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Protein pool turnover is a critically important cellular homeostatic component, yet it has been little explored in the context of heart failure (HF) pathophysiology. We employed in vivo 2H labeling/ proteome dynamics for non-biased discovery of turnover alterations involving functionally linked cardiac and plasma proteins in canine tachypacing-induced HF, an established preclinical model of dilated cardiomyopathy. Compared to control, dogs with congestive HF displayed bidirectional turnover changes of 28 cardiac proteins, i.e. reduced half-life of several key enzymes involved in glycolysis, homocysteine metabolism and glycogenesis, and increased half-life of proteins involved in proteolysis. Changes in plasma proteins were more modest: only 5 proteins, involved in various functions including proteolysis inhibition, hemoglobin, calcium and ferric-iron binding, displayed increased or decreased turnover rates. In other dogs undergoing cardiac tachypacing, we infused for 2 weeks the myokine Follistatin-like protein 1 (FSTL1), known for its ameliorative effects on HF-induced alterations. Proteome dynamics proved very sensitive in detecting the partial or complete prevention, by FSTL1, of cardiac and plasma protein turnover alterations. In conclusion, our study unveiled, for the first time in a large mammal, numerous HF-related alterations that may serve as the basis for future mechanistic research and/or as conceptually new molecular markers.

Background: Fontan circulation is characterized by many features commonly observed in heart failure that may affect physical growth regardless of pituitary gland dysfunction status. The aims of the present study were to investigate the prevalence of short stature and growth hormone deficiency (GHD) and determine the factors associated with short stature after Fontan surgery. Methods and Results: On retrospective evaluation of 47 patients after Fontan surgery, a very high prevalence of short stature was observed (38.3%). In the short stature group, 5 patients were diagnosed with GHD (10.6% of patients after Fontan Surgery), which is much higher than the frequency of 1/10,000 in the general population. Central venous pressure (CVP) was significantly higher (14.6±4.5 vs. 12.2±1.9 mmHg, P

We tested our hypotheses that central venous pressure (CVP) shows an excessive increase in response to volume overload in Fontan circulation according to the extent of the reduction in venous capacitance (Cv), and that the maximum CVP after volume loading is associated with hepatic congestion. Changes in CVP after angiography (volume loading) were examined in 40 patients with Fontan circulation and 29 controls with biventricular circulation. CVP significantly increased with angiography in both groups, but the changes were much more evident in the Fontan group than in controls (3.3 ± 2.0 vs. 0.9 ± 1.4 mmHg, p = 0.0003). Multivariate analysis demonstrated that reduced Cv was the only significant determinant of CVP increase, independent of the amount of injected contrast medium, blood volume, pulmonary resistance, and ventricular diastolic stiffness (p

Evidence has emerged that the failing heart increases utilization of ketone bodies. We sought to determine whether this fuel shift is adaptive. Mice rendered incapable of oxidizing the ketone body 3-hydroxybutyrate (3OHB) in the heart exhibited worsened heart failure in response to fasting or a pressure overload/ischemic insult compared with WT controls. Increased delivery of 3OHB ameliorated pathologic cardiac remodeling and dysfunction in mice and in a canine pacing model of progressive heart failure. 3OHB was shown to enhance bioenergetic thermodynamics of isolated mitochondria in the context of limiting levels of fatty acids. These results indicate that the heart utilizes 3OHB as a metabolic stress defense and suggest that strategies aimed at increasing ketone delivery to the heart could prove useful in the treatment of heart failure.

Background The incidence of late liver complications such as fibrosis or cirrhosis has increased among patients who have undergone the Fontan procedure. Magnetic resonance elastography (MRE) recently emerged as a technique to clinically evaluate liver fibrosis. However, few reports have described its use in evaluating liver fibrosis in children with congenital heart disease (CHD). Methods and results Fifty-seven children were examined and divided into four groups: 27 with CHD who underwent intracardiac repair (ICR); 16 with CHD who underwent the Fontan procedure (Fontan); 14 in a control group (control); and two with cirrhosis (cirrhosis). Liver stiffness (LS) was measured using MRE. Other assessments included central venous pressure (CVP) as determined by cardiac catheterization. Circulating biomarker levels were also determined. There were no significant differences in biomarker levels among the groups. However, the LS degree was significantly higher in the Fontan group than in the control group. On stepwise multivariate analysis, only the CVP level was a statistically significant independent predictor of LS. There was also a strong correlation between LS and CVP and between LS and time interval since Fontan surgery. Conclusions This study clearly demonstrated that LS was significantly increased after the Fontan procedure and that CVP was a predictor of LS. MRE is a highly sensitive tool that can evaluate liver fibrosis in children who undergo the Fontan procedure and enable earlier detection of LS than biomarkers.

The aortic root dilation in tetralogy of Fallot (TOF) is a long-term clinical problem, because a severely dilated aorta can lead to aortic regurgitation, dissection, or rupture, which can be fatal, necessitating surgical intervention. The details of the mechanism of aortic root dilation, however, are unclear. We have shown that aortic stiffness is increased in patients with repaired TOF, and may mirror the histological abnormality of elastic fiber disruption and matrix expansion. This aortic stiffness is related closely to the aortic dilation, indicating that aortic stiffness may be a predictor of outcome of aortic dilation. Furthermore, the aortic volume overload is a very important determinant of aortic diameter in TOF patients before corrective surgery. In addition, a chromosomal abnormality and the transforming growth factor-β signaling pathway, a major contributor to aortic dilation in Marfan syndrome, also affect this mechanism. In this way, aortic dilation in TOF patients is suggested to be a multifactorial disorder. The aim of this review was therefore to clarify the mechanism of aortic dilation in TOF, focusing on recent research findings. Studies linking histopathology, mechanical properties, molecular/cellular physiology, and clinical manifestations of aortic dilation facilitate appropriate treatment intervention and improvement of long-term prognosis of TOF.

