Aortic Isthmus and
C a rd i a c Mo n i t o r i n g o f
t h e G row t h - R e s t r i c t e d
Fetus
Ganesh Acharya, MD, PhD, FRCOGa,b, Ashlie Tronnes,
Juha Rasanen, MD, PhDc,*
MD
c
,
KEYWORDS
Fetal echocardiography Aortic isthmus doppler
Fetal circulation Fetal heart
Aortic isthmus is the segment of fetal aorta between the origin of the left subclavian
artery and the entry of the ductus arteriosus to the descending aorta (Fig. 1). This
segment represents an arterial watershed between the circulations in the upper
(including brain) and lower parts of the body (including placenta).1–3 Aortic isthmus is
the only arterial channel that connects 2 parallel ventricular pumps of the fetal heart.4
Experimental work, mainly in fetal sheep models,5–10 has established the pathophysiological basis for assessing aortic isthmus blood flow in human fetuses. Gestational age–
related normal physiologic changes in aortic isthmus blood flow pattern11–14 as well as
changes associated with pathologic conditions15–23 have been investigated in clinical
settings. Doppler echocardiographic assessment of the aortic isthmus blood flow
seems to be a promising tool that would help in early identification of fetal circulatory
compromise17,18,21,23 and prediction of short-term perinatal22 and long-term
neurodevelopmental24 outcomes. This article reviews the available scientific information and discusses the role of aortic isthmus in fetal circulation.
ANATOMIC CONSIDERATIONS
In sheep, because the head and neck vessels originate from a single brachiocephalic
artery, this segment of aorta is relatively longer (Fig. 2). In the human fetus, the
Financial disclosure and conflict of interest: The authors have nothing to disclose.
a
Women’s Health and Perinatology Research Group, Department of Clinical Medicine, Faculty
of Health Sciences, University of Tromsø, Sykehusveien 38, N-9038 Tromsø, Norway
b
Department of Obstetrics and Gynecology, University Hospital of Northern Norway,
Sykehusveien 38, N-9038 Tromsø, Norway
c
Department of Obstetrics and Gynecology, Oregon Health and Science University, 3181
Southwest Sam Jackson Park Road, Portland, OR 97239, USA
* Corresponding author.
E-mail address: [email protected]
Clin Perinatol 38 (2011) 113–125
doi:10.1016/j.clp.2010.12.006
perinatology.theclinics.com
0095-5108/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
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Fig. 1. Color Doppler image of a longitudinal view of the aortic and ductal arches in
a 26-week fetus demonstrating their anatomic relation and the aortic isthmus (AOI), which
is the segment of aortic arch located between the origin of the left subclavian artery (LSCA)
and the entry of the ductus arteriosus (DA) to the descending aorta (DAo). PA, main pulmonary artery.
segment is rather short (2–3 mm) and is narrower than the ascending aorta, descending aorta, and ductus arteriosus.25–27 However, the diameter of the aortic isthmus
relative to other vessels is not as small as reported in the animal models.25 The aortic
isthmus has a mean diameter of approximately 1 to 1.5 mm at the end of first trimester,
2 to 2.5 mm at midgestation,14,27–29 and 4 to 5 mm close to term.29,30 Despite its
important role in the fetal circulation, the aortic isthmus is not essential for in utero fetal
survival. Absence of blood flow through the aortic isthmus (eg, in case of an interrupted aortic arch) is easily compensated by the blood supplied to the lower part of the
body and placenta by the right ventricle via the ductus arteriosus. However, aortic
isthmus is essential for survival when the ductus arteriosus is closed postnatally.
PHYSIOLOGIC ASPECTS
The fetal left and right ventricles pump in a parallel circuit in contrast to the neonatal
and adult hearts, in which they pump in series. In the fetus, the right ventricular output
is primarily directed through the ductus arteriosus to the descending aorta and to the
lower part of the body, viscera, and placenta. A small but significant portion of the right
ventricular output is directed to the lungs.31,32 The left ventricular output mainly serves
the cephalic part of the fetus including the brain and upper extremities. However,
a significant proportion of the left-sided cardiac output is also directed toward the
lower part of the body and placenta.14 Although in sheep fetuses, only 10% combined
cardiac ventricular output (CCO) passes across the aortic isthmus,33 this amount is
significantly higher in human fetuses.14
Fetoplacental growth and maturation have a major effect on the fetal cardiovascular
dynamics. There is more than 10-fold increase in the fetal CCO, whereas the weightindexed CCO almost doubles during 11 to 20 weeks of gestation.14 During the second
half of pregnancy, the CCO increases 10-fold31,34,35 but the weight-indexed CCO
Aortic Isthmus Hemodynamics
Fig. 2. Specimen of a fetal sheep heart demonstrating aortic isthmus and its relation to
other major blood vessels. Note that in contrast to the human fetuses in which 3 vessels
(ie, brachiocephalic or innominate artery, left common carotid artery, and left subclavian
artery) originate from the aortic arch a single brachiocephalic artery arises in the sheep
fetuses.
