Download Simultaneous pulmonary trunk and pulmonary arterial wave

Am J Physiol Regul Integr Comp Physiol 294: R1554–R1562, 2008.
First published February 20, 2008; doi:10.1152/ajpregu.00743.2007.
Simultaneous pulmonary trunk and pulmonary arterial wave intensity analysis
in fetal lambs: evidence for cyclical, midsystolic pulmonary vasoconstriction
Joseph J. Smolich,1,2 Jonathan P. Mynard,1,2 and Daniel J. Penny1,2,3
1
Australia and New Zealand Children’s Heart Research Centre, Murdoch Children’s Research Institute; and 2Department
of Paediatrics, University of Melbourne and 3Department of Cardiology, Royal Children’s Hospital, Melbourne, Australia
Submitted 14 October 2007; accepted in final form 18 February 2008
IN THE FETUS, RIGHT VENTRICULAR (RV) output constitutes 56 –
67% of the combined ventricular output, while proximal pulmonary blood pressures are equal to or greater than in the aorta
(1, 16, 35, 38, 40 – 42). Despite the high pulmonary pressures,
only ⬃10% of RV blood entering the pulmonary trunk (PT)
passes to the fetal lungs, with the remainder crossing the ductus
arteriosus into the descending aorta (12, 35, 36, 42). The
physiological basis of this low blood flow to the fetal lungs is
incompletely understood, although factors such as a low O2
milieu and pronounced muscularity and reactivity to vasoconstrictors of the pulmonary vasculature have been implicated (5,
12, 36). However, the strikingly different blood flow profiles
within the fetal PT, which displays continuous forward flow
throughout systole (13, 36 –38), and major pulmonary arteries,
where forward flow occurs only in early systole (27, 36, 37),
suggests that detailed evaluation of hemodynamic interactions
between these anatomically proximate sites may provide new
insights into the mechanism(s) underpinning a low fetal lung
blood flow.
One powerful means of obtaining quantitative and temporal
information about specific components contributing to cardiovascular interactions is the relatively new method of wave
intensity analysis (WIA), an approach based on the premise
that circulatory function is accompanied by the propagation of
infinitesimal wavefronts defined by their pressure (P) and
velocity (U) effects (4, 31). In the time domain, the product of
changes in P and U (“wave intensity”) represents the instantaneous energy carried by the wavefronts (23, 46). Using WIA,
we can classify these waves into “forward-running” waves
arising from the heart, “backward-running” waves propagating
from the vasculature, “compression” waves increasing pressure, and “expansion” waves decreasing pressure (4). Calculation of wave speed enables separation of P and U into forward
and backward components and of net wave intensity into the
four wave types which may simultaneously exist in an overall
profile, namely, “forward compression waves” increasing pressure and velocity, “forward expansion waves” decreasing pressure and velocity, “backward compression waves” increasing
pressure but decreasing velocity, and “backward expansion
waves” decreasing pressure but increasing velocity (4, 23).
To date, only one study has applied WIA in the fetus, with
evaluation primarily of the RV-PT interaction (13). As in the
adult (17, 18), the fetal PT WIA was characterized by an initial
systolic forward compression wave (FCWis) associated with
impulsive RV ejection of blood, and a late-systolic forward
expansion wave (FEWls) occurring just prior to pulmonary
valve closure (13). However, in contrast to its absence from the
adult under normal conditions (17, 18), the fetal PT also
displayed a very prominent midsystolic backward compression
wave (BCWms) temporally associated with a midsystolic plateau in the flow profile (13). On the basis of its abolition by
ligation of the main pulmonary artery and the calculated
distance to the wave origin, it was concluded that this BCWms
arose from the pulmonary vasculature as a reflection of FCWis
(13). These findings are of particular relevance because they
suggest that the abrupt midsystolic cessation of flow observed
in fetal major pulmonary arteries (27, 36, 37) is related to the
presence of a BCWms, even larger than in the PT. If this is the
case, however, it is unlikely that vascular reflection alone could
underpin such a pulmonary arterial BCWms, as the relative
Address for reprint requests and other correspondence: J. J. Smolich, Dept.
of Cardiology, Royal Children’s Hospital, Flemington Road, Parkville, Victoria, Australia, 3052 (e-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
fetal pulmonary vascular interaction; fetal pulmonary blood flow; fetal
pulmonary blood pressure
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0363-6119/08 $8.00 Copyright © 2008 the American Physiological Society
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Smolich JJ, Mynard JP, Penny DJ. Simultaneous pulmonary
trunk and pulmonary arterial wave intensity analysis in fetal lambs:
evidence for cyclical, midsystolic pulmonary vasoconstriction. Am J
Physiol Regul Integr Comp Physiol 294: R1554–R1562, 2008. First
published February 20, 2008; doi:10.1152/ajpregu.00743.2007.—The
physiological basis of a characteristically low blood flow to the fetal
lungs is incompletely understood. To determine the potential role of
pulmonary vascular interaction in this phenomenon, simultaneous
wave intensity analysis (WIA) was performed in the pulmonary trunk
(PT) and left pulmonary artery (LPA) of 10 anesthetized late-gestation
fetal sheep instrumented with PT and LPA micromanometer catheters
to measure pressure (P) and transit-time flow probes to obtain blood
velocity (U). Studies were performed at rest and during brief complete
occlusion of the ductus arteriosus to augment pulmonary vasoconstriction (n ⫽ 4) or main pulmonary artery to abolish wave transmission from the lungs (n ⫽ 3). Wave intensity (dIW) was calculated as
the product of the P and U rates of change. Forward and backward
components of dIW were determined after calculation of wave speed.
PT and LPA WIA displayed an early systolic forward compression
wave (FCWis) increasing P and U, and a late systolic forward
expansion wave decreasing P and U. However, a marked midsystolic
fall in LPA U to near-zero was related to an extremely prominent
midsystolic backward compression wave (BCWms) that arose ⬃5 cm
distal to the LPA, was threefold larger than the PT BCWms (P ⬍
0.001), of similar size to FCWis at rest (P ⬎ 0.6), larger than FCWis
following ductal occlusion (P ⬍ 0.05) and abolished after main
pulmonary artery occlusion. These findings suggest that the absence
of pulmonary arterial midsystolic forward flow which accompanies a
low fetal lung blood flow is due to a BCWms generated in part by
cyclical vasoconstriction within the pulmonary microcirculation.