Background The mechanisms that regulate cerebral flow in patients after surgery for congenital heart diseases (CHDs) remain poorly understood. We tested our hypothesis that postoperative patients with CHD have disease- or hemodynamic-specific compensatory mechanisms for maintaining cerebral perfusion. Methods A total of 89 children with specific hemodynamics including Glenn (n = 14), Fontan (n = 19), repaired tetralogy of Fallot (n = 24), and control patients (n = 32) were enrolled. The resistance and blood flow distribution between the brain (Rc and CIc) and lower body (Rs and CIs) were calculated by measuring the hemodynamic changes resulting from inferior vena cava occlusion during cardiac catheterization. Results Despite considerable differences in cardiac index and superior vena cava pressure (SVCp), cerebral blood flow was preserved in all noncontrol groups, with a ratio between the vascular resistances in the cerebral and lower body circulation (Rc/Rs) that was significantly lower than that in controls. Interestingly, the reduced Rc/Rs of Glenn patients was mediated by the reduced Rc, whereas augmented Rs was conducive to the reduced Rc/Rs in the Fontan and tetralogy of Fallot groups. Multivariate analysis revealed that high SVCp was significantly associated with low Rc. Although low cardiac index was significantly associated with increased Rc and Rs, its impact was much greater on Rs than on Rc. Conclusions Compensatory mechanisms for cerebral flow regulation occur according to hemodynamic abnormality type in postoperative patients with CHD. Because such a regulation mechanism implies cerebral circulation fragility, further investigations are needed to address the impacts of cerebral circulation properties on neurodevelopmental outcomes.

Background FSTL1 (follistatin-like protein 1) is an emerging cardiokine/myokine that is upregulated in heart failure (HF) and is found to be cardioprotective in animal models of cardiac injury. We tested the hypothesis that circulating FSTL1 can affect cardiac function and metabolism under baseline physiological conditions and in HF. Methods and Results FSTL1 was acutely (10 minutes) or chronically (2 weeks) infused to attain clinically relevant blood levels in conscious dogs with cardiac tachypacing-induced HF. Dogs with no cardiac pacing and FSTL1 infusion served as control. 3 H-oleate and 14 C-glucose were infused to track the metabolic fate of free fatty acids and glucose. Cardiac uptake of lactate and ketone bodies and systemic respiratory quotient were also measured. HF caused a shift from prevalent cardiac and systemic fat to carbohydrate oxidation. Although acute FSTL1 administration caused minimal hemodynamic changes at baseline, in HF dogs it enhanced cardiac oxygen consumption and transiently reversed the changes in free fatty acid and glucose oxidation and systemic respiratory quotient. In HF, chronic FSTL1 infusion stably normalized cardiac free fatty acid, glucose, ketone body consumption, and systemic respiratory quotient, while moderately improving diastolic and contractile function. Consistently, FSTL1 prevented the downregulation of medium-chain acyl-CoA dehydrogenase—a representative enzyme of the free fatty acid oxidation pathway. Complementary in vitro experiments in primary cardiac and skeletal muscle myocytes showed that FSTL1 stimulated oxygen consumption through AMPK (AMP-activated kinase) activation. Conclusions These findings support a novel function for FSTL1 and provide the first direct evidence that a circulating cardiokine/myokine can alter myocardial and systemic energy substrate metabolism, in vivo.

Background It remains unclear whether systemic arterial beds other than the coronary arteries are truly healthy in patients without coronary artery lesions (CAL) after Kawasaki disease (KD). We tested the hypothesis that patients with KD without echocardiographic evidence of CAL during the acute phase of the disease have abnormal mechanical properties in systemic arteries later. Methods and results We studied 201 consecutive patients with KD (age 2–23 years, mean 10 ± 4 years; 109 male, 92 female) without CAL during the acute phase. Data were compared with those in 129 control subjects (age 2–25 years, mean 10 ± 4 years; 73 male, 56 female; control group). We examined arterial stiffness by using the brachial–ankle pulse wave velocity (baPWV) and the cardio-ankle vascular index (CAVI). The baPWV in the KD group was significantly higher than that in the control group (913 ± 121 cm/s vs. 886 ± 135 cm/s, p = 0.04). In contrast, there was no significant difference in CAVI (4.0 ± 1.0 vs. 4.2 ± 1.0, p = 0.9) between the two groups. Multivariate analysis indicated a highly significant difference in baPWV (higher baPWV in patients with KD than in controls, p = 0.004), after controlling for age, gender, body height and weight, and systolic and diastolic blood pressure, but no difference in CAVI between the groups. Conclusion Years after KD occurs in patients without apparent CAL during the acute phase, there is a small but significant change in systemic arterial properties, characterized by increased wall stiffness. The clinical importance of these findings must be clarified by performing long-term follow-up studies.

Background Production of N-terminal pro-brain natriuretic peptide (NT) and BNP is equimolar. Although NT clearance occurs only in the kidneys, BNP clearance occurs in the kidneys and other organs. This study tested the hypothesis that NT/BNP ratio in children may be independently related to cystatin C (CysC), a glomerular filtration rate marker, when diastolic function and age/body size are taken into consideration. Methods The study included 430 children (5.3 ± 4.9 years) with heart disease who had undergone cardiac catheterization and simultaneous BNP, NT, and CysC measurements. Pulmonary capillary wedge pressure (PCWP) was used as a ventricular diastolic stretch marker. Variables showing skewed distribution were transformed into a common logarithm. Results Univariate regression revealed that log NT/BNP was affected by PCWP (r = −0.12) and log CysC (r = 0.57). When age and the log of body surface area (BSA) were added to the stepwise regression, age was not adopted because of multicollinearity to log BSA, but PCWP (β = −0.10), log CysC (β = 0.22), and log BSA (β = −0.66) were independent factors of log NT/BNP. Conclusions Renal dysfunction independently increased NT/BNP, whereas high BSA decreased it and is the greatest determinant of NT/BNP. The observation that high PCWP decreased NT/BNP may suggest that worsening heart failure slows BNP clearance from other organs, a compensatory pathway of heart failure. These factors need to be considered when assessing BNP and NT.

