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Pulmonary agenesis is a complete absence of the pulmonary parenchyma, airways, and vasculature unilaterally or bilaterally. Although bilateral cases are lethal, the outcome of unilateral cases remains not well described. We performed a comprehensive literature review to assess the clinical features of pulmonary agenesis.Four database sources were searched on October 10, 2021 and two cases were included from our institution. Studies related to the clinical impact of comorbidity and intervention on the survival outcome in pulmonary agenesis were included for full-text review.We identified 259 patients-with right-sided (59%), left-sided (34%), and bilateral agenesis (7%)-among 195 articles and our two cases. Additional anomalies included cardiovascular (40%), skeletal (30%), gastrointestinal (20%), tracheal (20%: all stenoses), and genitourinary (14%) anomalies. Fifty-seven (24%) individuals in unilateral pulmonary agenesis had isolated disease. Outcomes related to survival were not uniformly reported, but the 2-year overall survival rate of unilateral agenesis was 62% and no subsequent death was reported until 13 years of age. The right-sided agenesis was more frequently associated with tracheal stenosis (27% vs. 11%, p = 0.003) than the left-sided disease. A multivariable analysis indicated that tracheal stenosis (hazard ratio [HR]: 2.2, 95% confidence interval [CI]: 1.3-4.1, p = 0.003) and gastrointestinal anomalies (HR: 2.0, 95% CI: 1.1-3.3, p = 0.010) were prognostic factors for mortality.The poor prognostic factors were tracheal stenosis, right agenesis, and gastrointestinal anomalies. Treatment for these comorbidities is a key point for improving the survival of unilateral pulmonary agenesis.

Aims Interatrial shunting (IAS) reduces left atrial pressure in patients with heart failure. Several clinical trials reported that IAS improved the New York Heart Association score and exercise capacity. However, its effects on haemodynamics vary depending on shunt size, cardiovascular properties, and stressed blood volume. To maximize the benefit of IAS, quantitative prediction of haemodynamics under IAS in individual patients is essential. The generalized circulatory equilibrium framework determines circulatory equilibrium as the intersection of the cardiac output curve and the venous return surface. By incorporating IAS into the framework, we predict the impact of IAS on haemodynamics. Methods and results In seven mongrel dogs, we ligated the left anterior descending artery and created impaired cardiac function with elevated left atrial pressure (baseline: 7.8 ± 1.0 vs. impaired: 11.9 ± 3.2 mmHg). We established extracorporeal left‐to‐right atrial shunting with a centrifugal pump. After recording pre‐IAS haemodynamics, we changed IAS flow stepwise to various levels and measured haemodynamics under IAS. To predict the impact of IAS on haemodynamics, we modelled the fluid mechanics of IAS by Newton's second law and incorporated IAS into the generalized circulatory equilibrium framework. Using pre‐IAS haemodynamic data obtained from the dogs, we predicted the impact of IAS flow on haemodynamics under IAS condition using a set of equations. We compared the predicted haemodynamic data with those measured. The predicted pulmonary flow [r2 = 0.88, root mean squared error (RMSE) 11.4 mL/min/kg, P

Introduction: Pulmonary agenesis is a complete absence of the pulmonary parenchyma, bronchi beyond the bifurcation, and pulmonary vasculature unilaterally or bilaterally. Because of the rare occurrence, its pathophysiology and outcome remain elusive. We evaluate the clinical features and risk factors for mortality due to pulmonary agenesis. Methods: Two patients we experienced are presented as index cases. All reported cases of pulmonary agenesis were collected from online and publication databases between 1955 and 2020. We assessed the impact of comorbidity and intervention on the survival outcome. Results: We identified 230 patients—138 (60%) with right-sided, and 14 (6%) with bilateral agenesis—among 164 articles and our cases. There were 93 (40%) cardiovascular, 70 (30%) skeletal, and 48 (21%) gastrointestinal anomalies; 47 (20%) tracheal stenoses; and 33 (14%) genitourinary anomalies. Fifty-two (23%) patients had isolated pulmonary agenesis. The 2-year overall survival (OS) rate was 66% and there was no subsequent death until 13 years of age. The right agenesis was significantly associated with a lower 2-year OS rate (58% vs. 78%, p=0.019) or more frequent tracheal stenosis (28% vs. 12%, p=0.006) than left-sided disease. A multivariable analysis indicated that tracheal stenosis (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.5-4.1, p=0.004) and gastrointestinal anomaly (HR 1.9, 95% CI 1.1-3.3, p=0.018) were prognostic factors for mortality. Conclusions: The poor prognostic factors were tracheal stenosis, right agenesis and gastrointestinal anomaly. Tracheal and gastrointestinal controls are targeted at birth and in infancy for the improved survival of unilateral pulmonary agenesis.

