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Arterial Pulse Wave Dynamics After Percutaneous Aortic Valve Replacement :
Fall in Coronary Diastolic Suction With Increasing Heart Rate as a Basis for
Angina Symptoms in Aortic Stenosis
Justin E. Davies, Sayan Sen, Chris Broyd, Nearchos Hadjiloizou, John Baksi, Darrel
P. Francis, Rodney A. Foale, Kim H. Parker, Alun D. Hughes, Andrew
Chukwuemeka, Roberto Casula, Iqbal S. Malik, Ghada W. Mikhail and Jamil Mayet
Circulation published online September 12, 2011
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Arterial Pulse Wave Dynamics After Percutaneous Aortic
Valve Replacement
Fall in Coronary Diastolic Suction With Increasing Heart Rate as a Basis
for Angina Symptoms in Aortic Stenosis
Justin E. Davies, MRCP; Sayan Sen, MRCP; Chris Broyd, MRCP; Nearchos Hadjiloizou, MRCP;
John Baksi, MRCP; Darrel P. Francis, FRCP; Rodney A. Foale, FRCP; Kim H. Parker, PhD;
Alun D. Hughes, PhD; Andrew Chukwuemeka, FRCS; Roberto Casula, FRCS; Iqbal S. Malik, FRCP;
Ghada W. Mikhail, FRCP; Jamil Mayet, FRCP
Background—Aortic stenosis causes angina despite unobstructed arteries. Measurement of conventional coronary
hemodynamic parameters in patients undergoing valvular surgery has failed to explain these symptoms. With the advent
of percutaneous aortic valve replacement (PAVR) and developments in coronary pulse wave analysis, it is now possible
to instantaneously abolish the valvular stenosis and to measure the resulting changes in waves that direct coronary flow.
Methods and Results—Intracoronary pressure and flow velocity were measured immediately before and after PAVR in 11
patients with unobstructed coronary arteries. Using coronary pulse wave analysis, we calculated the intracoronary
diastolic suction wave (the principal accelerator of coronary blood flow). To test physiological reserve to increased
myocardial demand, we measured at resting heart rate and during pacing at 90 and 120 bpm. Before PAVR, the basal
myocardial suction wave intensity was 1.9⫾0.3⫻10⫺5 W 䡠 m⫺2 䡠 s⫺2, and this increased in magnitude with increasing
severity of aortic stenosis (r⫽0.59, P⫽0.05). This wave decreased markedly with increasing heart rate (␤ coefficient⫽⫺0.16⫻10⫺4 W 䡠 m⫺2 䡠 s⫺2; P⬍0.001). After PAVR, despite a fall in basal suction wave (1.9⫾0.3 versus
1.1⫾0.1⫻10⫺5 W 䡠 m⫺2 䡠 s⫺2; P⫽0.02), there was an immediate improvement in coronary physiological reserve with
increasing heart rate (␤ coefficient⫽0.9⫻10⫺3 W 䡠 m⫺2 䡠 s⫺2; P⫽0.014).
Conclusions—In aortic stenosis, the coronary physiological reserve is impaired. Instead of increasing when heart rate rises,
the coronary diastolic suction wave decreases. Immediately after PAVR, physiological reserve returns to a normal
positive pattern. This may explain how aortic stenosis can induce anginal symptoms and their prompt relief after PAVR.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01118442.
(Circulation. 2011;124:00-00.)
Key Words: aortic stenosis 䡲 aortic valve 䡲 coronary arteries 䡲 coronary flow 䡲 heart valve prosthesis implantation
䡲 microvessels 䡲 wavelet analysis
U
ncorrected severe aortic stenosis has an extremely poor
prognosis, carrying a 3-year mortality of ⬎50%,1 which
rises to ⬎80% in subjects with significant cardiac comorbidity.2 As the severity of aortic stenosis increases, physiological
and pathological adaptations occur in the left ventricle (LV).3
These include increases in the inotropic state and the development of LV hypertrophy.4
Clinical Perspective on p ●●●
Although LV hypertrophy can be viewed as a physiological adaptation to the increase in afterload, it encompasses a
pathological hypertrophic response with increased extracellular matrix deposition and perivascular fibrosis.5 These
pathological changes slow myocardial relaxation, which in
turn diminishes normal ventricular filling and reduces coronary blood flow.6,7 This is compounded by the increase in
work and myocardial mass, which results in elevated myocardial oxygen demand and a decrease in microvascular
density,8 leading to reduced coronary vascular reserve.9 As
the severity of the aortic stenosis increases, this process is
exacerbated by ever-increasing afterload and decreasing coronary perfusion pressures, leading to the development of
ischemia, which has been reported with the use of several
different techniques.10 –12
When valvular stenosis is absent (and aortic pressure
closely matches LV pressure), the phasic nature of coronary
Received May 29, 2010; accepted July 27, 2011.