We examined the adaptive mechanism of the pulmonary ventricle (PV) in response to increased afterload secondary to pulmonary stenosis in tetralogy of Fallot (TOF, n = 47) and congenitally corrected transposition of the great arteries (cCTGA, n = 18), where the PV is morphologically different. We also elucidated the effects of such adaptation on systemic ventricular (SV) function. PV contractility, assessed by dp/dtmax, showed significant positive correlations with PV pressure (r = 0.82, p

Abnormal water metabolism is frequently observed after Fontan surgery. We hypothesized that patients' adrenal hormones show unique responses immediately after Fontan operation and that such a hormonal profile is related to postoperative hemodynamics and water imbalance. Twenty-eight patients who underwent a Fontan operation (n = 16) or a non-Fontan type operation (n = 12; controls) under cardiopulmonary bypass were studied. Postoperative urine cortisol and aldosterone levels were measured daily to minimize the influence of circadian rhythms and temporal hemodynamic variations. Cortisol excretion was markedly elevated on postoperative day (POD) 0 in controls, consistent with a stress-induced cortisol response. Cortisol excretion was not high on POD 0 in Fontan patients and was markedly lower than that in the controls (444 ± 150 vs 34 ± 6 μg/m(2)/day, p0.05), indicating an adrenal insufficiency status. Conversely, aldosterone levels were significantly higher in Fontan patients than in controls immediately after surgery and remained so thereafter. The cortisol-to-aldosterone ratio was significantly lower in Fontan patients on POD 0 (p0.05 vs controls); low cortisol-to-aldosterone ratios were associated with a longer pleural drainage duration and intensive care unit stay. Daily cortisol and aldosterone levels were significantly associated with postoperative hemodynamics; low cortisol levels correlated with low cardiac and urine outputs, whereas high aldosterone levels correlated with low cardiac output and increased blood pressure and central venous pressure. Thus, aldosterone-to-cortisol imbalance occurred specifically after the Fontan operation. This unique hormonal profile significantly affected patients' postoperative water balance and hemodynamics. Modulation of the adrenal hormone could be useful for reducing postoperative complications after the Fontan operation.

Recent studies have shown that bilateral pulmonary artery banding (bil-PAB) for hypoplastic left heart syndrome (HLHS) is not superior to the neonatal Norwood procedure in terms of overall mortality and neurodevelopmental outcome. We tested our hypothesis that bil-PAB is associated with negative hemodynamic effects on cerebral circulation.The acute effects of bil-PAB on cerebral circulation were assessed by serial measurements of cerebral Doppler flow velocities in 9 patients immediately after bil-PAB. To evaluate the chronic effects of bil-PAB on cerebral perfusion, the oxygen demand-supply balance between the lower and upper body, designated as oxygenation balance index (OBI), was calculated in another set of 13 patients using oxymetric data before stage II palliation. Data were compared with those of 13 patients who underwent the Norwood operation.The preoperative cerebral blood flow velocities of the patients were at the lowest levels reported in healthy neonates. Bil-PAB did not increase cerebral blood flow in the first week after the procedure. OBI was significantly lower in patients treated with bil-PAB (p0.005) than in those treated with the Norwood procedure, indicating impaired cerebral perfusion after bil-PAB. Importantly, the OBI in the bil-PAB group, but not in the Norwood group, significantly decreased with time after the procedure. In addition, cerebral perfusion was more vulnerable to the changes in pulmonary and systemic blood flow in the bil-PAB group than in the Norwood group.A hybrid approach followed by comprehensive stage II palliation may not be an optimal strategy for HLHS and should be evaluated further.

Elevated central venous pressure is a major cause of morbidity and mortality after the Fontan operation. The difference between mean circulatory filling pressure and central venous pressure, a driving force of venous return, is important in determining dynamic changes in central venous pressure in response to changes in ventricular properties or loading conditions. Thus, noninvasive central venous pressure and mean circulatory filling pressure estimation may contribute to optimal management in patients undergoing the Fontan operation. We tested the hypothesis that central venous pressure and mean circulatory filling pressure in those undergoing the Fontan operation can be simply estimated using peripheral venous pressure and arm equilibrium pressure, respectively.This study included 30 patients after the Fontan operation who underwent cardiac catheterization (median 8.6, 3.4-42 years). Peripheral venous pressure was measured at the peripheral vein in the upper extremities. Mean circulatory filling pressure was calculated by the changes of arterial pressure and central venous pressure during the Valsalva maneuver. Arm equilibrium pressure was measured as equilibrated venous pressure by rapidly inflating a blood pressure cuff to 200 mm Hg.Central venous pressure and peripheral venous pressure were highly correlated (central venous pressure = 1.6 + 0.68 × peripheral venous pressure, R = 0.86, P .0001). Stepwise multivariable regression analysis showed that only peripheral venous pressure was a significant determinant of central venous pressure. Central venous pressure was accurately estimated using regression after volume loading by contrast injection (R = 0.82, P .0001). In addition, arm equilibrium pressure measurements were highly reproducible and robustly reflected invasively measured mean circulatory filling pressure (mean circulatory filling pressure = 9.1 + 0.63 × arm equilibrium pressure, R = 0.88, P .0001).Central venous pressure and mean circulatory filling pressure can be noninvasively estimated by peripheral venous pressure and arm equilibrium pressure, respectively. This should help clarify unidentified Fontan pathophysiology and the mechanisms of Fontan failure progression, thereby helping construct effective tailor-made approaches to prevent Fontan failure.

The details of the ventricular-vascular dynamics of heart failure with preserved ejection fraction (HFpEF) in children remain poorly understood. We tested the hypothesis that pediatric HFpEF patients have ventricular systolic, diastolic, and arterial stiffening at rest as well as impaired reserve function associated with coronary supply/demand imbalance.We studied the ventricular pressure-area relationship in 22 pediatric HFpEF patients and 22 control subjects before and after dobutamine infusion and during abdominal compression. Coronary supply/demand balance was assessed by subendocardial viability ratio (SEVR) calculated from the aortic pressure waveform.Compared with controls, the HFpEF patients had significantly higher end-systolic (Ees) and arterial (Ea) elastance. Increased ventricular diastolic stiffness also occurred in the HFpEF patients, resulting in modest elevation of end-diastolic pressure (EDP) at rest (13.6±4.3 vs. 7.3±2.3mmHg, P0.0001). The difference in EDP became more evident with a preload increase through abdominal compression, indicating a limited diastolic reserve in HFpEF patients (EDP changes; 11.3±6.2 for HFpEF vs. 3.4±0.6mmHg for controls, P=0.016). The HFpEF patients exhibited impaired beta-adrenergic reserve in ventricular contractility and ventricular-arterial coupling in response to dobutamine infusion. SEVR was significantly lower in the HFpEF (0.64±0.11) than in the control (0.79±0.07, P0.0001) and was significantly correlated with LV diastolic stiffness and dobutamine-induced changes in ventricular contractility.HFpEF in children involves higher ventricular-arterial stiffness at rest as well as impaired systolic and diastolic reserve, which closely correlate with impaired coronary supply/demand balance.

