Implication of EZH2 in the Pro-Proliferative and Apoptosis-Resistant Phenotype of Pulmonary Artery Smooth Muscle Cells in PAH: A Transcriptomic and Proteomic Approach.

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by a sustained elevation of pulmonary artery (PA) pressure, right ventricular failure, and premature death. Enhanced proliferation and resistance to apoptosis (as seen in cancer cells) of PA smooth muscle cells (PASMCs) is a major pathological hallmark contributing to pulmonary vascular remodeling in PAH, for which current therapies have only limited effects. Emerging evidence points toward a critical role for Enhancer of Zeste Homolog 2 (EZH2) in cancer cell proliferation and survival. However, its role in PAH remains largely unknown. The aim of this study was to determine whether EZH2 represents a new factor critically involved in the abnormal phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell-cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and tricarboxylic acid cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.

Anterograde blood flow associated with modified Blalock-Taussig shunt does not modify pulmonary artery growth compared with modified Blalock-Taussig shunt alone.

BACKGROUND: The main difference between extreme tetralogy of Fallot (TOF) and pulmonary atresia with ventricle septal defect (PA/VSD) is anterograde pulmonary blood flow (APBF). It is speculated that the association of modified Blalock-Taussig shunt (mBTS) with APBF favours shunt thrombosis, but promotes better pulmonary artery growth. AIM: To compare pulmonary artery growth after mBTS between TOF and PA/VSD. METHODS: From 1995 to 2018, 77 mBTS procedures were performed in infants (aged<1 year): 45 for TOF; 32 for PA/VSD. Using a 1/1 propensity score-matched analysis, 38 patients were included (19 per group). Delta Nakata was defined as the difference in the Nakata index before biventricular repair and before mBTS. RESULTS: After matching, the preoperative Nakata index was similar in the two groups (TOF 101±34 vs. PA/VSD 106±35 mm2/m2; P=0.75). Age and weight were similar (TOF 24±20 days, 3.3±0.6kg vs. PA/VSD 24±33 days, 3.3±0.9kg; P=0.84 and P=0.77, respectively). There was no difference in rates of in-hospital mortality (TOF 0% vs. PA/VSD 10%; P=0.13) or mBTS thrombosis (TOF 15% vs. PA/VSD 10%; P=0.63). The left and right pulmonary artery diameters at time of biventricular repair were similar (TOF 7.5±2.2 and 6.7±2.1 vs. PA/VSD 8±2.7 and 7.1±2.5mm; P=0.43 and P=0.78, respectively), as were delta Nakata (TOF 112±102 vs. PA/VSD 107±66 mm2/m2; P=0.89), median age for biventricular repair (P=0.83) and reintervention rates (TOF 10% vs. PA/VSD 15%; P=0.67). CONCLUSIONS: We found no difference in pulmonary artery growth between APBF with mBTS versus mBTS alone. Thus, we could not show an increase in mBTS thrombosis with APBF.

[A Study on the Authenticity of Preoperative Pulmonary Bronchial Angiography by DeepInsight Software].

BACKGROUND: Precise segmentectomy has become the first choice of surgical treatment for pulmonary nodules and early lung cancer, and the key and difficult point of the surgery lies in the precise location and resection of the lesion. DeepInsight is an auxiliary software for precise lung surgery jointly developed by our center and Neusoft Company, which can determine the precise anatomy of the lung and locate the location of lung lesions before operation. This study is to verify the authenticity and reliability of DeepInsight lung bronchial angiography assisted surgery. METHODS: In this study, 1,020 patients with pulmonary nodules <2.0 cm in diameter were included in the Department of Thoracic Surgery Jiangsu Provincial People's Hospital from August 1, 2016 to December 31, 2019. Computed tomographic angiography (CTA) was performed on all the included patients before surgery. The DeepInsight software was used to perform preoperative bronchial angiography on the operative side of the lung to identify the affected pulmonary segments, pulmonary arteries and pulmonary veins. Two thoracic surgeons independently assessed the visibility of the affected pulmonary vessels using the 5-point method, and the χ² test assessed the consistency between observers. In addition, virtual imaging and real anatomy of pulmonary vessels on the operative side were performed during the operation, and the involved pulmonary vessels were finally determined by 2 chief physicians of thoracic surgery. RESULTS: There were no statistically significant differences between the number and spatial anatomy of the vessels involved in the pulmonary virtual imaging using DeepInsight software before operation and the number of vessels involved during operation in 1,020 patients. And the consistency among observers is quite satisfactory. CONCLUSIONS: The DeepInsight software virtual imaging of pulmonary bronchial vessels can accurately reconstruct the actual pulmonary vessels and assist the completion of pulmonary segmental resection.

