Ebook Advances in hemodynamic research: Part 2

(BQ) Part 2 book Advances in hemodynamic research presents the following contents: Congenital heart disease and circulatory physiology, hemodynamics in coronary arterial disease and myocardial perfusion, application to cardiovascular surgery, reperfusion hemodynamics as an early predictor of cardiac function in a DCDD setting,...

PART II: CLINICAL APPLICATION OF

Chapter 6

Takashi Honda1, Kagami Miyaji2 and Masahiro Ishii1

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: thonda@med.kitasato-u.ac.jp

1 HEMODYNAMICS AND VENTRICULAR FUNCTION IN FETAL

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 well-oxygenated 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 radionuclide-labeled 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)

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

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

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 intra-atrial 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

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

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

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

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

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

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

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

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

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

4.1 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

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

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 well-known 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

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

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

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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Chapter 7

When the IVPD is analyzed using color M-mode imaging, the spatial and temporal information can be analyzed simultaneously This allows the pressure difference at each location to be determined, despite being limited to a one-dimensional scan line of the left ventricle IVPD may also elucidate new aspects and mechanisms of diastolic function Although at present, the original program in each institution, which is not commercially available is required to analyze color M-mode data to estimate IVPD, overcoming this difficulty will allow new insights into the diastolic function in both clinical and research settings This chapter discusses the significance, advantages, and impacts of IVPD analyses in both settings



Corresponding Author address E-mail: kentaka@juntendo.ac.jp

Keywords: intraventricular pressure difference (IVPD), diastolic heart failure

The cardiovascular system is very complex The heart, especially the left ventricle (LV), plays the most important role in the circulatory system There is growing recognition that congestive heart failure, caused predominantly by an abnormality in diastolic function, is both common and causes significant morbidity and mortality (Aljaroudi W et al 2012, Halley et

al 2011) However, the mechanisms underlying diastolic dysfunction remain unclear The sucking force, which sucks blood from the left atrium into the LV, is now understood to play

an important role in diastolic function during the early diastole (Ohara et al 2012, Yotti et al

2005, Notomi et al.2008) The intraventricular pressure difference (IVPD) between the left atrium (LA) and the apex of the LV, which is the driving force of LV suction, ranges only from 2 to 5 mmHg in the adult human, and the IVPD duration is very short (Ohara et al

2012, Yotti et al 2005, Notomi et al.2008) It begins around the time that the mitral valve opens and continues until the peak of the E wave at the mitral valve Despite this small pressure difference and short duration, IVPD is the key force behind diastolic function This chapter will first describe the history of the research and the theory for IVPD to explain the mechanisms of IVPD based on current research and clinical studies Second, the chapter will explain with detailed, practical methods how to investigate IVPD using echocardiography Third, it will provide data on some cardiac diseases related to new research projects using IVPD

2.1 Definitions

In this chapter, IVPD is defined as the pressure difference during early diastole between two points, the mitral annulus and the LV apex (Popovi et al 2006, Thomas et al 2005) IVPD is defined as the change in pressure over a certain distance L, in this case the base to apex distance The relationship between IVPD and the intraventricular pressure gradient (IVPG) is described by Equation (7.1)

In other words, IVPG is the derivative of IVPD with respect to location However, cardiologists tend to use “IVPG” to describe the pressure difference, whereas a physicist would use “IVPD”, reserving the word “gradient” to describe the rate of pressure change along a line In this text, the physics definition is used However, readers should be aware that this is not always the case in the cardiology literature Later in the text, IVPD in the right

ventricle (RV) is discussed IVPD in the RV between the tricuspid valve and the RV apex is represented as RV-IVPD

2.2 Clinical Background of IVPD and Development of IVPD

In 1930, Katz 1930 speculated that the left ventricle relaxed actively and had the ability

to “exert a sucking action to draw blood into its chamber.” Despite this speculation that diastole in the very early period was associated with active relaxation and was not an entirely passive process, this hypothesis was not supported until 1979 when Ling et al Ling et al

1979 reported the presence of regional IVPD between the base and apex of the LV in a canine model They speculated that these gradients resulted in the active “sucking” of blood into the

LV from the left atrium Courtois and colleagues subsequently validated these findings in

1988 (Courtois et al 1988) Later, they demonstrated a strong relationship between diastolic IVPD and systolic function, with regional ischemia-induced changes in LV function having a direct effect on IVPD (Courtois et al 1990).Based on those results, they speculated that IVPD was related to regional elastic recoil, or the potential energy stored during LV systole, and that impairments in regional systolic function would have a significant effect on LV

“suction.”