Objective To search the predictive factors of infliximab resistance in intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) patients. Study design. Twenty-seven patients with KD who received infliximab after 4–5 g/kg of IVIG therapy from 2013 to 2015 were consecutively recruited in this study. They were divided into two groups: patients who responded to infliximab (infliximab-responsive group, n = 15) and patients who required additional therapy for the disease control (infliximab-resistant group, n = 12). We analyzed the clinical and laboratory parameters just before the infliximab treatment including serum levels of procalcitonin and cytokines with respect to the infliximab response. Results Serum procalcitonin concentration (P = 0.017), neutrophils to lymphocytes ratio (P = 0.013), and % neutrophils (P = 0.004) were higher, and serum sodium concentration (P = 0.017) was lower in infliximab-resistant group than those of infliximab-responsive group, respectively. Multivariate logistic regression analyses indicated that higher procalcitonin concentration (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.00–5.00, P = 0.046) and lower sodium levels (OR 0.64, 95% CI 0.32–1.00, P = 0.047), but not other variables, were associated with infliximab-resistance. Serum procalcitonin concentrations positively correlated with the serum levels of interleukin-6, soluble tumor necrosis factor receptor type 1 and type 2, respectively. Analyses of the receiver operating characteristic (ROC) curve showed that the cut-off value of procalcitonin 2.0 ng/ml had 58.3% of sensitivity and 93.3% of specificity. ROC analysis yielded an area under the curve (AUC) of 0.739 to predict infliximab-resistance. Conclusion Serum procalcitonin might be an effective biomarker to predict infliximab resistance in severe KD patients who are refractory to IVIG treatment.

Portosystemic venous shunt (PSVS) is a vascular anomaly between the portal and systemic veins, resulting in several critical complications. Although PSVS is often associated with congenital heart diseases, the clinical association between Fontan circulation and PSVS has not been elucidated. This study aimed to investigate the clinical features of Fontan patients with PSVS. Two hundred thirteen patients who underwent Fontan procedure are being followed up at Adult Congenital Heart Disease clinic in Kyushu University Hospital. Among them, 139 adult patients underwent cardiac catheterization between January 1, 2011 and September 30, 2019. Medical records were reviewed to investigate the laboratory, echocardiography, and cardiac catheterization findings, as well as clinical manifestations and outcomes. Eleven Fontan patients received the diagnosis of PSVS. The median age at cardiac catheterization was 25 (range 18–45) years. Fontan operation was performed using extracardiac conduit or lateral tunnel 22 (16–35) years previously. Ten patients presented with chronic heart failure [New York Heart Association class 2 (n = 5) and 3 (n = 5)]. The median level of peripheral oxygen saturation was 87 (70–95)%. Cardiac catheterization showed increased cardiac index [5.3 (2.72–14.3) L/min/m2] with or without high central venous pressure [18 (9–25) mmHg]. Although the pulmonary vascular resistance was within the normal range, the systemic vascular resistance was decreased [7.08 (1.74–18.6) Wood units]. Fontan patients complicated with PSVS had increased cardiac output. The presence of PSVS in Fontan circulation might be associated with unfavorable long-term outcome.