FETAL PULMONARY ARTERIAL WAVE INTENSITY ANALYSIS
METHODS
Experiments were approved by the institutional Animal Ethics
Committee and conformed to guidelines of the National Health and
Medical Council of Australia.
Surgical preparation. Ten Border-Leicester cross ewes were anesthetized at a gestation of 137 (2) days [mean (SD), term ⫽ 147 days]
with intramuscular ketamine 5 mg/kg and xylazine 0.1 mg/kg, followed by 4% isoflurane delivered by mask. Animals were placed in a
supine position, and the trachea was intubated. Anesthesia was then
maintained with isoflurane (2–3%), nitrous oxide (⬃30%), and oxygen-enriched air (⬃70%) delivered via volume-controlled ventilator
(900C Servo, Siemens-Elema, Solna, Sweden), supplemented by an
intravenous infusion of ketamine (1–1.5 mg 䡠 kg⫺1 䡠 h⫺1) and midazolam (0.1– 0.15 mg 䡠 kg⫺1 䡠 h⫺1). Oxygen saturation was monitored
continuously with a cutaneous pulse-oximetry sensor (Oximas
Dura-Y, Tyco Healthcare, Pleasanton, CA) applied to the ear. The
right common carotid artery was cannulated through a neck incision
for monitoring of blood pressure (90308 Multiparameter Monitor,
Spacelabs. Medical, Redmond, WA) and for blood gas sampling. On
the basis of frequent arterial blood gas analysis (ABL 620, Radiometer, Copenhagen, Denmark), ventilation of the ewe was adjusted to
maintain arterial O2 tension at 100 –120 mmHg and arterial CO2
tension at 35– 40 mmHg.
The pregnant horn of the uterus was exposed through a midline
laparotomy, and the fetal head, left forelimb, and upper thorax were
exteriorized through a hysterotomy. A multilumen cannula was inserted via the fetal left external jugular vein into the right atrium for
fluid administration, and a polyvinyl catheter was passed via the left
common carotid artery into the ascending aorta for pressure measurement. A thoracotomy was performed in the 3rd left interspace, and the
3rd and 4th ribs were removed to increase exposure of the heart and
great vessels. After incision of the overlying pericardium, 10 –14 mm
“A series” and 4 – 6 mm “S series” transit-time flow probes (Transonic
Systems, Ithaca, NY) were placed around the PT and LPA, respectively. A cannula with its tip directed toward the heart was inserted
into the pulmonary trunk through an adventitial purse-string suture
distal to the flow probe on this vessel and connected to a polyvinyl
catheter to measure pressure. Through separate purse string sutures,
one 2.5 F micromanometer catheter (Millar Instruments, Houston,
TX) was inserted into the pulmonary trunk just distal to the flow
probe, while another 2.5 F micromanometer catheter was inserted into
the pulmonary trunk close to the base of the main pulmonary artery
and its tip advanced into the left pulmonary artery. The edges of the
pericardial incision were then loosely reapproximated over the left
pulmonary artery flow probe.
Physiological data. Aortic and pulmonary trunk blood pressures
were measured via the fluid-filled catheters with a transducer (Transpac IV, Abbott Critical Care Systems, Sligo, Ireland), referenced to
atmospheric pressure at the level of the left atrium and calibrated
against a water manometer before each experiment. Pressure signals
from fluid-filled catheters were processed using a transducer amplifier
(Transbridge TBM4M, World Precision Instruments, Sarasota, FL).
High-fidelity pulmonary trunk and left pulmonary artery pressures
were measured by interfacing micromanometers with transducer control units (TCB-500, Millar Instruments). PT and LPA flows were
measured with a transit-time flowmeter (model T206; Transonic
Systems). All physiological signals were digitized at a sampling rate
of 1,000 Hz using an analog-to-digital convertor (iNet-100B, GW
Instruments, Somerville, MA) interfaced with programmable acquisition and analysis software (Spike2, Cambridge Electronic Design,
Cambridge, UK). No data filtering was employed, apart from application of a 48-Hz low-pass filter at the time of analysis to remove
electrical interference from signals. PT and LPA micromanometer
signals were calibrated by matching mean values to the mean pressure
of the fluid-filled pulmonary trunk catheter.
Experimental protocol. Hemodynamic variables were allowed to
stabilize for 10 –15 min after completion of surgery. After withdrawal
of blood samples for blood gas analysis, hemodynamic data were
recorded onto a computer in all fetuses. In fetal subgroups, data were
also recorded before, during, and after a brief (15–20 s) complete
occlusion of the main pulmonary artery (n ⫽ 3) or ductus arteriosus
(n ⫽ 4) with a vascular clamp. A brief period of ductal occlusion was
specifically chosen because it results in pulmonary vasoconstriction
not masked by shear stress-induced vasodilation occurring with longer
(⬎1 min) periods of occlusion (44). Hemodynamic variables rapidly
attained a new steady-state level after clamping of either vessel and
quickly returned to baseline following removal of the clamp (Supplemental data for this article are available online at the American
Journal of Physiology—Regulatory, Integrative and Comparative
Physiology Web site.). At the end of the experiment, animals were
killed with a pentobarbital sodium overdose (100 mg/kg), and the
position of catheters was checked.
Wave intensity analysis. As WIA uses pressure and velocity data,
PT and LPA blood flows were converted to velocity (U) using
cross-sectional area derived from the nominal size of the flow probe
(17, 18, 32, 45). After generation of an ensemble average of highfidelity pressure (P) and U signals from a mean of 66 beats at baseline
(range 42–100), 35 beats during occlusion of the ductus arteriosus
(range 20 – 49), and 37 beats during occlusion of the main pulmonary
artery (range 25–50), the rates of change of PT and LPA blood
pressure (dP/dt) and velocity (dU/dt), and the product of these differentials (wave intensity, dIW), were derived. Note this calculation
yielded a “time-corrected” dIW (i.e., dP/dt 䡠 dU/dt) that is independent
of the digitizing sample rate (8, 21, 32, 34), which contrasts with dIW
defined by absolute changes in P and U between samples (i.e., dP 䡠 dU)
used in a number of previous reports (13, 17, 18, 23, 25, 31, 45, 46).