From the Imperial College London, International Centre for Circulatory Health, National Heart and Lung Institute (J.E.D., S.S., C.B., N.H., J.B., D.P.F.,
R.A.F., K.H.P., A.D.H., I.S.M., G.W.M., J.M.), and Imperial College Healthcare NHS Trust (R.A.F., A.C., R.C., I.S.M., G.W.M., J.M.), London, UK.
Correspondence to Justin Davies, MRCP, International Centre for Circulatory Health, St. Mary’s Campus, Paddington, London, W2 1LA, UK. E-mail
[email protected]
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.110.011916
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October 4, 2011
blood flow is governed principally by the impedance of the
coronary microcirculation.13–17 Our group has demonstrated
similar findings in humans using wave intensity analysis.7,18
Specifically, during systole, when the LV is contracting,
coronary flow is limited by compression of the coronary
microcirculation by the contracting myocardium. It is not
until LV relaxation occurs that compression of the microcirculation is relieved and coronary blood flow increases.
To date, it has not been possible to acutely modulate afterload
resulting from aortic stenosis in humans to study its effects on
coronary physiology, which could improve our understanding of
symptoms such as breathlessness and angina. Percutaneous
aortic valve replacement (PAVR) offers a radical new approach
to treatment and provides an opportunity to study the effects of
relief of aortic stenosis while avoiding the need for thoracotomy
or pericardiotomy, which can lead to alterations in LV and right
ventricular function and arterial hemodynamics.
We conducted this study to assess whether PAVR leads to
an immediate improvement in coronary hemodynamics and
physiological reserve to account for the reduction in symptoms of angina and breathlessness.
Methods
Eleven patients (age, 80⫾9 years) scheduled for PAVR with fluoroscopically unobstructed coronary arteries participated in the study
(Table 1). Transthoracic echocardiography was performed in all
subjects, and was repeated 5 to 7 days after PAVR (Table 2). In addition
to Doppler parameters, 2 dimensional measurements were calculated
offline on a McKeeson workstation. Exclusion criteria included any
previous coronary intervention, significant regional wall motion abnormalities, cardiac dysrhythmias, or the use of nitrates in the preceding 24
hours. All subjects gave written informed consent in accordance with
the protocol approved by the local ethics committee.
Table 1.
Baseline Demographics
Female, n (%)
9 (82)
Age, y
80⫾9
LV mass, g
164⫾53
BSA LV mass, g
100⫾30
Peak gradient, mm Hg
81⫾24
Mean gradient, mm Hg
48⫾15
Area, cm2
0.6⫾0.1
Echocardiographic parameters, mm
LV EDD
40⫾10
LV ESD
30⫾13
LV PWD (d)
11⫾3
LV SD (d)
13⫾3
LV PWD (s)
15⫾3
LV SD (s)
16.5⫾3
Tissue Doppler, cm/s
S⬘ septal
4.8⫾1.9
E⬘ septal
4.7⫾2.1
Weight, kg
63⫾15
BMI, kg/m2
24⫾3
Hypertension, n (%)
7 (64)
Diabetic, n
0
Medications, n (%)
Statin
9 (82)
Antiplatelet
10 (90)
ACEI or A2
4 (36)
␤-blocker
1 (9)
␣-blocker
1 (9)
Study Protocol
Calcium antagonist
3 (27)
Patients were intubated and ventilated, and a right ventricular pacing
wire was positioned in the right ventricle via the right femoral vein.