remains relatively constant at approximately 400 to 425 mL/min/kg fetal weight.32,35
The right ventricle has a slightly larger output than the left ventricle as early as the first
trimester,14 and near term, the right ventricle contributes to 60% of the total CCO.31
Approximately 20% to 32% of CCO is directed to the placenta for gas and nutrient
exchange during the second half of pregnancy.35
Despite the parallel arrangement of the fetal ventricular pumps, blood ejected from
the left and right ventricles mix at several locations. Shunts and watersheds are important components of the fetal circulation that regulate blood flow distribution to different
organs to ensure adequate oxygenation, nutrient supply, and waste disposal.
The classically described shunts in the fetal circulation are the foramen ovale, ductus
arteriosus, and ductus venosus. The aortic isthmus represents the arterial watershed
between the brachiocephalic (including brain) and subdiaphragmatic (including
placenta) circulations,1 whereas the left portal vein represents the venous watershed
between the umbilical (placental) and systemic (splanchnic) circulations.36 It has been
argued that a true shunt, by definition, diverts blood from one circuit to another and
that the aortic isthmus is the only true shunt in the fetal circulation.4 However, the
aortic isthmus does not behave like a classical shunt because physiologic fetal shunts
normally close after birth but the watersheds remain patent.
The aortic isthmus forms a critical communication between the parallel circuits of
the fetal right and left ventricles. Because of its unique position, blood flow from the
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right and left ventricular circuits has opposite effects on blood flow through the aortic
isthmus.4,11 Blood ejected from the left ventricle causes forward flow through the
aortic isthmus, whereas that from the right ventricle causes reduction in the forward
flow.4,11 Therefore, aortic isthmus flow is a measure of the balance between the
2 ventricular circuits’ ejection force, duration, and volume and their downstream
impedance. In diastole, when the semilunar valves are closed, the direction of blood
flow across the aortic isthmus is mainly affected by cerebral and placental vascular
impedances.4 Under physiologic circumstances, the cerebral vascular impedance is
higher than the placental vascular impedance throughout gestation. Therefore, in
a normal fetus, regardless of the gestational age, blood flows forward through the
aortic isthmus both in systole and diastole.
EXPERIMENTAL STUDIES ON ANIMAL MODELS
Several experimental studies in animal models5–10 have laid the groundwork for
establishing the role of aortic isthmus in fetal circulation. Although most of these
studies were acute experiments with their associated drawbacks, their findings
have been the basis for performing clinical studies in human fetuses. A strong
positive correlation was found between placental volume blood flow and forward
aortic isthmus volume blood flow in fetal lamb during a stepwise increase in resistance to placental blood flow by umbilical vein compression.6 Because oxygen
delivery to fetus is closely related to placental blood flow, the aortic isthmus volume
blood flow is likely to reflect fetal oxygen delivery. An increase in placental vascular
resistance causing a 50% reduction in umbilical blood flow was associated with
reversed aortic isthmus diastolic blood flow in sheep fetuses even though the umbilical artery diastolic blood flow remained forward.6 Using similar experimental design,
Fouron and colleagues5 showed that the appearance of reversed diastolic flow in the
umbilical artery indicates that the cerebral vascular resistance is lower than the
placental vascular resistance. This difference in resistance is associated with redistribution of fetal circulation and reversal of diastolic flow in the aortic isthmus leading
to a shift of preplacental blood with low oxygen content toward the brain. However,
during an acute increase in placental vascular resistance, despite the contamination
of ascending aortic blood destined for the brain by preplacental blood leading to
a significant drop in arterial oxygen content, oxygen delivery to the fetal brain is
preserved as long as the net blood flow through the aortic isthmus is antegrade.9
Maternal oxygen administration normally increases fetal cerebral vascular resistance.