However, the latter can be obtained from time-corrected wave dIW by
dividing by the square of the sampling frequency (25).
To separate P, U, and dIW into forward and backward components,
wave speed was obtained by derivation of dP/dU and use of the
relation ␳c ⫽ dP/dU (23), where ␳ is blood density (assumed as 1,050
kg/m3) and c is wave speed. Using ensemble-averaged P and U data,
dP/dU was calculated using least squares linear regression from the
P-U slope during early systole, when the contribution of backwardrunning waves is minimal (23, 24, 32). Hardware-related time lags
between P and U data points (18) were corrected by aligning the peak
second derivatives of these signals, resulting in a highly linear
early-systolic P-U relation for both the PT (R2 ⫽ 0.9998 ⫾ 0.0001)
and LPA (R2 ⫽ 0.9996 ⫾ 0.0004).
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magnitude of the PT BCWms is already double or more that of
typical reflected BCWms seen in the fetal (13) or adult ascending aorta (23, 32), or the adult PT in hypoxia (18). An
alternative possibility, suggested by the increased vasoreactivity (12) and potent myogenic responses (3, 44) known to occur
within the immature pulmonary vasculature, is that vasoconstriction per se also contributes to the genesis of a pulmonary
arterial BCWms.
This study, in which simultaneous PT and left pulmonary
artery (LPA) WIA was undertaken in anesthetized fetal lambs,
therefore had two main aims. The first was to characterize
PT-LPA interaction by comparison of wave intensity profiles at
these sites, including their contribution to changes in local
blood pressure and flow/velocity. The second was to determine
the potential role of pulmonary vasoconstriction in generation
of a pulmonary arterial BCWms. Studies were performed under
resting conditions in all fetuses and in a subgroup of animals
during brief occlusion of either the ductus arteriosus to increase
pulmonary vasoconstriction via a pressure-induced rise in vessel stretch (44) or the main pulmonary artery to abolish wave
transmission from the pulmonary vasculature.
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FETAL PULMONARY ARTERIAL WAVE INTENSITY ANALYSIS
RESULTS
Fig. 1. Blood pressure (A), flow (B), and velocity (C) profiles in the fetal
pulmonary trunk (thick line) and left pulmonary artery (thin line).
As per convention (4), wave direction was referenced to the
direction of blood flow, such that waves arising from the right
ventricle were defined as forward-running and those propagating from
the vasculature as backward-running. Using established methodology
(8, 17, 18, 32), the intensity of forward-running waves (dIW⫹) was
calculated as (dP/dt ⫹ ␳c 䡠 dU/dt)2/(4␳c) and that of backward-running
waves (dIW⫺) as ⫺(dP/dt ⫺ ␳c 䡠 dU/dt)2/(4␳c). Waves causing a
pressure increase were classified as compression waves and those
producing a pressure decrease as expansion waves, with this characteristic defined by the sign of the pressure difference across the respective
forward-running wavefront, given by (dP/dt)⫹ ⫽ 1/2 (dP/dt ⫹ ␳c䡠dU/dt)
and the backward-running wavefront, given by (dP/dt)⫺ ⫽ 1/2 (dP/dt ⫺
␳c䡠dU/dt). Thus, a forward-running wave was a compression wave if
(dP/dt)⫹ ⬎ 0 and an expansion wave if (dP/dt)⫹ ⬍ 0. Similarly, a
backward-running wave was classified as a compression wave if
(dP/dt)⫺ ⬎ 0 and an expansion wave if (dP/dt)⫺ ⬍ 0 (17, 18, 32).
The time interval between wave intensity peaks was obtained from
separated WIA profiles and an overall distance to the origin of
backward-running waves estimated from the product of wave speed
and one-half the time interval between the peaks of the backward and
preceding forward compression wave (18, 32). Note that this distance
is an approximation, since only a single wave speed (obtained from
the PT or LPA) was used in calculations, whereas available informa-
Resting fetal blood gases and hemodynamics. Ascending
aortic pH was 7.282 (0.030), Hb 12.8 (1.3) g/dl, Hb O2
saturation 71 (7) %, PO2 24.7 (2.4) mmHg, PCO2 52.3 (3.6)
mmHg, base excess ⫺2.9 (1.8) mmol/l, mean ascending aortic
pressure 59 (7) mmHg, mean PT pressure 60 (6) mmHg, and
heart rate 142 (19) beats/min.
Resting pressure, velocity and wave intensity profiles. Systolic blood pressure profiles in the PT and LPA were similar,
except that a shoulder in the midportion of the ascending limb
was more pronounced in the former (Fig. 1A). As in previous
reports, PT (13, 38) and LPA (27, 36, 37) flow profiles
displayed an early systolic peak and a late-systolic negative
flow, but a midsystolic flow attenuation, occurring in conjunction with rising pressure, was more marked in the LPA (Fig.
1B). Peak positive, mean, and peak negative flows were all
greater in the PT. However, peak positive U was similar in the
PT and LPA, suggesting that the difference in peak positive
flow was largely attributable to differing vessel diameters,
while peak negative U was greater in the LPA and mean U was
approximately threefold greater in the PT (Fig. 1C, Table 1).
PT WIA displayed an early systolic FCW (FCWis), a large
midsystolic BCW (BCWms), and a late-systolic FEW (FEWls).
