Successful Pacemaker Setting Using Treadmill Exercise Test in a Child with Fontan Circulation.

The usefulness of a treadmill exercise test for determining optimal pacemaker settings remains unknown. An 8-year-old boy with Fontan circulation and a dual-chamber pacemaker for a rate-dependent advanced atrioventricular block suffered from dullness and poor school attendance. Although the pacemaker log showed an atrial tachycardia/fibrillation episode, treadmill exercise testing revealed sinus tachycardia, which converted to a 2:1 atrioventricular block. The pacemaker setting was optimized, with improvement in the patient's condition.Treadmill exercise testing helps optimize dual-chamber pacemaker settings in children with complex congenital heart disease involved in energy-consuming physical activities and having a wide working range in sinus rate.

Efficacy of a Subcutaneous Implantable Cardioverter Defibrillator in a Child with Early Repolarization Syndrome.

An early repolarization (ER) pattern or J waves are considered to be a benign finding observed in the healthy population, however, it has been pointed out that the ER pattern seen in the inferolateral leads could be an independent risk factor for fatal arrhythmias. We present a pediatric case in which early repolarization syndrome (ERS) was suspected due to the presence of ER or J waves in the inferior leads, which eventually disappeared after the administration of pilsicainide. During the follow-up period, several fatal ventricular arrhythmias were recorded after implantation of a subcutaneous implantable cardiac defibrillator (S-ICD). This report describes the efficacy of S-ICDs in a child with an ER pattern after aborted sudden cardiac death.

Steroid-Refractory Protein-Losing Enteropathy with Gastrointestinal Bleeding in a Patient with Fontan Circulation.

Protein-losing enteropathy (PLE) is one of the major complications after a Fontan operation. Some PLE patients suffer from concurrent gastrointestinal bleeding. An effective treatment regimen for such patients has not been established yet. Further, it remains unknown whether PLE and gastrointestinal bleeding coexist independently, or protein losing is associated with gastrointestinal bleeding. We report a 7-year-old steroid-refractory post-Fontan PLE case suggesting the latter pathogenesis together with a literature review.

Blood reservoir function in patients with Fontan circulation and asplenia syndrome.

Splanchnic circulation constitutes a major portion of the vasculature capacitance and plays an important role in maintaining blood perfusion. Because patients with asplenia syndrome lack this vascular bed as a blood reservoir, they may have a unique blood volume and distribution, which may be related to their vulnerability to the haemodynamic changes often observed in clinical practice. During cardiac catheterisation, the mean circulatory filling pressure was calculated with the Valsalva manoeuvre in 19 patients with Fontan circulation, including 5 patients with asplenia syndrome. We also measured the cardiac output index and circulatory blood volume by using a dye dilution technique. The blood volume and the mean circulatory filling pressure and the venous capacitance in patients with asplenia syndrome were similar to those in the remaining patients with Fontan circulation (85 ± 14 versus 77 ± 18 ml/kg, p = 0.43, 31 ± 8 versus 27 ± 5 mmHg, p = 0.19, 2.8 ± 0.6 versus 2.9 ± 0.9 ml/kg/mmHg, p = 0.86). Unexpectedly, our data indicated that patients with asplenia syndrome, who lack splanchnic capacitance circulation, have blood volume and venous capacitance comparable to those in patients with splanchnic circulation. These data suggest that (1) there is a blood reservoir other than the spleen even in patients with asplenia; (2) considering the large blood pool of the spleen, the presence of a symmetrical liver may represent the possible organ functioning as a blood reservoir in asplenia syndrome; and (3) if this is indeed the case, there may be a higher risk of hepatic congestion in patients with Fontan circulation with asplenia syndrome than in those without.

Improvement in Dyssynchrony with Pharmacological Ablation of Right-Sided Accessory Pathway-Induced Cardiomyopathy in Infants.

Right-sided accessary pathways in patients with Wolff-Parkinson-White (WPW) syndrome may cause cardiac dyssynchrony and dilated cardiomyopathy, with a characteristic septal shape, irrespective of any supraventricular tachycardia episodes. We report on two infants (13 and 5 months), whose right-sided accessary pathway-induced dilated cardiomyopathy was successfully treated by flecainide for the first time. After the flecainide administration, an abnormal aneurysmal dilation of the basal interventricular septum was almost restored to normal, and the decreased ejection fraction recovered. Flecainide use may be an important therapeutic option for this entity to avoid catheter ablation during infancy.

Case of Incomplete Kawasaki Disease with No Symptoms Except Fever Causing the Development of Coronary Aneurysm.

