HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models.

Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.

Comparison of Two Percutaneous Atrial Septal Defect Occluders for Device Healing and Nickel Release in a Chronic Porcine Model.

AIMS: To investigate the healing process and nickel release of the Hyperion occluder (Comed BV, Netherlands), as compared to the Amplatzer septal occluder (ASO) (St. Jude Medical Inc., St. Paul, MN, USA) in a chronic swine model. BACKGROUND: Some long-term complications occurring after percutaneous atrial septal defect (ASD) closure may be partially associated with an inappropriate healing of the device and increased nickel release. There is no direct comparative study of different occluders for healing and nickel release. METHODS: After percutaneous ASD creation, 12 pigs were implanted with 15 mm Hyperion (n = 6) and 15 mm ASO (n = 6) devices. After 1 month (n = 3 for each device) and 3 months (n = 3 for each device) of follow-up, device explantation was performed and healing was assessed using histopathological workup. Systemic and tissular nickel release was performed. RESULTS: Implantation was successful in 100% without complications. Device coverage was observed as early as 1 month after implantation and was almost complete after 3 months. A granulation tissue with a predominantly mononuclear inflammatory reaction was observed in contact with nitinol wires while an inflammatory reaction was seen in contact with textile fibers. We found no statistically significant difference between the 2 devices whether for histological grading scores or systemic nickel release, regardless to follow-up duration. CONCLUSIONS: In this preclinical study, we demonstrated that Amplatzer septal occluder and Hyperion occluder were not significantly different for device healing and nickel release processes.

An Unusual Cause of Neonatal Heart Failure.

Hypertension is an important and under-recognized cause of acquired cardiomyopathy in newborns. Half the etiologies of neonatal hypertension are undetermined. We present a rare case of severe neonatal hypertension with ventricular dysfunction secondary to substance exposure during pregnancy. This case report emphasizes the importance of a well-focused prenatal history on maternal medications and substance use.

Impact of Sophrology on cardiopulmonary fitness in teenagers and young adults with a congenital heart disease: The SOPHROCARE study rationale, design and methods.

BACKGROUND: Recent advances in the field of congenital heart disease (CHD) have significantly improved the overall prognosis. Now more attention is being given to health-related quality of life (HRQoL) and promotion of physical activity. Non-invasive relaxation therapy may be effective in cardiac patients concerned with exercise-induced dyspnoea. The SOPHROCARE randomised trial aims to assess the impact of Caycedian Sophrology on cardiopulmonary fitness in adolescents and young adults with CHD. METHODS: The SOPHROCARE trial is a nationwide, multicentre, randomised, controlled study in CHD patients aged from 13 to 25 years old. Patients will be randomised into 2 groups (8 Sophrology group sessions vs. no intervention). The primary outcome is the change in percent predicted maximum oxygen uptake (VO2max) between baseline and 12-month follow-up. A total of 94 patients in each group is required to observe a significant increase of 10% in VO2max with a power of 80% and an alpha risk of 5%. The secondary outcomes are: clinical outcomes, cardiopulmonary exercise test parameters (VE/VCO2 slope, ventilatory anaerobic threshold, oxygen pulse, respiratory response to hypercapnia), health-related quality of life score (PedsQL), physical and psychological status. CONCLUSION: After focusing on the survival in CHD, current research is opening on secondary prevention and patient-related outcomes. We sought to assess in the SOPHROCARE trial, if a Sophrology program, could improve exercise capacity and quality of life in youth with CHD. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03999320).

Pulmonary Atresia With Ventriculocoronary Arterial Connections and a Large Conoventricular Septal Defect.

Ventriculocoronary arterial connections are typically found in patients with pulmonary atresia with an intact ventricular septum. This report describes a case of ventriculocoronary arterial connections in a patient with pulmonary atresia with a ventricular septal defect. Our case supports recent data suggesting a primary coronary artery developmental anomaly in pulmonary atresia. (Level of Difficulty: Advanced.).

Role of animal models for percutaneous atrial septal defect closure.

As for any preclinical development of new implantable device, bench testing has been followed by experimental studies on large animal models for the development of atrial septal defect closure devices. Various models have been used according to studied species (porcine, ovine or canine model) and whether the septal defect was percutaneously or surgically created. Animal models of percutaneous atrial septal defect closure aim to assess the healing process and device endothelialisation, as well as the development of magnetic resonance imaging guided procedures, the short-term effects of volume overload on right ventricular contractility through haemodynamic studies and the understanding of other complications such as nickel hypersensitivity. Each technique has its own advantages and drawbacks, and leads to different punch-related, acute septal injuries that could have an effect on the healing process after device implantation. It has been suggested that some long-term, major device-related complications such as thrombosis or infective endocarditis may be associated with an inappropriate healing process or insufficient endothelialisation of the device, leading industrial companies to pay a great deal of attention to the healing process. Tissue reactions in animal models were shown to adequately reproduce the healing response after device implantation in humans, with an endothelial device coverage observed as early as 30 days after implantation and complete after 3 to 6 months. Research perspectives may evaluate both animal models and in-vitro studies in parallel with a view to clarify the endothelialisation process using human endothelial cells through in-vitro experiments. Self-sensing device for detecting the presence of endothelial cells on the surface of intracardiac occluders and high-resolution imaging techniques that could non-invasively assess the complete endothelialisation of a device would also be promising tools which would need large animal models studies before their clinical application.