Chylothorax is a serious complication of congenital cardiac surgery and is significantly associated with increased morbidity and mortality. Central venous obstruction, which is often related to the insertion of central venous catheters for postoperative management, is known to be an important risk factor for treatment failure and mortality associated with this condition. We present the case of a 6-month-old girl with refractory chylothorax after surgical repair of tetralogy of Fallot. The chylous drainage continued for more than 2 months despite maximal conservative therapy (water restriction, total parenteral nutrition, and infusion of somatostatin and steroid) and surgical ligation of the thoracic duct. Subsequently, we observed stenosis of the superior vena cava (SVC) caused by large thrombi possibly associated with the prolonged use of central venous catheter placed in the internal jugular vein. Because transcatheter balloon dilation failed to relieve the stenosis, we performed stent implantation for the SVC and innominate vein. After the procedure, chylous drainage dramatically reduced, and the patient was discharged from the hospital. In conclusion, central venous obstruction due to thrombosis should be routinely examined when chylothorax is diagnosed and is resistant to conservative therapy after congenital heart surgery. Stent implantation can effectively relieve the venous obstruction and thus be a life-saving treatment option for this difficult condition.

Background: Conventional parameters of circulation that are routinely used in neonatal intensive care units, including blood pressure, have been reported to be inadequate in improving prognosis of very-low-birth-weight (VLBW) infants. Recently, the importance of evaluating the blood flow to each organ, including both vital and nonvital organs, has been increasingly recognized. Objectives: To study the changes in peripheral perfusion occurring in VLBW infants of less than 32 weeks’ gestation during the extrauterine transitional period. Methods: In 32 VLBW infants of less than 32 weeks’ gestation, forehead blood flow (FBF) and lower-limb blood flow (LBF) were measured for 48 h after birth using a novel laser Doppler flowmeter, and the indices of vascular resistance were estimated. Superior vena cava (SVC) blood flow was measured by echocardiography. Changes in these variables of circulation as well as the correlations were evaluated. Results: Both FBF and LBF significantly increased at 24 h, while the SVC flow remained unchanged over the same period. Both forehead and lower-limb vascular resistance indices significantly decreased at 24 h. LBF was negatively and positively correlated with estimated upper body vascular resistance and SVC flow, respectively. Conclusions: The increase in the peripheral blood flow along with the decrease in the peripheral vascular resistance indices, without an increase in the systemic blood flow at 24 h of age, indicated vasodilation in skin and subcutaneous tissue during the transitional period in VLBW infants. FBF and LBF can be useful parameters as indicators of both peripheral and systemic circulation.

The objective of this study was to determine the effects of the level of inhaled oxygen during resuscitation on the levels of free radicals and anti-oxidative capacity in the heparinized venous blood of preterm infants. Forty four preterm infants35 weeks of gestation with mild to moderate neonatal asphyxia were randomized into two groups. The first group of infants were resuscitated with 100% oxygen (100% O(2) group), while in the other group (reduced O(2) group), the oxygen concentration was titrated according to pulse oximeter readings. We measured total hydroperoxide (TH) and redox potential (RP) in the plasma within 60 min of birth. The integrated excessive oxygen ( summation operator(FiO(2)-0.21) x Time(min)) was higher in the 100% O(2) group than in the reduced O(2) group (p0.0001). TH was higher in the 100% O(2) group than in the reduced O(2) group (p0.0001). RP was not different between the 100% O(2) and reduced O(2) groups (p = 0.399). RP/TH ratio was lower in the 100% O(2) group than in the reduced O(2) group (p0.01). We conclude that in the resuscitation of preterm infants with mild to moderate asphyxia, oxidative stress can be reduced by lowering the inspired oxygen concentration using a pulse oximeter.

Background The myocardial performance index (MPI) has emerged as a Doppler-derived index for global ventricular function capable of estimating combined systolic and diastolic performance. While several studies have reported its load-dependency, responses of the MPI to various hemodynamic changes have not been fully characterized. Methods and results The response characteristics of the MPI were examined and compared with ejection fractions (EF) by changing hemodynamic parameters within the physiological range in a lumped parameter model of the cardiovascular system. At baseline, the MPI was 0.42 and the EF was 0.68. Heart rate increase resulted in a decrease in EF and an increase in the MPI. Reduction in end-systolic elastance decreased EF and increased the MPI. Volume overload and ventricular stiffening did not affect EF but paradoxically reduced the MPI. Increased afterload due to higher systemic resistance resulted in a decrease in EF and increase in the MPI, but afterload increase caused by reduced arterial compliance led to a decrease in both EF and MPI. These MPI characteristics caused paradoxical improvement of the MPI during disease progression of chronic heart failure in a simulation of mitral regurgitation. Conclusions The MPI is affected by a wider variety of hemodynamic parameters than EF. In addition, it is predicted to decrease paradoxically with volume overload, reduction in arterial compliance, or ventricular diastolic stiffening. These MPI characteristics should be considered when assessing cardiovascular dynamics using this index.

Introduction: Fontan patients with right ventricular morphology (RV-F) are associated with worse outcome and exercise capacity compared with those with left ventricular morphology (LV-F). Diminished cardiac reserve is one of major mechanisms of impaired exercise capacity in heart failure patients. However, it remains unclear whether and how rest and reserve functions differ between RV-F and LV-F. Hypothesis: We assessed the hypothesis that rest and reserve functions in RV-F may be worse than those in LV-F. Methods: This study included 28 RV-F and 17 LV-F (6.0 vs 6.2 years. p=N.S.). Ventricular pressure-area relationships were determined during cardiac catheterization, both before and after β-adrenergic stimulation with dobutamine (5 microg/kg/min) and increased heart rates by atrial pacing. Results: There were no significant differences in heart rate, central venous pressure, and pulmonary vascular resistance between RV-F and LV-F. End-systolic pressure in RV-F was lower than that in LV-F (89 vs 97mmHg), while end-systolic and end-diastolic volume in RV-F were larger than those in LV-F. Consistently, contractile function in RV-F was worse than that in LV-F (20.1±10.5 vs 30.8±19.7 mmHg/cm2 хm2 in Ees index; and 978±237 vs 1186±297 mmHg/s in dp/dt max). The worse contractile function in RV-F was persisted after dobutamine (24.9 vs 45.1 mmHg/cm2 хm2 in Ees index; and 1721 vs 2241 mmHg/s in dp/dt max). Furthermore, the response of Ees index to faster heart rate in RV-F was blunted, which was in striking contrast to positive chronotropic response in LV-F (Figure). Conclusions: Compared with LV-F, RV-F has worse systolic function at rest and markedly attenuated chronotropic reserve in systolic function, which can be responsible for worse outcome in RV-F. Given the lack of definitive therapy for Fontan failure, development of medical therapy to improve rest and reserve function should be pursued for better prognosis in Fontan patients.