Although the existence of the sucking force was proved, its mechanism still remained unclear There had been two theories as to the mechanisms underlying IVPD Ling et al 1979 reported that IVPD could be due to viscoelastic myocardial properties and local acceleration

of blood In contrast to this theory, Courtois et al 1990 reported that IVPD was due to differences in regional elastic recoil of the LV wall To elucidate this issue, Nikolic et al

1995 developed a very unique experimental system using a mitral valve occluder implanted in the mitral annulus The mitral valve was occluded to produce non-filling diastole, and the base-to-apex pressure gradient was observed, regardless of the presence or absence of filling through the mitral valve from the LA to the LV Thus, they concluded that IVPDs are related both to changes in LV shape and to the magnitude of elastic restoring forces and, furthermore, that the shape of the ventricle is not dependent on the hydrodynamics of blood inflow As described above, although the presence of IVPD between the left ventricular base and apex during early diastole was reported, the clinical implications of this phenomenon were not fully appreciated Before the methods to measure IVPD using echocardiography were developed, IVPD was not routinely measured in clinical practice because it required an invasive procedure with high-fidelity pressure measurements in the LV with cardiac catheterization Greenberg et al 2001 made a historical turning point for the measurements of IVPD They developed a system to calculate transmitral pressure differences across a normal mitral valve into the unsteady flow from the Bernoulli equation using a full digital velocity map captured by echocardiography, based on color M-mode (Greenberg et al 1996) Later, they extended this concept and applied basic hydrodynamic principles to the non-invasively obtained spatiotemporal velocity distribution of left ventricular inflow to calculate IVPD (Greenberg et al 2001) These methods have since been used in several studies

2.3 The Mechanisms Underlying IVPD

IPVD plays a key role in diastolic function The mechanisms underlying diastolic function should be reviewed to provide insight into IVPD Diastole encompasses the period

of time beginning when the myocardium loses its ability to generate force and shortens until the time it returns to its resting force and length The physical and physiologic properties that define diastolic filling are a complex interaction of active and passive components The simultaneous interaction among (1) the dimensions of the mitral valve, (2) left atrial filling/emptying properties, (3) the passive compliance of the LV, and (4) the rate and duration of LV relaxation (tau: an active and energy-consuming process) defines the transmitral filling gradient that allows for diastolic filling (Yellin et al 2000).At the organelle level, relaxation occurs in a series of energy-consuming steps beginning with the release of calcium from troponin C, detachment of the actin-myosin cross-bridge, phosphorylation of phospholamban, sarcoplasmic reticulum calcium ATPase–induced calcium sequestration into the sarcoplasmic reticulum, sodium/calcium exchanger–induced extrusion of calcium from the cytoplasm, slowing of the cross-bridge cycling rate, and extension of the sarcomere to its rest length (Brucks et al 2005, Cheng et al 1993, Cheng et al 2005, Courtois et al 1988, Dabiri et al 2004) The mechanisms to supply adequate energy and regenerate them must work for this process at a sufficient rate and to a sufficient extent Cheng et al 1993, Courtois

et al 1988, Dabiri et al 2004) The rate and extent of these cellular processes determine the rate and extent of active ventricular relaxation The actual location of this elastic storage remains controversial, but it likely involves both the myocyte and the myocardial interstitium

At the sarcomere level, titin is a molecular spring causing energy to be stored during systole that helps restore the sarcomere in early diastole (Helmes et al 1996, Lahmers et al 2004) Helmes et al 1996 and 2003 explained titin-based restoring forces that the relengthening velocity of the sarcomere is inversely related to end-systolic length, a microscopic analogy of ventricular contraction below equilibrium volume Therefore, diastolic suction involves deformation of the protein titin that occurs when sarcomeres are stretched above and shortened below slack length, (Kass et al 2004) which affects acute deformation of the LV, such as the untwisting motion during isovolumic relaxation time (IVRT) (Notomi et al 2006)

