Ebook Advances in hemodynamic research: Part 2

PART II: CLINICAL APPLICATION OF
HEMODYNAMIC RESEARCH



In: Advances in Hemodynamics Research
Editor: Keiichi Itatani

ISBN: 978-1-63483-187-1
© 2015 Nova Science Publishers, Inc.

Chapter 6

CONGENITAL HEART DISEASE
AND CIRCULATORY PHYSIOLOGY
Takashi Honda1, Kagami Miyaji2 and Masahiro Ishii1
1

Department of Pediatrics, Kitasato University School of Medicine, Japan
2
Department of Cardiovascular Surgery,
Kitasato University School of Medicine, Japan

ABSTRACT
The physiological basis of congenital heart diseases in most cases is an abnormality
in hemodynamics. Therefore, a timely diagnosis based on echocardiography has
contributed to the medical practice for patients with congenital heart diseases.
Echocardiography has clarified not only the hemodynamics of children, but also that of
fetuses, and fetal therapies based on the fetal echocardiography findings are now being
developed. The technical innovations in echocardiography are remarkable. Vector flow
mapping echocardiography made it possible to visualize the blood flow and to analyze

the energy dynamics. Cardiac magnetic resonance imaging is also a promising imaging
modality, because a three-dimensional evaluation and an assessment of the myocardial
characteristics are possible without limitations such as poor echo window, which often
affects the hemodynamic evaluation on echocardiography. Owing to recent innovations
in diagnosis, medical treatment and surgical techniques, long- term survival can be
expected even in patients with complex congenital heart diseases. At present, we are
consequently facing new problems regarding the medical practice for adult patients after
surgeries for Tetralogy of Fallot and single ventricular anomalies. The accumulation of
knowledge on the hemodynamics in these adult patients will show us the direction that
should be taken to overcome long-term life-threatening complications. In this chapter, we
discuss the characteristics of the hemodynamics in patients with CHD from fetus to adult,
and propose ways to improve the life expectancy and activities of daily living in patients
with CHD.

Keywords: congenital heart disease, right ventricle, single ventricle


Corresponding Author address E-mail:


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1. HEMODYNAMICS AND VENTRICULAR FUNCTION IN FETAL
AND NEONATAL PERIOD
1.1. Fetal Circulation
In order to preferentially supply oxygen to the brain and heart, fetal circulation has
distinct physiological mechanisms. The placenta serves as a site for gas exchange, and
oxygenated blood returns to the ductus venosus thorough the umbilical vein, and welloxygenated blood from the ductus venosus, as well as blood from left hepatic vein, streams

into the left atrium and ventricle through the foramen ovale. (Figure 6.1) In contrast, the
blood flow from the superior and inferior vena cava streams into the right ventricle without
passing through the foramen ovale (Rudolph AM 1985). Several studies using radionuclidelabeled microspheres have clarified the distribution of these streams (Edelstone et al. 1979,
Reuss et al. 1980). In addition, a sharp ridge at the entrance of the ductus venosus into the
inferior vena cava (Bristow et al. 1981) and the difference in velocity between the inferior
vena cava and the ductus venosus blood flow are considered to contribute to this blood
distribution (Schmidt et al. 1996). In addition, although the pressures in the ascending aorta
and descending aorta are almost identical, the aortic isthmus serves as a site of functional
separation. Rudolph AM 1985 reported that inflation of a balloon lead a dramatic fall in the
right ventricular function, and this study clarified the role of the aortic isthmus as a site of
functional separation.
As a consequence of these complicated but desirable mechanisms, the blood from the
placenta streams into the right atrium through the inferior vena cava, and the majority of the
blood passes through the foramen ovale into the left atrium and ventricle. And the left
ventricle ejects this oxygenated blood flow towards the brain, heart and upper extremities.
Therefore, the brain can be supplied with a high amount of oxygen. And the blood flow from
the superior vena cava subsequently returns to the right atrium, and the majority of the blood
flows into the right ventricle, and then provides oxygen for internal organs and lower
extremities.
In order to maintain the fetal circulation, patency of foramen ovale and ductus arteriosus,
as well as high pulmonary vascular resistance, are essential. Approximately 1-20% of the
combined ventricular output is reported to be distributed to the lungs (Rasanen et al. 1998).
Therefore, the fetal circulation would be inhibited if these elements were impaired. For
example, premature closure of the foramen ovale is associated with mitral and/or aortic
atresia/stenosis and endocardial fibroelastosis, and has also been postulated to be a cause of
hypoplastic left heart syndrome (HLHS) (Nowlen et al. 2000). On the other hand, premature
closure of the ductus arteriosus causes all of the right ventricular output to be ejected into the
left and right pulmonary arteries, leading to pulmonary hypertension. In addition, right
ventricular dysfunction and tricuspid regurgitation occur as consequences of the increased
right ventricular afterload (Gewillig et al. 2009). As nonsteroidal anti-inflammatory drugs

(NSAIDs) inhibit the synthesis of prostaglandins, the use of NSAIDs for pregnant women
would cause of premature closure of the fetal ductus arteriosus (Shastri et al. 2013).