Incomplete Kawasaki disease (iKD), which does not satisfy the standard KD diagnostic criteria because the required number of principal symptoms is not met, sometimes causes coronary aneurysms. Here we report the case of a patient with iKD who presented with only one principal symptom that resulted in the development of coronary aneurysm, as evidenced by angiography.

Importance of dynamic central venous pressure in Fontan circulation.

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 < 0.05). Importantly, the use of a venodilator was associated with increased Cv and the resultant suppression of CVP elevation with volume load. In addition, CVP levels both at baseline (p = 0.02) and after volume loading (p = 0.01) were weakly but significantly correlated with the plasma levels of γ-glutamyl transpeptidase, a marker of hepatic congestion; however, multivariate analysis revealed that the CVP level after volume loading was a more important determinant of hepatic congestion. The results of this study highlight the importance of assessing dynamic in addition to static CVP for a better understanding of Fontan circulation. The potential importance of Cv as a therapeutic target for improving Fontan physiology needs further elucidation.

First Pediatric Case of Infective Endocarditis Caused by Serratia Liquefaciens.

Infective endocarditis (IE) caused by Serratia liquefaciens has been reported in only 2 adults. We experienced the first pediatric (neonatal) case of IE caused by S. liquefaciens, with mitral valve vegetation 4 days after a palliative heart surgery. This report underscores the importance of treating for both gram-positive and gram-negative bacteria in IE cases until the blood cultures elucidate the details.

A 1-year-old boy with long pauses caused by paroxysmal atrioventricular block and sinus arrest: Vagal reflex and effect of pacing.

Paroxysmal atrioventricular block (PAVB) is rare in children. A 1-year-old boy presented with PAVB and sinus arrest that resulted in refractory life-threatening symptomatic long pauses. Continuous heart rate variability analysis with high time resolution (wavelet analysis) revealed an abrupt increase in parasympathetic activity just before a long pause, which indicated a vagal reflex. Although a pacemaker is not always effective because of a concomitant vasodepressive response in such cases, the complete stabilization after pacemaker implantation in this case supports the necessity and usefulness of pacemaker implantation in patients with reflex-induced highly symptomatic bradycardia.

Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer.

In patients with prostate cancer (PCa), serum prostate-specific antigen (PSA) is a useful marker for evaluating the effects of androgen deprivation therapy (ADT). Intuitively, most urologists expect that a more rapid PSA decline in response to ADT would be positively associated with extended survival. Recently, we have reported that prolonged gradual serum PSA decline after ADT is strongly associated with favorable prognosis in PCa patients, however, the mechanism remains unknown. We investigated the role of fibroblasts in serum PSA decline after ADT. We performed in vitro experiments using androgen-sensitive, androgen receptor (AR)-positive prostate epithelial cell lines (LNCaP, 22Rv1, and RWPE-1 cells), commercially available prostate stromal cells (PrSC), and primary cultures of prostate fibroblasts (pcPrFs). In LNCaP and 22Rv1 cells, PSA production was increased by co-culture with fibroblasts under androgen-deprived conditions. In an in vivo model using LNCaP cells, serum PSA declined rapidly after ADT becoming undetectable within 14 days in mice inoculated with LNCaP cells alone. In contrast, when LNCaP cells were co-inoculated with fibroblasts, serum PSA levels were still high on 14 days post ADT and did not drop to undetectable levels until 21 days post ADT. Tumor volumes and Ki67 labeling indices were not altered between days 14 and 21 post ADT in mice inoculated with LNCaP cells; however, those in mice inoculated with LNCaP cells plus fibroblasts decreased gradually. PSA protein was detected in all tumors on 21 days post ADT by immunohistochemical staining. Microvessel densities were higher on 14 days post ADT for tumors from mice inoculated with LNCaP cells plus fibroblasts as compared with LNCaP cells alone. In summary, co-inoculation of fibroblasts with LNCaP cells prolonged serum PSA decline after ADT and enhanced the efficacy of ADT. Prolonged serum PSA decline may indicate the presence of protective fibroblasts that preserve the AR dependence of PCa cells, improving treatment efficacy.

Novel mechanisms for cerebral blood flow regulation in patients with congenital heart disease.

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.

Prevalence, implication, and determinants of worsening renal function after surgery for congenital heart disease.

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 < 0.05), even after controlling for age and operative factors. In addition, multivariate regression analysis revealed that central venous pressure, rather than cardiac output, was an independent determinant of WRF. Postoperative management to relieve venous congestion may help ameliorate or prevent WRF and thereby improve outcomes in patients with CHD.

Mechanism of aortic root dilation and cardiovascular function in tetralogy of Fallot.

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-ß 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.