At the chamber level, this process causes acute LV pressure decline during IVRT, then

LV chamber filling, which occurs with variable LV pressures (auxotonic relaxation) The major determinant of diastolic suction is the elastic energy stored during systole To generate elastic potential energy, the LV volume must fall under a critical value during contraction to generate suction (Nikolic et al 1988, Beli et al 2000, Solomon et al 1998) This process is affected both by active relaxation and by passive stiffness

Nikolic et al 1988 previously showed that the suction volume during diastole from the

LA to the LV was directly related to the magnitude of the LV elastic recoil, or potential energy, forces This finding means that IVPDs are directly related to LV geometry and influenced by the elastic recoil, reflecting the potential energy stored during systole and representing a mechanism by which the LV can adequately fill under low filling pressures Early work investigating the determinants of IVPD by Courtois et al 1988 demonstrated significant decreases in IVPD with acute coronary occlusion In addition, they showed a relationship between decreases in IVPD and extensive regional systolic dysfunction These findings contributed to their speculation of the relationship between IVPD and the elastic recoil of the LV and provided a mechanism to maintain LV filling at lower diastolic pressure

These observations are consistent with previous reports of both a relationship between IVPD and endo-systolic volume (ESV) and a relationship between the change in IVPD and changes

in ESV (Firstenberg et al 2001) Furthermore, the lack of a relationship between IVPD and left atrial pressures and the fact that these early pressure differences exist without inflow from the LA to the LV (Nikolic et al 1995) suggest that they may represent intrinsic properties of the LV and transmitral pressure differences

From the view point of the energy store in the LV structure, Ashikaga et al 2004 have shown significant deformation within the myocardium as the counter helixes contract against each other, storing significant energy in the interstitium as a global LV “spring” (Robinson et

al 1986, Krams et al 1994) The isovolumic pressure decay and rapid left ventricular (LV) filling during IVRT and early diastole are characterized by a series of consecutive events that partially overlap in time As LV pressure starts to decline before mitral valve opening, conformational changes occur within the heart that are reflective of the release of energy stored during previous systole (Nikolic et al 1988) Mitral valve opening is immediately followed by the development of IVPD (Courtois et al 1988) Finally, LV inflow is accelerated by IVPD to reach peak filling velocity (Nakatani et al 2001) It is widely accepted that the appearance of IVPD in early diastole reflects LV suction (Nikolic et al 1995); in other words, the low-pressure field created by outward-directed elastic forces that aim to restore a non-stressed LV shape (Nikolic et al 1988) It is also accepted that IVPD facilitates early LV filling (Little et al 2005) LV systolic torsional deformation is one of the mechanisms by which potential energy is stored during ejection, to be later released during diastole, contributing to the creation of suction (Notomi et al 2008) In systole, as the base and apex of the heart rotate in the opposite direction and generate twisting of the heart muscle, part of the energy used in contraction is stored within the extracellular collagen matrix (Waldman et al 1988) and compresses titin within the myocytes (Granzier et al 2005) During relaxation, this energy is promptly released and manifested by LV untwisting About 40% of the LV untwisting occurs during IVRT (Rademakers et al 1992); the untwisting rate is proportional to the rate of isovolumic pressure decay (Dong et al 2002); and there is a positive association between the untwisting rate and IVPD (Notomi et al 2006) These three phenomena have been shown to follow each other temporally, starting with isovolumic pressure decay, followed by untwisting, whose peak coincides with mitral valve opening, and ending with IVPD that peaks early during LV filling