Comparative analysis on the anti-inflammatory/immune effect of mesenchymal stem cell therapy for the treatment of pulmonary arterial hypertension.

Despite the advancement of targeted therapy for pulmonary arterial hypertension (PAH), poor prognosis remains a reality. Mesenchymal stem cells (MSCs) are one of the most clinically feasible alternative treatment options. We compared the treatment effects of adipose tissue (AD)-, bone marrow (BD)-, and umbilical cord blood (UCB)-derived MSCs in the rat monocrotaline-induced pulmonary hypertension (PH) model. The greatest improvement in the right ventricular function was observed in the UCB-MSCs treated group. The UCB-MSCs treated group also exhibited the greatest improvement in terms of the largest decrease in the medial wall thickness, perivascular fibrosis, and vascular cell proliferation, as well as the lowest levels of recruitment of innate and adaptive immune cells and associated inflammatory cytokines. Gene expression profiling of lung tissue confirmed that the UCB-MSCs treated group had the most notably attenuated immune and inflammatory profiles. Network analysis further revealed that the UCB-MSCs group had the greatest therapeutic effect in terms of the normalization of all three classical PAH pathways. The intravenous injection of the UCB-MSCs, compared with those of other MSCs, showed superior therapeutic effects in the PH model for the (1) right ventricular function, (2) vascular remodeling, (3) immune/inflammatory profiles, and (4) classical PAH pathways.

Arterial duct stent versus surgical shunt for patients with duct-dependent pulmonary circulation: a meta-analysis.

BACKGROUND: Both systemic-pulmonary shunt and arterial duct stent could be the palliation of duct-dependent pulmonary circulation. We aimed to compare the safety and efficacy of the two approaches. METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched through December 2019 for studies comparing stent implantation and surgical shunt in duct-dependent pulmonary circulation. The baseline characteristics included ventricle physiology and cardiac anomaly. The main outcomes were hospital stay and total mortality. Additional outcomes included procedural complications, intensive care unit (ICU) stay, pulmonary artery growth at follow-up, and other indexes. A random- or fixed-effects model was used to summarize the estimates of the mean difference (MD)/risk ratio (RR) with 95% confidence intervals (CIs). RESULTS: In total, 757 patients with duct-dependent pulmonary circulation from six studies were included. Pooled estimates of hospital stay (MD, - 4.83; 95% CI - 7.92 to - 1.74; p < 0.05), total mortality (RR 0.44; 95% CI 0.28-0.70; p < 0.05), complications (RR 0.49; 95% CI 0.30-0.81; p < 0.05) and ICU stay (MD, - 4.00; 95% CI - 5.96 to - 2.04; p < 0.05) favored the stent group. Significant differences were found in the proportions of patients with a single ventricle (RR 0.82; 95% CI 0.68-0.98; p < 0.05) or a double ventricle (RR 1.23; 95% CI 1.07-1.41; p < 0.05) between the stent and shunt groups. Additionally, pulmonary artery growth showed no significant differences between the two groups. CONCLUSION: Arterial duct stent appears to have not inferior outcomes of procedural complications, mortality, hospital and ICU stay, and pulmonary artery growth in selected patients compared with a surgical shunt. TRIAL REGISTRATION: CRD42019147672.

Insufficient development of vessels and alveoli in lungs of infants with trisomy 18-Features of pulmonary histopathological findings from lung biopsy.

The aim of this study was to evaluate the features of pulmonary histopathological changes in cases of trisomy 18 complicated with congenital heart disease and pulmonary arterial hypertension. Twenty-eight patients with trisomy 18 underwent open lung biopsy at the time of primary operation in our hospital between 2008 and 2019. We compared these histopathological findings with those from previously described groups without trisomy 18. Mean age at primary cardiac surgery was 37 days (range, 9-69 days). According to the Heath-Edwards (HE) classification, 1, 8, 12, and 5 patients were graded as 0, 1, 2, and 3, respectively, whereas 2 patients were not classifiable due to medial defects in the small pulmonary arteries (MD). Four (14.3%) and 13 (46.4%) patients presented with MD and hypoplasia of the small pulmonary arteries (HS). Fifteen (53.6%) and 21 (75.0%) patients presented with alveolar hypoplasia (AH) and alveolar wall thickening (AT). MD, HS, and AH in trisomy 18 were present frequently, differing significantly from previous reports. These findings might be associated with congenital inadequate development of vessels and alveoli in the lung, contributing to a high risk of PAH in trisomy 18.