The left coronary artery was intubated with a Judkins left guide
catheter; then, a sensor-tipped wire was passed into the proximal
segment of the left main stem. Pressure and velocity recordings from
aorta and coronary arteries were made with 0.014-in-diameter
sensor-tipped wire (Combowire, Volcano Corp). Pressure and velocity were recorded for 1 minute at the intrinsic heart rate and then
during pacing at 90 and 120 bpm. Afterward, PAVR was performed,
and an identical set of pressure- and flow-velocity measurements
were made in the coronary arteries again at the intrinsic rate and
during pacing. Fluoroscopic images were used to ensure that the 2
measurement sets were made at identical locations.
Diuretic
7 (63)
Analysis of Hemodynamic Data
Analog output feeds were taken from the pressure-velocity console
and ECG, fed into a National Instruments DAQ-Card AI-16E-4, and
acquired at 1 kHz with Labview. Data were analyzed offline with a
custom software package designed with Matlab (Mathworks, Natick,
MA). The blood pressure and Doppler velocity recordings were
filtered with a Savitzky-Golay filter19 and ensemble averaged with
the ECG R wave for timing. Peak wave intensity was calculated for each
wave in the left main stem and is reported in Table 3.18 A repeating
pattern of 5 main waves was identified in each subject (Figure 1).
Pressure and velocity-time integrals (VTIs) were calculated and
VTI.min product calculated by multiplying VTI by heart rate. Values of
VTI are corrected for body surface area and LV mass. All microcirculatory wave intensity values are reported as magnitudes (ie, positive).
The coronary physiological reserve was calculated as the difference (␦)
in the peak intensity of the backward decompression (or suction) wave
between resting and increased heart rate (90 and 120 bpm).
Angina, n (%)
Chest pain
Breathlessness
Presyncope/syncope
2 (18)
11 (100)
1 (9)
LV indicates left ventricular; BSA, body surface area; EDD, end-diastolic
diameter; ESD, end-systolic diameter; PWD, posterior wall diameter; SD, septal
diameter; (d), diastolic; (s), systolic; BMI, body mass index; and ACE, angiotensinconverting enzyme inhibitor. Values are mean⫾SD when appropriate.
Percutaneous Aortic Valve Implantation
A 7F venous sheath was positioned in the femoral vein, and an 8F
arterial sheath was positioned in the femoral artery. A temporary
pacing wire was advanced via the femoral vein into the right
ventricular apex to achieve a minimum pacing threshold of ⬍1 V.
With the use of an AL1 diagnostic catheter, an 0.035-in guidewire
was used to cross the aortic valve via the femoral artery, and the
stenotic valve was prepared using aortic valvuloplasty with appropriate upsizing of the femoral arterial sheath. After valvuloplasty, the
percutaneous valve was advanced through the stenotic aortic valve
and deployed during a phase of rapid right ventricular pacing. In 10
cases, Edwards Sapien valves (Edwards Lifesciences) were used; in
a single case, a Corevalve (Medtronic) was used. The mean valve
diameter was 24.75 mm (range, 23–29 mm). Interprocedural aortography and transesophageal echocardiography were performed to
check the position of the valve immediately before, during, and after
valve deployment.
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Davies et al
Table 2. Echocardiographic Parameters Before and After
Percutaneous Aortic Valve Replacement
After PAVR
P
81⫾24
18⫾10
⬍0.001
Velocity time integral, cm
110⫾20
44⫾12
⬍0.001
Peak velocity, m/s
4.4⫾0.7
2.5⫾0.6
⬍0.001
VTI
28⫾13
22⫾7
Peak velocity, m/s
0.8⫾0.3
Results
Aortic valve
Left ventricular outflow tract
0.29
1⫾0.2
3
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Before PAVR
Peak gradient, mm Hg
Changes in Coronary Hemodynamics After PAVR
0.2
Aortic regurgitation
None
3
3
...
Mild
7
7
...
Moderate
1
1
...
Statistical Analysis
STATA 11 (StatCorp LP) was used for analyses. The sample size
was chosen (following our pilot study) to detect a 1.0⫻105W 䡠 m⫺2 䡠 s⫺2 reduction in microcirculatory diastolic suction wave,
assuming an SD of 0.4⫻105 W 䡠 m⫺2 䡠 s⫺2 with an ␣ of 0.05 at 90%
power. Correlation was assessed with the Pearson correlation coefficient. Mixed linear models were used to account for the repeated
measures in comparisons of changes in hemodynamic variables at
differing heart rates (intrinsic and 90 and 120 bpm). A value of
P⬍0.05 was taken as statistically significant.