From the view point of the coordination of ventricular motion, another aspect of the mechanisms causing IVPD can be realized The timing of events during LV relaxation is programmed like a precision machine and is closely related to the mechanisms causing IVPD The peak dP/dt at the apex is slightly delayed relative to that at the subaortic region and mitral tip (Steine et al 2002) These small temporal differences probably reflect the ventricular activation time and lead to a small delay in the onset of relaxation in the apex relative to the basal region (Sengupta PP et al 2006, Ashikaga et al 2007) During IVRT, however, pressure falls at a faster rate at the apex than at the base; therefore, early diastolic minimum pressure is reached first in the apex During volume loading and after coronary micro-embolization, however, tau is similar in all regions It seems likely that regional differences in tau contribute

to the early diastolic mitral-to-apical pressure differences measured (Steine et al 2002) The twisting motion provides another aspect of the coordination of LV motion during diastole Peak LV untwisting precedes IVPD (Notomi et al 2006) and is a strong predictor of IVPD (Notomi et al 2008), which is manifested in part by apical pressure decline An obvious manner in which untwisting can affect LV suction is through a change of LV shape

As opposed to depolarization, repolarization, and therefore relaxation, progresses from the

epi- toward the endocardial layers and occurs almost simultaneously at the basal and apical sites (Yan et al 1998) Because subepicardial fibers are predominantly responsible for twisting due to the hammer theory, it is reasonable that the first motion detectable during relaxation is untwisting (Ashikaga et al 2004) This is closely followed by a change of orientation in the myocardial sheets that becomes less perpendicular toward the long axis and that in turn leads to sub-endocardial radial thinning (Rosen et al 2004, Davis et al 1999) This initial very early change causes a continuous apical LV pressure drop during the diastolic suction phase The importance of this apical relaxation to LV suction was proved by Davis et al 1999 and Steine et al 1999

2.4 Measuring IVPD Using Echocardiography

Previously, cardiac catheterization was needed to measure IVPD, but Greenberg et al

2001 reported a non-invasive method of IVPD measurement using echocardiography without the risk and expense of cardiac catheterization

Figure 7.1 IVPD measurement A Four-chamber view showing mitral inflow B corresponding color M-mode Doppler image C three dimensional profile of IVPD Color M-mode Doppler images (B) are recorded with the cursor parallel to mitral inflow in an apical 4-chamber view (A) Euler’s equation, shown in Equation 7.2, is used to calculate the pressure gradient at each point The pressure difference

at each point along a scan line is measured relative to the position of the mitral annulus at the aortic valve closure by calculating the line integral between them A three-dimensional profile of IVPD is generated, and the peak IVPD in early diastole is identified (C) IVPD: intraventricular pressure difference AoV: aortic valve closure

Color M-mode images were obtained using the apical 4-chamber view Kamiguchi et al 2006, Firstenberg et al 2000, Yotti et al 2005), apical long axis view (Steine et al 2002) or 4-chamber view by trans-esophageal echocardiography (Ronber et al 2003) and analyzed using an image-processing algorithm (Figure 7.1).

(Asada-𝜕𝑃

Images were reconstructed using a de-aliasing technique, as shown in Equation (7.2), where P is the pressure, ρ is the constant blood density as 1060 kg/m3, u is the velocity, s is a position along the streamline of the transmitral flow measured with color Doppler M-mode line, and t is the time used to calculate the relative pressures within the region of interest from the reconstructed velocity field (Greenberg et al 2001, Asada-Kamiguchi et al 2006, Ronber

et al 2003, Firstenberg et al 2000, Steine et al 2002) The pressure difference at each point along a scan line was measured relative to the position of the mitral annulus at aortic closure

by calculating the line integral between them (Greenberg et al 2001, Yotti et al 2005) (Figure 7.2) The first term on the right side of Equation 7.2 is the inertial component, and the second term is the convective component

Figure 7.2 Left ventricular IVPD in normal subjects A Three-dimensional profile of IVPD B temporal profile of IVPD C spatial profile of IVPD at the peak IVPD The red line represents IVPD, the blue line represents inertial IVPD, and the green line represents convective IVPD The positive pressure decrease is caused by the inertial acceleration In contrast, convective forces decelerate blood flow and generate a negative gradient The IVPD is the result of the instantaneous sum of these two pressure differences IVPD, intraventricular pressure difference

Inertial and convective forces obey different physiological determinants Theoretically, the inertial component of IVPD should be caused by the impulse developed by myocardial restoration forces (Thomas et al 1991, Greenberg e tal 1996) The convective IVPD should

be determined by filling flow velocity and chamber geometry (Courtois et al 1988)