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Figure 6.1. The fetal circulation. The blood flow from the placenta returns to the right atrium through
the umbilical vein, and subsequently streams into the left atrium and ventricle through the foramen
ovale. As the aortic isthmus works as a site of functional blood flow separation, this well-oxygenated
blood flow from the left ventricle mainly supplies oxygen to the brain and upper extremities. In
contrast, the blood flow from the superior and inferior vena cava streams into the right ventricle,
subsequently providing oxygen to the internal organs and lower extremities. AAo = ascending aorta,
DA = ductus arteriosus, Dao = descending aorta, IVC = inferior vena cava, LA = left atrium, LHV =
left hepatic vein, LPA = left pulmonary artery, LV = left ventricle, PA = pulmonary artery, PV =
pulmonary vein, RA = right ventricle, RHV = right hepatic vein, RPA = right pulmonary artery, RV =
right ventricle, SVC = superior vena cava, and UV = umbilical vein.

There are other unique characteristics associated with the fetal circulation. First, the right
ventricle is dominant during the fetal period. The right ventricle ejects 60-65%, and the left
only 35-40% of combined ventricular output (Rudolph AM 1985). Therefore, severe tricuspid
regurgitation, which can be seen in fetuses with Ebstein‘s anomaly, often leads to fetal heart
failure or death (Roberson et al. 1989, Oberhoffer et al. 1992). Second, decreasing heart rate
by vagal stimulation resulted in a marked decrease in ventricular function. In addition,
electrical pacing above the resting rate of 160-180/min caused the ventricular output to reach
a maximum of about 15% above the resting level (Rudolph et al. 1976), indicating that the
fetal heart is functioning near its maximum performance. Third, Thornburg et al. 1983

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reported that reducing the ventricular pressure below its resting level caused a dramatic
decrease in cardiac output, and that increasing the ventricular pressure produced only a small
increase in the cardiac output in fetal lambs. Meanwhile, inflation of a balloon also caused a
dramatic decrease in the right ventricular cardiac output (Gilbert et al. 1982). Therefore, it is
considered that the fetal ventricle functions are near the top of their performance, and there is
little functional reserve that can be used in response to increased volume and pressure
workload.

Figure 6.2. Twin-to-twin transfusion syndrome (TTTS). In twins with TTTS, placental anastomosis
vessels allow the blood to pass from one fetus (donor twin) to the other (recipient twin). The subsequent
circulatory disequilibrium causes the donor twin to have a decreased blood volume, impairing its
development and growth; whereas, the recipient twin has an increased blood volume, leading to fetal
heart failure. Fetoscopic laser photocoagulation (FLP) corrects this circulatory disequilibrium by
intercepting the placental anastomosis vessels, leading to improvement of the twins‘ conditions.

Recently, several centers for highly advanced medical treatment have started fetal cardiac
intervention in order to interrupt the progression of diseases based on the prenatal diagnosis,
and to subsequently improve the perinatal and lifelong outcomes. Fetoscopic laser
photocoaglation (FLP) is a novel treatment for fetuses with twin-to-twin transfusion
syndrome (TTTS) (Senate et al. 2004, Sago et al. 2010). TTTS is a severe disease that can
occur in monochorionic twin pregnancy, and results from circulatory disequilibrium caused
by vascular anastomosis between the circulation of the donor and the recipient (Figure 6.2).
Some recipient twins have been reported to suffer from pulmonary stenosis or lethal
cardiomyopathy, in addition to cardiomegaly and hydrops fetalis (Zosmer et al. 1994);
whereas, there are a donor twin report with coarctation of the aorta and hypoplastic arch (van
den Boom et al. 2010). FLP procedure improves the fetal hemodynamics, and is expected to

prevent these cardiac complications. Although rapid changes in fetal hemodynamics may
possibly lead to right ventricular load on donor twins (Mineo et al. 2014), this procedure has
already become an established treatment. Severe aortic stenosis is known to impede the left


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ventricular development and subsequently lead to HLHS. Recently, fetal aortic valvuloplasty
has been performed in advance research facilities to prevent progression to HLHS (Freud et
al. 2014). Fetal cardiac interventions are also attempted for other structural heart diseases,
such as an intact or highly restrictive atrial septum, which also leads to HLHS, and pulmonary
atresia with an intact ventricular septum, which leads to right ventricular hypoplasia
(Schidlow et al. 2014).