However, this response is lost when the placental vascular resistance is increased by
umbilical vein compression.7
The above-mentioned experimental studies had a crucial role in demonstrating the
importance of aortic isthmus in the fetal circulation. However, umbilical vein compression not only increases the placental vascular resistance but also leads to hypoxia and
cerebral vasodilatation, which are known to reduce cerebral vascular resistance and
cause redistribution of circulation. In a chronic near-term sheep model, the authors
have shown that fetal hypooxygenation causes a relative increase in the aortic isthmus
retrograde blood flow component.10 In addition, umbilical vein compression causes
a reduction in fetal cardiac output by decreasing the preload. Obviously, decreased
cardiac output causes a decrease in the aortic isthmus blood flow. However, reversed
flow in the aortic isthmus can be exclusively caused by the decrease in cardiac output
only if the output of the left ventricle is significantly lower than that of the right.
The authors’ preliminary findings show that when fetal cardiac output and oxygenation
Aortic Isthmus Hemodynamics
remain unchanged, the aortic isthmus flow pattern is mainly affected by the placental
vascular resistance.
CLINICAL STUDIES IN HUMAN FETUSES
Clinical studies have demonstrated the feasibility of recording aortic isthmus blood
flow velocity waveforms in the human fetuses11–13,37 starting as early as 11 weeks
of gestation.14 Abnormalities in the aortic isthmus blood flow pattern have been shown
to be useful in the evaluation of fetal circulatory compromise,15,17,19–23 which has been
recently shown to predict perinatal22 and neurodevelopmental24,38 outcomes in
placental insufficiency.
EVALUATION OF AORTIC ISTHMUS BLOOD FLOW USING DOPPLER
Technical aspects of aortic isthmus Doppler blood flow velocimetry in human fetuses
have been described in detail elsewhere.3 The aortic isthmus can be visualized and
blood flow measured either in a longitudinal aortic arch view (Fig. 3) or in the 3-vessel
view (Fig. 4). Use of power Doppler may facilitate the visualization in difficult cases.
In the longitudinal view, proper imaging of the aortic isthmus requires visualization
of the origin of the left subclavian artery and the descending thoracic aorta (Fig. 5).
The sample volume should be placed just distally to the origin of the left subclavian
artery in order to obtain reliable waveforms. The 3-vessel–trachea view is obtained
in the transverse view of the fetal thorax. In this view, the pulmonary trunk, ductus arteriosus, transverse aortic arch, aortic isthmus, and superior vena cava are visualized,
Fig. 3. Aortic isthmus blood flow velocity waveforms obtained in a longitudinal aortic arch
view using color-directed pulsed wave Doppler (top left). Visualization may be improved by
using power Doppler (top right). Note the ductus arteriosus blood flow waveforms in the
background (lower panels). AOI, aortic isthmus, DAo, descending aorta, LSCA, left subclavian artery.
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Fig. 4. Aortic isthmus blood flow velocity waveforms in a 3-vessel–trachea view using colordirected pulsed wave Doppler. AOI, aortic isthmus; DA, ductus arteriosus; DAo, descending
aorta; PA, main pulmonary artery.
but it is difficult to see the origin of the left subclavian artery. Therefore, the sample
volume should be placed in the aortic arch, close to where the aortic arch and the
ductus arteriosus converge with the descending aorta (see Fig. 4).
Other important details to optimize measurements include setting the Doppler scale
to high velocity to reduce aliasing and adjusting the sample volume according to the
Fig. 5. A B-mode image of a longitudinal aortic arch view demonstrating the aortic isthmus
(arrow). AA, transverse aortic arch; AAo, ascending aorta; AOI, aortic isthmus; DAo,
descending aorta; LSCA, left subclavian artery.
Aortic Isthmus Hemodynamics
gestational age and the size of the aortic isthmus. Measurements should not be taken
during fetal movement, and the insonation angle should be kept as close to zero as
possible and always less than 30 .