From the temporal profile of the LV apex pressure relative to left atrial pressure, the peak IVPD from the mitral valvular annulus to the LV apex is calculated (Courtois et al 1988) Color M-mode images were obtained using the apical 4-chamber view (Asada-Kamiguchi et

al 2006, Firstenberg et al 2000, Yotti et al 2005), apical long axis view (Steine et al 2002)

or 4-chamber view by trans-esophageal echocardiography (Ronber et al 2003) and analyzed using an image-processing algorithm (Figure 7.1)

The resolution of the color Doppler and the temporal and spatial resolution of color Doppler M-mode images are important, as they determine the degree of accuracy for the partial derivative terms of the Euler equation (Greenberg et al 2001)

However, resolution was already acceptable using equipment in 2000 to 2005, and equipment has become much more developed in the past decade Thus, this issue is resolved

if the recent commercially available machines are used to measure IVPD

The LV inflow tract shows a complex three-dimensional geometry Therefore, no straight line could ever be expected to coincide with a streamline throughout diastole The accuracy of the pressure estimate is also related to the degree to which the ultrasound scan line approximates an inflow streamline through the center of the mitral valve (Greenberg et al 2001) It has been shown through a computational model that accurate results can be achieved when the scan line is placed within the central 60% of the valve orifice or when an angular misalignment is made up to 20°

The particular concern is the presence of vortices that form at the leaflet tips, which may affect the flow from the LA into the LV During early diastolic filling, blood flows across the mitral valve from the LA into the LV, and the inflow jet produces a vortex ring (Domenichini

et al 2007, Hong et al 2007, Kilner et al 2000) The strength of the vortex ring continues to increase until the vortex ring is pinched off from the mitral leaflet tips At the point when the inflow jet is terminated, the primary vortex ring detaches from the inflow jet and pinches off Vortex ring formation within the LV inflow tract is predicted to improve LV filling efficiency and has been investigated as a possible metric of cardiac function (Kilner et al 2000) As these vortices are formed outside the central flow region, as long as the scan line is placed on the central stream line, the accuracy of the measurement of IVPD is proven (Stewart et al 2012)

3.1 Relationship between IVPD and Systolic and Diastolic Function

Firstenberg et al (Firstenberg et al 2001) showed that IVPD is directly related to Emax, which is the gold standard measurement of systolic cardiac function and is assessed only by using cardiac catheterization with a micromanometer Steine et al 1999 also showed a strong correlation between IVPD and tau, which is the gold standard measurement of diastolic function and is assessed only by using cardiac catheterization with a micro manometer

Firstenberg et al (Firstenberg et al 2001, Firstenberg et al 2008) showed that IVPD correlated linearly with improvements in regional tau

3.2 Simultaneous Analysis of Spatial and Temporal Information

The estimation of diastolic function using IVPD offers several advantages over the conventional diastolic parameters that are currently in clinical use Pulsed Doppler techniques can measure velocity information at one point in space and at one point in time

In contrast, IVPD as measured by echocardiography from the color M-mode Doppler includes velocity information along the whole scan line from the mitral valve to the apex in space and during the whole diastolic duration in time Ohara et al 2012 effectively leveraged those benefits to determine the mechanisms of diastolic function In their study, they divided the IVPD into two parts: from the left atrium to the mid-LV and from the mid-LV to the LV apex With dobutamine infusion, total IVPD increased by a mean 2.20 ± 1.95 mmHg in normal controls and by only 0.73 ± 1.33 to 1.08 ± 1.57 mmHg in patients with diastolic dysfunction Iwano et al (Iwano et al 2015) compared 151 patients with HFpEF, 101 patients with HFrEF and 28 normal controls While basal IVPD were not significantly different among groups (HFpEF, 1.59 ± 0.62 mm Hg; HFrEF, 1.49 ± 0.75 mm Hg; controls, 1.80 ± 0.61 mm Hg; P = NS, analysis of variance), apical IVPDs were decreased in both HF groups (HFpEF, 1.18 ± 0.56 mm Hg [P < 01 vs controls]; HFrEF, 0.87 ± 0.48 mm Hg [P < 01 vs controls]; controls, 1.65 ± 0.62 mm Hg), resulting in decreased total IVPDs in patients with

