Publications by authors named "Maurice Beghetti"

180 Publications

Nitric Oxide-cGMP Pathway Modulation in an Experimental Model of Hypoxic Pulmonary Hypertension.

J Cardiovasc Pharmacol Ther 2021 May 8:10742484211014162. Epub 2021 May 8.

Department Cœur-Vaisseaux, Cardiac Surgery Center, 30635University Hospital of Lausanne, Lausanne, Switzerland.

Manipulation of nitric oxide (NO) may enable control of progression and treatment of pulmonary hypertension (PH). Several approaches may modulate the NO-cGMP pathway in vivo. Here, we investigate the effectiveness of 3 modulatory sites: (i) the amount of l-arginine; (ii) the size of plasma NO stores that stimulate soluble guanylate cyclase; (iii) the conversion of cGMP into inactive 5'-GMP, with respect to hypoxia, to test the effectiveness of the treatments with respect to hypoxia-induced PH. Male rats (n = 80; 10/group) maintained in normoxic (21% O) or hypoxic chambers (10% O) for 14 days were subdivided in 4 sub-groups: placebo, l-arginine (20 mg/ml), the NO donor molsidomine (15 mg/kg in drinking water), and phoshodiesterase-5 inhibitor sildenafil (1.4 mg/kg in 0.3 ml saline, i.p.). Hypoxia depressed homeostasis and increased erythropoiesis, heart and right ventricle hypertrophy, myocardial fibrosis and apoptosis inducing pulmonary remodeling. Stimulating anyone of the 3 mechanisms that enhance the NO-cGMP pathway helped rescuing the functional and morphological changes in the cardiopulmonary system leading to improvement, sometimes normalization, of the pressures. None of the treatments affected the observed parameters in normoxia. Thus, the 3 modulatory sites are essentially similar in enhancing the NO-cGMP pathway, thereby attenuating the hypoxia-related effects that lead to pulmonary hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/10742484211014162DOI Listing
May 2021

Double-root inversion for complex malposition of the great arteries with tricuspid valve straddling.

Multimed Man Cardiothorac Surg 2021 03 8;2021. Epub 2021 Mar 8.

University Hospital of Geneva University Hospital of Laussane Switzerland.

Dextro-transposition of the great vessels associated with pulmonary stenosis, double-outlet right ventricle, and straddling of the tricuspid valve is an uncommon condition. Several treatment options are available for this malformation, but most of them are not optimal. For patients with transposition of the great vessels, the gold standard procedure, which is an arterial switch procedure, would usually be performed, whereas for patients with pulmonary stenosis, a Rastelli operation or a Nikaidoh procedure would be proposed. Both of these methods have several advantages and disadvantages. Selected patients can qualify for the double-root rotation procedure, which is limited by the function of the pulmonary and aortic valves, the position of the coronary arteries, and the skill of the surgeon[1]. After a thorough analysis of all the preoperative test results, our patient qualified for a surgical correction of the malformation. Due to preexisting pulmonary regurgitation and severe dilation of the pulmonary root, the patient was not considered a good candidate for the arterial switch operation. Therefore, it was decided that the double-root inversion was the best option. Introduction The double-root inversion gives the patient the possibility of avoiding a reoperation. If the patient were to have the Nikaidoh or the Rastelli procedure, we know that the pulmonary graft would eventually have to be replaced. For this reason, we would like to share our experience with the double-root inversion method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1510/mmcts.2021.016DOI Listing
March 2021

Long-term outcome of liver transplantation for congenital extrahepatic portosystemic shunt.

Liver Transpl 2021 Mar 22. Epub 2021 Mar 22.

Service d'Hépatologie et de Transplantation Hépatique et de radiologie Pédiatriques. Groupement Hospitalier Paris Sud (GHUPS), Hôpital Bicêtre, LE KREMLIN BICETRE, France.

We read with great interest the report by Uchida et al on the long-term outcomes of liver transplantation for congenital porto-systemic shunts (CPSS). We are in full agreement with the authors that there is an era effect in this report as we now know that most of the indications for liver transplantation in this series can be corrected by endovascular or surgical closure: hyperammonemia, hepatopulmonary syndrome, non-malignant nodules. The other notable feature of this report is the young age of patients at transplant with 19/26 patients having undergone transplantation before the age of 9 years, and 14/26 before the age of 5 years, of which two were for portopulmonary hypertension (POPH).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lt.26055DOI Listing
March 2021

Reliable Detection of Intrapulmonary Shunts Using Contrast-Enhanced Echocardiography in Children With Portal Hypertension or Portosystemic Shunt.

J Pediatr Gastroenterol Nutr 2021 07;73(1):73-79

Pediatric Sport Medicine and Obesity Care Program, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Switzerland.