Effects of Aortic Stenosis on
Coronary Hemodynamics
The baseline and pacing hemodynamic variables are summarized in Table 3. The microcirculatory decompression (suction) wave increased with increasing severity of aortic stenosis (r⫽0.59, P⫽0.05; Figure 2). After PAVR, resting
coronary systolic pressure (115⫾9 versus 106⫾11 mm Hg;
P⫽0.38), peak coronary flow velocity (54⫾6 versus 44⫾6
cm 䡠 s⫺1; P⫽0.2), and intrinsic heart rate remained unchanged
(73⫾4 versus 73⫾3 bpm; P⫽0.96). Coronary waves were
similar before and after PAVR, except for the backward decompression (suction) wave, which fell significantly in magnitude
(1.9⫾0.3 versus 1.1⫾0.1⫻10⫺5 W 䡠 m⫺2 䡠 s⫺2; P⫽0.02).
The relationship between the LV wall contractility and
backward decompression wave was assessed before and after
PAVR. Before PAVR, the backward decompression wave
was found to be poorly related to the change in ⌬septal and
⌬posterior diastole-systole diameters (r⫽⫺0.01; P⫽0.98;
Figure 3, top). However, after PAVR, this relationship
improved significantly (r⫽⫺0.45, P⫽0.036; Figure 3,
bottom).
Table 3. Summary of Hemodynamic Variables Before and After Percutaneous Aortic Valve Replacement at Rest and at 90 and 120 bpm
Resting
At 90 bpm
At 120 bpm
Before PAVR
After PAVR
Before PAVR
After PAVR
Before PAVR
After PAVR
P
Forward compression
1.7⫾0.4
2.7⫾0.6
1.4⫾0.4
1.8⫾0.3
1.0⫾0.3
1.9⫾0.3
0.58
Forward decompression
0.9⫾0.1
1.0⫾0.2
0.7⫾0.2
0.9⫾0.1
0.7⫾0.2
1.0⫾0.2
0.09
Early backward compression
1.8⫾0.6
1.2⫾0.3
1.5⫾0.5
1.1⫾0.1
1.4⫾0.4
1.5⫾0.2
0.15
Late backward compression
0.6⫾0.1
0.7⫾0.3
0.7⫾0.1
0.7⫾0.2
0.6⫾0.1
0.9⫾0.2
0.78
Backward decompression (suction)
1.9⫾0.3
1.1⫾0.1
1.4⫾0.3
1.0⫾0.5
1.1⫾0.2
1.4⫾0.2
0.001
⫺2
Peak wave intensity, ⫻10 W 䡠 m
5
⫺2
䡠s
Flow velocity, cm/s
Minimum
2⫾5
7⫾2
2⫾6
5⫾2
4⫾6
5⫾3
0.66
Maximum
54⫾6
44⫾6
58⫾4
45⫾4
60⫾7
52⫾5
0.67
Mean
27⫾3
26⫾4
29⫾3
25⫾2
29⫾5
28⫾2
0.23
VTI, cm
VTI
VTI.min
49⫾12
21⫾4
19⫾4
17⫾2
18⫾5
16⫾2
0.037
3587⫾982
1561⫾300
1706⫾332
1494⫾216
2120⫾621
1937⫾273
0.006
⫺27⫾11
Change from before to after PAVR
⫺2.3⫾3
⫺1.5⫾4
Pressure, mm Hg
Minimum
54⫾5
53⫾6
56⫾4
56⫾7
56⫾4
58⫾7
0.15
Maximum
115⫾9
106⫾11
93⫾10
79⫾22
83⫾6
94⫾11
0.65
Mean
82⫾6
76⫾8
72⫾5
72⫾8
69⫾5
74⫾9
0.99
dP/dtmax
0.4⫾0.05
0.4⫾0.03
0.3⫾0.03
0.4⫾0.03
0.3⫾0.03
0.4⫾0.03
0.10
dP/dtmin
⫺0.4⫾0.05
⫺0.4⫾0.05
⫺0.3⫾0.03
⫺0.3⫾0.03
⫺0.2⫾0.03
⫺0.4⫾0.04
0.83
63⫾6
58⫾7
44⫾3
43⫾5
37⫾3
39⫾4
0.026
73⫾4
73⫾3
90
90
120
120
Pressure-time integral
Heart rate, bpm
PAVR indicates percutaneous aortic valve replacement; VTI, velocity-time integral. Hemodynamic variables are given as mean⫾SE. P represents the statistical
significance of the mixed linear models for changes in hemodynamic variables at differing heart rates (intrinsic and at 90 and 120 bpm).
