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Introduction: Over time and despite optimal medical management of patients with pulmonary hypertension (PH), the right ventricle (RV) function deteriorates from an adaptive to maladaptive phenotype, leading to RV failure (RVF). Although RV function is well recognized as a prognostic factor of PH, no predictive factor of RVF episodes has been elucidated so far. We hypothesized that determining RV metabolic alterations could help to understand the mechanism link to the deterioration of RV function as well as help to identify new biomarkers of RV failure. Methods: In the current study, we aimed to characterize the metabolic reprogramming associated with the RV remodeling phenotype during experimental PH induced by chronic-hypoxia-(CH) exposure or monocrotaline-(MCT) exposure in rats. Three weeks after PH initiation, we hemodynamically characterized PH (echocardiography and RV catheterization), and then we used an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry to analyze RV and LV tissues in addition to plasma samples from MCT-PH and CH-PH rat models. Results: CH exposure induced adaptive RV phenotype as opposed to MCT exposure which induced maladaptive RV phenotype. We found that predominant alterations of arginine, pyrimidine, purine, and tryptophan metabolic pathways were detected on the heart (LV+RV) and plasma samples regardless of the PH model. Acetylspermidine, putrescine, guanidinoacetate RV biopsy levels, and cytosine, deoxycytidine, deoxyuridine, and plasmatic thymidine levels were correlated to RV function in the CH-PH model. It was less likely correlated in the MCT model. These pathways are well described to regulate cell proliferation, cell hypertrophy, and cardioprotection. These findings open novel research perspectives to find biomarkers for early detection of RV failure in PH.

Introduction Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown aetiology. We aimed to better understand familial recurrence pattern. Methods An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, leading to investigate 1043 unrelated ccTGA probands. Results Atrioventricular block at diagnosis and laterality defects were observed in 35.4% and 29.9%, respectively. ccTGA associated with primary ciliary dyskinesia in 10 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (d-TGA: 28.4%), laterality defects (13.6%) and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and d-TGA and 9 familial co-segregation of ccTGA and laterality defects. In one family there was co-segregation of ccTGA, d-TGA and heterotaxy syndrome in 3 distinct relatives. Conclusion ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, d-TGA, laterality defects and in some cases primary ciliary dyskinesia strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Aims Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, Group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, Group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown. Methods and results We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in right ventricle and left ventricle. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular oedema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, right ventricle, left ventricle, and left atrium of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular oedema in AAC-Kcnk3-mutated rats. Conclusions Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.

International audience; Heart failure is the main cause of death in patients with pulmonary arterial hypertension and congenital heart disease. We used an original approach in a 15-year-old girl with rapidly progressive right heart failure secondary to severe pulmonary arterial hypertension and partial anomalous pulmonary venous return. After surgical congenital heart defect repair on cardiopulmonary bypass, she was weaned off bypass using a central Novalung for 11 days, then started on triple specific pulmonary vasodilator therapy.

Background Recently mutations in ABBC8 have been identified in patients with pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1 a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. In 2018, Bohnen M et al., demonstrated that each identified ABCC8 mutation leads to a loss of ABCC8/Kir6.2 function. However, the role of SUR1/Kir6.2 channel in PAH is unclear. We hypothesized that SUR1/Kir6.2 dysfunction contributes to pulmonary arteries (PA) remodeling in PAH and consequently, pharmacological activation of Sur1/Kir6.2 function could alleviate experimental pulmonary hypertension (PH) Methods and results We demonstrated that SUR1 and Kir6.2 expression are not significantly altered in lung and PA from human PAH or experimental models of PAH (monocrotaline (MCT) and Sugen/Hypoxia rats). In contrast, SUR1 and Kir6.2 expression are strongly reduced in right ventricular tissues from MCT rats. Using myograph experiments on isolated PA we showed that pharmacological activation of SUR1/Kir6.2 channels by diazoxide leads to PA relaxation. Moreover, the pharmacological inhibition of SUR1/Kir6.2 channels by nateglinide (100 μmol/L) before treatment with a thromboxane A2 mimetic causes PA hypercontraction. In vivo, long term (during 3 weeks of MCT-exposure) pharmacological activation of SUR1/Kir6.2 with diazoxide (20 mg/kg/day) significantly prevented MCT-induced PH in rats. Additionally, in vivo short term administration of diazoxide (last week of MCT-exposure) improved cardiac output and pulmonary vascular resistance. Finally, long-term exposure (3 weeks) to diazoxide in control rats had no consequences on hemodynamics, demonstrating the safety of this compound. Conclusions In PAH and experimental PH, SUR1/Kir6.2 expression are the same as in controls. In vivo long term pharmacological activation of SUR1/Kir6.2 alleviated MCT-induced PH. These results demonstrate that SUR1/Kir6.2 should be considered as a new therapeutic target and evaluated more thoroughly.

Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD. ispartof: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY vol:63 issue:1 pages:118-131 ispartof: location:United States status: published

Background Cardiac magnetic resonance (CMR) imaging with velocity encoding along all three directions of flow, known as 4DFlow CMR, provides both anatomical and functional information. Few data are available on the usefulness of 4DFlow CMR in everyday practice. Here, our objective was to investigate the usefulness of 4DFlow CMR for assessing congenital heart disease (CHD) in everyday practice. Methods From 2017 to 2019, consecutive patients who underwent 4DFlow CMR were included prospectively at a single high-volume centre. The parameters recommended by an expert's consensus statement for each diagnosis (congenital valvulopathy, septal defect, complex CHD, tetralogy of Fallot, aortic abnormalities) were assessed by two blinded experienced readers. 4DFlow CMRs that provided all recommended parameters were considered successful. Inter-observer and intra-observer agreement were investigated. Results We included 187 adults and 60 children covering broad ranges of weight (4.5–142 kg) and age (0.1–67 years). 4DFlow CMR was always the second-line imaging modality, after inconclusive echocardiography, and was successful in 231/247 (91%) patients, with no significant difference between children and adults (54/60, 90%; and 177/187, 95%; respectively; p = .13). Longer time using 4DFlow CMR at our centre was associated with success; in children, older age was also associated with exam success. There was an about 12-month learning curve in children. The success rate was lowest in neonates. Inter-observer and intra-observer agreement were substantial. Conclusion Our results suggest that 4DFlow CMR usually provides a comprehensive assessment of CHD in adults and children. A learning curve exists for children and the investigation remains challenging in neonates.

Extracorporeal life support and heart and/or lung transplant are the last resort in children with end-stage cardiac and/or pulmonary failure and short-term life threaten. Currently, circulatory support is used as a bridge to recovery or as a bridge to transplant but not as a destination therapy. The Excor Berlin Heart is the long-lasting external pneumatic ventricular assist system that is currently available from infancy to adulthood. Long-term prognosis after pediatric cardiac and/or pulmonary transplant is conditioned by the occurrence of graft failure, coronary disease of the cardiac graft, viral infections and bronchiolitis obliterans of the pulmonary graft, the incidence of which increase with time. The scarcity of grafts and the risk of acute rejection due to lack of compliance with immunosuppressive treatment require the transplant specialized teams to choose the best candidates according to psychosocial and biological criteria. The next expected developments concern mainly long-term ventricular assistance with systems that allow for greater autonomy and a return to the child's home.

Background In pediatric cardiac surgery, early extubation has been proved to be a safe and beneficial practice in most situations. However, it is not known if it is feasible in high-risk infants, notably neonates and infants undergoing complex surgical procedures. The aim of the study was to compare the prevalence of early extubation in a population of high-risk infants at two different eras and the factors associated with the duration of mechanical ventilation. Methods We compared two historical matched cohorts of 27 neonates and infants under 1 year of age. One cohort included patients of the year 2014 and the other patients of 2018 and 2019. The main endpoint was early extubation defined as extubation in the first 24 hours (H24) after surgery. We also analyzed hemodynamic variables, inotropic drugs use and presence or absence of delayed sternal closure. Results The duration of mechanical ventilation was significantly shorter in the more recent cohort (median of 40 h versus 69 h in the former cohort), data using the Kaplan–Meier method are presented in Fig. 1, with a log-rank test not significant. The rate of extubation before H24 after surgery, though more elevated, was not significantly different. This was associated with the use of a different inodilator (milrinone in the first era and enoximone in the second era) and a less frequent use of vasopressors. We also observed less delayed sternal closures in the second period (only 2 patients whereas there were 10 patients in the first period). In a subgroup analysis comparing infants without delayed sternal closure, the observed trends were still present but there was no significant difference on the main endpoint and the duration of mechanical ventilation. Conclusion Early extubation after pediatric cardiac surgery in high-risk infants tends to be more prevalent in recent times. Facilitating factors and best practices are not yet precisely defined especially concerning the hemodynamic management of patients.

