hg not present before;
of successive infinitesimal waves that propagate
2) need for a >2-fold increase in the dosage of
through vessels (18). Arterial waves can originate
an antihypertensive drug to achieve BP control; or
either from the LV (forward traveling) or from pe-
3) incorporation of an additional antihypertensive
ripheral vasculature reflections (backward traveling).
drug to the pre-procedural regimen. Patients under-
Waves are further classified by their effect on pres-
went clinical follow-up, blinded to the results of
sure as compression (increased pressure) or expan-
vascular hemodynamics, every 3 months during the
sion w (decreased pressure) waves. We used the
6 months’ post-procedure.
ensemble-averaged pressure and velocity signals to
derive the rates of change of aortic pressure (dP/dt)
INVASIVE
DATA
PROCESSING
AND
ANALYSIS.
and velocity (dU/dt) (Figure 1, Online Appendix). It
Volumetric flow rate (ml/s) was calculated from linear
has been proposed that changes in aortic pressure
flow velocity measurements (cm/s) by means of a
can be attributed not only to forward or backward
calibration constant (cm 2) obtained as K ¼ SV/TVI,
wave motion but also to changes in aortic volume
where TVI represents the time-velocity integral and
(19). Because we anticipated a potential effect of
SV is the simultaneously obtained thermodilution SV.
TAVR on aortic pressure and volume, we also
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C EN T RA L IL LUSTR AT I ON
Systemic Vascular Load in Aortic Stenosis
Aortic impedance and wave intensity analysis are shown in a patient before (A) and after (B) transcatheter aortic valve replacement (TAVR). Aortic systolic and pulse
pressures increased after TAVR. Fourier decomposition of the simultaneous aortic pressure and velocity signals shows that SVR and the first 3 harmonic frequencies of
the impedance spectrum (Z) increase after TAVR. Wave intensity analysis was used to separate total wave intensity into contributions from the forward (dIwþ) and
backward (dIw-) traveling waves. Compression waves (salmon) increase pressure, and expansion waves (green) decrease aortic pressure. The forward compression wave
(FCW) increases immediately after TAVR. BCW ¼ backward compression wave; BEW ¼ backward expansion wave; dIw ¼ wave intensity; FEW ¼ forward expansion wave;
LA ¼ left atrium; LV ¼ left ventricle; SVR ¼ systemic vascular resistance.
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Systemic Vascular Load in Aortic Stenosis
F I G U R E 1 High-Fidelity Pressure and Flow Velocity Signal Processing
100
400
50
200
Aortic Flow Velocity (cm/s)
Aortic Pressure (mm Hg)
A
0
0
Time
B
C
150
D
250
140
140
130
130
120
110
100
90
80
70
Aortic Pressure (mm Hg)
200
Aortic Flow Velocity (cm/s)
Aortic Pressure (mm Hg)
150
150
100
120
110
100
90
80
70
50
60
60
0
50
0
500
Time (ms)
1000
50
0
500
1000
0
Time (ms)
40
80
120
160
Aortic Flow Velocity (cm/s)
Simultaneous high-fidelity pressure and flow velocity signals (A), ensemble signal average method (B and C), and wave speed estimation by
slope of the pressure-velocity relationship during early systole (D) are shown. See Online Appendix for details.
performed WIA taking reservoir pressure effect
SBP is the cuff systolic BP, MG is the Doppler-derived
into account (Online Figures 1 and 2) (19). All invasive
mean transvalvular pressure gradient, and SVI noninv
data were analyzed using custom-built algorithms
is the noninvasive SV index (SVI) measured by
(Matlab; Mathworks, Natick, Massachusetts), and re-
cross-sectional echocardiography and pulsed-wave
sults for 3 to 5 hemodynamic runs were averaged for
Doppler (2).
each patient.