NORMAL AORTIC ISTHMUS BLOOD FLOW PATTERNS
Blood flow through the aortic isthmus changes its profile through gestation. Before 20
weeks, forward flow is present uniformly through the whole cardiac cycle.11,14
Between 20 and 25 weeks, a narrow incisura is noted at the end systole because of
a brief reversal of flow followed by an acceleration of flow in early diastole.11 By 31
weeks, almost all fetuses show a short reversal of the aortic isthmus flow velocity in
the late systole.11 However, this brief flow reversal is recorded less often when the
insonation is performed in the 3-vessel–trachea view. The brief reversal of flow in
the late systole is thought to occur as a result of delayed onset and longer acceleration
time of the ductal flow velocity at the isthmus-ductus junction.8 Generally, blood flow
in the aortic isthmus starts and peaks earlier than in the ductus arteriosus. This pattern
can be demonstrated by simultaneously recording the Doppler blood flow velocity
waveforms from these 2 vessels using a large sample volume (Fig. 6). Furthermore,
a brief late systolic reversal of the aortic isthmus blood flow may be explained by
observations in the fetal lamb, which show that the preejection period of the right
ventricle is longer than that of the left,39 resulting in an ejection delay that may allow
the right ventricle to affect the last milliseconds of systolic flow in the isthmus.11
PARAMETERS USED TO DESCRIBE AORTIC ISTHMUS BLOOD FLOW
The most commonly used parameters to describe aortic isthmus blood flow are the
isthmic flow index (IFI) and the pulsatility index (PI). The IFI is a velocity-time integral
(VTI)–based index and is calculated as IFI 5 (systolic VTI 1 diastolic VTI)/ systolic
VTI.12 The following 5 patterns or types of IFI are described4,12:
Type I: IFI is greater than 1, describing antegrade flow present in both systole and
diastole.
Fig. 6. Doppler blood flow velocity waveforms recorded simultaneously from the aortic
isthmus and ductus arteriosus using a large sample volume, demonstrating that blood
flow in the aortic isthmus starts and peaks earlier than in the ductus arteriosus. AOI, aortic
isthmus; DA, ductus arteriosus.
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Type II: IFI is equal to 1, corresponding to an absence of diastolic flow.
Type III: IFI is between 0 and 1, signifying some diastolic flow reversal but
predominant antegrade flow.
Type IV: IFI is equal to 0, signifying that the antegrade and retrograde flows are
equal, that is, net flow is zero.
Type V: IFI is less than 0, meaning net flow through the isthmus is retrograde.4
In normal physiologic states, small variations in the aortic isthmus Doppler flow may
not result in large variations in IFI. In pathologic states, it is important to know whether
the diastolic flow is antegrade (IFI1) or retrograde (IFI1), which can be identified
visually (Fig. 7). Furthermore, the classification of IFI into more types does not seem
to improve the predictive value for adverse perinatal outcome.12 Reference ranges
for IFI are available for the second half of pregnancy.12
The PI is a velocity-based index, and it is calculated as PI 5 (PSV EDV)/TAMXV,
where PSV is the peak systolic velocity, EDV is the end-diastolic velocity, and TAMXV
is the time-averaged maximum velocity. Reference ranges for this parameter are available for the both halves of pregnancy.13,14 The aortic isthmus PI has been proposed as
a better parameter for predicting fetal outcomes than IFI.13
The aortic isthmus volume blood flow (Qai) is estimated noninvasively from its inner
diameter and blood velocities as: Qai (mL/min) 5 TAMXV (cm/s) p (diameter [cm]/
2)2 60, and the fraction of cardiac output distributed to the fetal upper body and brain
is calculated as: (LVCO Qai)/CCO, where LVCO is the left ventricular cardiac output.14
Reference ranges for Qai are available for 11 to 20 weeks of gestation but not for the
second half of pregnancy.
REPRODUCIBILITY OF AORTIC ISTHMUS BLOOD FLOW MEASUREMENT
Several studies have evaluated the feasibility and reliability of aortic isthmus Doppler
velocimetry.13,14,40,41 A recent multicenter study showed that adequately trained individuals can visualize and identify the aortic isthmus easily, but accurate placement of
the Doppler sample volume to obtain blood flow velocity waveforms is more
challenging.41 For most of the measured parameters, including PI, IFI, absolute
velocities, and Qai, the intraclass correlation coefficient (ICC) for intraobserver and/
or interobserver reliability has been reported to be greater than or equal to 0.5, which
is considered clinically useful. In a study that compared aortic isthmus PI measurements in the longitudinal aortic arch view and the 3-vessel view in normally grown
and growth-restricted fetuses, high reliability (ICC>0.95) for aortic isthmus PI
measurements was observed in both views.40 These findings are in agreement with
those of another study, showing that the 3-vessel view is as reliable as the traditional
longitudinal aortic arch view.37
FETAL CONDITIONS AFFECTING AORTIC ISTHMUS BLOOD FLOW
Increased lower body and placental vascular impedance, such as in intrauterine
growth restriction (IUGR),15,17 decreased upper body and cerebral impedance, such
as in cerebral arteriovenous fistula,16 and/or fetal hypoxemia cause an increase in
the aortic isthmus retrograde blood flow component in human fetuses. Left ventricular
dysfunction or outflow obstruction leading to decreased output causes decreased
flow through the aortic isthmus. In severe cases of aortic atresia (hypoplastic left
heart), blood from the ductus arteriosus flows retrograde across the aortic isthmus
to supply the upper extremities, brain, and the coronary arteries. In fetuses with
Aortic Isthmus Hemodynamics
Fig. 7. Aortic isthmus pulsed wave Doppler velocity waveforms demonstrating a gradual
deterioration from normal (upper two panels) to abnormal pattern (lower two panels).