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Figure 2. Increase in microcirculatory decompression (suction)
wave with increasing peak aortic valve gradient.
increasing heart rate (␤ coefficient⫽0.23⫻10⫺3 W 䡠 m⫺2 䡠 s⫺2;
P⬍0.001).
Before PAVR, the VTI was also found to decrease significantly with increasing heart rate (intrinsic rate, 49⫾12 cm
versus 120 bpm 18⫾5 cm; P⬍0.004). After PAVR, however,
the VTI remained unchanged with increasing heart rate
(intrinsic rate, 21⫾4 cm versus 120 bpm 16⫾2 cm; P⫽0.06).
Discussion
Figure 1. Changes in coronary wave intensity analysis in a subject with severe aortic stenosis before and after percutaneous
aortic valve replacement (PAVR). Coronary wave intensity analysis was calculated in the left main stem through the use of
simultaneous invasive measurements of pressure and flow
velocity in a subject with severe aortic stenosis before (top) and
after (bottom) PAVR.
Assessment of Physiological Coronary Reserve in
Subjects With Severe Aortic Stenosis Before and
After Percutaneous Aortic Valve Replacement
Physiological coronary reserve was assessed by pacing at 90
and 120 bpm (Table 3). The microcirculatory decompression
(suction) wave fell with increasing rate before PAVR (␤
coefficient⫽⫺0.16⫻10⫺4 W 䡠 m⫺2 䡠 s⫺2; P⬍0.001; Figure
4). After PAVR, this pattern was reversed, and the microcirculatory decompression (suction) wave was found to increase significantly (␤ coefficient⫽0.9⫻10⫺3 W 䡠 m⫺2 䡠 s⫺2;
P⫽0.014; Figure 4). Overall, comparing the changes before
and after PAVR resulted in a significant beneficial increase in
delta microcirculatory decompression (suction) wave with
In aortic stenosis, the normal coronary physiological reserve
is impaired. Instead of increasing when heart rate rises, the
coronary diastolic suction wave decreases paradoxically. This
phenomenon is reversed immediately after PAVR when this
physiological reserve returns to a normal positive pattern.
Accounting for the Detrimental Hemodynamics in
Severe Aortic Stenosis
Normal coronary perfusion is maintained by the balance (or
coupling) between the pressure originating from the proximal
(aortic) and distal (microcirculatory) ends of the coronary
circulation. When the aortic valve is normal, these pressures
are closely related during ejection because LV chamber
pressure is a major determinant of both intramyocardial stress
and aortic pressure.20 Any difference in the observed aortic
and microcirculatory originating pressure waveforms observed early in systole is attributable to time delays in
physiological processes for the period that the aortic valve
remains shut (eg, the isovolumic contraction phase at the
onset of systole).
Because pressures at either end of the coronary artery are
so closely matched during systole, net changes in coronary
flow velocity during this period are normally minimal. In
diastole, aortic valve closure decouples pressure in the aorta,
and aortic pressure decays from end-systolic pressure in a
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Davies et al
Figure 3. Change in septum and posterior wall thickness from diastole to systole before and after percutaneous aortic valve
replacement (PAVR). Change in left ventricular (LV) wall thickness
in the septum and posterior walls from diastole to systole was
plotted vs the backward decompression wave before and after
PAVR. This relationship is poor before PAVR but improves after
PAVR. This poor relationship before PAVR supports the timevarying elastance model (in which high LV pressures are only
partially transmitted through the lumen and into the intramyocardial vessels). After PAVR, afterload falls and the change in wall
thickness from diastole to systole becomes more closely related
to the backward decompression wave. This supports the
intramyocardial pump model (in which the degree of compression and decompression of the intramyocardial vessels determines the magnitude of waves). A pair of points was plotted for
each patient (n⫽22). As a result of identical changes in posterior
and septum dimensions in some patients, some points are not
visible because they are superimposed on one another.
quasiexponential manner, whereas LV pressures and myocardial stress fall rapidly. As a result, the pressure gradient for
coronary perfusion increases, resulting in an acceleration of
coronary blood flow.