Influence of Left Ventricular Stiffness on Hemodynamics in Patients With Untreated Atrial Septal Defects.

BACKGROUND: Although left ventricular (LV) stiffening with age is believed to increase left-to-right shunting in patients with atrial septal defects (ASD), clinical data have not confirmed this. We sought determinants of the pulmonary-to-systemic flow ratio (Qp/Qs) in patients with untreated ASD. METHODS AND RESULTS: We retrospectively studied 180 patients with ASD who underwent percutaneous ASD closure between 2007 and 2011. Qp/Qs and LV stiffness were measured before ASD closure.The median age of the subjects was 18 years, and 117 (65.0%) were female. The mean ASD size adjusted for square root of body surface area (BSA) was 14.4±4.2 mm/m, and the Qp/Qs was 2.28±0.74. Adjusted ASD size most strongly related to Qp/Qs (r=0.74, P<0.0001). Multivariate analysis revealed that LV stiffness was a significant predictor of Qp/Qs, independently of adjusted ASD size and vascular resistance (P=0.0015). Based on the multivariate model that accounts for the effects of LV stiffness and vascular resistance, the minimal adjusted diameter that can cause a Qp/Qs of 2.0 was predicted to be 7.3 mm/m. CONCLUSIONS: Qp/Qs in ASD can change significantly depending on LV stiffness, suggesting that it would increase with age. An ASD >7.3 mm/m in diameter has the potential to cause significant left-to-right shunting, and may require closure regardless of hemodynamic status at the time of assessment.

Oxygen supply to the fetal cerebral circulation in hypoplastic left heart syndrome: a simulation study based on the theoretical models of fetal circulation.

Hypoxia due to congenital heart diseases (CHDs) adversely affects brain development during the fetal period. Head circumference at birth is closely associated with neuropsychiatric development, and it is considerably smaller in newborns with hypoplastic left heart syndrome (HLHS) than in normal newborns. We performed simulation studies on newborns with CHD to evaluate the cerebral circulation during the fetal period. The oxygen saturation of cerebral blood flow in newborns with CHD was simulated according to a model for normal fetal circulation in late pregnancy. We compared the oxygen saturation of cerebral blood flow between newborns with tricuspid atresia (TA; a disease showing univentricular circulation and hypoplasia of the right ventricle), those with transposition of the great arteries (TGA; a disease showing abnormal mixing of arterial and venous blood), and those with HLHS. The oxygen saturation of cerebral blood flow in newborns with normal circulation was 75.7 %, whereas it was low (49.5 %) in both newborns with HLHS and those with TA. Although the oxygen level is affected by the blood flow through the foramen ovale, the oxygen saturation in newborns with TGA was even lower (43.2 %). These data, together with previous reports, suggest that the cerebral blood flow rate is decreased in newborns with HLHS, and the main cause was strongly suspected to be retrograde cerebral perfusion through a patent ductus arteriosus. This study provides important information about the neurodevelopmental prognosis of newborns with HLHS and suggests the need to identify strategies to resolve this unfavorable cerebral circulatory state in utero.

Aortic root dilatation and aortic stiffness in patients with single ventricular circulation.

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<0.001) after controlling for age and aortic pressure, factors known to influence PWV (P<0.001, analysis of covariance). There was a strong positive correlation between aortic root diameter and PWV (P<0.001). Multivariate analysis adding aortic flow (index of aortic volume load) to independent variables in 25 pre-Glenn patients with directly calculated aortic flow volume showed that PWV was an independent determinant of aortic dilatation (P<0.001). CONCLUSIONS: In patients with SiV circulation and dilated aorta, aortic stiffness is increased and is an independent determinant of aortic dilatation. To improve prognosis of Fontan circulation, further studies on whether aortic stiffness modulation reduces the progression of aortic dilatation and resultant aortic regurgitation are warranted.

Direct measurement of aortic regurgitation with phase-contrast magnetic resonance is inaccurate: proposal of an alternative method of quantification.