STATISTICAL ANALYSIS. Differences between pre-
Noninvasive valvulo-arterial impedance (ZVA) was
and post-TAVR hemodynamic data were analyzed by
calculated as: ½ZVA ¼ ðSBP þ MGÞ=SVInoninv , where
paired t tests. Responses between groups were
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compared using unpaired t tests. Correlation between
quantitative variables was analyzed using the linear
T A B L E 2 Invasive Indices of Systemic Hemodynamics and
Valvular Function
Pearson correlation coefficient (r), and 95% confidence interval (CI) for the fitting was plotted. The
intraclass correlation coefficient (r ic, absolute agreement) was used to compare different methods. Out-
Index
Pre-TAVR Post-TAVR p Value
Global hemodynamics
Heart rate, beats/min
81 15
87 19
Stroke volume index, ml$m2
41 8
33 10 <0.001
0.17
come analysis was performed by binary logistic
Cardiac index, l$min$m2
3.3 0.8 2.8 1.1 <0.001
regression models, accounting for improvement in
Systolic blood pressure, mm Hg
130 24 162 23
New York Heart Association (NYHA) functional class
Diastolic blood pressure, mm Hg
59 11
67 11
0.08
at follow-up. SVI pre- and post-TAVR and its changes
Mean blood pressure, mm Hg
82 14
98 12
0.01
were entered separately in these models, adjusting
Pulse pressure, mm Hg
62 24
73 21
0.017
for
Peak systolic LV pressure, mm Hg
186 36 162 23
0.003
age
and
pre-implantation
functional
class.
Because of the risk of overfitting in small samples,
overall performance of the model was calculated using 1,000 bootstrap resamples to estimate the C index
(20,21). Values of p < 0.05 were considered significant.
23 7
26 7
0.004
49 19
10 3
<0.0001
Valvular function
Mean transvalvular pressure
gradient, mm Hg
2
Aortic valve area, cm
0.7 0.2 1.4 0.4 <0.0001
Values are mean SD.
RESULTS
INDICES
End-diastolic LV pressure, mm Hg
0.003
LV ¼ left ventricular; TAVR ¼ transcatheter aortic valve replacement.
OF
AORTIC
STENOSIS
AND
SYSTEMIC
HEMODYNAMICS. The large reduction in the trans-
valvular pressure gradient caused by TAVR was followed by significant increases in systolic, mean, and
pulse systemic arterial pressure values (Table 2).
Consequently, LV peak systolic pressure decreased by
only a mean of 10% (186 36 mm Hg vs. 162 23
mm Hg, respectively; p ¼ 0.003) and remained >140
mm Hg in 70% of patients, varying widely among
patients (Figure 2). After TAVR, SVI (41 8 ml/m 2 vs.
33 10 ml/m 2, respectively; p < 0.001) and cardiac
index (3.3 0.8 l/min/m 2 vs. 2.8 1.1 l/min/m 2,
respectively; p <0.001) decreased (Figure 2). Patients with and without residual aortic regurgitation
showed no significant differences in post-procedural
LV end-diastolic pressure (31 9 mm Hg vs. 26 10
mm Hg, respectively; p ¼ 0.22).
SYSTEMIC VASCULAR LOAD. A significant increase
in systemic vascular resistance, E a, and the first 3
harmonic frequencies of Z were observed after TAVR
(Table 3, Central Illustration). The augmentation index
and wave speed velocity increased as well, whereas C
decreased (Table 3). The amount of decrease in C after
TAVR was inversely related to baseline systolic BP
(r ¼ 0.72; p < 0.0001). SVI post-TAVR was strongly
related to indices of continuous and pulsatile arterial
load (Figure 3). Changes in SVI and arterial load
indices (C, E a, systemic vascular resistance, and Zc)
were not significantly different among patients who
did and did not require RV pacing after the procedure
(p $ 0.1 for all).
TAVR was followed by a significant increase in for-
significantly. Pulse pressure and Zc increased, as
measured by both the conventional and reservoir
approach methods (Online Table 1); the reflection
coefficient increased following TAVR, whereas the
distance to reflection was only found to decrease by
using the reservoir method. Pulse pressure correlated directly with compression waves (r ¼ 0.53 and
r ¼ 0.62 for peak FCWs and BCWs, respectively),
directly with the backward expansion wave (r ¼ 0.70),
and inversely with the forward expansion wave
(r ¼ 0.65; p < 0.0001 for all, pooled data and reservoir approach). The Z va did not change significantly
with TAVR (4.1 1.2 mm Hg/ml/m 2 vs. 3.9 1.4
mm Hg/ml/m 2, respectively; p ¼ 0.59).