Objectives: The aim of this study was to analyze if contrast-enhanced echocardiography (CEE) is as reliable as lung perfusion scintigraphy (LPS) to detect intrapulmonary shunting (IPS) in children with portal hypertension (PHTN) or congenital/surgical portosystemic shunts (PSS) and to define the number of cardiac cycles required to exclude intrapulmonary shunting.

Methods: Inclusion criteria for this cross-sectional study were: (1) presence of PHTN or PSS diagnosed on abdominal ultrasound, (2) technically valid saline contrast echocardiography, (3) lung perfusion scintigraphy within 6 months of CEE. The number of cardiac cycles between right atrial opacification and the arrival of contrast in the left atrium were counted. We analyzed our CEE data at three and five cardiac cycles and compared them with LPS results.

Results: The study population was composed of 78 children (38 girls, 49%) ages 2.1-18.8 years (mean 9.8). Sixty-nine patients had PHTN (88%), and nine had a PSS (11%). Eleven subjects (14%) presented evidence of IPS on LPS. Peripheral oxygen saturation was lower in the subjects with IPS detected on LPS (95.3 ± 1.7% vs 99.0 ± 1.4%; P < 0.01). Comparison of LPS with CEE before three and five cardiac cycles showed that CEE is highly specific (95.7%) as early as three cardiac cycles with markedly better sensitivity (72.7%) when using five cardiac cycles. Furthermore, a negative study using five cardiac cycles ruled out IPS with a 95% negative predictive value. The cardiac cycle at which the bubbles appeared in the left atrium was inversely correlated to the shunt index measured using LPS (r = -0.563; P = 0.001).

Conclusion: CEE is sufficient for the screening of IPS in children with PHTN or congenital/surgical PSS, obviating the need for LPS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000003079DOI Listing
July 2021

"Micro-Bentall" procedure.

Multimed Man Cardiothorac Surg 2020 12 24;2020. Epub 2020 Dec 24.

University Hospital of Geneva University Hospital of Laussane Switzerland.

Truncus arteriosus, an anomaly of the conotruncus, is an extremely rare congenital heart disease that affects 1.19% of all patients with congenital heart diseases.  We present a surgical technique using an 8-mm cryopreserved aortic root homograft in the aortic position and a 12-mm pulmonary valved conduit in the right position that allowed us to correct this rare congenital malformation.  The cryopreserved aortic root homograft was considered a priority option for surgical correction.  The neonatal Bentall (micro-Bentall) procedure is a surgically demanding procedure but can be performed successfully by an experienced surgeon.  If we were performing a non-salvage procedure, we would have chosen a decellularized allograft.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1510/mmcts.2020.079DOI Listing
December 2020

Home respiratory polygraphy in obstructive sleep apnea syndrome in children: Comparison with a screening questionnaire.

Int J Pediatr Otorhinolaryngol 2021 Apr 27;143:110635. Epub 2021 Jan 27.

Pediatric Pulmonary Unit, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva and University of Geneva, Switzerland. Electronic address:

Objectives: The prevalence of obstructive sleep apnea syndrome (OSAS) in children referred for sleep-disordered breathing reaches up to 59%. We aimed to test the adequacy of a questionnaire compared to home respiratory polygraphy (HRP), in 45 subjects (5-16 years-old), without maxillofacial malformations nor other comorbidities, presenting with symptoms compatible with OSAS.

Methods: All children passed a 12-items questionnaire (Obstructive Airway Child test: OACT) and the HRP. OSAS was classified in severity according to the apnea-hypopnea index (AHI).

Results: With HRP, 60% and 15% children were detected to have at least mild (AHI ≥1) and moderate (AHI >5) OSAS, respectively. The sensitivity of the questionnaire to detect mild and moderate OSAS was good (93% and 71%, respectively) but the specificity was very low (11% and 34%). However, an OACT score under 61 showed a very good negative predictive value for moderate and severe OSAS (87%). With the questionnaire, we could have avoided a complementary PSG or HRP in 25/45 (56%) of our subjects as in children with mild OSAS and without comorbidities only clinical observation is usually advised.

Conclusions: The OACT questionnaire has shown to be a good and quick instrument to exclude moderate and severe OSAS in our population of children without maxillofacial malformations. Indeed children scoring under 61 could avoid a constraining and expensive sleep exam. However, if the score is above this cut-off, the performance to recognize OSAS is low and the child's evaluation must be completed by a HRP or PSG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijporl.2021.110635DOI Listing
April 2021

Selexipag for the treatment of pulmonary arterial hypertension.

Expert Rev Respir Med 2021 May 31;15(5):583-595. Epub 2020 Dec 31.

Pulmonary Hypertension Program, Geneva University Hospitals, Geneva, Switzerland.

Introduction: : Pulmonary arterial hypertension (PAH) is a rare pulmonary vasculopathy. This review focuses on selexipag, a prostacyclin receptor agonist validated for the treatment of PAH.