Changes in Coronary Hemodynamics After PAVR
5
Figure 4. Improvement in physiological reserve in subjects with
aortic stenosis after percutaneous aortic valve replacement
(PAVR). Physiological reserve was assessed by measuring the
microcirculatory decompression (suction) wave at rest and then
by pacing at 90 and 120 bpm. Before PAVR, the microcirculatory decompression (suction) wave decreased with increasing
heart rate. After PAVR, the reverse was observed, and the
microcirculatory decompression (suction) wave increased with
increasing heart rate.
With increasing workload, this mechanism is exaggerated.
The increased extremes of LV luminal pressure and intramyocardial pressure create a larger coronary perfusion
pressure gradient, resulting in increased coronary blood flow
in early diastole.
The importance of ventricular pressure in the determination of coronary perfusion pressures by this coupled mechanism has previously been reported during pharmacological
stress in dogs and, more recently, in humans by comparing
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Figure 5. Decoupling of mechanisms of
coronary perfusion in subjects with severe
aortic stenosis. In the coupled mechanism,
rising left ventricular (LV) luminal pressure is
transmitted across throughout the myocardium, compressing small perforating microcirculatory vessels. When the LV pressure
exceeds the aortic pressure, the aortic
valve opens, raising pressure at the proximal end of the coronary artery. During diastole, this process is reversed; left ventricular
relaxation leads to closure of the aortic
valve and decompression of the small
microcirculatory vessels. This decompression generates a suction wave accelerating
coronary blood flow, which is aided by
maintenance of high perfusion pressures
from the aorta, which falls more slowly. In
the decoupled mechanism in aortic stenosis, the delicate balance between LV pressure and aortic pressure is lost, and pressures originating at the microcirculatory end
far exceed those from the aortic end.
the difference in coronary myocardial decompression (suction) wave subtended by either the LV or right ventricle.21,22
Testing Physiological Reserve
Previous studies in animal models in the absence of aortic
stenosis have demonstrated a marked increase in backwardoriginating waves with physiological stressors.23 In our human subjects, we expected to observe similar changes with
pacing before PAVR at 90 and 120 bpm. Unexpectedly,
rather than seeing an increase in backward decompression
(suction) wave with physiological stress, we observed a
marked fall, the opposite of what had been reported by Sun et
al23 when performing similar experiments in dogs in the
absence of aortic stenosis.
We hypothesize that the fall in microcirculatory suction wave
with pacing was due to decoupling of the normal mechanisms
essential for maintenance of normal coronary perfusion (Figure
5). To test this theory, we repeated identical pacing studies after
PAVR. In these studies, we found that the microcirculatory
originating suction wave no longer decreased but was found to
increase by ⬇50%, suggesting the restoration of mechanisms
contributing to physiological reserve. This is likely to be a result
of a marked reduction in afterload (and consequent left shift on
the Frank-Starling curve), a reduction in myocardial stress, and
a recoupling of normal regulatory mechanisms for control of
coronary perfusion (Figure 5).
This detrimental fall could also be exacerbated by the effects
of time-varying elastance in which, in conditions of extreme
pressure loading, LV pressure is only partially transmitted from
the lumen into the intramyocardial vessels.15 Such changes
would limit the close relationship between LV pressure and
microcirculatory compression and lead to partial dissociation
between pressure and decompression wave. After PAVR, when
extreme afterload is reduced, this process would be reversed
because lower LV pressure would lessen the influence of the
time-varying elastance effects. It is possible to observe this
experimentally from the altered relationship between the change
in LV wall thickness (⌬LV thickness) in the septum and
posterior wall from diastole to systole before and after PAVR.
Before PAVR, the ⌬LV wall thickness is poorly related to the
decompression wave (r⫽0.01, P⫽0.97; Figure 3, top), implying
that pressure transmission is diminished by the time-varying
elastance effects. However, after PAVR, this relationship becomes stronger (r⫽0.45, P⫽0.036; Figure 3, bottom) as the
shielding effects of the time-varying elastance are reduced.