HF (HFpEF, 2.55 ± 0.80 mm Hg [P < 01 vs controls]; HFrEF, 2.16 ± 0.80 mm Hg [P < 01

vs controls]; controls, 3.17 ± 0.91 mm Hg) They concluded that in HF patients apical IVPD was reduced in relation to reduced longitudinal function and the basal IVPD was maintained

by increased LA pressure manifested as preserved E wave They concluded that, as the mechanism increasing IVPD, the augmentation of IVPD from the mid-LV to the apex was decreased in patients with diastolic dysfunction Thus, the analysis of regional IVPD can detect the mechanisms of diastolic dysfunction Yotti et al 2005 applied this benefit to find the disc ordination of IVPD in patients with DCM by focusing on the timing of peak IVPD along the LV long axis They found that IVPD originated near the base and propagated toward the apex In the normal heart, the local temporal delay was very small, and IVPD reach its maximum almost simultaneously at both the base and apex This propagation was slower in patients with dilated cardiomyopathy (DCM) compared to normal controls because their gradient time delay was significantly prolonged As the peak value of the IVPD was reached at different moments along the long axis cavity, the suction became disorganized and IVPD was subsequently reduced (Yotti et al 2005) These new approaches providing both location and temporal information enable the examination of the mechanisms underlying diastolic function Like other diastolic parameters, IVPD is also affected both by diastolic function and LA pressure Inertial component of Euler equation is influenced by both LV suction and LA pressure causing driving force from LA to LV It is difficult to differentiate them There are 2 ways to differentiate two components First is to analyze spatial distribution

of IVPD describe in this section Second is to detect the response to sympathetic augmentation of IVPD by exercise or dobutamine infusion described at the section 7.3.4

3.3 Analysis of Inertial and Convective IVPD

As shown in Euler’s equation, IVPD is calculated using two components: inertial and convective IVPD (Greenberg et al 2001, Yotti et al 2005, Ohara et al 2012) The positive apex-to-base pressure drop was caused by the inertial acceleration of blood, which generated

a suction force In contrast, convective forces decelerated blood flow and generated a negative gradient as the pressure rose from base to apex in opposition to flow (Yotti et al 2005) Because the total IVPD is the result of the instantaneous sum of these two pressure gradients of opposite sign, the total IVPD was smaller than the inertial IVPD component Yotti et al 2005 showed that although the peaks of the inertial and convective IVPD components were not reached simultaneously, the peak total IVPD closely correlated with the peak value of these two components: total IVPD = 0.2 + 0.88 × Inertial IVPD - 0.40 × Convective IVPD (adjusted R2 = 0.85, P < 0.0001) in normal subjects They determined that the negative convective IVPG was generated close to the cardiac base They also found that although patients with a restrictive filling pattern showed similar values of total IVPD, they showed a trend toward a higher inertial IVPD and a significantly higher absolute convective IVPD than did patients with nonrestrictive filling

Figure 7.3 Left ventricular IVPD in patients with cardiac dysfunction: case 1 A Three-dimensional profile of IVPD B temporal profile of IVPD C spatial profile of IVPD at the peak IVPD The data are from a patient with cancer using anthracycline for chemotherapy In this case, the torsion and

untwisting rate was decreased as assessed by speckle tracking imaging The peak IVPD is relatively low due to the decreased inertial IVPD at the mid and apical portions of the LV As the sucking force decreased, diastolic function is thought to be decreased in this case IVPD, intraventricular pressure difference

Ohara et al 2012 showed a similar trend in patients with diastolic dysfunction In their study, with impaired relaxation, the reduced adrenergic response to dobutamine stress was predominately due to reduced inertial acceleration, whereas with more severe diastolic dysfunction, it was predominately due to greater convective deceleration

Their results provided very unique and useful information for assessing diastolic function

in various cardiac diseases (Figure 7.3, Figure 7.4)