Areas Covered: We review the structure, mechanisms of action, pharmacokinetics, and pharmacodynamics of selexipag. Clinical efficacy and tolerability are discussed using the main clinical trial published for selexipag (GRIPHON) and its post-hoc analysis.

Expert Opinion: Selexipag should be added as a triple oral combination therapy in case of insufficient response to oral combination therapy with endothelin receptor antagonist and phosphodiesterase 5 inhibitor. However, selexipag should not replace parenteral prostacyclin in high-risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17476348.2021.1866990DOI Listing
May 2021

A 13-Year-Old Male With Diagnosed Idiopathic Pulmonary Hypertension: Is it Really Idiopathic?

Chest 2020 12;158(6):e295-e298

Pediatric Cardiology Unit, University Hospitals of Geneva, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, University of Geneva and Lausanne, Switzerland.

Case Presentation: A 13-year-old male was referred after incidental finding of cardiomegaly on chest radiograph and signs of pulmonary hypertension on subsequent cardiology consult. He was diagnosed with idiopathic pulmonary hypertension, and came to our center for a second opinion. He was born from consanguineous parents. He reported to be asymptomatic in his daily life. He was not on medications. Family history was not contributive.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2020.07.016DOI Listing
December 2020

Outcome of paediatric portopulmonary hypertension in the modern management era: A case report of 6 patients.

J Hepatol 2021 Mar 1;74(3):742-747. Epub 2020 Dec 1.

Pediatric Cardiology Unit, Children's University Hospital, Geneva, Switzerland; Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Children's University Hospitals, Lausanne and Geneva, Switzerland; Pulmonary Hypertension Program, University Hospitals of Geneva, Geneva, Switzerland.

Portopulmonary hypertension is a rare but serious complication of portal hypertension or portosystemic shunting. Portopulmonary hypertension is an indication for liver transplantation or shunt closure. However, liver transplantation is contraindicated in patients with severe pulmonary arterial hypertension. Reported mortality rates are high in children with portopulmonary hypertension and there are scarce recommendations on its management. Our aim was to report on our real-world experience of managing portopulmonary hypertension in a specialised centre. We describe a series of 6 children with portopulmonary hypertension. Their median age at diagnosis was 13 years (range 10-15). The underlying liver conditions were cirrhosis of unknown origin (1), congenital portocaval shunts (3), biliary atresia (1), and portal vein cavernoma with surgical mesenterico-caval shunt (1). Median mean pulmonary arterial pressure was 47 mmHg (range 32-70), and median pulmonary vascular resistance was 6.6 Wood units (range 4.3-15.4). All patients except one were treated with a combination of pulmonary arterial hypertension-specific therapy (phosphodiesterase type 5 inhibitors and/or endothelin receptor antagonists and/or prostacyclin analogues). Three patients then benefited from shunt closure and the others underwent liver transplantation. Five patients showed improvement or stabilisation of pulmonary arterial hypertension with no deaths after a mean follow-up of 39 months. Based on our limited experience, early and aggressive treatment with a combination of pulmonary arterial hypertension-specific therapy significantly improves patients' haemodynamic profile and enables the performance of liver transplantation and shunt closure with satisfactory outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.11.039DOI Listing
March 2021

Unexpected Acceleration in Treprostinil Delivery Administered by a Lenus Pro® Implantable Pump in Two Patients Treated for Pulmonary Arterial Hypertension.

Front Med (Lausanne) 2020 30;7:539707. Epub 2020 Oct 30.

Division of Pneumology, University Hospitals of Geneva, Genève, Switzerland.

Intravenous treprostinil administration by an implantable pump is an attractive option for pulmonary arterial hypertension (PAH) treatment and is the subject of recent publications. Short-term studies are promising, but there is still a lack of long-term prospective data. We analyzed the treprostinil flow rate administered by the Lenus Pro® implantable pump in 2 patients suffering from PAH during follow-up times of respectively 4.2 and 3 years. The flow rate delivered by the pumps in these 2 patients exceeded the manufacturer admitted margin of error within 2 years and continued to increase to reach, respectively, 158 and 120% of the expected flow rate at the end of the follow up. In one case, the implantable pump had to be removed for this reason. The flow rate of the withdrawn pump determined in the laboratory reached 173% of the predicted value. This correlated with the measurement, which suggests a continuous flow increase even after pump removal and without treprostinil use. Spontaneous flow increase from such an implantable pump is a potentially major pitfall, which needs to be identified and actively managed by the responsible clinicians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2020.539707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662390PMC
October 2020

Immunological assessment of pediatric multisystem inflammatory syndrome related to COVID-19.

J Pediatric Infect Dis Soc 2020 Nov 12. Epub 2020 Nov 12.

Children's Hospital of Geneva, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.

Background: Recently, cases of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 have been reported worldwide. Negative RT-PCR testing associated with positive serology in most cases suggests a post-infectious syndrome. Because the pathophysiology of this syndrome is still poorly understood, extensive virological and immunological investigations are needed.