FOLLOW-UP. In the 48 h following TAVR, a hyper-
tensive response was observed in 12 patients (52%);
10 patients required intensification of their antihypertensive therapy and 1 initiation of treatment.
During 6 months of follow-up, 5 patients had
their discharge antihypertensive therapy intensified,
whereas no patient had reduced doses of these drugs.
NYHA functional class did not improve in 14 patients
(61%). Improvement in functional class after TAVR
was directly related to post-procedural SVI (oddsratio [OR]: 2.8 [95% CI: 1.1 to 7.3] per 5 ml; bootstrapped C index: 0.67; p ¼ 0.03) and inversely to the
fall in SVI observed after TAVR (OR: 0.3 [95% CI: 0.1
to 0.9] per 5 ml; p ¼ 0.05), whereas it was not related
to pre-TAVR SVI (p ¼ 0.4).
DISCUSSION
ward compression waves (FCW) and backward compression waves (BCW) (Table 3, Central Illustration),
The present study clarifies important aspects of
whereas
vascular adaptation to calcific degenerative AS.
expansion
waves
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did
not
change
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Systemic Vascular Load in Aortic Stenosis
F I G U R E 2 Hemodynamic Changes After TAVR
250
250
250
p< 0.0001
p= 0.003
200
100
150
100
60
Stroke Volume Index (ml·m-2)
150
Peak LV Pressure (mm Hg)
200
Systolic Blood Pressure (mm Hg)
Mean Pressure Gradient (mm Hg)
200
150
100
40
20
50
50
50
p= 0.003
0
0
Pre
0
Pre
Post
TAVR
Post
TAVR
p< 0.001
0
Pre
Post
TAVR
Pre
Post
TAVR
Boxplots and individual value plots (patients showing a decrease [salmon] or increase [blue] in SVI after TAVR) show values of mean pressure
gradient, systolic blood pressure, peak left ventricular pressure, and SVI. SVI ¼ stroke volume index; TAVR ¼ transcatheter aortic valve
replacement.
Using WIA, we demonstrated that valvular ob-
described abnormally high steady and pulsatile
struction blunts the conversion of LV ejection blood
components of systemic arterial load in patients with
momentum
system.
degenerative calcific AS. However, few studies have
Dampened FCWs are reflected as abnormally low
analyzed the status of intrinsic vascular properties in
BCWs at the aortic bifurcation sites, and both
AS invasively. Laskey et al. (8) compared 18 patients
effects result in low systolic and pulse arterial
with symptomatic degenerative calcific AS to 11
pressures.
after
younger control subjects and found higher vascular
TAVR, demonstrating that the characterization of
resistance and impedance and reduced arterial
systemic vascular properties in AS is conditioned by
compliance in patients with AS. Differences between
the upstream obstruction. The relief of the outflow
groups became particularly evident during exercise
into
This
FCWs
in
situation
the
arterial
changes
acutely
obstruction immediately raises FCWs and BCWs,
(8). However, our study’s results suggest that these
increasing arterial pressures and vascular imped-
observations should be interpreted cautiously. By
ance and induces a stiffer vascular behavior. In our
analyzing the acute response to TAVR, we showed
study, the augmented vascular load correlated with
that valve stenosis per se influences all metrics
post-procedural
was
characterizing the arterial tree. Noticeably, classical
limited to a small sample size, we found an inverse
values of vascular function obtained in our study pre-
relationship
mid-term
TAVR did not differ from previously reported values
clinical benefit and the change in SVI observed
in age-matched hypertensive populations (22). How-
post-TAVR.
ever, WIA showed that compression and expansion
VASCULAR TREE IN DEGENERATIVE CALCIFIC AS.
waves in AS are much lower than previously reported
Noninvasive (4) and mathematical (5) methods have
normal values (23). We found that immediately after
SVI.