BACKGROUND: Phase-contrast magnetic resonance (MR) has been widely used for quantification of aortic regurgitation. However there is significant practice variability regarding where and how the blood flow data are acquired. OBJECTIVE: To compare the accuracy of flow quantification of aortic regurgitation at three levels: the ascending aorta at the level of the right pulmonary artery (level 1), the aortic valve hinge points at end-diastole (level 2) and the aortic valve hinge points at end-systole (level 3). MATERIALS AND METHODS: We performed cardiovascular MR in 43 children with aortic regurgitation. By using phase-contrast MR, we measured the systolic forward, diastolic retrograde and net forward flow volume indices at three levels. At each level, the following comparisons were made: (1) systolic forward flow volume index (FFVI) versus left ventricular cardiac index (LVCI) measured by cine ventricular volumetry; (2) retrograde flow volume index (RFVI) versus estimated aortic regurgitation volume index (which equals LVCI minus pulmonary blood flow index [QPI]); (3) net forward flow volume index (NFVI) versus pulmonary blood flow index. RESULTS: The forward flow volume index, retrograde flow volume index and net forward flow volume index measured at each of the three levels were significantly different except for the retrograde flow volume index measured at levels 1 and 3. There were good correlations between the forward flow volume index and the left ventricular cardiac index at all three levels, with measurement at level 2 showing the best correlation. Compared to the forward flow volume indices, the retrograde flow volume index had a lower correlation with the estimated aortic regurgitation volume indices and had widely dispersed data with larger prediction intervals. CONCLUSION: Large variations in systolic forward, diastolic retrograde and net forward flow volumes were observed at different levels of the aortic valve and ascending aorta. Direct measurement of aortic regurgitation volume and fraction is inaccurate and should be abandoned. Instead, calculation of the aortic regurgitation volume from more reliable data is advised. We recommend subtracting pulmonary blood flow from systolic forward flow measured at the aortic valve hinge points at end-diastole as a more accurate and consistent method for calculating the volume of aortic regurgitation.

Activation of FGF2-FGFR signaling in the castrated mouse prostate stimulates the proliferation of basal epithelial cells.

The prostate gland is unique in that it undergoes rapid regression following castration but regenerates completely once androgens are replaced. Residual ductal components play an important role in the regeneration of a fully functional prostate. In this study, to examine how androgen status affects prostate structure and components, we conducted histopathological studies of the involuted and regenerated mouse dorsolateral prostate (DLP). In the castrated mouse DLP, the number of luminal epithelial cells decreased in a time-dependent manner. On Day 14 postandrogen replacement, the number of luminal epithelial cells was completely restored to the baseline level. In contrast, the number of basal epithelial cells gradually increased in the castrated mouse prostate. The Ki67-labeling index of prostate basal epithelial cells was significantly increased after castration. The number of basal epithelial cells decreased to baseline after androgen replacement. After castration, mRNA expression levels of specific growth factors, such as Fgf2, Fgf7, Hgf, Tgfa, and Tgfb, were relatively abundant in whole mouse DLPs. In organ culture experiments, basal epithelial proliferation was recapitulated in the absence of dihydrotestosterone (DHT). The proliferation of basal epithelial cells in the absence of DHT was suppressed by treatment with an FGF receptor inhibitor (PD173074). Moreover, FGF2 treatment directly stimulated the proliferation of basal epithelial cells. Taken together, these data indicated that the FGF2-FGF receptor signal cascade in the prostate gland may be one of the pathways stimulating the proliferation of basal epithelial cells in the absence of androgens.

An Extremely Preterm Infant Born at 23 Weeks' Gestation With an Interrupted Aortic Arch Complex: A Case Report.

We present a case of an infant male born at 23 weeks' gestation with an interrupted aortic arch (IAA) complex. We treated the patient with hypoxic gas ventilation to address developing systemic undercirculation in the acute postnatal phase. As the symptoms of bronchopulmonary dysplasia evolved, hypoxic gas ventilation was no longer required to stabilize the hemodynamics. The patient was discharged home after undergoing the palliative surgical procedure of bilateral pulmonary artery banding and ductus arteriosus stent implantation. Although he suffered from pulmonary hypertension, it was controllable with oxygen supplementation and pulmonary vasodilators. There are limited therapeutic options available for extremely preterm infants with critical congenital heart defects (CHDs). Hypoxic gas ventilation might be considered as one of the options, with its risks taken into account, to manage extremely preterm infants with CHDs with pulmonary overcirculation before performing surgical interventions.

Transient Recovery of Complete Atrioventricular Block Due to Maternal Anti-SS-A Antibody Through Antenatal Steroid Administration After 27 Weeks of Gestation.

Maternal anti-SS-A antibodies may cause complete atrioventricular block or myocardial damage in a fetus. Effective treatment for this has not been established. Although antenatal steroids may be a treatment option for anti-SS-A antibody-related myocarditis or atrioventricular block, a complete atrioventricular block is usually considered irreversible once established. Previous reports have indicated that, in cases where antenatal steroids were effective for atrioventricular block, they were administered earlier in the pregnancy. Here we present a case where maternal steroid administration initiated from 27 weeks, which is beyond the recommended optimal treatment period, was effective in altering a complete atrioventricular block to a grade I atrioventricular block.