In addition, a small and constant BEW was temporally
associated with the shoulder of the ascending limb of the PT
pressure pulse, while several smaller midsystolic FCWs
(FCWms) evident both before and after the peak of BCWms were
associated with further increases in pressure and rebound increases in velocity (Fig. 2, left). WIA in the LPA also demonTable 1. Baseline fetal pulmonary trunk and left pulmonary
artery blood flows and velocities
Blood flow, ml/min
Peak positive
Mean
Peak negative
Blood velocity, m/s
Peak positive
Mean
Peak negative
PT
LPA
P
3442 (942)
957 (341)
⫺438 (218)
542 (241)
70 (61)
⫺174 (72)
⬍0.001
⬍0.001
⬍0.01
0.58 (0.17)
0.16 (0.07)
⫺0.08 (0.05)
0.51 (0.14)
0.06 (0.04)
⫺0.17 (0.07)
⬎0.3
⬍0.001
⬍0.01
Data are expressed as means (SD); n ⫽ 10. PT, pulmonary trunk; LPA, left
pulmonary artery.
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tion suggests that wave speed varies within different pulmonary
arterial segments and within each beat (2).
The cumulative intensity of forward-running (IW⫹) and backwardrunning waves (IW⫺), which is directly related to wave energy, was
calculated by integrating the respective dIW over the wave duration (8,
32). In addition, because forward-running compression, forwardrunning expansion, and backward-running compression wave profiles
had major and minor components, total IW for these waves was also
calculated. The contribution of waves to P and U was obtained by
measuring changes in the forward or backward components of P and
U between wave onset and offset.
Statistical analysis. Statistical analyses were performed using Statistical Package for the Social Sciences ver. 12.0.1 (SPSS, Chicago,
IL). Differences in PT and LPA WIA and the effects of vascular
occlusion on wave profiles were evaluated using repeated-measures
ANOVA. Results are expressed as means (SD), and significance was
taken at the P ⬍ 0.05 level.
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FETAL PULMONARY ARTERIAL WAVE INTENSITY ANALYSIS
Table 2. Fetal pulmonary trunk and left pulmonary artery
wave intensity analysis
PT
Fig. 2. Net blood pressure (A) and blood velocity (B), shown in thick line with
forward and backward components shown in thin lines, as well as net wave
intensity (C) and separated forward and backward wave intensities (D) in the
fetal pulmonary trunk (left) and left pulmonary artery (right). Abbreviations in
D are the same as in Table 2.
strated a FCWis, and FEWls, smaller FCWms, and an inconsistent
BEW, present in only 3 of the 10 fetuses. However, the most
striking feature at this site was an extremely prominent BCWms of
similar size to the preceding FCWis (Fig. 2, right).
Wave speed, m/s
Peak dIW, Wm⫺2s⫺2 ⫻106
FCWis
FEWls
BCWms
BEW
IW (Wm⫺2s⫺1 ⫻104)
FCWis
FCWtotal
FEWls
FEWtotal
BCWms
BCWtotal
BEW
Peak dIW ratios
BCWms/FCWis
BEW/FCWis
IW ratios
BCWms/FCWis
BEW/FCWis
3.6 (0.9)
LPA
2.7 (0.7)
P
0.03
2.43 (0.83)
1.68 (1.11)
⫺0.52 (0.43)
⫺0.09 (0.10)
1.85 (0.54)
1.12 (0.67)
⫺1.56 (0.44)
0.03
0.03
⬍0.001
3.22 (1.01)
3.58 (1.13)
1.88 (1.28)
2.22 (1.31)
⫺0.85 (0.73)
⫺0.98 (0.83)
⫺0.09 (0.12)
2.62 (0.62)
2.94 (0.73)
1.29 (0.86)
1.63 (0.75)
⫺2.48 (0.80)
⫺2.57 (0.86)
0.1
0.1
0.03
0.04
⬍0.001
⬍0.001
0.22 (0.17)
0.03 (0.03)
0.89 (0.39)
⬍0.001
0.24 (0.19)
0.02 (0.02)
0.95 (0.33)
⬍0.001
Data are expressed as means (SD); n ⫽ 10. BCWms and BCWtotal, midsystolic and total backward compression wave; BEW, backward expansion wave;
FCWis and FCWtotal, initial systolic and total forward compression wave;
FEWls and FEWtotal, late-systolic and total forward expansion wave; dIW,
wave intensity; IW, cumulative wave intensity.
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Resting wave intensity analysis. Data are presented in Tables 2
and 3. Wave speed in the PT was ⬃30% higher than in the
LPA (P ⫽ 0.03).
Peak FCWis dIW⫹ in the PT occurred 6 (3) ms earlier (P ⬍
0.001) and was ⬃30% greater (P ⫽ 0.03) than in the LPA.
FCWis comprised ⬃90% of total FCW IW⫹ and was associated
with a similar increase in U at both sites, but ⬃25% higher rise
in P in the PT (P ⬍ 0.001).
Peak FEWls dIW⫹ in the PT occurred 6 (3) ms earlier (P ⬍
0.001) and was ⬃50% greater (P ⫽ 0.03) than the LPA. FEWls
comprised ⬃85% of total FEW IW⫹ and produced a similar
reduction in U at both sites but was associated with a ⬃35%
greater fall in P in the PT (P ⬍ 0.001).
In contrast to the forward-running waves, BCWms peak
dIW⫺ in the LPA occurred 4 (4) ms earlier (P ⫽ 0.02) and was
3-fold larger (P ⬍ 0.001) than in the PT. Furthermore, whereas
the magnitude of BCWms IW⫺ was 24 (19) % of FCWis IW⫹ in
the PT, it comprised 95 (33) % of FCWis IW⫹ in the LPA (P ⬍
0.001), with no significant difference between the amplitudes
of LPA BCWms IW⫺ and FCWis IW⫹ (P ⬎ 0.6). Compared
with the PT, the LPA BCWms produced a ⬃50% greater rise in
P (P ⬍ 0.001) and double the fall in U (P ⬍ 0.001). Using the
interval between BCWms peak dIW⫺ and peak FCWis dIW⫹ in
the PT [51 (8) ms] and LPA [41 (12) ms], the calculated origin
of BCWms from the measurement site in the PT [8.9 (2.3) cm]
was almost double that from the LPA [5.3 (1.7) cm, P ⫽
0.001].