Improvement in fetal pulmonary hypertension and maturity after reversal of ductal constriction: prospective cohort study.

OBJECTIVES: To test the hypotheses that estimated mean pulmonary arterial pressure (MPAP) decreases and pulmonary vascular maturation, assessed by the ratio of pulmonary arterial flow acceleration time to ejection time (AT/ET ratio), increases after reversal of fetal ductus arteriosus constriction by reducing maternal intake of the causal agent (prostaglandin inhibitors, such as polyphenol-rich foods or non-steroidal anti-inflammatory drugs), and that these effects are independent of gestational age, which are inferences not yet demonstrated in the clinical setting. METHODS: This was a prospective cohort study comparing Doppler echocardiographic ductal flow dynamics, MPAP and pulmonary arterial flow AT/ET ratio in third-trimester fetuses (≥ 28 weeks' gestation) with ductus arteriosus constriction, at the time of diagnosis and after 2 weeks of reduced maternal intake of prostaglandin inhibitors either by suspending the use of pharmacological agents with potential for prostaglandin inhibition or by restricting the consumption of polyphenol-rich foods. MPAP was estimated using the Dabestani equation (MPAP = 90 - (0.62 × AT)), and pulmonary vascular maturity was assessed using the AT/ET ratio, according to reported validation studies. Student's t-test was used for comparison of variables at diagnosis with those after reversal of ductal constriction. Change in MPAP and pulmonary AT/ET ratio between the two assessments was compared with the expected change in the same gestational period in normal fetuses based on reference curves of MPAP and pulmonary AT/ET ratio constructed in normal fetuses from healthy pregnant women at 19-37 weeks' gestation, encompassing the same gestational age range as the study group (28-37 weeks). RESULTS: Seventy pregnancies with fetal ductus arteriosus constriction were included in the study. After 2 weeks of reduced maternal intake of prostaglandin inhibitors, normalization of mean systolic (change from 1.86 ± 0.34 m/s at diagnosis to 1.38 ± 0.41 m/s; P < 0.001) and diastolic (change from 0.41 ± 0.11 m/s to 0.21 ± 0.065 m/s; P < 0.001) ductal velocities and of mean pulsatility index (change from 1.99 ± 0.20 to 2.55 ± 0.42; P < 0.001) was demonstrated. MPAP decreased between the assessments (change from 66.7 ± 6.90 mmHg at diagnosis to 54.5 ± 6.70 mmHg after 2 weeks; P < 0.001) and mean pulmonary AT/ET ratio increased (change from 0.20 ± 0.06 to 0.33 ± 0.07; P < 0.001). Change in MPAP between diagnosis and after 2 weeks of reduced maternal intake of prostaglandin inhibitors was -12.2 ± 0.30 mmHg, which was 5.3-times higher than that in 305 normal fetuses over 2 weeks during the same gestational period (-2.3 ± 0.19 mmHg) (P < 0.001), and change in pulmonary AT/ET ratio between the two assessments was 0.13 ± 0.08, which was 8.7-times higher than that in normal fetuses in the same gestational period (0.015 ± 0.08) (P < 0.001). CONCLUSIONS: Resolution of fetal ductal constriction is followed by a fall in MPAP and by an increase in pulmonary vascular maturity, to a significantly greater degree than is observed in normal fetuses in the same gestational-age period. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Progression in Fontan conduit stenosis and hemodynamic impact during childhood and adolescence.

OBJECTIVE: To characterize changes in Fontan conduit size over time and determine if cross-sectional area (CSA) affects cardiac output, pulmonary artery growth, and exercise capacity. METHODS: We conducted a retrospective cross-sectional study of patients with Fontan physiology who underwent cardiac magnetic resonance imaging or cardiac catheterization between January 2013 and October 2019. We collected Fontan and pulmonary artery measurements, hemodynamic data, and cardiopulmonary exercise test data. We identified 158 patients with an extracardiac Fontan. We measured minimum and mean Fontan conduit CSA and assessed whether these correlated with Nakata index, cardiac index, or exercise capacity. RESULTS: Minimum Fontan CSA decreased by a median of 33% (24%, 40%) during a mean follow-up of 9.6 years. Median percentage decrease in Fontan CSA did not differ among 16-, 18-, and 20-mm conduits (P = .29). There was a significant decrease in the minimum Fontan CSA (33% [25%, 41%]) starting less than 1-year post-Fontan. Median Nakata index was 177.6 mm2/m2 (149.1, 210.8) and was not associated with Fontan CSA/BSA (ρ = 0.09, P = .29). Fontan CSA/BSA was not associated with cardiac index (ρ = -0.003, P = .97). A larger Fontan CSA/BSA had a modest correlation with % predicted oxygen consumption (ρ = 0.31, P = .013). CONCLUSIONS: Fontan conduit CSA decreases as early as 6 months post-Fontan. The minimum Fontan CSA/BSA was not associated with cardiac index or pulmonary artery size but did correlate with % predicted peak oxygen consumption.