Rationale: Pulmonary arterial hypertension is a severe lethal cardiopulmonary disease. Loss of function mutations in KCNK3 (potassium channel subfamily K member 3) gene, which encodes an outward rectifier K + channel, have been identified in pulmonary arterial hypertension patients. Objective: We have demonstrated that KCNK3 dysfunction is common to heritable and nonheritable pulmonary arterial hypertension and to experimental pulmonary hypertension (PH). Finally, KCNK3 is not functional in mouse pulmonary vasculature. Methods and Results: Using CRISPR/Cas9 technology, we generated a 94 bp out of frame deletion in exon 1 of Kcnk3 gene and characterized these rats at the electrophysiological, echocardiographic, hemodynamic, morphological, cellular, and molecular levels to decipher the cellular mechanisms associated with loss of KCNK3. Using patch-clamp technique, we validated our transgenic strategy by demonstrating the absence of KCNK3 current in freshly isolated pulmonary arterial smooth muscle cells from Kcnk3 -mutated rats. At 4 months of age, echocardiographic parameters revealed shortening of the pulmonary artery acceleration time associated with elevation of the right ventricular systolic pressure. Kcnk3 -mutated rats developed more severe PH than wild-type rats after monocrotaline exposure or chronic hypoxia exposure. Kcnk3 -mutation induced a lung distal neomuscularization and perivascular extracellular matrix activation. Lungs of Kcnk3 -mutated rats were characterized by overactivation of ERK1/2 (extracellular signal–regulated kinase1-/2), AKT (protein kinase B), SRC, and overexpression of HIF1-α (hypoxia-inducible factor-1 α), survivin, and VWF (Von Willebrand factor). Linked with plasma membrane depolarization, reduced endothelial-NOS expression and desensitization of endothelial-derived hyperpolarizing factor, Kcnk3 -mutated rats presented predisposition to vasoconstriction of pulmonary arteries and a severe loss of sildenafil-induced pulmonary arteries relaxation. Moreover, we showed strong alteration of right ventricular cardiomyocyte excitability. Finally, Kcnk3 -mutated rats developed age-dependent PH associated with low serum-albumin concentration. Conclusions: We established the first Kcnk3 -mutated rat model of PH. Our results confirm that KCNK3 loss of function is a key event in pulmonary arterial hypertension pathogenesis. This model presents new opportunities for understanding the initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.

Background: Monoallelic mutations in the gene encoding bone morphogenetic protein receptor 2 ( Bmpr2 ) are the main genetic risk factor for heritable pulmonary arterial hypertension (PAH) with incomplete penetrance. Several Bmpr2 transgenic mice have been reported to develop mild spontaneous PAH. In this study, we examined whether rats with the Bmpr2 mutation were susceptible to developing more severe PAH. Methods: The zinc finger nuclease method was used to establish rat lines with mutations in the Bmpr2 gene. These rats were then characterized at the hemodynamic, histological, electrophysiological, and molecular levels. Results: Rats with a monoallelic deletion of 71 bp in exon 1 (Δ 71 rats) showed decreased BMPRII expression and phosphorylated SMAD1/5/9 levels. Δ 71 Rats develop age-dependent spontaneous PAH with a low penetrance (16%–27%), similar to that in humans. Δ 71 Rats were more susceptible to hypoxia-induced pulmonary hypertension than wild-type rats. Δ 71 Rats exhibited progressive pulmonary vascular remodeling associated with a proproliferative phenotype and showed lower pulmonary microvascular density than wild-type rats. Organ bath studies revealed severe alteration of pulmonary artery contraction and relaxation associated with potassium channel subfamily K member 3 (KCNK3) dysfunction. High levels of perivascular fibrillar collagen and pulmonary interleukin-6 overexpression discriminated rats that developed spontaneous PAH and rats that did not develop spontaneous PAH. Finally, detailed assessments of cardiomyocytes demonstrated alterations in morphology, calcium (Ca 2+ ), and cell contractility specific to the right ventricle; these changes could explain the lower cardiac output of Δ 71 rats. Indeed, adult right ventricular cardiomyocytes from Δ 71 rats exhibited a smaller diameter, decreased sensitivity of sarcomeres to Ca 2+ , decreased [Ca 2+ ] transient amplitude, reduced sarcoplasmic reticulum Ca 2+ content, and short action potential duration compared with right ventricular cardiomyocytes from wild-type rats. Conclusions: We characterized the first Bmpr2 mutant rats and showed some of the critical cellular and molecular dysfunctions described in human PAH. We also identified the heart as an unexpected but potential target organ of Bmpr2 mutations. Thus, this new genetic rat model represents a promising tool to study the pathogenesis of PAH.

IntroductionA reduction in pulmonary artery relaxation is a key event in the pathogenesis of pulmonary arterial hypertension (PAH). Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in airway epithelial cells plays a central role in cystic fibrosis; CFTR is also expressed in pulmonary arteries and has been shown to control endothelium-independent relaxation.Aim and objectivesWe aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models.Methods and resultsReverse-transcriptase quantitative PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in pulmonary arteries from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myography on human, pig and rat pulmonary arteries, we demonstrated that CFTR activation induces pulmonary artery relaxation. CFTR-mediated pulmonary artery relaxation was reduced in pulmonary arteries from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularisation. Pathologic assessment of lungs from patients with severe cystic fibrosis (F508del-CFTR) revealed severe pulmonary artery remodelling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularisation. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats.ConclusionsCFTR expression is strongly decreased in pulmonary artery smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces pulmonary artery relaxation.