3.4 IVPD during Exercise and Dobutamine Infusion

Currently, exercise intolerance is thought to be important in predicting outcomes in various heart diseases, (Piepoli et al 2004, Diller et al 2005) and IVPD is proven to play an important role in exercise intolerance (Rovner et al 2005) Left ventricular diastolic function has been considered to be essential in exercise tolerance and IVPD During exercise, increased IVPD is associated with enhanced acceleration of blood flow across the mitral valve, while filling is maintained at a low pressure in the left atrium (Rovner et al 2005)

Figure 7.4 Left ventricular IVPD in patients with cardiac dysfunction: case 2 A Three-dimensional profile of IVPD B temporal profile of IVPD C spatial profile of IVPD at the peak IVPD The data are from a patient undergoing chemotherapy with anthracycline for cancer In this case, the LV shows uncoordinated abnormal motion as assessed by speckle tracking imaging The uncoordinated motion of the LV might cause the larger convective IVPD The peak IVPD is relatively small due to the large convective IVPD IVPD, intraventricular pressure difference; LV, left ventricle

In the normal LV, adrenergic stimulation increases contractility, myocardial restoration forces, and the resulting ventricular suction (Yotti et al 2005) Increased adrenergic tone also decreases filling time, an effect that could reduce the filling volume and elevate diastolic pressure However, increased diastolic suction causes rapid filling and lowers minimum LV pressure (Nikolic et al 1995, Cheng et al 1993) Consequently, enhanced diastolic suction acts as a compensatory mechanism to maintain low pulmonary pressures in situations of increased contractility

During exercise, LV preload acutely increases, the heart rate increases with decreases in the duration of the diastolic stage, and the stroke volume increases; all of these physiological changes result in cardiac output (Ronver et al 2005)

Therefore, the ability of the LV to augment its relaxation potential and increase the suction of the blood from the LA may play an important role in increasing the filling rate at low filling pressures at a higher heart rate (Ronver et al 2005) In patients with heart failure, this augmentation is diminished secondarily to abnormal LV diastolic function (MacGowan et

al 2001, McKelvie et al 1995, Pepi et al 1999), producing symptoms of dyspnea with exercise and providing for poor aerobic capacity

In most normal individuals, the limiting factors that influence V˙ O2 max are the skeletal muscle mass and the capacity of the cardiovascular system (Vanoverschel et al 1993) In patients with heart failure, exercise capacity may be limited by the number of frequently coexisting factors, such as decreased contractility, diastolic dysfunction, chronotropic incompetence, oxygen metabolism, or skeletal muscle mass (Genovesi-Ebert et al 1994) During peak exercise, the duration of diastasis is greatly diminished to account for the increase in heart rate

Yet, for the heart to increase cardiac output, the diastolic mechanics must adjust to the decrease in time to fill (Thomas et al 1992), which is done at low filling pressures; rather, early relaxation is increased to provide for a “suction” force and high LV compliance (MacFarlane et al 1991) Popović et al 2006 showed that the change in stroke volume and IVPDs during exercise showed a strong correlation (r = 0.96, P = 0.0002) Ronver et al 2005 clearly demonstrated the relationship of IVPD and exercise capacity in patients with diastolic heart failure In their study, the change in IVPD was higher in normal subjects compared with patients with heart failure Furthermore, increases in IVPD correlated with peak V˙ O2 max and were the strongest predictors of exercise capacity, which means that the ability to augment diastolic LV relaxation represented by increased IVPD with exercise has the strongest relationship with exercise intolerance

It is reasonable that a strong relationship exists between the ability to increase IVPD with exercise and V˙ O2 max max (Ronver et al 2005), because both V˙ O2 max and IVPD are highly correlated with the Tau index (Rovner et al 2005, Steine et al 1999) Therefore, if these methods are used to evaluate cardiac function in acquired or congenital heart disease, it

is possible that IVPD during exercise may be considered a strong predictor for outcomes

3.5 IVPD in Patients with Dilated Cardiomyopathy

The observation of a limited suction response to dobutamine in patients with DCM helps

to explain why LV filling pressures may rise disproportionately during stress, leading to exercise-related dyspnea in these subjects (Yotti et al 2005)