Long-term evolution of stents implanted in branch pulmonary arteries.

BACKGROUND: Branch pulmonary artery stenosis complicates the management of congenital heart diseases. Surgical branch pulmonary artery angioplasty is associated with a high reintervention rate. As an alternative, percutaneous or intraoperative branch pulmonary artery stents have been implanted to improve efficiency, but long-term evaluations are limited. AIM: To describe the long-term evolution of branch pulmonary artery stents. METHODS: We conducted a retrospective cohort study at Tours University Hospital. All stents implanted by surgery or catheterization in branch pulmonary arteries with a minimum follow-up of 12 months and at least one catheterization control were included. The primary endpoint combined cardiovascular mortality, surgical or percutaneous reintervention for stent complication or new stent implantation. RESULTS: Between 2007 and 2017, 76 stents in 51 patients were included (62 stents implanted by surgery, 14 by catheterization). At implantation, the patients' mean age and weight were 4.7years (interquartile range 4.2years) and 17.3kg (interquartile range 11.0kg), respectively. Mean branch pulmonary artery minimum diameter was 4.1±2.1mm (mean Z-score-4.9±2.9), and mean initial stent diameter was 9.1±3.1mm. During a follow-up of 5.3years (range 0-11.2 years), freedom from primary endpoint was 86.8% (95% confidence interval 79.6-94.8%) at 1 year, 71.5% (95% confidence interval 61.9-82.7%) at 5years and 69.6% (95% confidence interval 59.6-81.2%) at 10 years. We did not identify any factors associated with major adverse cardiovascular events. Among stents without major adverse cardiovascular events, the mean branch pulmonary artery diameter Z-score at last evaluation had increased by +4.8±3.2 compared with the initial diameter (P<0.001). After stent implantation, a median of 2 re-expansions were performed for each stent (range 0-7). CONCLUSIONS: Stent implantation should offer a good long-term solution for branch pulmonary artery stenosis, although iterative re-expansions are required.

Short to medium term outcomes of right ventricular outflow tract stenting as initial palliation for symptomatic infants with complete atrioventricular septal defect with associated tetralogy of Fallot.

OBJECTIVES: To assess the impact of right ventricular outflow tract (RVOT) stenting as the primary palliation in infants with complete atrioventricular septal defect with associated tetralogy of Fallot (cAVSD/TOF). BACKGROUND: Historically, palliation of symptomatic patients with cAVSD/TOF has been achieved through surgical systemic to pulmonary artery shunting. More recently RVOT stenting has evolved as an acceptable alternative in patients with tetralogy of Fallot. METHODS: Retrospective review of all patients with cAVSD/TOF who underwent RVOT stenting as palliation over a 13-year period from two large tertiary referral centers. RESULTS: Twenty-six patients underwent RVOT stenting at a median age of 57 days (interquartile range [IQR] 25.5-106.5). Median weight for stent deployment was 3.7 kg (IQR 2.91-5.5 kg). RVOT stenting improved oxygen saturations from a median of 72% (IQR 70-76%) to 90% (IQR 84-92%), p < .001. There was a significant increase in the median Z-score for both branch pulmonary arteries at median follow-up of 255 days (IQR 60-455). Eight patients required RVOT stent balloon dilatations and 8 patients required re-stenting for progressive desaturation. The median duration between reinterventions was 122 days (IQR 53-294 days). Four patients died during the follow-up period. No deaths resulted from the initial intervention. To date, definitive surgical intervention was achieved in 19 patients (biventricular repair n = 15) at a median age of 369 days (IQR 223-546 days). CONCLUSION: RVOT stenting in cAVSD/TOF is a safe and effective palliative procedure in symptomatic infants, promoting pulmonary artery growth and improving oxygen saturations.

c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells.