The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications.

Background Early and easy to do detection of left ventricular (LV) failure is crucial to improve following and outcomes of patients with right ventricular (RV) overload in congenital heart diseases. Electrical cardiometry (Osypka medical) is easy handling, even in medical office or in pre-hospital condition, and can provide cardiac output, and a new contractility index (ICON) supposed to be independent from load conditions. ICON have never been previoulsy challenged to our knowledge. Objectives We aim to compare ICON with the only contractility parameter independent from load conditions: the elastance slope (Emax). Methods Using porcine models of Fallot repaired and pulmonary hypertension (PH), we assess LV function using conductance catheter and electrical cardiometry devices over 4 months after surgery. We measured ICON, Emax, Contractile reserve (ΔEmax) and VIC (respiratory variations of ICON) at basal state and after adrenergic stimulation (Dobutamine). Results Three animals of each group were compared with 6 controls. Non parametric correlation (spearman) hightlights at basal state a non significant and low correlation between ICON and Emax and ΔEmax (r = 0.5). However after Dobutamine, correlation is important and strong with r = 0.98 between ICON/Emax (0.05) and 0.89 between VIC/Emax. We did not find strong correlation between ΔEmax and VIC or ΔICON. Conclusion These results obtain on a small in vivo/animal cohort highlight than electrical cardiometry device could be a usefull and easy handling (4 skin patchs) tool for LV failure and loss of contractility early screening, specially after adrenergic stimulation and stress conditions. It could provide precious help in patients following.

Objectives:Mechanical circulatory support for pediatric heart failure patients with the Berlin Heart EXCOR ventricular assist system is the only approved and established bridging strategy for recovery or heart transplantation. In recent years, the burden of thromboembolic events has led to modifications of the recommended antithrombotic therapy. Therefore, we aimed to assess modifications of antithrombotic practice among the European EXCOR Pediatric Investigator Group members.Methods:We sent a questionnaire assessing seven aspects of antithrombotic therapy to 18 European hospitals using the EXCOR device for children. Returned questionnaires were analyzed and identified antithrombotic strategies were descriptively compared to “Edmonton protocol” recommendations developed for the US EXCOR pediatric approval study.Results:Analysis of 18 received surveys revealed substantial deviations from the Edmonton protocol, including earlier start of heparin therapy at 6–12 h postoperatively and in 50% of surveyed centers, monitoring of heparin effectiveness with aPTT assay, administering vitamin K antagonists before 12 months of age. About 39% of centers use higher international normalized ratio targets, and platelet inhibition is changed in 56% including the use of clopidogrel instead of dipyridamole. Significant inter-center variability with multiple deviations from the Edmonton protocol was discovered with only one center following the Edmonton protocol completely.Conclusion:Current antithrombotic practice among European EXCOR users representing the treatment of more than 600 pediatric patients has changed over time with a trend toward a more aggressive therapy. There is a need for systematic evidence-based evaluation and harmonization of developmentally adjusted antithrombotic management practices in prospective studies toward revised recommendations.

Summary Background Transcatheter pulmonary valvuloplasty in neonates with pulmonary atresia and intact ventricular septum (PA-IVS) or duct-dependent pulmonary valve stenosis (DD-PVS) has become a reasonable alternative to surgical right ventricle decompression. Aim To investigate mid-term outcomes following pulmonary valvuloplasty. Methods Sixty-five neonates with PA-IVS (n = 29) or DD-PVS (n = 36) (median age 4 days; mean weight 3.0 kg) undergoing pulmonary valvuloplasty were reviewed retrospectively. Procedural data and clinical outcomes were assessed. Results Pulmonary valvuloplasty was successful in 59 patients (90.8%). Preterm birth, larger tricuspid valve annulus diameter and PA-IVS correlated with procedural failure. Eleven patients (18.6%) required a Blalock-Taussig shunt during early follow-up, despite valvuloplasty. These neonates had smaller tricuspid and pulmonary valve annulus Z-scores (–1.9 vs. –0.8 [p = 0.04] and –2.5 vs. –0.9 [P = 0.005], respectively) and a higher incidence of “bipartite” right ventricle (P = 0.02). Mean follow-up was 5.4 ± 3.3 years. Mortality after successful valvuloplasty was 8.5% (n = 5). Among the 54 survivors, biventricular repair was achieved in 52 patients (96.3%), including nine with a previous Blalock-Taussig shunt. The cumulative rate of subsequent surgery (excluding Blalock-Taussig shunt) was 13.7% (95% confidence interval 6.8–26.7%) and 16.4% (95% confidence interval 8.5–30.4%) at 2 and 4 years, respectively. Secondary surgery was significantly more frequent in PA-IVS compared with DD-PVS, and in neonates with a Blalock-Taussig shunt (P = 0.003 and 0.01, respectively). Conclusions Selected neonates with DD-PVS or PA-IVS managed by transcatheter pulmonary valvuloplasty had a good mid-term outcome. In neonates with a borderline small right ventricle, a hybrid strategy with a supplementary source of pulmonary blood flow can be efficient to achieve biventricular repair.