Methods: We report a series of four pediatric patients admitted to Geneva University Hospitals with persistent fever and laboratory evidence of inflammation meeting published definition of MIS-C related to COVID-19, to whom an extensive virological and immunological workup was performed.

Results: RT-PCRs on multiple anatomical compartments were negative whereas anti-SARS-CoV-2 IgA and IgG were strongly positive by ELISA and immunofluorescence. Both pseudo- and full virus neutralization assays showed the presence of neutralizing antibodies in all children, confirming a recent infection with SARS-CoV-2. Analyses of cytokine profiles revealed an elevation in all cytokines, as reported in adults with severe COVID-19. Although differing in clinical presentation, some features of MIS-C show phenotypic overlap with haemophagocytic lymphohistiocytosis (HLH). In contrast to patients with primary HLH, our patients showed normal perforin expression and NK cell degranulation. The levels of soluble IL-2 receptor (sIL-2R) correlated with the severity of disease, reflecting recent T-cell activation.

Conclusion: Our findings suggest that MIS-C related to COVID-19 is caused by a post-infectious inflammatory syndrome associated with elevation in all cytokines, and markers of recent T-cell activation (sIL-2R) occurring despite a strong and specific humoral response to SARS-CoV2. Further functional and genetic analyses are essential to better understand the mechanisms of host-pathogen interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jpids/piaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717282PMC
November 2020

Risk Factors for Postprocedural Arterial Ischemic Stroke in Children With Cardiac Disease.

Stroke 2020 09 19;51(9):e242-e245. Epub 2020 Aug 19.

Department of Neonatology, University of Basel Children's Hospital (UKBB), Switzerland (M.I.H.).

Background And Purpose: Cardiac pathologies are the second most frequent risk factor (RF) in children with arterial ischemic stroke (AIS). This study aimed to analyze RFs for AIS in children with cardiac disease and cardiac intervention.

Methods: Data were drawn from the Swiss Neuropediatric Stroke Registry. Patients with cardiac disease and postprocedural AIS registered from 2000 until 2015 were analyzed for the cause of cardiac disease and for potential RFs.

Results: Forty-seven out of 78 children with cardiac disease had a cardiac intervention. Of these, 36 presented a postprocedural AIS. Median time from cardiac intervention to symptom onset was 4 days (interquartile range, 2-8.5); time to diagnosis of AIS was 2 days (interquartile range, 0-5.8). Main RFs for postprocedural AIS were hypotension, prosthetic cardiac material, right-to-left shunt, arrhythmias, low cardiac output, and infections.

Conclusions: In children with postprocedural AIS, time to diagnosis was delayed. Most patients presented multiple potentially modifiable RFs as hemodynamic alterations and infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.120.029447DOI Listing
September 2020

Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic.

Circulation 2020 08 17;142(5):429-436. Epub 2020 May 17.

M3C-Necker Enfants Malades, AP-HP, Paris, France (Z.B., M.M., F.B., D.K., A.L., S.A., J.A., M.G., M.O., S.M.-M., A.M., L.H., S.R., D.B.).

Background: Cardiac injury and myocarditis have been described in adults with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the multisystem inflammatory syndrome in children as defined by the US Centers for Disease Control and Prevention.

Methods: Over a 2-month period, contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state.

Results: Thirty-five children were identified and included in the study. Median age at admission was 10 years (range, 2-16 years). Comorbidities were present in 28%, including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one-third; 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation. Inflammation markers were suggestive of cytokine storm (interleukin-6 median, 135 pg/mL) and macrophage activation (D-dimer median, 5284 ng/mL). Mean BNP (B-type natriuretic peptide) was elevated (5743 pg/mL). Thirty-one of 35 patients (88%) tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. All patients received intravenous immunoglobulin, with adjunctive steroid therapy used in one-third. Left ventricular function was restored in the 25 of 35 of those discharged from the intensive care unit. No patient died, and all patients treated with extracorporeal membrane oxygenation were successfully weaned.

Conclusions: Children may experience an acute cardiac decompensation caused by severe inflammatory state after SARS-CoV-2 infection (multisystem inflammatory syndrome in children). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048360DOI Listing
August 2020

SCN8A heterozygous variants are associated with anoxic-epileptic seizures.

Am J Med Genet A 2020 05 10;182(5):1209-1216. Epub 2020 Feb 10.

Pediatric Neurology Unit, Child and Adolescent Department, Geneva University Hospitals, Geneva, Switzerland.

Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61513DOI Listing
May 2020

Effects of oral sildenafil on exercise capacity in children with pulmonary arterial hypertension: a randomised trial.

Open Heart 2019;6(2):e001149. Epub 2019 Dec 3.

Division of Pediatric Cardiology, Department of Pediatrics and Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, USA.