Background: It is well recognized that oxidative stress is responsible for fat accumulation and tissue inflammation, and causes endothelial cell damage that leads to the initiation of atherosclerosis. We and others have previously reported that vascular stiffness is increased with impaired vascular endothelial function in patients after Fontan operation. We hypothesized that increased oxidative stress is associated with vascular endothelial dysfunction and arterial stiffening in patients with Fontan circulation Methods: Relationship of oxidative stress with endothelial function and arterial stiffness was examined in 16 Fontan patients. Endothelial function and arterial stiffness of forearm artery was measured by flow mediated dilatation. We also measured central arterial stiffness by calculating aortic pulse wave velocity (PWV) during catheter drawback from the ascending aorta to the iliac bifurcation at the time of cardiac catheterization. Oxidative stress was estimated by measuring serum levels of oxidized low-density lipoprotein (LDL) and superoxide dismutase (SOD) activity in the urine as an anti-oxidant. Results: PWV of the ascending aorta but not of the descending aorta was significantly and positively correlated with oxidized LDL level (P Conclusion: Increased oxidative stress is associated with vascular endothelial dysfunction and central and peripheral arterial stiffening in patients with Fontan circulation. Antioxidant therapy may improve vascular health and thereby patient’s outcome after Fontan operation.

Background: High central venous pressure (CVP) is a key driver of developing late complications in patients after Fontan operation. However, we often realize diversity of clinical outcome among patients with similar levels of CVP measured at resting condition during catheterization. We hypothesized that CVP variably increases with exercise and that degree of the increase is associated with clinical outcomes. We also hypothesized that venous capacitance (VC) is an important determinant of the CVP elevation. Methods: Dynamic changes in CVP estimated from continuous monitoring of peripheral venous pressure were measured during treadmill exercise (TM) in 21 Fontan patients and 10 age-matched control patients with biventricular (BV) circulation. The VC was calculated during temporal occlusion of inferior vena cava (IVC) at the time of catheterization. Results: Fontan patients exhibited significantly shorter duration of exercise with limited increases in heart rate and cardiac output. CVP significantly increased during exercise in both groups, but the degree of CVP elevation was much higher in Fontan patients than in controls (Fontan: from 10.8 to 18.4 mmHg vs. control: from 4.3 to 8.8 mmHg, P Conclusions: CVP of the Fontan circulation easily rises during exercise in proportion to the reduced VC, and the degree of CVP rise may be a contributor of hepatic complication. These results suggest the importance of assessing dynamic CVP in patients after Fontan operation. The results also suggest potential importance of daily life modification and/or medical treatment to minimize the dynamic changes in CVP to improve the prognosis of Fontan patients. VC may be a viable target for this purpose.

The aortic root dilation in tetralogy of Fallot (TOF) is a long-term clinical problem, because a severely dilated aorta can lead to aortic regurgitation, dissection, or rupture, which can be fatal, necessitating surgical intervention. The details of the mechanism of aortic root dilation, however, are unclear. We have shown that aortic stiffness is increased in patients with repaired TOF, and may mirror the histological abnormality of elastic fiber disruption and matrix expansion. This aortic stiffness is related closely to the aortic dilation, indicating that aortic stiffness may be a predictor of outcome of aortic dilation. Furthermore, the aortic volume overload is a very important determinant of aortic diameter in TOF patients before corrective surgery. In addition, a chromosomal abnormality and the transforming growth factor-β signaling pathway, a major contributor to aortic dilation in Marfan syndrome, also affect this mechanism. In this way, aortic dilation in TOF patients is suggested to be a multifactorial disorder. The aim of this review was therefore to clarify the mechanism of aortic dilation in TOF, focusing on recent research findings. Studies linking histopathology, mechanical properties, molecular/cellular physiology, and clinical manifestations of aortic dilation facilitate appropriate treatment intervention and improvement of long-term prognosis of TOF.

We hypothesized that the myocardial oxygen supply-demand balance is impaired in patients after a Norwood procedure and that an abnormal oxygen supply-demand balance is associated with pronounced activation of the renin-angiotensin-aldosterone system and worse clinical outcome after this procedure.To investigate the myocardial oxygen supply-demand balance, the subendocardial viability ratio (SEVR) was measured in 29 hypoplastic left heart syndrome patients after the Norwood procedure, in 27 patients with pulmonary atresia whose pulmonary blood flow was supplied from the aortopulmonary (AP) shunt, and in 30 control patients who were considered to have normal biventricular circulation. The SEVR in Norwood (0.57 ± 0.18) and AP shunt (0.66 ± 0.10) patients was significantly reduced compared with that in controls (0.94 ± 0.25, p0.001 vs Norwood and AP shunt).After controlling for heart rate, the SEVR was significantly lower in Norwood than in AP shunt patients (p0.001). Importantly, the SEVR was significantly lower in Norwood patients with poor clinical outcomes (cardiac arrest before second-stage operation, progressive tricuspid regurgitation, or reduction of ejection fraction0.35) than in the remaining Norwood patients (0.51 ± 0.12 vs 0.69 ± 0.22, p0.01). An SEVR of less than 0.52 had a more than 76% probability of having a poor outcome (p0.05). Furthermore, a lower SEVR was significantly correlated with more pronounced renin-angiotensin-aldosterone system activation and elevated natriuretic peptides in serum. Multiple regression analysis revealed that increased aortic stiffness and a smaller neoaorta relative to the native descending aorta were independent determinants of reduced SEVR.Myocardial oxygen supply-demand imbalance is intrinsic to Norwood circulation but may be improved by technical refinement of aortic reconstruction or afterload-reducing medication with renin-angiotensin-aldosterone system blockade.

switch procedure. Pulmonary artery banding is not a benign procedure, and mechanical support after surgery can be unpredictable, with the potential for significant bleeding issues as a result of anticoagulation. In this particular case, the presence of a restrictive muscular VSD provided the opportunity to stent the VSD open to allow preparation of the left ventricle. Stenting the VSD obviated the need for initial palliative surgery and allowed easy monitoring of the progress of the left ventricle. One caveat with this technique is that not all VSDs are amenable to stenting, because the risk of inducing heart block is high in the more commonly seen perimembranous type of VSD. In this reported case, the VSD was muscular, however, which made the risk of heart block low. The use of interventional cardiology procedures for initial palliation is a relatively new and promising alternative. Some groups have explored stenting of the right