Aims Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are severely reduced in pulmonary vascular cells, promoting PH-like phenotype at the morphologic and haemodynamic levels. Since KCNK3 channel is also expressed in both the human and rodent heart, we aimed to elucidate the pathophysiological role of KCNK3 channel in right ventricular (RV) hypertrophy (RVH) related to PH. Methods and results Using whole-cell Patch-clamp technique, we demonstrated that KCNK3 is predominantly expressed in adult rat RV cardiomyocytes compared to the left ventricle cardiomyocytes and participates in the repolarizing phase of the RV action potential. We revealed a reduction in KCNK3 function prior to development of RVH and the rise of pulmonary vascular resistance. KCNK3 function is severely reduced in RV cardiomyocytes during the development of RVH in several rat models of PH (exposure to monocrotaline, chronic hypoxia, and Sugen/hypoxia) and chronic RV pressure overload (pulmonary artery banding). In experimental PH, we revealed a reduction in KCNK3 function before any rise in pulmonary vascular resistance and the development of RVH. KCNK3 mRNA level is also reduced in human RV tissues from PAH patients compared to non-PAH patients. In line with these findings, chronic inhibition of KCNK3 in rats with the specific inhibitor (A293) induces RV hypertrophy which is associated with the re-expression of foetal genes, RV fibrosis, RV inflammation, and subsequent loss of RV performance as assessed by echocardiography. Conclusion Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.

PDE3 is considered as the main isoform controlling cardiac function in large mammals. Recently, we showed that PDE4 controls cAMP levels upon β-adrenergic (βAR) regulation in human atrial [1] and canine ventricular cells [2] . However, it was reported that it does not influence contractility of human failing myoardium [3] . Thus, a role for PDE4 to control cardiac excitation-contraction coupling (ECC) in larger mammals is controversial. Here, we investigated the role of PDE4 to control cAMP levels and ECC in a porcine model of repaired tetralogy of Fallot (rToF), which leads to heart failure. PDE4A, 4B and 4D isoforms were detected in the heart, with decreased expression in rToF. Isolated right ventricular myocytes (RVMs) from control (Ctrl) and rToF pigs were loaded with 1 μM Fura-2 and paced at 1 Hz to record simultaneously Ca2+ transients and sarcomere shortening, or infected with an adenovirus encoding the cAMP FRET sensor epacH187 to evaluate intracellular cAMP levels. In Ctrl RVMs, inhibition of PDE3 with cilostamide (Cil, 1 μM) or PDE4 with Ro-201724 (Ro, 10 μM) modestly affected basal cAMP levels while concomitant inhibition of both enzymes had a strong influence (+130 ± 14%, n = 12, P

Background Early and easy to do detection of left ventricular (LV) failure is crucial to improve following and outcomes of patients with right ventricular (RV) overload in congenital heart diseases. Electrical cardiometry (Osypka medical) is easy handling, even in medical office or in pre-hospital condition, and can provide cardiac output, and a new contractility index (ICON) supposed to be independent from load conditions. ICON have never been previously challenged to our knowledge. Objectives We aim to compare ICON with the only contractility parameter independent from load conditions: the elastance slope (Emax). Methods Using porcine models of Fallot repaired and pulmonary hypertension (PH), we assess LV function using conductance catheter and electrical cardiometry devices over 4 months after surgery. We measured ICON, Emax, Contractile reserve (ΔEmax) and VIC (respiratory variations of ICON) at basal state and after adrenergic stimulation (Dobutamine). Results Three animals of each group were compared with 6 controls. Non parametric correlation (spearman) hightlights at basal state a non significant and low correlation between ICON and Emax and ΔEmax (r = 0.5). However after Dobutamine, correlation is important and strong with r = 0.98 between ICON/Emax (0.05) and 0.89 between VIC/Emax. We did not find strong correlation between ΔEmax and VIC or ΔICON. Conclusion These results obtain on a small in vivo/animal cohort highlight than electrical cardiometry device could be a useful and easy handling (4 skin patchs) tool for LV failure and loss of contractility early screening, specially after adrenergic stimulation and stress conditions. It could provide precious help in patients following.