Right aortic arch with aberrant left subclavian artery (RAA/aLSCA) is a rare aortic arch anomaly. The clinical association of aLSCA stenosis with RAA/aLSCA has not yet been fully elucidated. The aim of this study was to investigate the diagnosis, incidence, management and outcome of aLSCA stenosis in infants with prenatally diagnosed RAA/aLSCA. Ten fetuses who were diagnosed as having RAA/aLSCA in Kyushu University Hospital between January 2011 and December 2014 were enrolled. The maternal and child medical records were reviewed to investigate sex, gestational age at the fetal diagnosis, gestational age and body weight at birth, the findings of computed tomography (CT), Doppler ultrasonography of the vertebral artery and angiography, and the complications and outcomes of aLSCA stenosis. In 8 of 10 patients, aLSCA stenosis was identified on the first CT examination after birth. No patients had dysphagia or respiratory distress. The stenosis spontaneously resolved in 3 patients. In 4 of the 5 remaining patients, aLSCA stenosis progressed, including one case in which complete occlusion occurred-the case was associated with retrograde flow from the left vertebral artery supplying the distal LSCA. Balloon angioplasty was successfully used to treat stenosis in two cases. The subclavian steal phenomenon and developmental problems were not observed in any patients. aLSCA stenosis was identified in 80% of patients with RAA/aLSCA after birth. The early detection and elective treatment of stenotic lesions may be required to prevent complete occlusion during the development of the cardiovascular and cerebrovascular systems.

Background Left ventricular non-compaction (LVNC) is a cardiomyopathy characterized by prominent trabeculae and intertrabecular recesses. We present the cases of 3 girls with the sameryanodine receptor type 2(RYR2) mutation who had phenotypes of both catecholaminergic polymorphic ventricular tachycardia (CPVT) and LVNC .Methods and Results:Clinical characteristics and genetic background of the 3 patients were analyzed retrospectively. Age at onset was 5, 6, and 7 years, respectively. Clinical presentation included syncope during exercise in all 3 patients and cardiac arrest in 2 patients. LVNC diagnosis was confirmed on echocardiography according to previously defined criteria. Exercise stress testing provoked ventricular arrhythmia in two of the patients. Beta-blockers (n=3) and flecainide (n=2) were given, and an implantable cardioverter defibrillator was used in 1 patient. Genotyping identified the sameRYR2-R169Q missense mutation and no other CPVT- or LVNC-related gene mutations. Functional analysis of the mutation using HEK293 cells with single-cell Ca2+imaging and [3H]ryanodine binding analysis, indicated a gain of function: a reduced threshold for overload-induced Ca2+release from the sarcoplasmic reticulum and increased fractional Ca2+release. Conclusions The rare association of LVNC and CPVT phenotypes withRYR2mutations is less likely to be coincidental. Screening for life-threatening arrhythmias using exercise or pharmacologic stress tests is recommended in LVNC patients to prevent sudden cardiac death in those with preserved LV function.

BackgroundDuctal patency is mandatory to manage patients with ductal-dependent pulmonary circulation. The aim of this study is to elucidate the morphological and haemodynamic features of ductus arteriosus with right ventricular outflow tract obstruction, and investigate the appropriate perinatal management.Patients and methodsPatients with prenatal diagnosis of right ventricular outflow tract obstruction at our institution between 2010 and 2015 were included in the study. Reverse orientation of the ductus arteriosus is defined as an inferior angle of 90°. We retrospectively reviewed the shape and flow pattern of ductus arteriosus and the clinical characteristics of the cases.ResultsA total of 39 patients were enrolled. The shape was divided into normal orientation (n=15) and reverse orientation (n=24) of the ductus arteriosus. There was no significant difference in the type of oxygen saturation at birth and age at shunt operation between both the groups. However, the median narrowest diameter of ductus arteriosus in the normal orientation group was significantly smaller than that in the reverse orientation group (2.0 [1.0–5.4] versus 3.0 [1.3–4.4] mm, pConclusionsNormal orientation pattern might have high incidence of an early narrowing or closure of ductus arteriosus at birth. The critical patients need careful evaluation by repeated foetal echocardiography and further maternal interventions.