Objective: The 16-week, randomised, double-blind Sildenafil in Treatment-Naïve Children, Aged1-17 years, with Pulmonary Arterial Hypertension (STARTS-1) study assessed the effect of sildenafil on cardiopulmonary exercise testing (CPET) in treatment-naïve paediatric patients with pulmonary arterial hypertension (PAH) and included a long-term extension (STARTS-2). CPET has rarely been performed in paediatric patients and we assessed both aerobic capacity with peak oxygen consumption (PVO) and ventilatory inefficiency with the slope of ventilation to carbon dioxide production (VE/VCO slope).

Methods: Patients (aged 1-17 year) were randomised to low (10 mg), medium (10-40 mg) and high (20-80 mg) sildenafil dose groups. Patients previously treated with placebo in STARTS-1 were randomised to one of three blinded sildenafil dose groups for STARTS-2. CPET was assessed by cycle ergometry at baseline, week 16, and year 1.

Results: Of the 234 children randomised, 115 could exercise. At week 16, the combined sildenafil dose group had a 7.7% increase in mean PVO percent change from baseline compared with placebo (95% CI -0.2% to 15.6%; p=0.056); at year 1, a significant increase in mean percent change in PVO from baseline was only observed in the low-dose group (mean of 12.4% and 95% CI 3% to 21.8%). For VE/VCO slope, at week 16, the combined dose group had a -9.7% mean change from baseline compared with placebo (95% CI -14.9% to -4.5%; p<0.001); at year 1, there were no significant changes for any dose group.

Conclusions: Sildenafil monotherapy (combined sildenafil dose group) appeared to improve short-term VE/VCO slope versus placebo but did not significantly improve PVO in treatment-naïve paediatric patients with PAH who were developmentally able to exercise.

Trial Registration Number: NCT00159913 for A1481131, NCT00159874 for A1481156.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/openhrt-2019-001149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927510PMC
February 2021

Recommendations from the Association for European Paediatric and Congenital Cardiology for training in pulmonary hypertension.

Cardiol Young 2019 Nov 26;29(11):1323-1327. Epub 2019 Sep 26.

Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover, Germany.

Pulmonary hypertension is a complex and progressive condition that is either idiopathic or heritable, or associated with one or multiple health conditions, with or without congenital or acquired cardiovascular disease. Recent developments have tremendously increased the armamentarium of diagnostic and therapeutic approaches in children and young adults with pulmonary hypertension that is still associated with a high morbidity and mortality. These modalities include non-invasive imaging, pharmacotherapy, interventional and surgical procedures, and supportive measures. The optimal, tailored diagnostic and therapeutic strategies for pulmonary hypertension in the young are rapidly evolving but still face enormous challenges: Healthcare providers need to take the patient's age, development, disease state, and family concerns into account when initiating advanced diagnostics and treatment. Therefore, there is a need for guidance on core and advanced medical training in paediatric pulmonary hypertension. The Association for European Paediatric and Congenital Cardiology working group "pulmonary hypertension, heart failure and transplantation" has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S104795111900235XDOI Listing
November 2019

Vasoreactive Pulmonary Arterial Hypertension Manifesting With Misleading Epileptic Seizure: Diagnostic and Treatment Pitfalls.

Front Pediatr 2019 4;7:262. Epub 2019 Jul 4.

Pediatric Cardiology Unit and Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Lausanne University Hospital (CHUV), Geneva University Hospitals (HUG), University of Geneva, Geneva, Switzerland.

A 5-year-old girl presented with acute nocturnal episodes of loss of consciousness following abdominal pain and crying. Epilepsy was primarily diagnosed but the course of the disease was suggestive of pulmonary hypertension. An adapted invasive assessment of pulmonary pressure and pharmacological challenge allowed for diagnosing vasoreactive pulmonary arterial hypertension. Initial treatment with sildenafil was not effective. Thus, calcium channel blockers were introduced when positive vasoreactivity was confirmed and permitted to stop the occurrence of the syncope and dramatically improved clinical status. At 2 years follow-up she is well without any complaint and in functional class I. Echocardiography shows a slightly enlarged but not hypertrophied right ventricle with a nearly normalized estimated right ventricular pressure. The last catheterization shows subnormal values of pulmonary arterial pressure (mean pulmonary artery pressure: 24 mmHg) and pulmonary vascular resistance (5, 4 Wood unitsm), normalizing with inhaled Nitric Oxide (mean pulmonary artery pressure of 14 mmHg and pulmonary vascular resistance of 1.5 Wood unitsm). Vasoreactive pulmonary arterial hypertension is a rare entity in children but it should not be misdiagnosed with seizures due to the presence of syncopal episodes. According to current knowledge, this form seems to have a better prognosis than non-reactive pulmonary arterial hypertension and the treatment of choice remains as calcium channel blockers. The management of this case was characterized by successive mishaps and potentially harmful mistakes and underscores the potential risk with pediatric PH evaluation in non-expert centers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2019.00262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621927PMC
July 2019

Treatment of pediatric pulmonary arterial hypertension: A focus on the NO-sGC-cGMP pathway.