Hypoplastic left heart syndrome (HLHS) is a severe anomaly. In France prenatal diagnostic is systematically associated with proposal for pregnancy termination. However still many newborns are referred for surgical management. The aim of the present study was to evaluate our recent experience with Norwood type univentricular palliation with particular emphasis to the surgical technique used. The records of 44 consecutive patients who underwent procedure by Marie-Lannelongue and Jacques-Cartier Hospitals’ team between 2010 and 2018 were reviewed. The study group included 28 (64%) HLHS, 6 (14%) hypolplastic left heart complex, 2 (4.5%) unbalanced AV canal. Norwood-Sano procedure was performed in 29 (66%), conventional Norwood in 7 (16%). A modification of Norwood- procedure using a intravascular Aorta-pulmonaru artery separation patch with hole was performed in 6 and the remaining 2 underwent hybrid-2 stage management. Three patients who underwent conventional Norwood procedure had been managed for biventricular pathway initially however converted in single ventricle pathway. The mortality occurred in 8 (18%, 70% CL 13-25%) patients including all death until stage 2, superior cavopulmonary shunt procedure. The outcome after Norwood-Sano/conventional Norwood procedures were superior to the modified technique (P = 0.19). From 36 survivors, 16 had their 2nd stage and 6 their 3rd stage with total cavo-pulmonary shunt procedure. Two patients were converted to biventricular repair. One patient died after 2nd stage. Despite the lack of conviction for referral, the management of HLHS and similar conditions were managed with favourable outcome. Technical modification that excludes conventional techniques, associated with poorer outcomes, must be avoided.

OBJECTIVES: Electrical cardiometry and heart ultrasound might allow hemodynamic evaluation during transportation of critically ill patients. Our aims were 1) to test feasibility of stroke volume monitoring using electrical cardiometry or ultrasound during transportation and 2) to investigate if transportation impacts on electrical cardiometry and ultrasound reliability. DESIGN: Prospective, pragmatic, feasibility cohort study. SETTING: Mobile ICUs specialized for neonatal and pediatric transportation. PATIENTS: Thirty hemodynamically stable neonates and infants. INTERVENTIONS: Patients enrolled underwent paired stroke volume measurements (180 before/after and 180 during the transfer) by electrical cardiometry (SVEC) and ultrasound (SVUS). MEASUREMENTS AND MAIN RESULTS: No problems or malfunctioning occurred neither with electrical cardiometry nor with ultrasound. Ultrasound lasted on average 90 (10) seconds, while 45 (15) seconds were needed to instigate electrical cardiometry monitoring. Coefficient of variation was higher for SVUS (before/after: 0.57; during: 0.66) than for SVEC (before/after: 0.38; during: 0.36). Correlations between SVEC and SVUS before/after and during the transfer were r equal to 0.57 and r equal to 0.8, respectively (p always \textless 0.001). Bland-Altman analysis showed that stroke volume tends to be higher if measured by electrical cardiometry. SVEC measured before (5.5 [2.4] mL), during (5.4 [2.4] mL), and after the transfer (5.4 [2.3] mL) are similar (p = 0.955); same applies for SVUS before (2.6 [1.5] mL), during (2.4 [2] mL), and after (2.9 [2] mL) the transfer (p = 0.268). CONCLUSIONS: Basic hemodynamic monitoring is feasible during pediatric and neonatal transportation both with electrical cardiometry and ultrasound. These two techniques show comparable reliability, although stroke volume was higher if measured by electrical cardiometry. The transportation itself does not affect the reliability of stroke volume measurements.

Background Pulmonary arterial hypertension (PAH) is a dreaded complication of ostium secundum atrial septal defects (ASD). Shunt closure indication remains controversial in patients with severe PAH. Purpose To investigate late outcome in selected patients with severe PAH who underwent percutaneous ASD closure. Methods We retrospectively included 14 patients (median age 47.5 years old) with mean pulmonary artery pressure (PAPm) > 40 mmHg and/or pulmonary vascular resistance indexed (PVRi) > 8 UW.m2, with persistent left to right shunting, who underwent percutaneous ASD closure. Results Three patients (21.4%) had ASD and coexisting etiology of PAH (chronic thromboembolic pulmonary hypertension, n = 1; familial form of PAH, n = 1; BMPR2 mutation, n = 1). All patients had dyspnea with 6 (42.8%) in WHO functional class (FC) 3–4. Four patients (28.6%) received PAH drugs (monotherapy, n = 3; triple therapy including intravenous prostacyclin, n = 1). Median [interquartile] PAPm and PVRi were 44 mmHg [41–47] and 9.7 UW.m2 [8.0–10.3]. Median delay between symptoms onset and shunt closure was 12 months [6–18]. Median Qp/Qs was 2.0 [1.6–2.2]. During early follow-up, WHO FC 2 was unchanged in 3 patients (21%), while the remaining 11 patients (79%) had clinical improvement. No patient died. After a median follow-up of 93 months [43–133], all patients were in WHO FC 1 or 2. PAPm at last catheterization (n = 10) had decreased in all cases. Median PAPm was 28 mmHg [26–32]. PAPm was below 25 mmHg in 3 cases. Median PVRi was 8.0 UW.m2 [6.4–9.0]. The 4 patients without catheterization were in WHO-FC 1 and with normal pulmonary pressure on echography. Five patients receiving PAH therapy (monotherapy, n = 3; double therapy, n = 2). Three patients died (one from lung infection, 6 years after closure and two from cancer, 1 and 2 years after closure). Conclusion Improved WHO FC and decreased pulmonary pressure are observed in carefully selected patients with severe PAH after ASD closure.