In the PT, peak BEW dIW⫺ occurred 11 (2) ms after peak
FCWis dIW⫹, constituted 3% of the magnitude of peak FCWis
dIW⫹, and had a calculated origin 2.9 (1.9) cm distal to the
measurement site.
Effect of transient vascular occlusion. Ductal occlusion
produced similar morphological alterations of wave intensity
profiles in the PT (Fig. 3) and LPA (Fig. 4), with the main
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Fig. 3. Net blood pressure (A) and blood velocity (B), shown in thick line with
forward and backward components shown in thin lines, as well as net wave
intensity (C) and separated forward and backward wave intensities (D) in the
fetal pulmonary trunk before (left) and after occlusion of the ductus arteriosus
(right). Abbreviations in D are the same as in Table 2.
Fig. 4. Net blood pressure (A) and blood velocity (B), shown in thick line with
forward and backward components shown in thin lines, as well as net wave
intensity (C) and separated forward and backward wave intensities (D) in the
fetal left pulmonary artery before (left) and after occlusion of the ductus
arteriosus (right). Abbreviations in D are the same as in Table 2.
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FETAL PULMONARY ARTERIAL WAVE INTENSITY ANALYSIS
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changes comprising a decrease in the magnitude of FCWis and
an increase in the amplitude of FCWms and BCWms. The
magnitude of peak BCWms dIW⫺ increased after ductal occlusion in both the PT [from 0.38 (0.18) to 1.28 (0.29) W䡠m⫺2s⫺2 ⫻
106, P ⬍ 0.01] and LPA [from 1.95 (0.56) to 3.23 (0.79)
W䡠 m⫺2s⫺2 ⫻ 106, P ⬍ 0.05]. Importantly, the amplitude of
BCWms IW⫺ was uniformly greater than FCWis IW⫹ following
ductal occlusion, with the BCWms/FCWis ratio increasing from
0.25 (0.19) to 1.25 (0.34) in the PT (P ⫽ 0.01) and from 0.92
(0.16) to 1.86 (0.58) in the LPA (P ⬍ 0.05).
In the PT, occlusion of the main pulmonary artery was
accompanied by disappearance of not only BCWms but also of
most of the FCWms occurring after this BCWms, with loss of
BEW (Fig. 5). As little or no pulsatile P and U was present, no
significant LPA wave intensity profiles were detected after
occlusion of the main pulmonary artery (Supplemental data for
this article are available online at the American Journal of
Physiology—Regulatory, Integrative and Comparative Physiology Web site.).
DISCUSSION
Using the novel approach of simultaneous WIA in the fetal
PT and LPA, this study has provided new insights into the
hemodynamic interaction between these sites, and, in particular, the basis of their markedly different blood flow profiles and
the associated low level of blood flow to the fetal lungs.
The most striking finding in our study was an extremely
prominent pulmonary arterial midsystolic backward-running
compression wave (BCWms), similar in amplitude to the preceding early-systolic forward compression wave (FCWis) under baseline conditions. As evident by its temporal features
(Fig. 2), amplitude (Table 2), and effect on U (Table 3), this
very large BCWms was responsible for the characteristic abrupt
decline in flow to near-zero occurring after a brief initial
systolic period of forward flow in major fetal pulmonary
arteries (27, 36, 37). This BCWms also made a major contribution to the local systolic pressure profile, producing a rise
that was equivalent in magnitude to that of FCWis (Table 3).
In accord with a previous report (13), a prominent BCWms
was also present within the fetal PT WIA (Fig. 2) and was
responsible for the midsystolic plateau in the PT blood flow/
velocity profile. However, the magnitude of this BCWms was
only ⬃30% that of the LPA BCWms (Table 2), with associated
smaller quantitative effects on P and U (Table 3).
Taken together, several results indicate that the LPA BCWms
arose from within the lungs and gave rise to the PT BCWms.
Thus, the peak of the pulmonary arterial BCWms preceded the
PT BCWms peak, while its amplitude exceeded that of the PT
BCWms, even when both were enhanced after occlusion of the
ductus arteriosus. In accord with the finding obtained from a
single fetus (13), occlusion of the main pulmonary artery also
abolished the PT BCWms. Finally, the distance of 8.9 cm from
the PT to the origin of BCWms, which is similar to a value of
9.4 cm reported previously (13), was appropriately larger than
the distance of 5.3 cm calculated from the LPA.
It is widely considered that the mechanism underlying a
BCWms is a reflection of the preceding FCWis from “closedend” reflection sites (18, 20, 22, 23, 25, 31). In accord with this
view and using PT WIA alone, it was concluded that the large
fetal PT BCWms was a reflection of FCWis from the pulmonary
Fig. 5. Net blood pressure (A) and blood velocity (B), shown in thick line with
associated forward and backward components shown in thin lines, as well as
net wave intensity (C) and separated forward and backward wave intensities
(D) in the fetal pulmonary trunk before (left) and after occlusion of the main
pulmonary artery (right). Abbreviations in D are the same as in Table 2.
vasculature (13). However, the combined use of PT and LPA
WIA in the present study indicated that vascular reflection was
not the sole mechanism underlying the fetal LPA BCWms, and
by implication, the PT BCWms. Specifically, as the magnitude
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FETAL PULMONARY ARTERIAL WAVE INTENSITY ANALYSIS
Table 3. Blood pressure and velocity effects of fetal
pulmonary trunk and left pulmonary artery wavefronts
Pressure change, mmHg
FCWis
FEWls
BCWms
Velocity change, m/s
FCWis
FEWls
BCWms
PT
LPA
P
13.0 (1.9)
⫺8.3 (3.5)
6.7 (3.1)
10.5 (0.9)
⫺6.1 (3.4)
10.3 (2.5)
⬍0.003
⬍0.001
⬍0.001
0.49 (0.15)
⫺0.32 (0.19)
⫺0.26 (0.16)
0.53 (0.12)
⫺0.30 (0.14)
⫺0.52 (0.13)
⬎0.6
⬎0.5
⬍0.001
Data are expressed as means (SD); n ⫽ 10. Abbreviations are the same as
used in Table 2.