Pediatr Pulmonol 2019 10 16;54(10):1516-1526. Epub 2019 Jul 16.

M3C-Paediatric Cardiology, Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France.

Objective: While pulmonary arterial hypertension (PAH) is rare in infants and children, it results in substantial morbidity and mortality. In recent years, prognosis has improved, coinciding with the introduction of new PAH-targeted therapies, although much of their use in children is off-label. Evidence to guide the treatment of children with PAH is less extensive than for adults. The goal of this review is to discuss the treatment recommendations for children with PAH, as well as the evidence supporting the use of prostanoids, endothelin receptor antagonists (ERAs), and phosphodiesterase type 5 inhibitors (PDE5i) in this setting.

Data Sources: Nonsystematic PubMed literature search and authors' expertise.

Study Selection: Articles were selected concentrating on the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway in PAH. The methodology of an ongoing study evaluating the sGC stimulator riociguat in children with PAH is also described.

Results: Despite recent medical advances, improved therapeutic strategies for pediatric PAH are needed. The efficacy and tolerability of riociguat in adults with PAH have been well trialed.

Conclusion: The pooling of data across trials, supplemented by registry data, will help to confirm the safety and tolerability of prostanoids, ERAs, and PDE5i in children. Ongoing studies will clarify the place of sGC stimulators in the treatment strategy for pediatric PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ppul.24442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771736PMC
October 2019

Effects of PDE-5 Inhibition on the Cardiopulmonary System After 2 or 4 Weeks of Chronic Hypoxia.

Cardiovasc Drugs Ther 2019 08;33(4):407-414

Department Cœur-Vaisseaux, Cardiac Surgery center, University Hospital of Lausanne, Lausanne, Switzerland.

Purpose: In pulmonary hypertension (PH), hypoxia represents both an outcome and a cause of exacerbation. We addressed the question whether hypoxia adaptation might affect the mechanisms underlying PH alleviation through phosphodiesterase-5 (PDE5) inhibition.

Methods: Eight-week-old male Sprague-Dawley rats were divided into two groups depending on treatment (placebo or sildenafil, a drug inhibiting PDE5) and were exposed to hypoxia (10% O) for 0 (t0, n = 9/10), 2 (t2, n = 5/5) or 4 (t4, n = 5/5) weeks. The rats were treated (0.3 mL i.p.) with either saline or sildenafil (1.4 mg/Kg per day).

Results: Two-week hypoxia changed the body weight (- 31% vs. - 27%, respectively, P = NS), blood hemoglobin (+ 25% vs. + 27%, P = NS) and nitrates+nitrites (+ 175% vs. + 261%, P = 0.007), right ventricle fibrosis (+ 814% vs. + 317%, P < 0.0001), right ventricle hypertrophy (+ 84% vs. + 49%, P = 0.007) and systolic pressure (+ 108% vs. + 41%, P = 0.001), pulmonary vessel density (+ 61% vs. + 46%, P = NS), and the frequency of small (< 50 µm wall thickness) vessels (+ 35% vs. + 13%, P = 0.0001). Most of these changes were maintained for 4-week hypoxia, except blood hemoglobin and right ventricle hypertrophy that continued increasing (+ 52% vs. + 42%, P = NS; and + 104% vs. + 83%, P = 0.04). To further assess these observations, small vessel frequency was found to be linearly related with the right ventricle-developed pressure independent of hypoxia duration.

Conclusions: Thus, although hypoxia adaptation is not yet accomplished after 4 weeks, PH alleviation by PDE5 inhibition might nevertheless provide an efficient strategy for the management of this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10557-019-06887-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689028PMC
August 2019

Impact of Liver Diseases on Heart and Lungs.

JACC Cardiovasc Imaging 2019 10 15;12(10):2071-2075. Epub 2019 May 15.

Department of Radiology, APHP, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France, and University Paris Diderot, Sorbonne Paris Cité, Paris, France; INSERM U1149, Centre de Recherche de L'inflammation, CRI, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmg.2019.03.020DOI Listing
October 2019

Meaningful and feasible composite clinical worsening definitions in paediatric pulmonary arterial hypertension: An analysis of the TOPP registry.

Int J Cardiol 2019 08 25;289:110-115. Epub 2019 Apr 25.

M3C-Necker, Paediatric Cardiology, Reference Centre for Complex Congenital Heart Diseases, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France.

Background: Composite clinical worsening (cCW) outcomes might allow measurement of disease progression in paediatric pulmonary arterial hypertension (PAH). This TOPP registry analysis investigated three cCW outcomes and their predictive strength for lung transplantation/death.