Accumulating data in adults indicate the prognostic importance of worsening renal function (WRF) during treatment of acute heart failure. Venous congestion appears to play a dominant role in WRF; however, data regarding WRF in children with congenital heart disease (CHD) are limited. The present study was conducted to elucidate the prevalence and characteristics of WRF after surgery for CHD in children. We also tested our hypothesis that, similar to adult heart failure, venous congestion is an important determinant of WRF independent of cardiac output in this population. Fifty-five consecutive pediatric patients who underwent cardiovascular surgery for CHD were studied (median age 0.7 years; range 3 days to 17 years). The degree of WRF was assessed by the difference between the maximum levels of postoperative serum creatinine (Cr) and preoperative serum Cr. There was a high prevalence of WRF in the present cohort: an increase in Cr level was observed in 47 patients (85 %) and a Cr increase ≥0.3 mg/dL was seen in 23 (42 %). Importantly, WRF was significantly associated with a worse clinical outcome of a longer stay in the intensive care unit and hospital (both p

High-flow nasal cannula (HFNC) therapy supports respiratory effort with a minimal elevation in airway pressure. We examined hemodynamic effects of HFNC therapy in a 10-year-old girl with Fontan circulation, in which positive airway pressure has deleterious hemodynamic effects. The HFNC therapy at 30 L/min improved oxygenation without an increase in central venous pressure. It also reduced heart rate, and systemic and pulmonary vascular resistance, and increased cardiac output. In addition, the HFNC therapy improved the cerebral circulation measured by near-infrared spectroscopy. Thus, HFNC therapy may be a potentially useful noninvasive ventilation modality, particularly for patients with Fontan circulation.

Background: In adult heart failure, higher heart rates (HR) are known to be associated with increased risks of myocardial infarction and sudden cardiac death. Thus, HR modulation has been increasingly recognized as a potentially effective therapy for heart failure. HR may also be a useful therapeutic target in patients after the Fontan surgery, in which effective treatment to improve prognosis remains to be established. We hypothesized that lower HR is associated with better mid-term outcomes in Fontan patients. Methods: We retrospectively analyzed 24-hour Holter ECG in 56 consecutive patients in the chronic phase (at least 1 year) after the Fontan operation and in the sinus rhythm (mean age; 19 years, range; 9-49 years). Data for minimum, maximum, and average HR were extracted. We then examined the relationships between HR values and mid-term hemodynamic and clinical (6-min walk-distance) outcomes. Mid-term outcomes were assessed both at 1-3 years (mean 1.5 years) after the initial Holter recording (Group 1) and at more than 3 years (mean 4.9 years) after the initial Holter recording (Group 2). Results: Lower values of mean and minimum HR were significantly correlated with lower CVP in both groups (P Conclusions: The present study demonstrated for the first time that lower HR can lead to better mid-term outcomes of hemodynamics and exercise capacity in Fontan patients. HR can be an important therapeutic target to improve the prognosis after the Fontan operation.

Background: Neurodevelopmental delay and cerebral atrophy coupled with reduced blood flow are reportedly closely linked in patients with congenital heart diseases (CHD). However, the mechanisms to regulate cerebral flow in the same are unclear. Cardiac output and underlying cerebral arterial resistance that is constructed during infancy may affect blood perfusion. We tested our hypothesis that cerebral blood flow in patients with repaired CHD is affected by the original features of CHD. Method: Ninety children including 50 patients with biventricular repaired CHD (ToF 27, TGA 15, CoA+VSD 8), 15 with a single ventricle (SV: Glenn7/Fontan8) and 25 with negligible shunts and otherwise normal stracture heart were enrolled. During cardiac catheterization, cardiac index (CI), blood pressure, central venous pressure were measured before and after inferior vena cava occlusion. Assuming that cerebral resistance (Rc) and lower body resistance (Ri) are constant during IVC occlusion, the resistance and blood distribution to the brain and lower body were calculated as a parallel resistance circuit. The impacts of hemodynamics on the cerebral circulation were analyzed. Result: The cerebral portion of cardiac index (CIc) was negatively correlated with age (CIc=1.88-0.06*Age, p Conclusion: Apart from the strong governance of cerebral blood flow by cardiac output, cardiovascular property before anatomical repair and cavo-pulmonary connections have a significant impact on the cerebral circulation. Long-term effects of abnormal cerebral circulation warrants further studies.

Introduction: Left ventricular–arterial coupling (LVAC), the ratio of end–systolic to effective arterial elastance (Ees/Ea), determines end–systolic pressure and stroke volume in a given preload. LV diastolic chamber stiffness (LV–K) is an important diastolic property to affect LV filling. However, the relationship between Ees/Ea and LV–K in children remains unestablished. Aldosterone (ALD) accelerates LV and arterial stiffening. Hypothesis: This study was undertaken to test the hypothesis that Ees/Ea may affect LV–K through ALD regulation in children. Methods: During catheterizations for children with biventricular circulation (N=75, median 2.5 years), blood samples for ALD were collected, and LV pressure and area relationships (PAR) were recorded using high-fidelity pressure–guidewire and echocardiographic AQ method during steady state and transient IVC occlusion. LV–K was obtained by dividing the pressure difference between LV minimal and end-diastolic pressure (EDP) by stroke volume. ALD levels were transformed into common logarithm. Results: Ees/Ea biphasically correlated to LV–K, which was approximated by downward convex parabola with a minimum at 0.9 of Ees/Ea (R=0.61, P Conclusions: To our knowledge, this is the first study to demonstrate that Ees/Ea bipahsically correlated to LV–K and ALD. Dilated LV with low Ees/Ea accompanies elevated filling pressure and shows restrictive physiology with higher LV–K. On the other hand, when Ees/Ea is higher than normal range, this study indicates that there should be an increased LV diastolic stiffness which is not always associated with wall hypertrophy. Because LVAC abnormality may induce LV stiffening associated with ALD activation, chronic inhibition therapy of renin–angiotensin system to keep Ees/Ea within appropriate range may inhibit LV stiffening directly and through LVAC & LV–K interaction.

Congenital brain tumors (CBTs), defined as tumors presenting within 60 days after birth, are extremely rare and account for only 0.5–1.9% of all pediatric brain tumors. Teratoma is the most common type of CBT, although there are many other poorly described forms. Prenatal diagnosis of CBT is often difficult and usually based on clinical characteristics and radiological findings with magnetic resonance imaging and ultrasonography. The prognosis of patients with CBT depends on the histopathological features of the tumor and its location. Even after several investigations have been performed, a clear direction for diagnosis and treatment of fetal intracranial tumors is still lacking. Further studies are thus needed to clarify its clinical characteristics and establish recommendations for management.