Congenital diaphragmatic hernia (CDH) is a relatively rare malformation, but it has a high mortality rate. Its association with congenital heart disease lowers survival rate due to severe acidosis and desaturation caused by persistent pulmonary hypertension of the neonate. We describe herein a case of CDH with transposition of the great arteries and intact ventricular septum, in a patient who was prenatally diagnosed, managed with extracorporeal oxygenation (ECMO) support and successfully treated with both CDH repair and Jatene procedure, with no respiratory or circulatory sequelae. In conclusion, precise prenatal estimation is essential, and ECMO is a useful therapeutic option in these complex cases.

There is limited information available regarding the role of infliximab (IFX) following the acute phase of Kawasaki disease (KD). We aimed to evaluate whether IFX is associated with coronary artery aneurysm (CAA) regression.Between 2005 and 2016, we identified 971 consecutive patients with KD from 3 tertiary institutions, and 49 (5%) with CAAs were enrolled in our study. Patients were divided into 2 groups: 27 who received IFX and 22 who did not. The persistence rate of CAAs was compared between the groups.Age, sex, and duration of the febrile period did not significantly differ between the groups. The maximum value of C-reactive protein was higher in the IFX- than in the non-IFX group. The maximum z-score of CAAs did not differ between the groups. The 2-, 4- and 6-year cumulative persistence rate of CAA was 24%, 24% and 24% in IFX-group, whereas 67%, 52% and 33% in non-IFX group, respectively (P = 0.03). The median duration of CAA regression was 1.1 vs. 4.6 years. Among those who developed medium- or large-sized CAAs, the 2-, 4- and 6-year cumulative persistence rate of CAA was 33%, 33% and 33% in IFX group, whereas 77%, 51% and 48% in non-IFX group, respectively (P = 0.047). Multivariate logistic regression analysis indicated that the maximum z-score (hazard ratio 0.72, p 0.001) and response to IFX (hazard ratio 4.56, p = 0.017) were independently related to regression.IFX therapy was observed to be effective for the early improvement of CAAs in patients with intravenous immunoglobulin-resistant KD.

OBJECTIVE Congenital portosystemic venous shunt (CPSVS) is a rare vascular malformation with a high risk of mortality from pulmonary arterial hypertension (PAH), but the treatment outcome of CPSVS closure remains elusive. Our aim was to investigate the clinical features and establish the optimal management of CPSVS with or without PAH. METHODS Twenty-four patients with CPSVS treated in Kyushu University Hospital between 1990 and 2015 were enrolled in this study. The patients were divided into a PAH group (n = 9) and a non-PAH group (n = 15). Clinical characteristics and outcomes were evaluated. RESULTS The first manifestation of CPSVS at diagnosis (28.5 [1-216] months) was hypergalactosemia in 13 (54%) or PAH in six (25%) patients. PAH was the cause of all three deaths. The PAH group had higher levels of serum total bile acid, manganese, and total bilirubin, along with higher pulmonary vascular resistance index (PVRI) than the non-PAH group (7.2 [5.1-38.1] vs 1.2 [0.5-3.3] unit/m2 , P

Background: Thrombotic microangiopathies (TMA) are microvascular occlusive disorders characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and red cell fragmentation. Post-operative TMA mostly occurs in adult patients with cardiovascular surgery, with the distinct pathophysiology from classical thrombotic thrombocytopenic purpura (TTP) although the exact pathophysiology remains unclear. Case presentation: A one-month-old infant developed TMA after the initial surgery of double outlet right ventricle. ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13) activity was sustained (64%) with the undetectable inhibitor. Von Willebrand factor (VWF) multimer analyses showed absent high-molecular weight multimers. Echocardiography disclosed severe mitral regurgitation. The mitral valve repair 32 days after the initial valvuloplasty led to prompt resolution of TMA. These suggested that TMA occurred in association with valvulopathy-triggered turbulent shear flow, mechanical hemolysis and endothelial damage. The consumption of large VWF multimers might account for the vascular high shear stress shown in Heyde syndrome. Conclusion: The youngest case of post-operative TMA underscores the critical coagulopathy after the first surgical intervention for congenital heart disease. Key words: cardiac surgery, thrombotic microangiopathy, von Willebrand factor multimers