1.2. Hemodynamics in Neonates
A shift from fetal to neonatal circulation can also be considered as a shift from placental
circulation to pulmonary circulation. When the placental circulation is interrupted at birth, the
amount of pulmonary blood flow increases approximately 10 times that during the fetal
period with spreading pulmonary alveolus and decreased pulmonary arterial resistance (Morin
et al. 1985). During the first hours after birth, the pulmonary arterial blood pressure may be
half that of the systemic pressure (Kramer et al. 1995). As the consequence of these changes,
oxygenation becomes possible in the lungs. The ductus arteriosus subsequently closes in the
first 15 hours due to the elevated arterial oxygen partial pressure and decreased production of
prostaglandin. In contrast, the foramen ovale closes due to an increase in the left atrial
pressure and extension of the ostium primum atrial septum.
The knowledge on these perinatal hemodynamic changes is of great importance when
managing neonates with congenital heart diseases. For example, persistent pulmonary
hypertension of the newborn (PPHN) is the condition that the pulmonary vascular resistance

does not sufficiently decrease. In neonates with PPHN, the systemic blood pressure cannot be
maintained, and the neonates develop insufficient oxygenation without appropriate
therapeutic intervention. Adequate lung recruitment and alveolar ventilation with 100%
oxygen, deep sedation and inhaled nitric oxide are effective to lower the pulmonary vascular
resistance. Maladaptation of the pulmonary circulation at birth due to neonatal
cardiopulmonary diseases, including birth asphyxia, sepsis, meconium aspiration and
respiratory distress, are all considered to be the causes of PPHN (Storme et al. 2013). Even in
normal neonates, it takes 2 to 6 weeks before the pulmonary vascular resistance decreases to
the adult level. Of note, the left-to-right shunting continues to increase during the first 2
months in infants with ventricular septal defect (VSD). In most patients with genetic
anomalies including 21 trisomy, the pulmonary vascular resistance is high by nature.
Preserving ductus arteriosus or foramen ovale is sometimes required in the management
of complex congenital heart diseases. In order to maintain the systemic blood flow in
neonates with HLHS and coarctation of the aorta (CoA), prostaglandin E1 is administered to
preserve the ductus arteriosus. In cases with pulmonary atresia (PA), prostaglandin E1 is also
administered to maintain the pulmonary blood flow (Kramer et al. 1995). Adequate intraatrial mixing is required in some cases with HLHS, PA and transposition of the great arteries
(TGA). In such cases without adequate intraatrial mixing, balloon atrial septostomy (BAS) is
performed (Rashkind et al. 1966). Therefore, rapid therapeutic intervention based on the
precise understanding of the hemodynamics is essential to improve the prognoses of neonates
with congenital heart diseases.


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2. THE IMPACT OF VENTRICULAR OVERLOAD
2.1. Ventricle with Pressure Overload
The pressure load on the ventricle is generally caused by ventricular outflow tract
stenosis. Aortic stenosis (AS) and CoA are typical congenital heart diseases associated with

pressure overload on the left ventricle. These diseased lesions are often accompanied by
HLHS. In contrast, pulmonary stenosis is a representative heart disease associated with
pressure overload on the right ventricle, and is one of the diagnostic requirements of tetralogy
of Fallot (TOF). Patients with several genetic disorders often have these stenotic lesions.
William‘s syndrome is often accompanied by supra-aortic stenosis and pulmonary stenosis,
while Allagile syndrome is accompanied by peripheral pulmonary stenosis. The first
pathophysiological change in the myocardium caused by pressure overload on the ventricles
is dilatation with wall thinning and wall stress elevation. Subsequent hypertrophy induces the
recovery of systolic function and normalizes the wall stress. This compensatory process helps
the left ventricle to eject sufficient systemic blood flow (Takaoka et al. 2002, Cingolani et al.
2003). On the pressure volume (P-V) loop, in response to left-shifting of the end diastolic P-V
relationship (EDPVR) due to increased pressure load, the end systolic P-V relationship
(ESPVR) also shifts to the left due to increase in the left ventricular mass (Figure 6.3A)
(Sugawa et al. 1988).
Stroke volume is consequently maintained in spite of the increase in pressure load on the
ventricle. However, hypertrophy is also considered to be an inducer of apoptosis of myocytes
as a result of hypoxia and mechanical loading (Hirota et al. 1999, Wernig et al. 2002). In the
ventricles with a severely high pressure load, replacement of degenerated myocytes by
collagen fibers is one of the contributors to diastolic dysfunction. In addition, the wall
thickness of the ventricle itself increases the stiffness (Schwartz et al. 1996). Consequently,
EDPVR further shifts to the left and stroke volume eventually decreases in severe cases
(Figure 6.3B) (Harris et al. 2002).
The current guidelines recommend that various parameters should be assessed to
determine the severity of stenotic lesions, including peak jet velocity, mean pressure gradient,
valve area and valve area indexed for the body surface area (Bonow et al. 2008). Several
recent studies have focused on the importance of taking into account the pressure recovery
phenomenon which occurs downstream from the valves (Baumgartner et al. 1990, Voelker et
al. 1992). Based on the pressure recovery phenomenon, Garcia et al. proposed a new index
based on the energy loss (EL) concept. According to their theory, a part of static pressure is
converted to dynamic pressure, leading to overestimation of the pressure gradient on

echocardiography (Figure 6.4). Pressure recovery may be relevant in patients with severe
stenotic lesions. The authors of that study therefore proposed that an evaluation of energy loss
would provide a novel index to assess the severity of stenotic lesions. Based on Garcia‘s
theory, Bahlmann et al. 2013 demonstrated that EL index provides independent and additional
prognostic information in patients with AS. In addition, vector flow mapping (VFM)
echocardiography has recently made it possible to measure EL based on energy dispersion.
We previously measured energy loss before and after the commisurotomy of stenotic
pulmonary valve in an infant with double outlet right ventricle (DORV) and VSD, and
demonstrated that energy loss significantly decreased (Honda et al. 2014). This dynamic


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change was caused by the improved profile of the main pulmonary arterial blood flow, likely
due to conversion from turbulent flow to linear flow. Therefore, EL is a parameter that can be
used to directly reflect the afterload on the ventricle, and future studies will indicate the
clinical utility of this novel parameter.