These findings add further evidence to support the time-varying
elastance model, in addition to demonstrating how its effects can
be modulated by changes in afterload.
Explaining Mechanisms of Angina
The decoupling of normal regulatory mechanisms of coronary
blood flow in aortic stenosis that we observed may help explain
why aortic stenosis patients with unobstructed arteries develop
symptoms of angina (Figures 4 and 5). In such subjects, even the
most modest increases in workload are unlikely to be met by an
appropriate increase in coronary perfusion pressure, making
them vulnerable to ischemia (Figure 5). This can be observed by
considering the change in VTI before and after PAVR. The VTI,
a measure of the quantity of blood being delivered to the
myocardium over the course of the cardiac cycle, decreases with
increasing heart rate before PAVR but remains unchanged after
PAVR. We hypothesize that this reduction in VTI with increased heart rate before PAVR is due to an attenuation of
coronary physiological reserve such that coronary blood flow
velocity cannot be sufficiently increased to compensate for the
increased heart rate (and most important, the reduction in length
of the diastolic perfusion phase). This is most striking in the
VTI.min product, in which a marked reduction can be seen
between resting and increased heart rates. These findings are
similar to the reduction in coronary vasodilator reserve observed
by Rajappan et al12 during pharmacological noninvasive PET
assessment, although phasic changes in coronary blood flow
were not measured. After PAVR, the physiological reserve is
improved so that an increase in heart rate is accompanied by a
relative increase in VTI (despite the shortening of the diastolic
perfusion phase).
We know that in humans coronary flow reserve is reduced in
aortic stenosis. Although this factor must in some way contribute
to the potential for ischemia to develop, it is not clear that
differences in the flow reserve account for angina symptoms.24
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Davies et al
Assessment of differential changes in waves occurring at different phases in the cardiac cycle in relation to symptoms may
provide a better understanding of the relationship of coronary
flow anginal symptoms. Although further studies are clearly
required, it is interesting that a previous study reported that
people with aortic stenosis and exertional symptoms showed
smaller increases in coronary flow velocity in response to atrial
pacing and dobutamine than those free of anginal symptoms.25
Acute Reduction in Microcirculatory Suction
Wave After Percutaneous Aortic
Valve Replacement
After PAVR, the microcirculatory decompression (suction)
wave was found to decrease at an intrinsic rate and the forward
compression wave to increase. This decrease in microcirculatory
decompression wave is compatible, and indeed predictable, by
the intramyocardial muscle-pump model first described by
Spaan et al.14 In the intramyocardial muscle-pump model,
forward coronary blood flow is explained by the expansion in
volume of the microcirculation (generating the suction wave)
after release of compression during systole. Compression and
recoil are interrelated in that larger compression leads to larger
recoil. Under circumstances of high LV pressure and intramural
stress, as observed in severe aortic stenosis, intramural vessels
are highly compressed in systole, and recoil is commensurately
increased to generate a large suction wave in early diastole
(Figure 2).
Further Prospective Studies and Improvement in
Coronary Perfusion With Left Ventricular
Hypertrophy Regression
In this study, we have observed marked changes in the
coronary physiological reserve in patients with severe aortic
stenosis undergoing PAVR in the absence of obstructive
coronary disease. It is likely that similar altered physiology
would be identified in younger subjects with aortic stenosis,
even in the presence of moderate coronary artery disease.
Currently, most of the work in the field assessing wave travel
in coronary arteries has concentrated on unobstructed vessels,18,21 so further studies are needed to confirm and quantify
the degree of coronary stenosis necessary to cause significant
impediment of wave travel. Additionally, from our findings,
we can only make interferences about temporal changes in
coronary physiological reserve with worsening aortic stenosis. To confirm such changes, a longitudinal assessment
needs to be performed to identify temporal changes in
coronary physiological reserve and angina symptoms with
progression in severity of aortic stenosis.
Left ventricular hypertrophy has previously been shown to
be detrimental to coronary hemodynamics.18 Although an
immediate reduction in afterload after PAVR can explain the
immediate improvement in physiological reserve and the
increase in exercise capacity, it is possible that, over time,
with regression of LV hypertrophy and reduction in LV mass
and myocardial oxygen demand, further benefit in both basal
and coronary physiological reserve will occur.