Angiogenic vasa vasorum (VV) expansion plays an essential role in the pathogenesis of hypoxia-induced pulmonary hypertension (PH), a cardiovascular disease. We previously showed that extracellular ATP released under hypoxic conditions is an autocrine/paracrine, the angiogenic factor for pulmonary artery (PA) VV endothelial cells (VVECs), acting via P2Y purinergic receptors (P2YR) and the Phosphoinositide 3-kinase (PI3K)-Akt-Mammalian Target of Rapamycin (mTOR) signaling. To further elucidate the molecular mechanisms of ATP-mediated VV angiogenesis, we determined the profile of ATP-inducible transcription factors (TFs) in VVECs using a TranSignal protein/DNA array. C-Jun, c-Myc, and Foxo3 were found to be upregulated in most VVEC populations and formed nodes connecting several signaling networks. siRNA-mediated knockdown (KD) of these TFs revealed their critical role in ATP-induced VVEC angiogenic responses and the regulation of downstream targets involved in tissue remodeling, cell cycle control, expression of endothelial markers, cell adhesion, and junction proteins. Our results showed that c-Jun was required for the expression of ATP-stimulated angiogenic genes, c-Myc was repressive to anti-angiogenic genes, and Foxo3a predominantly controlled the expression of anti-apoptotic and junctional proteins. The findings from our study suggest that pharmacological targeting of the components of P2YR-PI3K-Akt-mTOR axis and specific TFs reduced ATP-mediated VVEC angiogenic response and may have a potential translational significance in attenuating pathological vascular remodeling.

Pulmonary artery size is associated with functional clinical status in the Fontan circulation.

OBJECTIVE: In the Fontan circulation, non-pulsatile pulmonary blood flow is suggested to negatively affect pulmonary artery growth. The pulmonary vasculature is regarded a key determinant of outcome after Fontan completion. We hypothesised that in Fontan patients pulmonary artery size correlates with follow-up and functional clinical status. METHODS: This is a single-centre, cross-sectional cohort study. Thirty-nine paediatric and adult Fontan patients with a concomitant cardiac magnetic resonance (CMR) scan and a cardiopulmonary exercise test between 2012 and 2013 were included. CMR-derived left and right pulmonary artery cross-sectional areas were expressed as Nakata index. Functional status was defined as peak oxygen consumption (pVO2) indexed for weight, as percentage of predicted (pred) and as New York Heart Association Functional Class (NYHA-FC). RESULTS: Age at CMR was 18±7.2 years. Time since Fontan completion was 11.9±7.4 years. Nakata index was lower versus the reference values (238.6±78.5 vs 330±30 mm2/m2, p<0.001). Nakata index correlated negatively with age at CMR (r=-0.393, p=0.013) and time since Fontan completion (r=-0.341, p=0.034). pVO2 was 27.9±8.9 mL/min/kg and pVO2pred was 58.1%±14.1%. Nakata index correlated positively with pVO2 (r=0.468, p=0.003) and pVO2pred (r=0.353, p=0.028). Nakata index correlated negatively with NYHA-FC (r=-0.450, p=0.004). Nakata index was an independent predictor (ß=0.359, p=0.007) for pVO2 (adjusted R2=0.442, with maximum heart rate and oxygen pulse at peak exercise). CONCLUSIONS: Pulmonary artery size expressed as Nakata index is a novel independent predictor for functional clinical status. Nakata index negatively correlated with follow-up duration, suggesting that chronic abnormal non-pulsatile pulmonary blood flow plays a role in lagging pulmonary arterial growth in the Fontan circulation.

Pulmonary artery growth after Modified Blalock-Taussig shunt: A single center experience.

OBJECTIVE: This study evaluates growth of pulmonary artery (PA) between different age groups after Modified Blalock-Taussig shunt (MBTS) based on a single center experience. METHODS: We retrospective analyzed outcomes of 90 patients undergoing MBTS in our institute from January 1, 2010 to May 1, 2018. Patients were divided into three groups: Group 1, ≦2 months, Group 2, >2 months, ≦24 wmonths, Group 3, >24 months. The outcome included PA growth, overall survival rates and postoperative complications. RESULTS: 23 patients were involved in Group 1, while 49 in Group 2 and 18 in Group 3. The diameter of the PA, McGoon ratio, Nakata index and the oxygen saturation increased significantly after MBTS. Compared to pre-MBTS, there was no statistically significant increase of McGoon ratio in Group 3 after performing MBTS, but it witnessed less secondary cardiac surgery rate compared with Group 2 (11.11% vs. 48.98%, P = 0.005). Cumulative survival rates of three groups were 60.53%, 85.70%, 94.40% at 1 year; 60.53%, 78.30%, 87.75% at 3 years and 60.53%, 78.30%, 87.75% at 5 years. Multivariable analysis showed diastolic blood pressure <30 mmHg [OR 14.14 (1.92-104.32), P = 0.009], cardiopulmonary bypass use [OR 16.79 (2.05-137.67), P = 0.009] and single ventricle anomaly [OR 8.80 (1.18-65.54), P = 0.034] were predictors of perioperative mortality. CONCLUSION: MBTS in our institute is a conventional and effective procedure for growth of PA especially for patients younger than 24 months. Patients with biventricular anomaly, no cardiopulmonary bypass use in surgery and relatively high postoperative diastolic blood pressure will likely offer a good prognosis.