The net blood flow is retrograde in the lowest panel.
pulmonary atresia, the venous return passes to the left atrium via the foramen ovale
and the left ventricle provides the total cardiac output. In this situation, all blood
directed to the descending as well as the pulmonary circulation traverses the aortic
isthmus, resulting in increased aortic isthmus diameter and volume blood flow. Other
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congenital malformations that significantly reduce right ventricular output (eg,
tricuspid atresia, tetralogy of Fallot with severe pulmonary stenosis) may cause similar
hemodynamic changes in the aortic isthmus.
CLINICAL UTILITY OF AORTIC ISTHMUS BLOOD FLOW MEASUREMENT
Aortic isthmus Doppler velocimetry is most useful in monitoring fetuses with IUGR.
Chronic fetal hypoxemia is the major concern in IUGR, and appropriate timing of
delivery to avoid the consequences of hypoxemic injury remains the key management goal. Abnormal umbilical artery, middle cerebral artery, ductus venosus, and
umbilical vein Doppler parameters have been associated with an increased risk for
fetal hypoxemia and increased perinatal morbidity and mortality. Absent/reversed
flow in the umbilical artery and abnormal venosus Doppler results are late signs of
IUGR and indicate fetal cardiovascular compromise. There is some evidence in the
literature that the changes in aortic isthmus Doppler velocity waveforms appear
before the ductus venosus a wave reversal21 and that an abnormal PI in the aortic
isthmus is noticed on an average 1 week before the ductus venous.23 Fetuses
seem to maintain their cerebral oxygenation as long as the net blood flow through
the aortic isthmus is antegrade.9 However, the fetuses with net flow reversal in the
aortic isthmus have signs of increased systemic venous pressure,19 reduced blood
flow shunting through the foramen ovale, signs of cardiac dysfunction and increased
incidence of cesarean delivery because of fetal distress,20 and poor perinatal
outcome.22,42 Postnatal sequel of cerebral hypoxia may be avoided if the fetus is
delivered before decompensation. Two retrospective studies24,38 have assessed
the association between abnormal aortic isthmus Doppler results and neurodevelopmental outcome in children. These studies showed that the risk for suboptimal postnatal neurodevelopment is significantly high among fetuses with IUGR with abnormal
aortic isthmus blood flow pattern. An inverse association was found between IFI and
postnatal neurodevelopmental outcome, and an IFI cutoff value of 0.7 had the
highest overall predictive value.24 Therefore, serial assessment of aortic isthmus
hemodynamics may be valuable in monitoring fetal condition and timing delivery in
patients carrying fetuses with IUGR.
Another clinical utility of aortic isthmus blood flow measurement could be in the
assessment of cardiac function in fetuses at risk of developing heart failure.2
The extent of aortic isthmus flow reversal may help in assessing the severity of circulatory compromise in fetuses with cerebral arteriovenous fistula. Measurement of the
fetal cardiac output and Qai provides the possibility of assessing blood flow distributed
to the brachiocephalic circulation. Furthermore, retrograde aortic isthmus blood flow
in fetuses with severe left ventricular dysfunction or hypoplasia may indicate duct
dependency of the neonatal circulation.
SUMMARY
Aortic isthmus plays a crucial role in the fetal circulation. The evaluation of aortic
isthmus blood flow provides information that may improve the management of sick
fetuses. However, because of perceived technical difficulties, the clinical use of aortic
isthmus Doppler for fetal hemodynamic monitoring has been limited. Demonstration
that the measurements obtained in 3-vessel–trachea view are as reliable as those
obtained from a standard longitudinal aortic arch view has been an encouraging development. Changes in aortic isthmus blood flow pattern seem to reflect the fetal
cardiovascular status accurately and predict the perinatal and long-term
Aortic Isthmus Hemodynamics
neurodevelopmental outcome in IUGR. Aortic isthmus Doppler velocimetry is likely to
become an indispensable tool in the evaluation of fetal well-being.
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