between
Although
the
this
study
procedure’s
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T A B L E 3 Steady and Pulsatile Arterial Hemodynamics at Baseline and After TAVR
Factor
vasodilator pharmacological interventions (6). Our
study
demonstrates
the
negative
impact
this
Pre-TAVR
Post-TAVR
p Value
vascular response exerts on global hemodynamics of
Systemic vascular resistance index,
dyn∙s∙cm5∙m2
1841 562
2689 1271
<0.0001
patients undergoing TAVR. Although we did not
Arterial compliance, pressure decay method,
ml∙mm Hg1
1.20 0.79
0.72 0.33
0.002
Arterial compliance, area method, ml∙mm Hg1
1.18 0.77
0.74 0.36
<0.001
Z at fist harmonic frequency, dyn∙s∙cm5
519 219
763 280
<0.001
Z at second harmonic frequency, dyn∙s∙cm5
375 208
541 262
0.002
313 244
395 208
0.36
Frequency domain analysis
Z at third harmonic frequency, dyn∙s∙cm
5
5
repeat invasive studies during follow-up, the relatively large proportion of patients requiring antihypertensive therapy scaling during follow-up suggests
that our acute observations are not acute phase
transients. Similar observations of persistent hypertension have been reported after TAVR (12) and
surgical valve replacement (25).
258 139
326 193
0.06
Frequency of first Z minimum, Hz
3.9 1.5
4.6 1.1
0.6
Arterial elastance, mm Hg∙ml1
1.2 0.46
1.75 0.70
<0.001
and arterioles are probably responsible for the
1.09 0.40
1.63 0.65
<0.001
observed changes in pulsatile vascular load after
Augmentation index
392 232
750 739
0.025
Distance to reflection, m
0.11 0.72
0.12 0.09
0.06
Wave speed, m∙s1
3.57 2.05
4.62 2.01
0.034
responsible for this observation. Due to the nonline-
Characteristic impedance, dyn∙s∙cm5
192 124
247 141
0.05
arity of viscoelastic strain of the large conductance
Iw total forward wave, W∙m2∙s1∙104
9.09 4.84
10.83 4.84
0.03
Iw FCW, W∙m2∙s1∙104
deformation post-TAVR may also induce stiffer
5.64 2.97
7.37 3.00
0.001
Peak dIw FCW, W∙m2∙s2∙106
1.01 0.54
1.80 0.66
<0.001
behavior of the vascular tree (26).
Characteristic impedance, dyn∙s∙cm
Arterial elastance, resistance method,
mm Hg∙ml1
Wave intensity analysis
Changes in the tone of large conduction arteries
TAVR. We know vasoconstriction in arteriolar vessels
reduces arterial compliance (14). The viscoelastic
properties of large conductance arteries also may be
arteries, acute changes in the pressure-mediated
Forward wave
2
1
4
Iw FEW, W∙m ∙s ∙10
2.89 1.80
2.75 1.51
0.45
Peak dIw FEW, W∙m2∙s2∙106
0.51 0.31
0.46 0.30
0.68
VASCULAR TREE AND OUTCOME IN AS. Indirect ev-
idence has emphasized the complementary impact of
Backward wave
Iw total backward wave, W∙m2∙s1∙104
3.71 2.68
5.23 2.28
0.04
arterial hemodynamics on the symptomatic status
Iw BCW, W∙m2∙s1∙104
2.34 1.72
3.39 2.17
0.04
and outcome of patients with AS, both before (2,4)
Peak dIw BCW, W∙m2∙s2∙106
0.33 0.18
0.55 0.32
0.001
Iw BEW, W∙m2∙s1∙104
and after (27) valve intervention. The “double
0.87 0.76
1.15 1.00
0.19
Peak dIw BEW, W∙m2∙s2∙106
0.21 0.18
0.23 0.21
loaded” hypothesis integrates these additive effects
0.75
Reflection
Reflection coefficient
Distance to reflection, m
0.40 0.27
0.33 0.19
0.28
0.17 0.13
0.17 0.12
0.81
of valvular and vascular loads. On this basis, the Z VA
index has been found to correlate with SV and
outcome (3,28). However, in our study, Z VA did not
capture the hemodynamic changes observed with
Values are mean SD.