Methods: Patients ≤17 years with idiopathic/familial PAH or PAH-associated congenital heart disease diagnosed ≤3 months before enrolment were included. cCW outcomes included the following variables at enrolment and/or follow-up: all-cause death, PAH-related hospitalisation, lung transplantation, atrial septostomy (cCW1, 2 and 3), WHO FC deterioration, intravenous/subcutaneous prostanoids initiation, syncope (cCW2,3) and occurrence/worsening of ≥2 PAH symptoms (cCW3). The predictive value of CW (excluding transplantation and death) to transplantation or death was assessed. Predictive values of each cCW for lung transplantation/death were analysed by Cox proportional hazards models.

Results: From 255 patients, first-event rate/100 person-years (95% CI) were cCW1: 23.1(19.3,27.6), cCW2: 43.6(37.6,50.6), and cCW3: 46.3(40.0,53.7) with PAH-related hospitalisation as the most frequent first event in each. The cCW definitions comprised from endpoints (excluding transplantation and death), were associated with higher risk [hazard ratio (95% CI)] for lung transplantation/death [4.23(2.27,7.91), 3.25(1.65,6.39), 2.74(1.41,5.34), respectively]; individual parameters with higher risks were WHO FC deterioration [3.49(1.47,8.29)], PAH-related hospitalisation [2.62(1.32,5.20)] and occurrence/worsening of ≥2 PAH symptoms [2.13(1.02,4.45)].

Conclusions: These data support the use of cCW outcomes in paediatric PAH research. WHO FC deterioration, PAH-related hospitalisation, occurrence/worsening of ≥2 PAH symptoms may be important for risk assessment during clinical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2019.04.062DOI Listing
August 2019

Diagnosis and treatment of pediatric pulmonary arterial hypertension.

Expert Rev Cardiovasc Ther 2019 Mar 12;17(3):161-175. Epub 2019 Feb 12.

a Pediatric Cardiology Unit , University Children's Hospital of Geneva , Geneva , Switzerland.

Introduction: Pediatric pulmonary arterial hypertension (PAH) remains a rare and severe disease with a poor prognosis. PAH may be idiopathic, heritable or associated with systemic conditions in particular associated with congenital heart disease. Areas covered: A thorough and extensive diagnostic approach is required for a correct diagnosis. The outcome has improved over the last decade with a better diagnostic approach and with the initiation of new targeted therapies. However, there is still significant progress to achieve as there is still no cure for this devastating disease. Expert opinion: Adapted clinical studies to define the best therapeutic approach are needed. Even if the treatment approach is still mainly derived from adult data and expert consensus, several studies and registries are currently underway and should deliver important information in the next future. This review aims to give an overview of the current diagnosis and treatment strategies of PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14779072.2019.1576523DOI Listing
March 2019

Early Diagnosis in Pulmonary Arterial Hypertension: The Search for the Holy Grail.

Am J Respir Crit Care Med 2019 Jun;199(11):1306-1307

2 Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique University of Geneva Geneva, Switzerland and.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201812-2314EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543727PMC
June 2019

Selexipag treatment for pulmonary arterial hypertension associated with congenital heart disease after defect correction: insights from the randomised controlled GRIPHON study.

Eur J Heart Fail 2019 03 11;21(3):352-359. Epub 2019 Jan 11.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Bologna University Hospital, Bologna, Italy.

Aims: Patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) after defect correction have a poor prognosis compared with other CHD-PAH patients. Therefore, it is important that these patients are treated as early and effectively as possible. Evidence supporting the use of PAH therapies in patients with corrected CHD-PAH from randomised controlled trials is limited. The purpose of these analyses was to characterise the corrected CHD-PAH patients from the GRIPHON study and examine the response to selexipag.

Methods And Results: Out of the 110 patients diagnosed with corrected CHD-PAH, 55 had atrial septal defects, 38 had ventricular septal defects, 14 had persistent ducti arteriosus, and 3 had defects not further specified. Hazard ratios (HR) and 95% confidence intervals (CI) for the primary composite endpoint were calculated using Cox proportional hazard models. Compared with the non-CHD patients from GRIPHON, patients with corrected CHD-PAH were slightly younger, with a greater proportion being treatment-naive and in World Health Organization functional class I/II. The rate of the primary composite endpoint of morbidity/mortality was lower in patients with corrected CHD-PAH who were treated with selexipag compared with those treated with placebo (HR 0.58; 95% CI 0.25, 1.37). The most common adverse events were those known to be related to selexipag.

Conclusions: These post-hoc analyses of GRIPHON provide valuable information about a large population of patients with corrected CHD-PAH, and suggest that selexipag may delay disease progression and was well-tolerated in patients with corrected CHD-PAH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607487PMC
March 2019

Congenital Portosystemic Shunts: Current Diagnosis and Management.

J Pediatr Gastroenterol Nutr 2019 05;68(5):615-622

Pediatric Hepatology and Liver Transplantation Unit, Hôpital Bicêtre, Reference Centre for Pediatric Liver Diseases and Folfoie-DHU Hepatinov, Assistance Publique-Hôpitaux de Paris and INSERM UMR-S 1174, Université Paris-Sud, Paris-Saclay, Le Kremlin-Bicêtre, France.