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of the LPA BCWms and its preceding FCWis were similar at
rest (Table 2), reflection could only have produced this BCWms
if such reflection was near complete, a phenomenon unknown
in physiological systems. Even after complete occlusion of the
thoracic aorta, for example, the magnitude of BCWms still only
increases to 25– 40% of FCWis (23, 34). Moreover, the sizes of
the LPA and PT BCWms were markedly increased after occlusion of the ductus arteriosus, with both then exceeding the
amplitude of FCWis (Figs. 3 and 4). As vascular reflection can
return but not itself produce energy, this clearly indicated that
a significant mechanism other than reflection was involved in
generation of both the fetal LPA and PT BCWms.
As the fetal pulmonary arterial BCWms was equal to or
greater than FCWis, a plausible mechanism for this BCWms
was that it was in part generated by an impulsive compression
wave arising from the pulmonary vasculature during each
cardiac cycle. The most likely source of this impulsive compression wave was, in turn, a cyclical midsystolic vasoconstriction that, on the basis of our calculated distance to the origin of
the left pulmonary arterial BCWms (5.3 cm), arose from the
pulmonary microcirculation. Indeed, strong indirect support for
a significant myogenic origin of the pulmonary arterial BCWms
is provided by the striking transformation of the fetal pulmonary arterial flow pattern to one resembling the PT profile
following infusion of the vasodilator ACh (27, 37). Furthermore, the occurrence of BCWms after FCWis implies that this
cyclical pulmonary vasoconstriction was triggered by the preceding FCWis.
In our study, the peak of the pulmonary arterial BCWms
occurred ⬃40 ms after peak FCWis. Although the specific
myogenic pathway(s) and mediator(s) of this BCWms remain to
be defined, this temporal feature suggests that the mechanism
is distinct from that underlying the classical myogenic vasoconstrictor response occurring in response to increases in
intravascular pressure, which is believed to play a role in the
autoregulation of blood flow and setting of basal vascular tone
(10). Specifically, the latter type of myogenic constriction
typically occurs in 5–10 s (7, 26), although an interval of 300
ms has been measured using high-speed video analysis (28).
While abolition of the PT BCWms by occlusion of the main
pulmonary artery (Fig. 5) confirmed that this wave resulted
from proximal transmission of the pulmonary arterial BCWms,
the large reduction (⬃65%) in the magnitude of BCWms
between the LPA and PT indicated that such transmission was
only partial. As dissipation of wave energy (11) was probably
quite minor in the short distance between the LPA and PT, it is
likely that remaining portions of the LPA BCWms energy
entered the right pulmonary artery and ductus arteriosus, and
possibly also reflected back down the LPA and its branches.
FCWis is the manifestation of a ventricular impulse generated at the beginning of systole and provides the forward
momentum for blood movement from the ventricle into the
vasculature (45). The lesser magnitude and later occurrence of
FCWis in LPA, compared with PT (Table 2), are both consistent with an RV origin for FCWis.
As well as FCWis, however, smaller FCWms were also
detectable in the fetal PT and LPA at baseline. Although not
referred to, similar FCWms are clearly evident in published
figures of the fetal PT WIA profile (13). As is apparent in Fig.
2, FCWms produces a rebound increase in blood flow/velocity
following the characteristic abrupt midsystolic decline related
to BCWms. Such a rebound is also present in published recordings of the fetal main and left pulmonary arterial blood flow
profiles (27, 36, 37). At least two mechanisms probably contributed to FCWms. FCWms in the vicinity of the FCWis tail
region (Fig. 2) were most likely related to additional RV
impulsive contractions occurring after FCWis, perhaps reflecting incoordination in the RV systolic contraction pattern secondary to the known structural immaturity of the fetal myocardium (43). However, the observations that FCWms peaks
occurring after BCWms became more prominent after ductal
occlusion, which also augmented BCWms (Figs. 3 and 4) but
were diminished by occlusion of the main pulmonary artery
(Fig. 5) raises the possibility that these FCWms were related to
proximal reflection of this BCWms and/or transmission of
BCWms from the opposite pulmonary artery.
Recent data indicate that FEWls is the vascular manifestation
of a ventricular rarefaction (“suction”) wave (45), and as is
apparent from Fig. 2, this wave causes flow reversal at the end
of systole in the fetal PT and major pulmonary arteries. The
larger magnitude and earlier occurrence of FEWls in the PT
compared with LPA are consistent with an RV origin for this
wave. The explanation for peak negative velocity in the LPA
exceeding that in the PT (Table 1), despite FEWls causing a
similar decrease in velocity at both sites (Table 3), is that
velocity was lower in the LPA just before onset of FEWls due
to the much larger BCWms.
Although smaller than observed in the adult (17, 18), a BEW
was present in all fetal PT WIA (Fig. 2). In contrast, a BEW
was an inconsistent feature in the pulmonary arterial WIA,
possibly because it was masked by the very large pulmonary
arterial BCWms, which often commenced where a BEW was
apparent in the PT WIA. As BEW produced a transient reduction in blood pressure, this wave was responsible for the
prominent shoulder in the ascending limb of the PT pressure
waveform (Figs. 1 and 2). The disappearance of the PT BEW
during occlusion of the main pulmonary artery (Fig. 5) suggests that, as in the adult (17, 18), this wave may have arisen
from the presence of an “open-end” reflection site related to an
increase in cross-sectional area at downstream branching
points.
Three methodological issues require comment. First, separation of net wave intensity into forward and backward components was an essential part of wave intensity analysis in our
study, due to the extensive temporal overlapping of forwardand backward-running waves evident in both the fetal PT and
LPA (Figs. 2– 4). Second, wave speed in the fetal PT (3.6 m/s)
FETAL PULMONARY ARTERIAL WAVE INTENSITY ANALYSIS
6.
7.
8.
9.
10.
11.
12.
13.
14.