OBJECTIVE Chronic inflammation plays a key role in the development of atherosclerosis. Early progression of atherosclerosis has been reported in patients with RA. Cryopyrin-associated periodic syndromes (CAPS) are autosomal dominant autoinflammatory disorders caused by heterozygous NLRP3 gene mutations. Chronic infantile neurological cutaneous and articular (CINCA) syndrome is the most severe form of CAPS and patients display early onset of rash, fever, uveitis and joint manifestations. However, there has been no previous report on atherosclerosis in patients with CAPS. The objective of this study is to assess the development of atherosclerosis in patients with CINCA syndrome. METHODS Intima-media thickness (IMT) of the carotid arteries, stiffness parameter β, ankle brachial index (ABI) and pressure wave velocity (PWV) were evaluated by ultrasonography in 3 patients with CINCA syndrome [mean age 9.0 years (S.D. 5.3)] and 19 age-matched healthy controls [9.3 years (S.D. 4.3)]. RESULTS The levels of carotid IMT, stiffness parameter β and PWV in CINCA syndrome patients were significantly higher than those in healthy controls [0.51 mm (S.D. 0.05) vs 0.44 (0.04), P = 0.0021; 6.1 (S.D. 1.7) vs 3.9 (1.0), P = 0.0018; 1203 cm/s (S.D. 328) vs 855 (114), P = 0.017, respectively]. CONCLUSION Patients with CINCA syndrome showed signs of atherosclerosis from their early childhood. The results of this study emphasize the importance of chronic inflammation in the development of atherosclerosis. Further analysis on atherosclerosis in young patients with CINCA syndrome may provide more insights into the pathogenesis of cardiovascular disease.

Pathologic studies of the heart in patients with Kawasaki disease (KD) revealed vasculitis, valvulitis, myocarditis, and pericarditis. However, there have been no studies on the quantitative determination of multi-site echogenicity of the heart in KD patients. It is also undetermined whether the degree of echogenicity of each site of the heart in patients with KD might be related to the response to intravenous immunoglobulin (IVIG) treatment. In 81 KD patients and 30 control subjects, we prospectively analyzed echogenicity of the heart. Echogenicity was measured in four sites: coronary artery wall (CAW), mitral valve (MV), papillary muscle (PM), and ascending aortic wall (AAo wall) by the calibrated integrated backscatters (cIBs). The cIB values of all measurement sites at acute phase in KD patients were significantly higher than those in control subjects (KD patients vs control subjects; CAW, 19.8 ± 6.2 dB vs 14.5 ± 2.0 dB, p < 0.05; MV, 23.3 ± 5.3 dB vs 16.0 ± 3.3 dB, p < 0.05; PM, 22.4 ± 5.1 dB vs 12.7 ± 1.9 dB, p < 0.05; AAo wall, 25.3 ± 5.6 dB vs 18.3 ± 3.4 dB, p < 0.05). The cIB values of CAW at the acute phase in IVIG nonresponders were significantly higher than those in responders. Conclusion: Echogenicity of the heart in KD patients at the acute phase increased not only in the coronary artery wall but also in other parts of the heart. Echogenicity of CAW might be helpful in determining the unresponsiveness of IVIG treatment.

Background Congenital portosystemic shunts (CPSS) with intrahepatic portal vein (IHPV) hypoplasia or absence cause encephalopathy or pulmonary hypertension (PH). Acute shunt closure may result in postoperative portal hypertension. The aim of this study was to propose a surgical strategy according to the anatomical types of CPSS and IHPV. Methods Twenty-three CPSS patients were diagnosed from1990 to 2015. All patients were evaluated by computed tomography, angiography, and PV pressure monitoring under a shunt occlusion test. CPSS were categorized into 5 types according to the anatomical shunt location. Results The median age at diagnosis was 34months. Three of 23 total patients, who had an extrahepatic portosystemic shunt with a hypoplastic IHPV, died before treatment initiation because of severe PH. Fourteen cases received surgical or interventional treatment at the median age of 5years. A total of 6 cases received surgical therapy, including liver transplants for 2 absent IHPV cases. The remaining 8 cases received interventional coiling. All shunt ligations were successfully accomplished in 1-stage ligation without any complications. After the treatment, the hypoplastic IHPV gradually enlarged with an efficient portal inflow. Conclusion A precise pretreatment anatomical evaluation of CPSS and IHPV types is mandatory for the selection of surgical treatment. Level of evidence Diagnostic study – level II and treatment study – level III.