Congenital portosystemic shunts are increasingly recognized in several settings and at any age. The following are some of the most common presentations: prenatal ultrasound, neonatal cholestasis, incidental finding on abdominal imaging, or systemic complications such as unexplained cardiopulmonary or neurological disease, or the presence of liver nodules in a noncirrhotic liver. The purpose of the present review is to summarize clinical presentation and current recommendations for management, and highlight areas of future research. Illustrative examples from the veterinary literature complement our current lack of knowledge of this rare malformation often masquerading as a multisystem disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000002263DOI Listing
May 2019

An update on current and emerging treatments for pulmonary arterial hypertension in childhood and adolescence.

Expert Rev Respir Med 2019 02 11;13(2):205-215. Epub 2019 Jan 11.

b Pediatric Cardiology Unit , University Children's Hospital HUG, Pulmonary Hypertension Program HUG, Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique (CURCCCP), University of Geneva and Lausanne , Geneva and Lausanne , Switzerland.

Introduction: Pulmonary hypertension is a severe condition that can develop during childhood due to several different etiologies. During the last two decades, based on a better understanding of the underlying pathobiology leading to pulmonary arterial hypertension, targeted therapies have been developed and have improved the dreadful prognosis of the condition. However, curative therapy remains elusive. Areas covered: In this article, we will review the currently available drugs in pediatric pulmonary arterial hypertension and discuss the recommended management strategies. Expert commentary: Most of the drugtrials in pulmonary hypertension have been performed in adults, with extrapolation of the results to children. Most of the pediatric studies are non-controlled. The rarity of the disease and the lack of identifiable pediatric treatment goals and satisfactory trial end-points could explain the paucity of specific pediatric studies. An evolution has been made in the last few years regarding the treatment strategy of pulmonary arterial hypertension, with evidence that early combination therapy with at least two pulmonary vasodilators was beneficial on the survival. Children with pulmonary hypertension should be referred to experienced centers early, to benefit from a comprehensive initial assessment. Serial clinical and hemodynamic re-evaluation should assess treatment response and guide potential change in therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17476348.2019.1565998DOI Listing
February 2019

Evaluation of Macitentan in Patients With Eisenmenger Syndrome.

Circulation 2019 01;139(1):51-63

Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Italy (N.G.).

Background: Eisenmenger syndrome describes congenital heart disease-associated severe pulmonary hypertension accompanied by right-to-left shunting. The multicenter, double-blind, randomized, placebo-controlled, 16-week, phase III MAESTRO study (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity) evaluated the efficacy and safety of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome.

Methods: Patients with Eisenmenger syndrome aged ≥12 years and in World Health Organization functional class II-III were randomized 1:1 to placebo or macitentan 10 mg once daily for 16 weeks. Patients with complex cardiac defects, Down syndrome and background PAH therapy were eligible. The primary end point was change from baseline to week 16 in 6-minute walk distance. Secondary end points included change from baseline to week 16 in World Health Organization functional class. Exploratory end points included NT-proBNP (N-terminal pro-B-type natriuretic peptide) at end of treatment expressed as a percentage of baseline. In a hemodynamic substudy, exploratory end points included pulmonary vascular resistance index (PVRi) at week 16 as a percentage of baseline.

Results: Two hundred twenty six patients (macitentan n=114; placebo n=112) were randomized. At baseline, 60% of patients were in World Health Organization functional class II and 27% were receiving phosphodiesterase type-5 inhibitors. At week 16, the mean change from baseline in 6-minute walk distance was 18.3 m and 19.7 m in the macitentan and placebo groups (least-squares mean difference, -4.7 m; 95% confidence limit (CL), -22.8, 13.5; P=0.612). World Health Organization functional class improved from baseline to week 16 in 8.8% and 14.3% of patients in the macitentan and placebo groups (odds ratio, 0.53; 95% CL, 0.23, 1.24). NT-proBNP levels decreased with macitentan versus placebo (ratio of geometric means, 0.80; 95% CL, 0.68, 0.94). In the hemodynamic substudy (n=39 patients), macitentan decreased PVRi compared with placebo (ratio of geometric means, 0.87; 95% CL, 0.73, 1.03). The most common adverse events with macitentan versus placebo were headache (11.4 versus 4.5%) and upper respiratory tract infection (9.6 versus 6.3%); a hemoglobin decrease from baseline of ≥2 g/dL occurred in 36.0% versus 8.9% of patients. Five patients (3 macitentan; 2 placebo) prematurely discontinued treatment and 1 patient died (macitentan group).

Conclusions: Macitentan did not show superiority over placebo on the primary end point of change from baseline to week 16 in exercise capacity in patients with Eisenmenger syndrome.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01743001.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314514PMC
January 2019