Figure 6.3. (A) An illustration of the pressure-volume (P-V) loop in a patient with moderately increased
afterload. In response to the increased afterload, not only end diastolic pressure-volume relationship
(EDPVR) but also end systolic pressure-volume relationship (ESPVR) increases. Consequently, stroke
volume is preserved in spite of an increased afterload. (B) An illustration of the P-V loop in a patient
with severely increased afterload. As EDPVR shifts further to the left in cases with severe afterload, the
stroke volume eventually decreases.

Stiffened aorta is also considered to lead to an afterload on the left ventricle even if there
is no apparent stenotic lesion. Recently, the aortic arch in patients with TOF has attracted
much attention. Niwa et al. 2002 reported that the aortic root progressively dilates in adults

late after repair of TOF.


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Figure 6.4. The concept of energy loss. In severe valvular stenotic lesions, a part of the static pressure is
converted to dynamic pressure, causing overestimation of pressure gradient on echocardiography.
Instead, energy loss has been proposed as a novel parameter reflecting the severity of stenotic lesions.
TPG: transvalvular pressure gradient. Modified figure from Garcia et al. 2000

Figure 6.5. The streamlines and energy loss in the aortic arches of 2 infants with tetralogy of Fallot
(TOF). Streamline analysis on vector flow mapping (VFM) echocardiography showed turbulent flow in
a dilated aortic arch, and laminar flow in a non-dilated aortic arch. In addition, energy loss analysibyon
VFM echocardiography revealed that the peak energy loss in the systolic phase was greater in the
dilated aortic arch than in the non-dilated aortic arch (0.43 W/m vs. 0.07 W/m). These findings
indicated that the dilated aortic arch in TOF patients works as a ventricular afterload.


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Moreover, several studies have verified the abnormalities in the hemodynamics of the
aortic arch. Cheung et al. 2006 reported that the heart-femoral pulse wave velocity and wave
reflection were increased in TOF patients. Senzaki et al. 2008 also reported that the patients
with TOF had significantly higher characteristic impedance and pulse wave velocity than
those without. These characteristics of the systemic arterial hemodynamics are considered to
result from histological abnormalities in the aortic wall, and to increase the pulsatile load on

the left ventricle and decrease the cardiac output (Tan et al. 2005). In addition, Senzaki et al.
2008 also reported that an increase in aortic wall stiffness is closely associated with an
increase in aortic diameter; therefore, aortic wall stiffness may increase the circumferential
arterial wall stress, leading to aortic dilatation. In a patient-specific computational fluid
dynamic (CFD) study, Itatani et al. 2012 calculated the EL in the reconstructed aortic arch
after Norwood procedure. They emphasized the importance of decreasing energy loss in order
to reduce the afterload on the main ventricle. Dilated aortic arch affects the left ventricle as an
afterload in patients with TOF. Our preliminary data on VFM echocardiography indicated
that higher amount of energy loss was observed with a large vortex inside the aorta in TOF
patients with more dilated aortic arch (Figure 6.5). These findings also support the hypothesis
that dilated aortic arch works as a ventricular afterload.

2.2. Ventricle with Volume Overload
There are various congenital heart diseases associated with left-to-right shunting.
Ventricular septum and atrial septum are formed during the fetal period, and if the formations
are incomplete, the neonates have VSD and atrial septal defect (ASD). VSD and ASD
constitute 20-30% and 8-10% of congenital heart defects in children, respectively (Hoffman
et al. 1965, Minich et al. 2010). Therefore, volume overload with shunting is the most
common pathophysiological basis underlying congenital heart diseases. It is also important to
determine the regions where the excess volume is loaded. In infants with VSD, as left-to-right
shunting exists between the ventricular septum, the volume load is placed on the left
ventricle. In contrast, in infants with ASD, left-to-right shunting exists between the atrial
septum, so the volume load is placed on the right ventricle. Similarly, in patients with patent
ductus arteriosus (PDA) and major aortopulmonary collateral artery (MAPCA), which are
also common left-to-right shunting diseases, the volume overload is placed on the left
ventricle.
The changes caused by volume overload are relatively complex. First, the end-diastolic
volume and pressure increases to maintain the cardiac output. Accordingly, the sympathetic
nervous system is stimulated, and ESPVR becomes steeper (Figure 6.6A). Next, myocardial
remodeling, which plays an important role in compensating for the volume overload, is

initiated. Myocardial fibers proliferate in series in response to the dilation of the ventricle
(Yamakawa et al. 2000). Moreover, in order to normalize the thickness-to-dimension ratio
accompanying the morphological dilation of the ventricle, myocardial fibers also proliferate
in parallel. In addition to the mechanical stress itself, the renin-angiotensin system has been
reported to play an important role in this remodeling process (Cohn et al. 1995). The collagen
content is also reduced in this stage. However, in patients with chronic severe volume
overload, this remodeling process cannot keep pace with the workload. Ventricular
hypertrophy consequently fails to deal with the wall stress. A subsequent increase in stress


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impedes the myocardial blood flow, and myocardial fibrosis thus also increases. Ventricular
function consequently becomes impaired, and ESPVR drops (Figure 6.6B).