Background Percutaneous pulmonary valve implantation (PPVI) remains technically challenging. Purpose We describe the early results of PPVI with the SAPIEN 3 (S3) valve facilitated by a large delivery sheath. Methods We designed a prospective, single cohort study. Results Between December 2017 and April 2018, 16 patients (median age 24 y/o; median weight 70 kg) underwent PPVI with the SAPIEN 3 using a 65 cm, 26Fr GORE® DrySeal delivery sheath. Through the sheath, the landing zone was stented, then the valve implanted during the same procedure. PPVI was performed on native or patched outflow tract in 75.0% of patients. Pre-stenting was performed in 13 cases (81.3%). While advancing the sheath through the stent, stent migration occurred in one case. The stent was moved back and PPVI performed. Size 23, 26 and 29 valves were successfully implanted in 2, 3 and 11 cases, respectively. Median post valve gradient was 2 mmHg. Minor paravalvular leak was reported in 2 cases. Median fluoroscopy time was 18 min. Vessel access minimal hematomas and vessel access delayed healing were reported in 4 cases (25.0%) and in one case (6.3%) without any secondary procedure or blood transfusion. Conclusion A large delivery sheath allows a fast and safe PPVI with the S3 valve.

Background The SAPIEN 3 valve (S3) is the latest iteration of the SAPIEN valve family. It is deployed using a low profile flexible Commander delivery system. Hemodynamic outcomes and device durability are promising with SAPIEN valves, but percutaneous pulmonary valve implantation (PPVI) remains difficult. Moreover, the lack of valve covering increases the risk of tricuspid valve injury. Objectives To described the early results of a modified procedure for PPVI of the SAPIEN S3 valve using a delivery sheath. Methods We report the first consecutive cases of a modified procedure for PPVI of the SAPIEN S3 valve using a DryGore Seal 26French 65 cm delivery sheath. The sheath was used to stent the right ventricular outflow tract and then for the valve implantation. Results PPVI was performed using the modified technique in 15 patients (mean age 31 yo; mean weight 72.5 kg). The most common diagnoses were conotruncal defect (53.3%) and congenital aortic valve disease with Ross surgery (13.3%). A right-ventricle-to-pulmonary-artery tube had been inserted in 20.0% and a homograft or bioprosthesis implanted in 13.3% and 17.7% of patients, respectively. PPVI was performed on the native or patched RVOT in 73.3% of patients. Prestenting was performed in 12 cases with Andrastent XXL in 11 cases and eV3 LD max in 1 case. Prestenting was performed during the same procedure in all cases. While advancing the sheath through the stent, stent embolization occurred in one case. The stent was impacted and moved back with post dilatation and implantation of a second stent. SAPIEN 3 No. 23, No. 26 and No. 29 were implanted in 2, 3 and 10 cases. Valves were successfully implanted in all cases using the delivery sheath. Mean post valve gradient was 3 mmHg. Minor paravalvular leak was reported in 2 cases. Mean fluoroscopy time was 26.8 min. Groin hematoma were reported in 4 cases (26.7%). Conclusion A delivery sheath allows a fast and safe PPVI of SAPIEN S3 valve.

To investigate the accuracy of electrical cardiometry (EC) to measure stroke volume (SV) and cardiac output (CO) and to provide gestational age (GA) and birth weight (BW)-based reference data for SV and CO in hemodynamically stable preterm neonates.Prospective observational blinded study. Paired measurements of SV and CO on stable preterm infants without any hemodynamic compromise were carried out using EC (SVEC) and echocardiography (SVECHO).Seventy-nine preterm neonates (mean GA: 31±3.2 weeks) were enrolled. A good correlation was found for SV (r=0.743; P0.0001) and CO (r=0.7; P0.0001) measured by EC and echocardiography. These correlations remained significant after adjusting for GA, patent ductus arteriosus and type of respiratory support (SV: St.β=0.48, P0.0001 and CO: St.β=0.69, P0.0001). Mean biases (and variabilities) were -1.1 (from 0.7 to -2.9) ml and -0.21 (from 0.15 to -0.55) l min(-1) for SV and CO, respectively. Local regression shows a tendency for EC to overestimate SV and CO especially at higher values (at about2 ml and0.4 l min(-1), respectively). Coefficient of variation of SV was 48.9% and 52%, for EC and echocardiography. SV and CO rose with increasing GA and BW following an exponential equation (R(2)0.8).Measuring SV and CO with EC in hemodynamically stable preterm infants shows good correlation and variability similar to that of echocardiography. A trend to overestimation exists at highest values, but it is unlikely to be clinically significant. Reference GA and BW-based nomograms for SV and CO are provided.

