Synergic PDE3 and PDE4 control intracellular cAMP and cardiac excitation-contraction coupling in a porcine model

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Pumpless Lung Assist as a Bridge to Medical Therapy in a Teenager With Pulmonary Arterial Hypertension and Partial Anomalous Pulmonary Venous Return

International audienceHeart 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

Ca 2+ handling remodeling and STIM1L/Orai1/TRPC1/TRPC4 upregulation in monocrotaline-induced right ventricular hypertrophy

International audienceBackground Right ventricular (RV) function is the most important prognostic factor for pulmonary arterial hypertension (PAH) patients. The progressive increase of pulmonary vascular resistance induces RV hypertrophy (RVH) and at term RV failure (RVF). However, the molecular mechanisms of RVH and RVF remain understudied. In this study, we gained insights into cytosolic Ca 2+ signaling remodeling in ventricular cardiomyocytes during the pathogenesis of severe pulmonary hypertension (PH) induced in rats by monocrotaline (MCT) exposure, and we further identified molecular candidates responsible for this Ca 2+ remodeling. Methods and Results After PH induction, hypertrophied RV myocytes presented longer action potential duration, higher and faster [Ca 2+ ]i transients and increased sarcoplasmic reticulum (SR) Ca 2+ content, whereas no changes in these parameters were detected in left ventricular (LV) myocytes. These modifications were associated with increased P-Ser 16-phospholamban pentamer expression without altering SERCA2a (Sarco/Endoplasmic Reticulum Ca 2+-ATPase) pump abundance. Moreover, after PH induction, Ca 2+ sparks frequency were higher in hypertrophied RV cells, while total RyR2 (Ryanodine Receptor) expression and phosphorylation were unaffected. Together with cellular hypertrophy, the T-tubules network was disorganized. Hypertrophied RV cardiomyocytes from MCT-exposed rats showed decreased expression of classical STIM1 (Stromal Interaction molecule) associated with increased expression of muscle-specific STIM1 Long isoform, glycosylated-Orai1 channel form, and TRPC1 and TRPC4 channels, which was correlated with an enhanced Ca 2+-release-activated Ca 2+ (CRAC)like current. Pharmacological inhibition of TRPCs/Orai1 channels in hypertrophied RV cardiomyocytes normalized [Ca 2+ ]i transients amplitude, the SR Ca 2+ content and cell contractility to control levels. Finally, we showed that most of these changes did not appear in LV cardiomyocytes. Conclusions These new findings demonstrate RV-specific cellular Ca 2+ cycling remodeling in PH rats with maladaptive RVH and that the STIM1L/Orai1/TRPC1/C4-dependent Ca 2+ current participates in this Ca 2+ remodeling in RVH secondary to PH

Assistance circulatoire et transplantation d’organes thoraciques chez l’enfant

International audienceExtracorporeal 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.L’assistance circulatoire et la transplantation cardiaque et/ou pulmonaire pédiatrique sont les ultimes recours chez l’enfant ayant une défaillance cardiaque et/ou respiratoire terminale avec échec des traitements conventionnels et risque vital engagé à court terme. Actuellement, l’assistance circulatoire est utilisée en attente de récupération ou de transplantation mais pas en stratégie à long terme. Le Berlin Heart Excor est le système d’assistance ventriculaire pneumatique externe de longue durée actuellement disponible du nouveau-né jusqu’à l’âge adulte. Le pronostic à long terme après transplantation cardiaque et/ou pulmonaire pédiatrique est conditionné par la survenue d’une défaillance du greffon, par la maladie coronaire du greffon cardiaque, par les infections virales et la bronchiolite oblitérante du greffon pulmonaire, dont les incidences augmentent avec le temps. La pénurie de greffons et le risque de rejet aigu de greffon par défaut de compliance au traitement immunosuppresseur imposent un choix par les équipes spécialisées des candidats à la greffe en fonction de critères psychosociaux et biologiques. Les prochains développements attendus concernent surtout les assistances ventriculaires de longue durée avec des systèmes permettant d’envisager une plus grande autonomie et un retour à domicile de l’enfant

Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload

International audienceAbstract 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

Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension

International audienceAims: 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