Choice of shunt type for the Norwood I procedure: does it make a difference?

OBJECTIVES: This study aimed to compare pulmonary artery (PA) growth between patients who received a right ventricle-to-PA (RV-PA) shunt and those who received a modified Blalock-Taussig shunt (mBTS). METHODS: All consecutive patients with hypoplastic left heart syndrome who underwent the Norwood I procedure between 2001 and 2017 were included in the study. Pre-stage 2 angiograms were analysed to measure the size of the PA. The Nakata index was calculated to estimate PA growth. The ratio of the right PA to left PA cross-sectional area (RPA/LPA) was used to calculate the difference in growth between the 2 branches. Study end points were shunt failure, shunt-related mortality and growth of the PAs. RESULTS: A total of 223 patients with hypoplastic left heart syndrome (RV-PA group = 137, mBTS group = 86) underwent the Norwood I procedure, and 186 patients (RV-PA n = 116, mBTS n = 70) achieved the stage 2 procedure. PA growth was better in patients with mBTS (Nakata index: RV-PA = 282, mBTS = 315 mm2/m2, P = 0.021). LPA growth was worse compared to RPA growth in both groups (RPA/LPA: RV-PA = 1.21, mBTS = 1.29, P = 1.0). Patients with RV-PA shunts experienced more frequent shunt stenosis compared to patients with mBTS (26 vs 2, P < 0.010). Freedom from shunt failure was 83.3 ± 3.2% and 94 ± 2% at 6 months in the RV-PA and mBTS groups, respectively (P = 0.003). CONCLUSIONS: PA growth is significantly better in patients who received an mBTS. Moreover, patients with an RV-PA shunt more frequently experienced shunt failure due to shunt stenosis. However, survival after the NW procedure is not shunt dependent and growth of the LPA is less pronounced than RPA, regardless of the shunt type.

Reconstruction of the pulmonary artery by a novel biodegradable conduit engineered with perinatal stem cell-derived vascular smooth muscle cells enables physiological vascular growth in a large animal model of congenital heart disease.

Lack of growth potential of available grafts represents a bottleneck in the correction of congenital heart defects. Here we used a swine small intestinal submucosa (SIS) graft functionalized with mesenchymal stem cell (MSC)-derived vascular smooth muscle cells (VSMCs), for replacement of the pulmonary artery in piglets. MSCs were expanded from human umbilical cord blood or new-born swine peripheral blood, seeded onto decellularized SIS grafts and conditioned in a bioreactor to differentiate into VSMCs. Results indicate the equivalence of generating grafts engineered with human or swine MSC-derived VSMCs. Next, we conducted a randomized, controlled study in piglets (12-15 kg), which had the left pulmonary artery reconstructed with swine VSMC-engineered or acellular conduit grafts. Piglets recovered well from surgery, with no casualty and similar growth rate in either group. After 6 months, grafted arteries had larger circumference in the cellular group (28.3 ±â€¯2.3 vs 18.3 ±â€¯2.1 mm, P < 0.001), but without evidence of aneurism formation. Immunohistochemistry showed engineered grafts were composed of homogeneous endothelium covered by multi-layered muscular media, whereas the acellular grafts exhibited a patchy endothelial cell layer and a thinner muscular layer. RESULTS: show the feasibility and efficacy of pulmonary artery reconstruction using clinically available grafts engineered with allogeneic VSMCs in growing swine.

The efficiency of systemic-to-pulmonary shunts in older children with hypoplastic pulmonary arteries.