TAVR. The fact that Z VA did not improve acutely
BCW ¼ backward compression wave; BEW ¼ backward expansion wave; dIw ¼ intensity; FCW ¼ forward
compression wave; FEW ¼ forward expansion wave; Iw ¼ cumulative wave intensity; Z ¼ impedance; other
abbreviations are as in Table 2.
probably relates to its sensitivity to both the valvular
and the vascular compartments, which are competitively modified by therapy.
A
well-known
risk
factor
of
cardiovascular
TAVR, the transmission of blood momentum to the
morbidity and mortality, especially in elderly patients
arterial system improves, increasing FCWs. Stronger
(29), hypertension has been associated with worse
FCWs are reflected as stronger BCWs traveling toward
outcomes in patients who undergo TAVR (30). How-
the LV. Both effects raise mean, systolic, and pulse
ever, a hypertensive response after TAVR has also
arterial pressure levels.
been associated with a better prognosis (12). In a
Our results show that after TAVR, the vascular
previous study, higher BP after TAVR was related to
tree exhibits a stiffer behavior. This paradoxical ef-
higher SV and was attributed to an acute improve-
fect of rising continuous and pulsatile vascular load
ment of LV function; patients with stable BP after
after LV outflow relief was described previously (9).
TAVR experienced, on average, a reduction in post-
In patients undergoing percutaneous aortic valvu-
procedural SV (12). Similarly, our study suggests
loplasty, valvular-vascular interaction follows the
that a post-procedural reduction in SV is related to
properties of complementarity (both compartments
absence of clinical improvement. However, we have
contribute additively to afterload) and competitive-
shown that the acute hypertensive response after
ness (one compartment cannot be lowered without
TAVR is caused by increased vascular load rather than
raising the other one) (9,24). More recently, this
improved LV systolic function, so it should be
interaction was confirmed in AS patients undergoing
promptly identified and treated.
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JACC VOL. 65, NO. 5, 2015
Yotti et al.
FEBRUARY 10, 2015:423–33
Systemic Vascular Load in Aortic Stenosis
50
50
40
40
30
30
20
20
10
r= -0.80
p< 0.0001
r= -0.63
p= 0.001
1000
500
1500
2000
1.0
1.5
2.0
2.5
3.0
Arterial Elastance (mm Hg·ml-1)
0.4
0.8
1.2
1.6
Arterial Compliance (ml·mm Hg-1)
50
50
40
40
30
30
20
20
10
r= -0.70
p= 0.0002
500
r= -0.55
p= 0.007
750
1000
1250
250
Z @ 1 Hz (dyn·s·cm-5)
10
r= -0.57
p= 0.005
500
750
1000
Z @ 2 Hz (dyn·s·cm-5)
1250
250
500
Stroke Volume Index (ml·m-2)
Stroke Volume Index (ml·m-2)
SVRI (dyn·s·m2·cm-5)
10
r= 0.61
p= 0.002
Stroke Volume Index (ml·m-2)
Stroke Volume Index (ml·m-2)
F I G U R E 3 Correlation Between SVI and Indices of Arterial Load
750
Z @ 3 Hz (dyn·s·cm-5)
Scatterplots, linear fittings (dotted line), and 95% confidence intervals are shown for the fitting (gray ribbon) of indices of continuous and
pulsatile arterial load versus SVI. Colors are as in Figure 2. SVRI ¼ systemic vascular resistance index; TAVR ¼ transcatheter aortic valve
replacement; Z ¼ impedance.