Figure 6.6. (A) An illustration of the pressure-volume (P-V) loop in a patient with a moderately
increased volume load. In response to the increased volume load, end diastolic pressure-volume
relationship (EDPVR) shifts to the right. In addition, the stimulation of the sympathetic nervous system
makes end systolic pressure-volume relationship (ESPVR) steeper. Consequently, the ventricle
increases stroke volume. (B) An illustration of P-V loop in a patient with a severely increased volume
load. As EDPVR shifts further to the right in cases with severe afterload; however, the myocardial
hypertrophic changes associated with increased collagen makes ESPVR drop, leading to decreased
stroke volume.

Therefore, it is of clinical significance to ascertain the threshold of the volume overload
in patients with congenital heart diseases with left-to-right shunting. The current practice
guidelines suggest that the threshold for VSD patients should be a ratio of pulmonary to
systemic blood flow (Qp/Qs) >2.0 (Warnes et al. 2008). Researchers have already reported a

method to calculate Qp/Qs using echocardiography. However, some researchers also
demonstrated that there are several limitations to this method, such as the blood flow profiling
and influences of the beam angle (Kitabatake et al. 1984, Sabry et al. 1995). Although Qp/Qs


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can be estimated based on MRI (Beerbaum et al. 2001), the use of MRI is also limited
because of high heart rate and insufficient cooperation of patients in childhood.
In order to evaluate the pulmonary arterial pressure concurrently, catheterization is still
performed in Japan. We have focused on the intraventricular blood flow in patients with
ventricular volume load, and hypothesized that the amount of intraventricular energy loss
based on energy dispersion would increase in response to the volume load. We evaluated the
perioperative changes in intraventricular blood flow and energy loss in a 7-month-old female
with VSD (Figure 6.7).

Figure 6.7. The perioperative changes in the intraventricular energy loss in a 7-month-old female with
ventricular septal defect (VSD). The peak energy loss in the diastolic phase decreased from 200.3
mW/m to 58.3 mW/m after the VSD closure.


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The peak amount of energy loss in the diastolic phase significantly decreased from 200.3
mW/m to 58.3 mW/m after the VSD closure. It is easy to speculate that an increase in
intraventricular blood flow causes strong blood flow collisions, leading to high energy loss.

Therefore, a reduction of volume load after the VSD closure is considered to be reflected by
the decreased amount of intraventricular energy loss. Future studies with large populations
will clarify the utility of assessing the intraventricular energy as a new parameter reflecting
volume overload.

3. THE RIGHT VENTRICLE
3.1. Anatomical and Physiological Characteristics of Right Ventricle
The right ventricle consists of inlet, apical trabecular and outlet components, and is the
most anteriorly situated cardiac chamber (Haddad et al. 2008, Ho et al. 2006). The right
ventricle is crescent-shaped when viewed in cross-section, and triangular when viewed from
the side. The left ventricle has 3 muscle layers; an obliquely-oriented superficial layer,
longitudinally-oriented deep layer, and predominantly circular muscle layer between them
(Greenbaum et al. 1981). The circular muscle layer of the left ventricle is considered to make
complex movements, such as twisting (Streeter et al. 1969) and untwisting (Notomi et al.
2008) possible. In contrast, the right ventricle has only 2 muscle layers; a superficial muscle
layer parallel to the atrioventricular groove and a deep muscle layer is longitudinally aligned
to the apex of the heart. The simpler structure of the right ventricular myocardium associates
with the fact that the right ventricle has lower vascular resistance and greater pulmonary
arterial distensibility than the left ventricle. Additionally, it is believed that this simplicity
contributes to the high compliance of the right ventricle, and enables it to accommodate the
changes in the preload on the heart.
These anatomical and physiological characteristics also influence the blood flow pattern
in the right ventricle. We observed the intraventricular blood flow based on 3-dimensional
cine phase contrast MRI or 4D flow MRI (Figure 6.8), and found that in the left ventricle, a
large vortex is formed that helps multidirectional streams of blood merge with minimal flow
collision during the diastolic phase. Because the mitral inflow should be turned to the aortic
outflow, large vortices are formed as if blood flow ―jumps on a spring‖. During the systolic
phase, the vortex preferentially moves blood into the left ventricular outflow tract. In the right
ventricle, the blood flow from the superior vena cava collides with that from the inferior vena
cava, and helical blood flow streams into the right ventricle. In contrast to the left ventricle,

no large vortex is formed in the right ventricle in the long axis plane (Frontal view in Figure
6.8), but helical spiral flow is formed inside the chamber (Lateral view in Figure 6.8). This
helical flow called ―secondary vortex flow‖ in fluid mechanics, facilitates to enlarge the right
ventricular free wall and this helical flow helps the right ventricle act as a flow volume
reservoir. The anatomical and physiological characteristics of the ventricles greatly contribute
to their features.