BACKGROUND: To investigate the effects of systemic-to-pulmonary shunts (SPSs) in older children with hypoplastic pulmonary arteries and the factors affecting the development of the pulmonary arteries. METHODS: Eighty-six children (older than 3 years) who received SPSs were retrospectively analyzed. The perioperative parameters, the postoperative diameter of the pulmonary artery were collected, and the factors influencing the growth of the pulmonary arteries after an initial palliative shunt operation were analyzed. RESULTS: Two patients died postoperatively (2.33%), and the pulse oxygen saturation (SpO2 ) increased from 71.70 ± 6.75% preoperatively to 85.20 ± 11.07% at discharge. During the follow-up period of 56 (10-99) months, 37 patients (43.02%) underwent subsequent procedures, and in the remaining patients, the McGoon ratio was increased from 0.96 ± 0.48 at the surgery to 1.30 ± 0.31 at the final assessment (P < 0.05). Univariate analysis indicated that age younger than 5 years old (P < 0.05), pulmonary artery forward flow (P < 0.05) and a diagnosis of tetralogy of Fallot (P < 0.05) played positive roles in the growth of the pulmonary artery after surgery, while children with a McGoon ratio less than 0.6 showed poor development of the pulmonary arteries (P < 0.05). Multivariate analysis showed that age younger than 5 years old (P < 0.05) and pulmonary artery forward flow (P < 0.05) were positive effectors on the growth of the pulmonary artery. CONCLUSIONS: Older children with cyanotic congenital heart disease benefited from a systemic-pulmonary shunt and showed increased postoperative oxygen saturation and development of the pulmonary arteries. Age younger than 5 years and pulmonary artery antegrade flow were the positive factors influencing the growth of the pulmonary arteries postoperatively.

Utility of the Medtronic microvascular plug™ as a transcatheter implantable and explantable pulmonary artery flow restrictor in a swine model.

BACKGROUND: A surgical pulmonary artery band (PAB) is used to control excessive pulmonary blood flow for certain congenital heart diseases. Previous attempts have been made to develop a transcatheter, implantable pulmonary flow restrictor (PFR) without great success. We modified a microvascular plug (MVP) to be used as a PFR. The objectives of this study were to demonstrate feasibility of transcatheter implantation and retrieval of the modified MVP as a PFR, and compare PA growth while using the PFR versus PAB. METHODS AND RESULTS: The PFR was implanted in eight newborn piglets in bilateral branch pulmonary arteries (PAs). Immediately post-PFR implantation, the right ventricular systolic pressure increased from a median of 20-51 mmHg. Transcatheter retrieval of PFR was 100% successful at 3, 6, and 9 weeks and 50% at 12-weeks post-implant. A left PAB was placed via thoracotomy in four other newborn piglets. Debanding was performed 6-weeks later via balloon angioplasty. On follow-up, the proximal left PA diameters in the PFR and the PAB groups were similar (median 8 vs. 7.1 mm; p = 0.11); albeit the surgical band sites required repeat balloon angioplasty secondary to recurrent stenosis. By histopathology, there was grade II vessel injury in two pigs immediately post-retrieval of PFR that healed by 12 weeks. CONCLUSIONS: Transcatheter implantation and retrieval of the MVP as a PFR is feasible. PA growth is comparable to surgical PAB, which is likely to require reinterventions. The use of the MVP as a PFR in humans has to be trialed before recommending its routine use.

Reintervention Burden and Vessel Growth After Surgical Reimplantation of a Pulmonary Artery During Childhood.

Children requiring reimplantation of a branch pulmonary artery (PA) are at risk for postoperative stenosis and impaired growth of the reimplanted PA. Outcomes and risk factors for reintervention and impaired growth are incompletely described. We reviewed data on patients who underwent reimplantation of a branch PA between 1/1/99 and 5/1/15 at a single center. The primary outcome was reintervention to treat postoperative stenosis. The secondary outcome was "catch-up" growth (faster diameter growth of the affected PA compared with the unaffected PA from the preoperative to follow-up measurements.). Twenty-six patients were identified with a total follow-up of 102.2 patient-years (median 2.5 years). Diagnoses included LPA sling (n = 12) and isolated PA of ductal origin with (n = 7) or without (n = 7) tetralogy of Fallot (ToF). All had primary repair of the anomalous PA. Seventeen (65%) had reintervention with median time to first reintervention of 69 (range 1-1005) days and median of 1.5 (range 1-6) reinterventions. 94% of reinterventions were transcatheter (53% balloon and 41% stent angioplasty). Patients with reintervention were younger (hazard ratio 0.75 per log-day, p = 0.02) and lower weight (hazard ratio 0.18 per log-kg, p = 0.02) at initial repair. Of the 18 with PA growth data, 8 (44%) had catch-up growth. There were no identified differences between those who did and did not demonstrate catch-up growth. Despite a practice of primary reimplantation and aggressive postoperative reintervention, these results suggest that changes in strategy are needed or that there are intrinsic patient factors that have more influence on longer-term reimplanted PA growth.