LV IMPACT. Because no striking changes in chamber
STUDY LIMITATIONS. The flow acquisition system
systolic volume are expected during TAVR, the
measures aortic flow velocity by using a very small
observation of post-procedural increased arterial load
Doppler sample volume. Therefore, signals may
suggests that the hemodynamic benefits of valvular
sometimes be noisy in highly turbulent flows, as in
replacement on LV systolic wall stress may be lower
AS, and not account for the average flow velocity for
than expected, particularly in patients with relatively
the full cross-section of the aorta where measure-
low transvalvular pressure gradients. Although peak
ments are obtained. The geometry of the Corevalve
LV pressure decreases after TAVR, it frequently
prosthesis can modify the local mechanical properties
remained
post-
of the arterial wall in the aortic root. For this reason,
procedural vascular load may explain why patients
we acquired the invasive pressure and flow rate/
with paradoxically low-flow low-gradient AS fail to
velocity signals 5 cm distal to the aortic annulus,
improve values of N-terminal prohormone B-type
searching for the highest velocities at this point,
natriuretic peptide by 1 year after TAVR (31) and have
attempting to minimize the prosthesis’ local effects.
a higher mortality than patients with normal flow
To avoid these issues, we selected data with the
(32). Further large-scale studies are necessary to
highest quality available and implemented filtering
address the predictors of LV systolic stress improve-
and ensemble averaging to increase the signal-to-
ment. Nevertheless, in view of our data and those of
noise ratio. However, we cannot exclude the fact
others (6), intense medical therapy is recommended
that residual high-frequency noise may account for
in hypertensive patients with calcific degenerative
the relatively high Zc values that were measured.
AS, regardless of whether they finally do or do not
Although a stable conscious sedation level was
undergo valve replacement.
achieved in all cases, a certain vascular tone
higher
than
normal.
Increased
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432
Yotti et al.
JACC VOL. 65, NO. 5, 2015
Systemic Vascular Load in Aortic Stenosis
FEBRUARY 10, 2015:423–33
modification can be expected for sedating drugs.
impacts the post-procedural acute hemodynamic
Similarly, some degree of vascular changes could be
benefits of TAVR.
caused by adaptation to acute procedure-related
myocardial injury.
We studied an elderly and high-risk AS group;
therefore, the vascular hemodynamics and response
to TAVR could be different in younger patients.
Functional improvement was only assessed using
ACKNOWLEDGMENTS The author thank all members
of the staff of the Echocardiography and Catheterization Laboratories of the Hospital General Universitario Gregorio Marañón for their support for
patient recruitment and data collection.
NYHA functional classification; other tools such as
the 6-min walk test or quality-of-life questionnaires
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
would have increased the sensitivity to detect func-
Raquel Yotti, Department of Cardiology, Hospital
tional improvement. The small sample size was
General Universitario Gregorio Marañón, Dr. Esquerdo
designed to analyze the mechanistic changes in
46, 28007 Madrid, Spain. E-mail: raquel.yotti@salud.
vascular load. Thus, subgroup analyses need to be
madrid.org.
interpreted cautiously, and hard clinical endpoints
could not be analyzed. With the small sample size, we
also could not address the impact of potential con-
PERSPECTIVES
founders such as degree of mitral regurgitation.
Large-scale clinical studies are necessary to rule out a
COMPETENCY IN MEDICAL KNOWLEDGE: Relief
potential acute rebound effect post-intervention and
of AS raises forward and backward compression
confirm that post-TAVR measurements accurately
waves, increasing arterial pressure and both the
account for the true arterial load once the stenotic
steady and pulsatile components of systemic arterial
damping effect has been alleviated.
load.
COMPETENCY IN PROCEDURAL SKILLS:
CONCLUSIONS
The increased post-procedural systemic vascular load
Because valvular and vascular loads are tightly
coupled in AS, upstream obstruction can influence
the measurements of arterial properties. Low arterial
FCWs and BCWs caused by valvular stenosis produce
the hallmark signs of arterial hemodynamics in AS.
Relief of valvular obstruction with TAVR acutely increases compression waves, causing the arterial tree
to operate at a higher pressure and therefore
should be promptly treated when patients with AS
undergo TAVR, particularly when the transvalvular
pressure gradient is low.
TRANSLATIONAL OUTLOOK: Larger prospective
studies are needed to define the prognostic implications of changes in systemic vascular load that
immediately follow TAVR.
increasing the vascular load. This phenomenon
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A PP END IX For expanded Methods and
Results sections, including a supplemental
table and figures, please see the online version
of this article.
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