BACKGROUND This study tested the hypothesis that aortic stiffness is increased more in patients with single ventricular (SiV) circulation and dilated aorta than in those without aortic dilatation, and that aortic stiffness is an independent determinant of aortic dilatation in this type of patient. METHODS AND RESULTS Pulse wave velocity (PWV) and aortic size were measured during catheterization in 56 consecutive patients with SiV circulation (aortic dilatation, n=31 [observed/expected aortic root diameter >1.5]; without aortic dilatation, n=25). PWV was found to be significantly higher in the dilatation group than in the non-dilatation group (483.6±10.3 vs. 394.0±8.9 cm/s, P

The physiological limitations of the Fontan circulation have been extensively addressed in the literature. Many studies emphasized the importance of pulmonary vascular resistance in determining cardiac output (CO) but gave little attention to other cardiovascular properties that may play considerable roles as well. The present study was aimed to systemically investigate the effects of various cardiovascular properties on clinically relevant hemodynamic variables (e.g., CO and central venous pressure). To this aim, a computational modeling method was employed. The constructed models provided a useful tool for quantifying the hemodynamic effects of any cardiovascular property of interest by varying the corresponding model parameters in model-based simulations. Herein, the Fontan circulation was studied compared with a normal biventricular circulation so as to highlight the unique characteristics of the Fontan circulation. Based on a series of numerical experiments, it was found that 1) pulmonary vascular resistance, ventricular diastolic function, and systemic vascular compliance play a major role, while heart rate, ventricular contractility, and systemic vascular resistance play a secondary role in the regulation of CO in the Fontan circulation; 2) CO is nonlinearly related to any single cardiovascular property, with their relationship being simultaneously influenced by other cardiovascular properties; and 3) the stability of central venous pressure is significantly reduced in the Fontan circulation. The findings suggest that the hemodynamic performance of the Fontan circulation is codetermined by various cardiovascular properties and hence a full understanding of patient-specific cardiovascular conditions is necessary to optimize the treatment of Fontan patients.

Serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic factor, and its binding protein, placental growth factor (PlGF), are altered in women with preeclampsia. Recently, the sFlt-1/PlGF ratio has been shown to predict acute coronary syndrome in adults. However, few reports have described the use of the sFlt-1/PlGF ratio for evaluating an abnormal hemodynamic load in children with congenital heart disease (CHD). The sFlt-1/PlGF ratio was determined in 20 children with atrial septal defects (ASD), 26 children with ventricular septal defects (VSD), 57 children with tetralogy of Fallot (ToF), 35 children who were Fontan candidates (Fontan), and 14 controls. The preoperative sFlt-1/PlGF ratios in the ASD, VSD, and Fontan were significantly higher than those in the controls and were significantly decreased after surgical repair in the ASD and VSD. In the ToF, the sFlt-1/PlGF ratio was highest after first-stage repair and second-highest after final-stage palliation compared with the preoperative levels. The sFlt-1/PlGF ratio was highest after first-stage repair and much lower after final-stage palliation in the Fontan. Furthermore, these ratios correlated with the degree of the ventricular volume overload and hypoxia. Our study clearly demonstrated that the sFlt-1/PlGF ratio increases with volume overload and persistent hypoxia after surgery with CHD. These findings may prove useful in the management of CHD in children.

Most congenital heart diseases (CHDs) have specific hemodynamics, including volume and pressure overload, as well as cyanosis and pulmonary hypertension, associated with anatomical abnormalities. Such hemodynamic abnormalities can cause activation of neurohormones, inflammatory cytokines, fibroblasts, and vascular endothelial cells, which in turn contribute to the development of pathologic conditions such as cardiac hypertrophy, fibrosis, and cardiac cell damages and death. Measuring biomarker levels facilitates the prediction of these pathological changes, and provides information about the stress placed on the myocardial cells, the severity of the damage, the responses of neurohumoral factors, and the remodeling of the ventricle. Compared to the ample information on cardiac biomarkers in adult heart diseases, data from children with CHD are still limited. We reviewed cardiac biomarkers-specifically focusing on troponin as a biomarker of myocardial damage, amino-terminal procollagen type III peptide (PIIIP) as a biomarker of myocardial fibrosis and stromal remodeling, and B-type natriuretic peptide (BNP)/N-terminal proBNP as biomarkers of cardiac load and heart failure, by introducing relevant publications, including our own, on pediatric CHD patients as well as adults. Levels of highly sensitive troponin I are elevated in patients with atrial septal defects (ASDs) and ventricular septal defects (VSDs). PIIIP levels are also elevated in patients with ASD, VSD, pulmonary stenosis, and Tetralogy of Fallot. Measurement of BNP and N-terminal proBNP levels shows good correlation with heart failure score in children. In the treatment of children with CHD requiring delicate care, it is vital to know the specific degree of myocardial damage and severity of heart failure. Cardiac biomarkers are useful tools for ascertaining the condition of CHDs with ease and are likely to be useful in determining the appropriate care of pediatric cardiology patients.

We encountered a neonate with necrotizing enterocolitis (NEC) caused by Klebsiella pneumoniae. Clinical symptoms and inflammation did not improve despite intravenous administration of antibiotics. Bifidobacterium breve enemas were performed. After beginning enema, clinical symptoms and inflammation improved within 24 hours. Probiotic enema has high potential as a new therapy for NEC.

Information about the cerebral circulation in the Fontan physiology is scarce. We tested our hypothesis that cerebral perfusion is impaired in the Fontan circulation by analyzing wavefront behavior (wave intensity) and assessing arterial stiffness at the carotid artery.The carotid arterial wave intensity and stiffness were computed in 34 consecutive Fontan patients (11.5±8.6 years) and 20 control subjects (13.4±6.0 years) using an echocardiographic vascular tracking system, which enabled simultaneous measurements of instantaneous carotid arterial pressure and flow velocity.The carotid arterial blood flow was significantly lower in the Fontan patients than in the controls (p0.05). Wave intensity analysis demonstrated a significant decrease in the compression and acceleration wave, an important forward traveling wave for cerebral circulation, in the Fontan patients compared with the control subjects (31.0±2.6 versus 48.1±4.4 mm Hg⋅m⋅s3⋅10(3); p=0.001). In addition, the negative wave intensity normalized to the first positive wave, representing a wave reflection from peripheral cerebral vessels, was significantly increased in the Fontan patients compared with that in control subjects. Carotid arterial stiffness and central venous pressure were also significantly increased in the Fontan patients and were independent determinants of the decreased first positive wave, suggesting the pathophysiologic importance of carotid arterial stiffness and central venous pressure as inflow and outflow resistance to the cerebral circulation, respectively, in the Fontan physiology.These results suggest impaired cerebral perfusion caused by vascular stiffening and high central venous pressure in patients with Fontan circulation. Longitudinal studies examining the association between cerebral circulation and neurodevelopmental outcome after Fontan operation are warranted.