Background Evaluation of cardiac output in neonates might be difficult because of the complexity and risks of invasive classical procedures. New systems like electrical cardiometry (EC: Osypka Medical, Berlin, Germany and La Jolla, California, USA) have been proposed but few data are available in neonates. We investigated stroke volume (SV) using EC in term and preterm infants. Methods Eligible patients were neonates admitted to the NICU and undergoing echocardiography for any clinical reasons, without congenital heart disease. We measured SV with EC and echocardiography, within 10 min. Measurements were repeated 6 times by the same operator to calculate repeatability before and after echocardiography. Data have been compared with correlation and Bland-Altman analysis. Results 59 neonates were enrolled, allowing 150 paired measurements. Mean gestational age and birth weight were 33.9 ± 3.4 wks and 1988 ± 823 g, respectively. Results of Pearson correlation and Bland-Altman analysis for the whole population were (r = 0.611; p Correlation is maintained even with PDA (r = 0.627; p Gestational age seems to do not influence the correlation between EC and echo (Partial correlation coefficient r = 0.36; p Repeatability (coefficient of variation) was 46% for EC and 52% for echocardiography. There was no difference in SV measured by EC after 10 min (3.76 ± SD vs 3.78 ± SD; p = 0.56, Wilcoxon test). Conclusions EC is feasible, reproducible and quick. It could be an useful tool for continuous monitoring and haemodynamic evaluation in neonates. EC is particularly interesting for the clinical management of preterm neonates.

Background Electrical cardiometry (EC: Osypka Medical, Berlin, Germany and La Jolla, California, USA) is a new non-invasive technique for haemodynamic monitoring of neonates. No data are available for preterm babies during respiratory procedures, such as elective extubation or chest physiotherapy. We designed this study to clarify if these procedures have any haemodynamic consequences. Methods We assessed stroke volume (SV), cardiac output (CO), contractility index (ICON) and heart rate (HR) with EC before and after 5, 10, 15, 30 and 60 min from elective extubation or physiotherapy sessions with accelerated expiratory flow [Demont B et al , Physiotherapy 2007;93:12–16]. Functional echocardiography has been performed by the same operator before and after 60 min from the above-described respiratory procedures. Infants with congenital heart disease were not eligible. Results Eleven (for physiotherapy) and thirteen (for extubation) preterm infants were enrolled. Gestational age and birth weight were 29.2 ± 0.5 wks and 1313 ± 915 g, respectively. Fig.1 shows trends of SV, CO, ICON and HR before and after the procedures: no differences were noticed (p = 0.318 for SV; p = 0.559 for CO; p = 0.23 for ICON;p = 0.78 for HR, Friedman test). No differences were found analysing separately extubation and physiotherapy groups. Conclusions No haemodynamic changes are visible during elective extubation or chest physiotherapy in preterm infants. These preliminary results deserve further evaluation studying cerebral oxygenation with NIRS.

Introduction Regionalization in perinatal care improved neonatal survival for 2 decades. Perinatal transport is known to be a bad prognostic factor for preterm neonates born in second level centres. No data exist for babies born in TCC who had to be transferred to other TTC. We evaluate short term clinical outcomes of preterm infants transferred between TCC. Methods We retrospectively analysed all neonates aged ≤32 weeks gestation transferred before 6 h of life from the South Paris University Hospitals to another TCC. Transfer was due to organisational problems. Control group consisted of neonates born the month before or after the cases and matched for gestational age, birth weight and CRIB-II. Simple linear and logistic regressions were used for analysis. Results We included 60 cases and 60 controls. The two groups were similar for basic clinical characteristics. No difference in clinical features (RDS, infection related respiratory failure, air leaks, hypotension) were present between the groups (Table 1). Early outcomes (IVH, periventricular leucomalacy, NEC, BPD and NICU stay) rates were not influenced by the transfer transport ((Table 1) Conclusions Perinatal transfer for preterm babies born in a TCC is not a negative prognostic factor. It is conceivable that optimal care in delivery room is a keystone for better outcome.