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Figure 6.8. The streamlines in normal biventricular hearts. In the right ventricle, no large vortex was
found, and 2-dimensional blood flow moves into the pulmonary artery. In the left ventricle, a large
vortex was confirmed during the diastolic phase. This large vortex helps multidirectional streams of
blood merge with minimal flow collision, and preferentially moves blood into the left ventricular
outflow tract in the systolic phase.

3.2. Consideration in Tetralogy of Fallot
Tetralogy of Fallot (TOF) is characterized by 4 morphological features: (1) ventricular
septal defect, (2) over-riding of the aorta, (3) right ventricular outflow obstruction, (4) right
ventricular hypertrophy (Apitz et al. 2009, Chaturvedi et al. 2007). Many cases develop
cyanosis in the first few weeks and months of life, although the pulmonary blood flow is
adequate at birth. Most centers operate on children aged 3-6 months to improve the cyanosis.
It is widely recognized that the long-term fate of the right ventricle is determined by the
chronic pulmonary regurgitation (Apitz et al. 2009). Therefore, preservation of the pulmonary
valvular function has recently been considered to be the most important policy in the surgery
for TOF, even at the expense of modest residual stenosis (Van Arsdell et al. 2005). Right
ventricular failure is related to pulmonary regurgitation in most cases, and the amount of
pulmonary regurgitation is reported to correlate with the right ventricular volumes and

exercise dysfunction (Carvalho et al. 1992). Therefore, pulmonary valve replacement, before
irreversible myocardial change due to right ventricular volume load occurs, is of great
importance.
Therrien et al. 2005 have proposed the threshold for adequate reverse remodeling as 170
ml/m2 for the end-diastolic volume and 85 ml/m2 for end-systolic volume. In addition, the
relationships between QRS duration and the occurrence of ventricular tachycardia and sudden
death were reported (Gatzoulis et al. 1995). Gatzoulis et al. 2000 also reported that QRS
duration >180msec and the rate of change in QRS duration can be used as parameters to
predict the occurrence of ventricular arrhythmia and sudden death. Therefore, to determine
the optimal timing for pulmonary valve replacement, RV volume measurement by MRI and


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QRS duration on ECG are clinically important. In addition, the clinical utilities of brain
natriuretic peptide (BNP) and N-terminal pro-BNP levels to determine the indications for
reoperation indication have recently been supported by several reports (Kitagawa et al. 2014,
Hirono et al. 2014). Moreover, recent studies have demonstrated that ventricular fibrosis
detected by late gadolinium enhancement cardiovascular MRI has relationships with late
complications such as arrhythmia, ventricular function, exercise intolerance and
neurohormonal activation (Babu-Narayan et al. 2006, Wald et al. 2009). However, further
studies are warranted to establish the threshold for determining the timing for pulmonary
valve replacement based on these new parameters.
In order to elucidate the right ventricular function, ventricular-ventricular interaction is
also considered to be an important concept, but is not yet fully understood. As the right and
left ventricle share the same visceral cavity and common myocardial strands, the right
ventricle influences the left ventricle, and vice versa. The concept of ventricular-ventricular
interaction has been discussed for approximately 5 decades. Kelly et al. 1971 reported that

right ventricular volume loading influences the left ventricle pressure-volume relationship and
reduces the left ventricular function relative to left ventricular end-diastolic pressure. Bemis
et al. 1974 also reported that an elevation in right ventricular end-diastolic pressure not only
increases the left ventricular end-diastolic pressure, but also alters the geometry of the left
ventricle. Several reports on TOF patients have indicated that there is a positive correlation
between the right and left ventricular function (Geva et al. 2004, Tzemos et al. 2009), and
ventricular-ventricular interaction has been considered to underlie this relationship. However,
the clinical impact of ventricular-ventricular interaction has not fully clarified, and further
studies will be needed to elucidate the importance of this interaction.

4. FONTAN PHYSIOLOGY
4.1. Fontan Procedure
Fontan procedure is the surgery to establish the circulation of functional single ventricle
(Fontan et al. 1971). We call this circulation ―Fontan circulation‖, and in the Fontan
circulation, the superior and inferior vena cava directly connect to the bilateral pulmonary
arteries. In 1971, Fontan and Baudet first reported this operation for a patient with tricuspid
atresia, and the introduction of this procedure dramatically improved the life expectancy of
children with single ventricle (Cetta et al. 1996, Mair et al. 2001, and d‘Udekem et al. 2007).
As relatively low pulmonary vascular resistance and preserved ventricular function are
essential for the formation of Fontan circulation, a bidirectional Glenn anastomosis is
generally performed as an intermediate step. The bidirectional Glenn procedure is
advantageous of providing an adequate amount of pulmonary blood flow and reducing the
volume load on the main ventricle.
The surgical method associated with the connection of venous return and pulmonary
arteries has also been improved. Originally, the right atrium was isolated by the closure of
atrial septal defect and tricuspid valve, and the right atrial appendage was anastomosed to the
right pulmonary artery (atriopulmonary connection [APC] Fontan). Lateral tunnel was
subsequently introduced to establish better streaming of the venous return by baffling the