Stenting of the Right Ventricular Outflow Tract Promotes Better Pulmonary Arterial Growth Compared With Modified Blalock-Taussig Shunt Palliation in Tetralogy of Fallot-Type Lesions.

OBJECTIVES: This study sought to compare pulmonary arterial (PA) growth during palliation after right ventricular outflow tract (RVOT) stenting versus modified Blalock-Taussig shunt (mBTS) in patients coming forward for complete repair of tetralogy of Fallot-type lesions. BACKGROUND: RVOT stenting is a recent alternative to mBTS in the initial palliation of selected patients with Fallot-type lesions. METHODS: This was a retrospective, single-center study of nonrandomized, consecutive palliated Fallot patients over a 10-year period. Differential left PA (LPA) and right PA (RPA) growth was assessed by serial echocardiograms in 67 patients after mBTS (n = 28) or RVOT stent (n = 39). Statistical data analysis was performed using mixed model analysis. RESULTS: RPA z-scores in the mBTS group improved from median -2.41 (interquartile range [IQR]: -2.97 to -1.32) to -1.13 (IQR: -1.68 to -0.59). LPA z-scores improved from -1.89 (IQR: -2.33 to -1.12) to -0.32 (IQR: -0.88 to -0.05). In the RVOT stenting group RPA z-scores improved from -2.28 (IQR: -3.28 to -1.82) to -0.72 (IQR: -1.27 to +0.48), and LPA z-scores from -2.08 (IQR: -2.90 to -0.61) to -0.05 (IQR: -0.88 to +0.48). Mixed model analysis showed significantly better RPA and LPA growth after RVOT stenting. The benefit of RVOT stenting versus mBTS was 0.599 z-scores for the LPA and 0.749 z-scores for the RPA. Rise in oxygen saturations was greater with RVOT stenting (p = 0.012). Median time to complete repair was shorter in the RVOT stent group (227 [142 to 328] days) compared with the mBTS group (439 [300 to 529] days; p < 0.0003). CONCLUSIONS: RVOT stenting promotes better pulmonary arterial growth and oxygen saturations compared with mBTS in the initial palliation of Fallot-type lesions.

Cysteine-rich 61 (Cyr61) upregulated in pulmonary arterial hypertension promotes the proliferation of pulmonary artery smooth muscle cells.

Background: We aimed to evaluate the expression of cysteine rich 61 (Cyr61) in patients with pulmonary arterial hypertension (PAH) as well as monocrotaline (MCT) induced PAH rat, and further investigate the effects and potential mechanisms of Cyr61 on the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Methods and Results: Plasma samples were collected from 20 patients with idiopathic PAH, 20 connective tissue disease (CTD) associated PAH, 29 age-, gender- and disease matched CTD without PAH patients, and 28 healthy controls. ELISA was used to detect the level of Cyr61 in plasma. MCT-induced PAH (MCT-PAH) rat model was established by a single subcutaneous injection of MCT (60mg·kg-1). Lung tissues and pulmonary arteries of rats were collected, while the PASMCs were dissected and cultivated for in vitro experiments. Expression of Cyr61 in the lung tissues, pulmonary arteries and PASMCs were tested by immunohistochemical staining, western blot and quantitative real-time polymerase chain reaction. PASMCs from PAH rats were stimulated by exogenous recombinant Cyr61 protein and knocked down by small interfering RNA. Cell Counting Kit-8 assay was used to identify cell proliferation and the expression of p-AKT and AKT were analysed by western blot. The results showed plasma level of Cyr61 in PAH patients, especially CTD-PAH patients, were significant higher than that of CTD without PAH patients and healthy controls. Compared with wild rats, Cyr61 was overexpressed in the lung tissue, pulmonary arterial and PASMCs in PAH rats. Exogenous recombinant Cyr61 protein promoted the proliferation of PASMCs in a dose-dependent manner. While the expression of Cyr61 in PASMCs was inhibited by specific siRNA, cell proliferation was restrained and the expression of p-AKT declined. Conclusion: Plasma Cyr61 concentration in PAH patients was highly increased. Cyr61 could promote PASMCs proliferation via AKT pathway, indicating that Cyr61 may play a role in the pathogenesis of PAH.