A male newborn weighing 2334 g was delivered at 37 weeks of gestation by caesarean section because of prenatal ultrasound findings of fetal hydrops with atrioventricualr block, ventriucular tachycardia (VT), and impaired ventricular function. In spite of the intravenous administration of lidocaine, VT continued. He developed poor perfusion and systemic hypotension. After the intravenous administration of amiodarone, VT was terminated. The electrocardiogram revealed an extremely prolonged corrected QT interval (860 ms) with 2:1 atrioventricular block. Unfortunately, he died 18 h after birth in spite of the administration of lidocaine, beta-blocker and magnesium. Mutational analysis identified a novel heterozygous de novo mutation (F1486del) in SCN5A . This mutation is associated with the IFM motif in the linker between III and IV domains of Na v 1.5, which serves as an inactivation particle binding within the pore of sodium channels. This report demonstrates an interesting relationship between the clinical phenotype and the location of the mutation in long QT syndrome.

Purpose: Pulmonary valve replacement (PVR) improves right ventricular (RV) function in patients with tetralogy of Fallot (TOF). However, the impact of PVR on left ventricular (LV) function and the mechanism of improvement are still unclear. The purpose of this study is to clarify the impact of PVR on LV mechanical efficiency in adult patients with TOF. Methods: Fourteen patients with TOF (age 30.1±11.5 years) who underwent PVR for significant pulmonary insufficiency were enrolled in this study. We measured left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), contractility (end-systolic elastance; Ees), afterload (effective arterial elastance; Ea), and mechanical efficiency (ventriculoarterial coupling; Ea/Ees and the rate of stroke work and pressure-volume area; SW/PVA) on the basis of the echocardiographic data before, after and late after PVR. Ees, Ea and SW/PVA were approximated as follows: Ees=mean arterial pressure/minimal ventricular volume, Ea = maximal ventricular pressure / (maximal ventricular volume-minimal ventricular volume), and SW/PVA=1 / (1 + 0.5 Ea/Ees). Results: LVEDVI, stroke volume and ejection fraction increased significantly after PVR. Contractility (Ees) did not change but afterload (Ea) decreased, and LV mechanical efficiency (Ea/Ees and SW/PVA) improved significantly. These changes were observed just after PVR, and further improvement was not noted in the late period. ![Figure][1] Hemodynamic changes after PVR Conclusions: LV efficiency improves after PVR. Increased pulmonary forward flow and relief of the compression from the RV increase LVEDVI and stroke volume. LV afterload decreases to adapt the increase of stroke volume without the change of contractility. These changes result in the improvement of LV mechanical efficiency. [1]: pending:yes

Background Loeys–Dietz syndrome, also known as Marfan syndrome type II, is a rare connective tissue disorder caused by dominant mutations in transforming growth factor-beta receptors (TGFBR1 and 2). Case presentation We report a 7-year-old Japanese boy with Loeys–Dietz syndrome who carried a novel, de novo missense mutation in TGFBR2 (c.1142g > c, R381P). He showed dysmorphic faces and skeletal malformations that were typical in previous cases with Loeys-Dietz syndrome. The cardiac studies disclosed the presence of markedly dilated aortic root and patent ductus aorteriosus. The cranial magnetic resonance imaging (MRI) and angiography (MRA) detected the tortuous appearances of the bilateral middle cerebral and carotid arteries. Conclusion This study depicts the systemic vascular phenotypes of a child with Loeys–Dietz syndrome that were caused by a novel heterozygous mutation of TGFR2. A large cohort with serial imaging studies for vascular phenotypes will be useful for delineating the genotype-phenotype correlations of Loeys–Dietz syndrome.