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right atrium with an intraatrial patch. Recently, the venous return is routed by the insertion of
an extracardiac conduit between the inferior vena cava and the right pulmonary artery, and
extracardiac conduit modification leads to less supraventricular arrhythmia (d‘Udekem et al.
2007). Although the Fontan anastomosis is unique, the main ventricle, aortic arch, arteries
and vena cava were also unique in the Fontan patients. Although better management and
improved surgical techniques contributed to the better prognoses of Fontan patients, these
patients frequently develop heart failure, arrhythmia and long-term complications such as
protein losing enteropathy (PLE) (Mertens et al. 1998 and John et al. 2014), liver dysfunction
(Baek et al. 2010), thrombosis (Jacobs et al. 2007), renal dysfunction (Dimopoulos et al.
2008) and plastic bronchitis (Do et al. 2009) as a consequence of the Fontan physiology. In
this chapter, we will discuss the disadvantageous characteristics of the Fontan physiology.

4.2. Aortic Arch
Some cases require aortic arch reconstruction in complicated congenital heart anomaly
related to the single ventricle patients. Arch repair for the coarctation or interruption of the
aortic arch, DKS (Damus-Kaye-Stansel) procedure for the restricted systemic outflow
patients, and Norwood procedure are kind of procedures in aortic arch reconstruction. The
Norwood procedure is the operation for HLHS involving the reconstruction of a sufficient
systemic outflow. Recoarctation or obstruction of the aortic arch after the Norwood procedure
deteriorates the function of the single right ventricle, leading to a high mortality rate;
therefore, several surgical modifications have been introduced.

Figure 6.9 The streamlines and energy loss inside the aortic arch after the Norwood operation measured
with echocardiography VFM. There was a large vortex formed in the dilated aortic arch. High amount
of energy loss was confirmed in the dilated aortic arch during the systolic phase.

Cardis et al. 2006 has reported that patients with HLHS after the Norwood procedure had
increased aortic stiffness and decreased dispensability in the reconstructed aorta. Itatani et al.
2012 also reported a CT-based simulation study analyzing the streamline and energy loss in
aortic arches after the Norwood operation. We previously evaluated the streamlines and
energy loss in the dilated aortic arch after reconstruction using echocardiography VFM
(Figure 6.9). Our streamline analysis showed a large vortex inside the dilated aortic arch, and


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this finding was different from that of the CT-based simulation study. Echocardiography
VFM has advantages in the examination of flow around the valve. Regarding the energy loss,
high energy loss was confirmed at the dilated site. In addition, it is of great interest that the
energy loss time curve obtained from VFM was similar to that obtained from the numerical
simulation study (Itatani et al. 2012). The dilated aortic arch would be an afterload on the
main ventricle.

4.3. Main Ventricle and Vessels
Before the Glenn operation is performed, the oxygen supply to the heart is insufficient,
because the oxygenation is not complete. And, as the main ventricle needs to supply blood
with not only the systemic arteries but also pulmonary arteries with lower vascular resistance,
volume overload negatively affects the main ventricle. This overload leads to ventricular
hypertrophy, which has been reported to be related to the patient‘s prognosis (Seliem et al.
1989). In addition, after the Glenn operation, aortopulmonary shunts are sometimes formed.
This complication can also negatively affect as a volume overload. Atrioventricular valve
insufficiency also accompanies in the single-ventricle patients with a fixed frequency, and
this complication could be a volume overload for the main ventricle. Moreover, especially in
patients with HLHS, neoaortic valvular insufficiency would also cause volume overload.

Meanwhile, the dilated aortic arch also works as a pressure load, as stated above. It is wellknown that the vascular resistance is high in the Fontan patients. This finding can be regarded
as an adaptation that occurs to increase the venous capacity to propel the blood flow in the
pulmonary arteries. There are other negative features, such as an impaired heart rate response,
morphological abnormalities in the ventricle including the effect of the residual chamber
(Ohuchi et al. 2001), the single coronary artery observed in the right single ventricle (Baffa et
al. 1992) and RV-dependent coronary circulation in patients with pulmonary atresia.
Therefore, the main ventricle is exposed to various and complicated negative factors.

Figure 6.10. The results of a streamline analysis in the normal left ventricle in VFM. In the early
diastolic phase, 2 small vortices are formed around the mitral valve. The clockwise vortex on the right
side gradually becomes larger in the end diastolic phase. The blood flow is consequently directed to the
aorta in the systolic phase.