Perspectives and Significance
Our observation that the characteristically low lung blood
flow of the fetus is accompanied by a very prominent and
uniquely large pulmonary arterial BCWms that markedly attenuates midsystolic blood flow/velocity and substantially elevates local blood pressure has major potential implications for
both pulmonary physiology and pathophysiology in the perinatal period. As the striking midsystolic decline in fetal pulmonary arterial blood flow to near-zero is not observed postnatally (27, 37), it is tempting to speculate that a marked
diminution in the magnitude of the fetal pulmonary arterial
BCWms accompanies the fall in pulmonary blood pressures and
dramatic rise in pulmonary blood flow associated with lung
ventilation and birth (5, 12, 36). On the other hand, continued
presence of a large pulmonary arterial BCWms might be one
factor contributing to the increased pulmonary blood pressures
and reduced lung perfusion accompanying conditions such as
persistent pulmonary hypertension of the newborn (12).
15.
16.
17.
18.
19.
20.
21.
ACKNOWLEDGMENTS
22.
We thank Magdy Sourial, Dr. Kate Simpson, and Andrew Hattam for their
assistance with experimental studies.
23.
GRANTS
This work was supported by the Australia and New Zealand Children’s
Heart Research Centre.
24.
25.
REFERENCES
1. Anderson DF, Bissonnette JM, Faber JJ, Thornburg KL. Central shunt
flows and pressures in the mature fetal lamb. Am J Physiol Heart Circ
Physiol 241: H60 –H66, 1981.
2. Attinger EO. Pressure transmission in pulmonary arteries related to
frequency and geometry. Circ Res 12: 623– 641, 1963.
3. Belik J. Myogenic response in large pulmonary arteries and its ontogenesis. Pediatr Res 36: 34 – 40, 1994.
4. Bleasdale RA, Parker KH, Jones CJ. Chasing the wave. Unfashionable
but important new concepts in arterial wave travel. Am J Physiol Heart
Circ Physiol 284: H1879 –H1885, 2003.
5. Cassin S. Tone and responsiveness in the fetal and neonatal pulmonary
circulation. In: The Pulmonary Circulation: Normal and Abnormal. Mech-
26.
27.
28.
29.
AJP-Regul Integr Comp Physiol • VOL
anisms, Management, and the National Registry, edited by Fishman AP.
Philadelphia, PA: University of Pennsylvania, 1990, p. 161–169.
Cohn HE, Sacks EJ, Heymann MA, Rudolph AM. Cardiovascular
responses to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol
120: 817– 824, 1974.
D’Angelo G, Davis MJ, Meininger GA. Calcium and mechanotransduction of the myogenic response. Am J Physiol Heart Circ Physiol 273:
H175–H182, 1997.
Davies JE, Whinnett ZI, Francis DP, Manisty CH, Aguado-Sierra J,
Willson K, Foale RA, Malik IS, Hughes AD, Parker KH, Mayet J.
Evidence of a dominant backward-propagating “suction” wave responsible
for diastolic coronary filling in humans, attenuated in left ventricular
hypertrophy. Circulation 113: 1768 –1778, 2006.
Davies JM, Tweed WA. The regional distribution and determinants of
myocardial blood flow during asphyxia in the fetal lamb. Pediatr Res 18:
764 –767, 1984.
Davis MJ, Hill MA. Signaling mechanisms underlying the vascular
myogenic response. Physiol Rev 79: 387– 423, 1999.
Feng J, Long Q, Khir AW. Wave dissipation in flexible tubes in the time
domain: in vitro model of arterial waves. J Biomech 40: 2130 –2138, 2007.
Fineman JR, Soifer SJ, Heymann MA. Regulation of pulmonary vascular tone in the perinatal period. Annu Rev Physiol 57: 115–134, 1995.
Grant DA, Hollander E, Skuza EM, Fauchere JC. Interactions between
the right ventricle and pulmonary vasculature in the fetus. J Appl Physiol
87: 1637–1643, 1999.
Hanson KA, Ziegler JW, Rybalkin SD, Miller JW, Abman SH, Clarke
WR. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. Am J Physiol Lung Cell Mol Physiol 275: L931–
L941, 1998.
Henk CB, Schlechta B, Grampp S, Gomischek G, Klepetko W,
Mostbeck GH. Pulmonary and aortic blood flow measurements in normal
subjects and patients after single lung transplantation at 0.5 T using
velocity encoded cine MRI. Chest 114: 771–779, 1998.
Heymann MA, Iwamoto HS, Rudolph AM. Factors affecting changes in
the neonatal systemic circulation. Annu Rev Physiol 43: 371–383, 1981.
Hollander EH, Dobson GM, Wang JJ, Parker KH, Tyberg JV. Direct
and series transmission of left atrial pressure perturbations to the pulmonary artery: a study using wave-intensity analysis. Am J Physiol Heart
Circ Physiol 286: H267–H275, 2004.
Hollander EH, Wang JJ, Dobson GM, Parker KH, Tyberg JV.
Negative wave reflections in pulmonary arteries. Am J Physiol Heart Circ
Physiol 281: H895–H902, 2001.
Ivy DD, Kinsella JP, Abman SH. Endothelin blockade augments pulmonary vasodilation in the ovine fetus. J Appl Physiol 81: 2481–2487,
1996.
Jones CJ, Sugawara M. “Wavefronts” in the aorta–implications for the
mechanisms of left ventricular ejection and aortic valve closure. Cardiovasc Res 27: 1902–1905, 1993.
Jones CJ, Sugawara M, Kondoh Y, Uchida K, Parker KH. Compression and expansion wavefront travel in canine ascending aortic flow: wave
intensity analysis. Heart Vessels 16: 91–98, 2002.
Khir AW, Henein MY, Koh T, Das SK, Parker KH, Gibson DG.
Arterial waves in humans during peripheral vascular surgery. Clin Sci
(Lond) 101: 749 –757, 2001.
Khir AW, O’Brien A, Gibbs JS, Parker KH. Determination of wave
speed and wave separation in the arteries. J Biomech 34: 1145–1155,
2001.
Khir AW, Zambanini A, Parker KH. Local and regional wave speed in
the aorta: effects of arterial occlusion. Med Eng Phys 26: 23–29, 2004.