This study was undertaken to test the hypothesis that noninvasive echocardiographic indexes obtained using early diastolic mitral annular and inflow velocities reflect diastolic function in children. We included in this study 61 consecutive pediatric patients (age 0.4–13 years) who underwent cardiac catheterization for various heart diseases with biventricular circulation. Left ventricular (LV) pressure was measured using a high-fidelity manometer to obtain the time constant of relaxation (τ) and LV chamber stiffness (K). Echocardiography was simultaneously performed during catheterization. Data acquisition was repeated after the administration of dobutamine. The peak early mitral annular velocity (e′) and τ showed a significant inverse correlation (r = −0.42). Receiver-operating characteristic (ROC) analysis to determine the 90th percentile of τ yielded an area under the curve (AUC) of 0.86 for a septal e′6.2 cm/s, with sensitivity and specificity of 0.83. The dobutamine-induced changes in e′ closely correlated with those in τ (r = −0.69). The deceleration time (DT) showed a significant but weak negative correlation with K (r = −0.35), and ROC analysis to determine the 90th percentile of Κ yielded an AUC of 0.82 for a DT100 ms, with sensitivity of 0.80 and specificity of 0.77. The ratio of peak early mitral inflow velocity (E) to e′ (E/e′) significantly correlated with LV end-diastolic pressure (EDP; r = 0.48, P0.0005), and ROC analysis to determine the 90th percentile of EDP (12.96 mmHg) yielded an AUC of 0.81 for an E/e′16.4, with sensitivity of 0.71 and specificity of 0.93. The e′, DT, and E/e′ values in our study reflect the diastolic function in our pediatric population. However, the weak correlations between these indexes and invasive measures of diastolic function suggest that these indexes are useful in detecting diastolic dysfunction but not in determining the absolute values of diastolic dysfunction. Therefore, a future study is warranted to develop an efficient algorithm for systematic noninvasive evaluation of LV diastolic function in children.

Background: There is no information on heart failure (HF) with preserved ejection fraction (HFpEF, EF >50%) in children. Methods and Results: Through a retrospective review of 3,907 pediatric patients with cardiovascular disease, we examined the characteristics of pediatric HFpEF over a 10-year period. We identified 18 patients with HFpEF (0.5%). They were predominantly young children (1.1±0.9 years, no sex preponderance), who had undergone surgery for congenital heart disease. They also had concentric hypertrophy and diastolic dysfunction with elevated blood pressure. Notably, HFpEF patients had more pronounced elevation of serum aldosterone but less pronounced elevation of plasma brain natriuretic peptide (BNP) than 22 systolic HF patients (SHF, EF ≤50%) (aldosterone: 1,375±1,200 vs. 511±563pg/ml, P

Progressive aortic dilation occurs in patients with tetralogy of Fallot (TOF), possibly due to abnormal histopathology of the aortic media that weakens the aortic wall. This medial histopathology may be reflected as aortic stiffness, which in turn may predict progressive aortic dilation. To test this theory, we studied the relationship between aortic wall stiffness, measured by pulse wave velocity (PWV), and subsequent aortic dilation in 32 consecutive patients with repaired TOF. The ascending aortic diameter (AOD) was obtained by two-dimensional transthoracic echocardiography performed at baseline and at the follow-up examination, 7.6 ± 2.0 years after baseline. TOF patients exhibited significantly greater AODs than normal reference values, at baseline (19.8 ± 5.0 vs 14.3 ± 3.1 mm; P = 0.0001) and at the follow-up examination (25.9 ± 3.8 vs 18.1 ± 2.4 mm; P = 0.0001). The observed change in AOD during the follow-up period (0.83 ± 0.43 mm/year) was significantly larger than the change that would be expected by the patient’s growth (0.50 ± 0.25 mm/year; P = 0.0001). The PWV at baseline correlated positively with both AOD at follow-up (P = 0.0018) and the annual rate of aortic dilation (P = 0.0007). On multivariate regression analysis, PWV remained a significant and independent predictor of subsequent aortic dilation. These results suggest a causative role for aortic stiffening in the progressive aortic dilation noted in TOF, indicating that incorporating aortic stiffness as well as aortic diameter in the assessment of TOF aortopathy may help better define the need for, and the timing of, medical intervention.

OBJECTIVE: The present study tested the hypothesis that there is an intrinsic abnormality of aortic elasticity in infants/children with tetralogy of Fallot (TOF) before corrective surgery. The study also determined the independent and quantitative effects of aortic volume load on aortic dilation in this group of TOF patients. METHODS: Aortic stiffness (pulse wave velocity; PWV) and aortic volume load (aortic volume flow) were measured during catheterization in 37 infants and children with TOF before corrective surgery and in 55 control subjects. RESULTS: PWV was significantly higher in TOF patients than in controls, irrespective of age, sex, hemodynamic burden on the aortic wall, and existence of aorto-pulmonary shunt. Aortic diameter was also significantly greater in TOF patients than in controls. Multivariate regression analysis identified aortic volume load as an independent determinant of aortic dilation (aortic diameter = 0.72 × aortic flow + 26.1 × body surface area + 2.79, r 2 = 0.58, p< 0.001). Increased aortic-wall stiffness correlated with the increase in aortic diameter in patients with dominant left-to-right shunt (without aortic volume load); aortic diameter = 0.007 × PWV + 13.5 × body surface area (BSA) + 6.3 (r 2 = 0.73, p< 0.05). CONCLUSIONS: The present study highlighted the intrinsic abnormality of the mechanical property of the aortic wall as a feature of aortopathy in TOF. The study also indicated that aortic volume overload and, to a lesser extent, intrinsically high aortic stiffness correlated significantly with aortic dilation in TOF.