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Observations of the blood flow in hearts have recently shown preferable vortex formation
in adults (Itatani 2014, Pedrizzetti et al. 2014, and Sengupta et al. 2014), which can also be
observed in children. According to our preliminary data based on VFM echocardiography,
two small vortices are formed around the mitral valve in the early diastolic phase (Figure
6.10). The clockwise vortex on the right side gradually becomes larger and occupies the
ventricle in the end-diastolic phase. The blood flow is subsequently directed to the aorta in the
systolic phase. Therefore, utilizing this inertial force, the intraventricular vortex preferentially
moves the blood into the aorta. In addition, the observation of the energy loss based on VFM
echocardiography revealed that high amount of energy loss is detected only at the outer
periphery and center of the large vortex, indicating that the blood flow in the inner part of the
vortex can preserve the kinetic energy.

Figure 6.11. The results of streamline and energy loss analysis in the main ventricle of an infant with
tricuspid atresia. There was no significant large vortex in the ventricle. Instead, several small vortices
were confirmed during the diastolic phase, and high amount of energy loss was detected around the
vortices. The time-energy loss (time-EL) curve in this infant was significantly greater than that in a left
ventricle of a normal biventricular infant. These findings indicate that this infant is not able to utilize
the inertial force of the intraventricular vortex, leading to decreased energy efficiency.


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Takashi Honda, Kagami Miyaji and Masahiro Ishii

We show sequential images of the intraventricular blood flow in an infant with tricuspid
atresia (Figure 6.11). No significant large vortex was confirmed in the main ventricle. Instead
there were several small vortices coexisting and conflicting with each other. High amount of
energy loss was consequently detected around these vortices, and this finding indicates that
the energy efficiency is impaired in this single left ventricle. The pathophysiology underlying
the impaired energy efficiency is unclear; however, the abnormal morphology may cause the
inefficient intraventricular blood flow. In a 3-year-old male with hypoplastic left heart
syndrome, two vortices were observed in the right single ventricle during the early diastolic
phase; however, they vanished in the late diastolic phase, and these vortices did not
consequently work as inertial forces in this patient (Figure 6.12). Therefore, this right single
ventricle did not utilize any inertial force either. Future studies will be needed to elucidate the
influences of abnormal intraventricular vortex formation on the impaired ventricular function
in single-ventricle patients.

Figure 6.12. The results of a streamline analysis in the main ventricle of 3-year-old male with
hypoplastic left heart syndrome. Although 2 vortices were formed in the early diastolic phase, they
vanished in the late diastolic phase. Therefore, this right single ventricle did not utilize any inertial
force.

4.4. Fontan Anastomosis
Fontan anastomosis is an artificial structure, and a number of researchers have made
efforts to elucidate the non-physiological blood flow at the Fontan anastomosis site. Although
the flow drives of the pulmonary blood flow in the Fontan circulation have not yet been
clarified, the heartbeat, respiration and muscles of the lower extremities are all considered to
influence the blood flow pattern. Nakazawa et al. 1984 and DiSessa et al. 1984 revealed that
the pulmonary blood flow increases during the atrial diastole. Redington et al. 1991 and
Penny et al. 1991 clarified that the pulmonary blood flow increases in the inspiratory phase.
Fogel et al. 1997 analyzed the flow based on MRI, and verified that the pulmonary blood flow
increases from the end systolic phase to the early diastolic phase. Hjortdal et al. 2003
demonstrated that the pulmonary blood flow increases in response to the muscle contraction


Congenital Heart Disease and Circulatory Physiology

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of the lower extremities. Future studies are needed to elucidate the mechanisms of these flow
drives and the effects of complications on these flow drives.
Energy loss in the Fontan anastomosis has been considered to reflect the energy
efficiency, and several researches have focused on this novel parameter. Sharma et al. 1996
proposed the optimal connection site of the Fontan conduit with the lowest energy loss in the
Fontan anastomosis, by using glass models based on in vivo cardiac MRI geometric data. This
reported demonstrated that the energy losses of 1 and 1.5 times the diameter offset achieved
the minimal energy loss. Subsequent studies using computational fluid dynamics (CFD)
increased the understanding of the energy loss. de Lavel et al. 1996 subsequently
demonstrated that the minimal energy loss and blood flow distribution to the bilateral
pulmonary arteries could be achieved by enlarging the Fontan baffle (2.5 cm) and moving it
alongside the pulmonary artery angling the Fontan baffle toward the right pulmonary artery.

Itatani et al. 2011 reported that the lower limit of the pulmonary artery index was 110
mm2/m2, from the view of exercise tolerance. Marsden et al. 2007 also indicated that
respiration and exercise considerably influence EL in the Fontan anastomosis. In order to
determine the clinical importance of decreasing EL, we calculated the in vivo EL by
measuring simultaneous pressure and velocity data at supra and inferior vena cava and
bilateral pulmonary arteries, and compared EL with other cardiac functional parameters
(Honda et al. 2014). This small study revealed that EL correlates with diastolic function of the
main ventricle. A larger study reported by Khiabani et al. in 2015 clarified the relationship
between EL and exercise capacity. In order to achieve clinical application of EL assessment
in the Fontan anastomosis, it will be important to establish a further easy method for
measuring EL in future studies.

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