Changes in Coronary Hemodynamics After PAVR
7
procedures last ⬎90 minutes and can cause considerable
variations in hemodynamics, it is routine for the anesthetist to
administer intravenous fluids and, in extreme circumstances,
vasoactive drugs to maintain a stable blood pressure and to
offset any fluid losses that occur during the procedure. This
could affect hemodynamic measurements; however, any
change would be small compared with the marked reduction
in ventricular afterload after PAVR (pre-PAVR mean pressure gradient, 80⫾34 mm Hg). No significant difference in
administration of vasoactive drugs was found between the 2
measurement phases. In addition, no change in pharmacological therapies was made during assessment of coronary
physiological reserve, which took place over a period lasting
only 3 minutes in each subject.
Because of the nature of the typical population selected for
PAVR, we studied mainly symptomatic elderly women with
severe aortic stenosis. Caution is therefore warranted in extrapolating these observations to other groups, such as men or
younger patients undergoing conventional valve surgery, particularly because the latter group may have lesser degrees of
myocardial fibrosis and lower levels of ventricular wall stress.
Nevertheless, we believe that PAVR provides a more appropriate model to assess the immediate effects of relief of aortic
stenosis on coronary physiology because it is less complicated
by the effects associated with traditional open-chest valve
surgery.
A high proportion of our subjects were labeled hypertensive on the basis of office measurements over the preceding
years and had begun appropriate antihypertensive therapy.
Consequently, high blood pressure contributed to additional
afterload. However, high blood pressure is common in aortic
stenosis, and given the prevalence of hypertension in individuals ⬎55 years of age, hypertension could be regarded as the
norm rather than the exception.26 It is reasonable to assume
that given the good blood pressure control achieved (systolic,
123⫾9 mm Hg; diastolic, 56⫾12 mm Hg), the vast majority
of LV hypertrophy was due to the aortic stenosis as opposed
to increased afterload from high blood pressure.
Blood pressure was found to be lower after PAVR.
Although this finding seems surprising in view of the reduced
ventricular load and could indicate an adverse effect of
PAVR, a similar blood pressure response has been reported
after open-chest aortic valve replacement,27–29 which is
thought to be due to modulation of baroreflexes rather than
modulation of ventricular afterload per se.
We chose to use pacing rather than a pharmacological
agent to increase heart rate. Although drug therapies may
have more profound vasodilatory effects, these effects are not
limited to the coronary circulation but have differential
effects at different vascular beds and can cause large drops in
blood pressure in patients with critical aortic stenosis. On the
other hand, pacing is highly reproducible, is safe in patients
with critical aortic stenosis, is an intrinsic part of the PAVR
procedure, and is rapidly reversible on termination.
Conclusions
Study Limitations
Each subject undergoing PAVR was sedated and ventilated
during the entire course of the procedure. Because PAVR
Severe aortic stenosis is detrimental to coronary hemodynamics. These effects are due to severe LV pressure loading and
excessive ventricular wall stress. In subjects with severe
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8
Circulation
October 4, 2011
aortic stenosis, coronary physiological reserve is severely
impaired but improves immediately after PAVR. Quantifying
these severe limitations in coronary physiological reserve
may explain the angina symptoms and provide a tool for
functional assessment of significance of aortic stenosis and
the timing of valvular surgery.
Acknowledgments
All authors would like to acknowledge the support of the NIHR
Biomedical Research.
Sources of Funding
This work was funded by a grant from the Coronary Flow Trust.
Disclosures
Drs Davies (FS/05/006), Francis (FS/04/079), and Hadjiloizou (FS/
05/034) are British Heart Foundation fellows. Dr Sen is an MRC
fellow (G1000357).
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CLINICAL PERSPECTIVE
Using the new technique of percutaneous aortic valve replacement in combination with wave intensity analysis, we have
identified abnormalities in coronary physiology that are rapidly restored to normal after valve implantation. In addition to being
of mechanistic interest, quantification of coronary physiological reserve and in particular its paradoxical reversal may offer a
potential way of assessing the severity of aortic stenosis in the presence of comorbidities that may mimic or obscure anginal
symptoms. Although currently it is possible to do this analysis only with offline analysis tools, the computational processing
requirements are minimal and easily automatable, making online analysis a realistic vision for the future.
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