Koh TW, Pepper JR, DeSouza AC, Parker KH. Analysis of wave
reflections in the arterial system using wave intensity: a novel method for
predicting the timing and amplitude of reflected waves. Heart Vessels 13:
103–113, 1998.
Kolb B, Rotella DL, Stauss HM. Frequency response characteristics of
cerebral blood flow autoregulation in rats. Am J Physiol Heart Circ
Physiol 292: H432–H438, 2007.
Lewis AB, Heymann MA, Rudolph AM. Gestational changes in pulmonary vascular responses in fetal lambs in utero. Circ Res 39: 536 –541,
1976.
Loutzenhiser R, Bidani AK, Wang X. Systolic pressure and the myogenic response of the renal afferent arteriole. Acta Physiol Scand 181:
407– 413, 2004.
Nichols WW, O’Rourke, M. F. McDonald’s Blood Flow in Arteries.
London: Edward Arnold Publishers, 1990.
294 • MAY 2008 •
www.ajpregu.org
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on May 6, 2017
was higher than the reported value of 2.6 m/s (13), presumably
related to differences in anesthetic regimen and surgical approach. At first glance, a fall in wave speed between the PT and
LPA (Table 2) may seem surprising, as other data suggest that
wave speed increases from the central to peripheral vasculature
(2, 24). However, because wave speed is inversely related to
the square root of vessel distensibility (29), our finding could
be explained if, as in the adult (15), distensibility increased
between the PT and LPA. Finally, one potential limitation of
our study was that it was performed under general anesthesia
and open-chest conditions, an approach necessary because of
the extent of surgical instrumentation required. However,
blood gas data were comparable to those of unanesthetized
fetuses, while the average level of mean arterial blood pressure
in our study (59 – 60 mmHg) was at the upper end of the
normal range reported in chronically instrumented late-gestation fetal lambs (1, 6, 9, 19, 27, 30, 33, 39, 40, 42). In addition,
LPA flow (70 ml/min) was close to the range of 71– 87 ml/min
measured with transit-time flow probes in unanesthetized and
anesthetized late-gestation fetuses (14, 19, 33). It is thus
unlikely that the qualitative features of our findings were
affected by our experimental approach.
R1561
R1562
FETAL PULMONARY ARTERIAL WAVE INTENSITY ANALYSIS
39. Rudolph AM, Heymann MA. Circulatory changes during growth in the
fetal lamb. Circ Res 26: 289 –299, 1970.
40. Smolich JJ. NO modulates fetoplacental blood flow distribution and
whole body oxygen extraction in fetal sheep. Am J Physiol Regul Integr
Comp Physiol 274: R1331–R1337, 1998.
41. Smolich JJ, Berger PJ, Walker AM. Interrelation between ventricular
function, myocardial blood flow, and O2 consumption changes at birth in
lambs. Am J Physiol Heart Circ Physiol 270: H741–H749, 1996.
42. Smolich JJ, Soust M, Berger PJ, Walker AM. Indirect relation between
rises in oxygen consumption and left ventricular output at birth in lambs.
Circ Res 71: 443– 450, 1992.
43. Smolich JJ, Walker AM, Campbell GR, Adamson TM. Left and right
ventricular myocardial morphometry in fetal, neonatal, and adult sheep.
Am J Physiol Heart Circ Physiol 257: H1–H9, 1989.
44. Storme L, Rairigh RL, Parker TA, Kinsella JP, Abman SH. In vivo
evidence for a myogenic response in the fetal pulmonary circulation.
Pediatr Res 45: 425– 431, 1999.
45. Wang Z, Jalali F, Sun YH, Wang JJ, Parker KH, Tyberg JV.
Assessment of left ventricular diastolic suction in dogs using waveintensity analysis. Am J Physiol Heart Circ Physiol 288: H1641–H1651,
2005.
46. Zambanini A, Cunningham SL, Parker KH, Khir AW, Thom,
SAMcG, Hughes AD. Wave-energy patterns in carotid, brachial, and
radial arteries: a noninvasive approach using wave-intensity analysis. Am J
Physiol Heart Circ Physiol 289: H270 –H276, 2005.
AJP-Regul Integr Comp Physiol • VOL
294 • MAY 2008 •
www.ajpregu.org
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on May 6, 2017
30. Ovadia B, Bekker JM, Fitzgerald RK, Kon A, Thelitz S, Johengen MJ,
Hendricks-Munoz K, Gerrets R, Black SM, Fineman JR. Nitric oxideendothelin-1 interactions after acute ductal constriction in fetal lambs.
Am J Physiol Heart Circ Physiol 282: H862–H871, 2002.
31. Parker KH, Jones CJ. Forward and backward running waves in the
arteries: analysis using the method of characteristics. J Biomech Eng 112:
322–326, 1990.
32. Penny DJ, Mynard JP, Smolich JJ. Aortic wave intensity analysis of
ventricular-vascular interaction during incremental dobutamine infusion in
adult sheep. Am J Physiol Heart Circ Physiol 294: H481–H489, 2008.
33. Rairigh RL, Parker TA, Ivy DD, Kinsella JP, Fan ID, Abman SH.
Role of inducible nitric oxide synthase in the pulmonary vascular response
to birth-related stimuli in the ovine fetus. Circ Res 88: 721–726, 2001.
34. Ramsey MW, Sugawara M. Arterial wave intensity and ventriculoarterial interaction. Heart Vessels Suppl 12: 128 –134, 1997.
35. Rudolph AM. Distribution and regulation of blood flow in the fetal and
neonatal lamb. Circ Res 57: 811– 821, 1985.
36. Rudolph AM. Fetal and neonatal pulmonary circulation. Annu Rev
Physiol 41: 383–395, 1979.
37. Rudolph AM. Fetal and neonatal pulmonary circulation. Am Rev Respir
Dis 115: 11–18, 1977.
38. Rudolph AM. Organization and control of the fetal circulation. In: The
Physiological Development of the Fetus and Newborn, edited by Jones CT
and Nathanielsz PW. London: Academic, 1985, p. 343–353.