Toward the integration of global longitudinal strain analysis in the assessment of neonatal aortic coarctation? A preliminary study.

BACKGROUND: Coarctation of the aorta (CoA) is still challenging to diagnose in neonates with patent ductus arteriosus (PDA). Speckle tracking echocardiography allows reliable analysis of myocardial deformation in newborns and seems to provide important insides into regional changes in patients with left ventricular (LV) outflow tract obstruction. AIMS: To assess the interest of LV global longitudinal strain (GLS) measurement for predicting CoA in neonates with PDA and prenatal suspicion. METHODS: Prospective single-center study. Twenty-two newborns with prenatal suspicion of CoA were included. All newborns were evaluated in the first 12 hours of life. To assess the feasibility and the reproducibility of GLS, 14 healthy full-term newborns with PDA (group 3) were screened. CoA was diagnosed when DA closed, according to usual echocardiographic criteria. RESULTS: Six neonates developed CoA after DA closure (group 1) whereas 16 did not (group 2). Mean gestational age and birth weight were not different between the groups. GLS measurements were possible in 100%. Intra- and inter-observer variability of strain measurements was acceptable. GLS values were significantly lower in neonates who developed CoA (P=0.015). To predict CoA, cut-off value of -17.42% gave the best compromise for sensitivity (83%) and specificity (72%). Aortic arch dimensions were modestly correlated with strain values. The presence of a bicuspid aortic valve was not associated with significant lower GLS values. CONCLUSION: LV GLS analysis is a feasible and reproducible echocardiographic technique in newborns with PDA. Newborns who will develop CoA seem to have lower values of GLS than healthy neonates. Further studies are needed to confirm these preliminary results.

Hybrid Melody Valve Implantation in Mitral Position in a Child: Usefulness of a 3-Dimensional Printed Model for Preprocedural Planning.

We present the case of a 4-month-old child with atrioventricular canal associated with severe left atrioventricular valve dysfunction who previously underwent 3 surgical valve reconstructions without significant improvement. A Hybrid Melody valve (Medtronic, Minneapolis, MN) insertion was planned. Because of the low weight, the risk of left ventricular outflow tract obstruction was significant and therefore evaluated preprocedurally using a cardiac computed tomography-derived 3-dimensional printed model. In vitro tests showed good anchorage of the valve without subaortic obstruction and the procedure was then achieved with an excellent clinical result.

First Case of Q Fever Endocarditis Involving the Melody® Transcatheter Pulmonary Valve in an Afebrile Child.

In this article we report the first case of Q fever endocarditis in a 13 years old child with a percutaneous pulmonary Melody® valve. The patient had a new onset of Melody valve dysfunction associated with the combination of hepatosplenomegaly and pancytopenia but was afebrile. Although blood cultures were negative, we have further investigated in the direction of infective endocarditis by performing PCR detection and the serology of C. burnetii which were positive. A combination antibiotic therapy with doxycycline and hydroxychloroquine was started with good clinical evolution. Our case emphasizes the fact that any Melody valvular dysfuntion should be considered as a potential infective endocarditis despite the absence of typical bacterial features.

Tricuspid valve repair and pulmonary valve replacement in adults with repaired tetralogy of Fallot.

BACKGROUND: Pulmonary valve replacement (PVR) often is performed in adults with repaired tetralogy of Fallot (TOF). For patients who have tricuspid regurgitation (TR), tricuspid valve (TV) repair associated to PVR is still debated. OBJECTIVE: We sought to evaluate perioperative factors related to TV repair when performed at the time of PVR in patients with repaired TOF. METHODS: We retrospectively reviewed 104 patients with repaired TOF (or its equivalent) who underwent PVR (2002-2014). RESULTS: Mean age at initial complete correction and at PVR was 20.1 ± 17.2 months and 26.3 ± 9.5 years, respectively. Forty-one patients had significant preoperative TR: 24 were moderate (group M) and 17 were severe (group S). A total of 16 TV repair were performed (8 for each group). Moderate and severe tricuspid regurgitation observed in the first year following the initial complete repair were significantly associated with severe TR at PVR (P < .001). In group M patients, TR was improved regardless of TV repair, whereas, in group S, residual significant TR was reported in 7 patients who did not have TV repair. No cases were observed for patients who underwent concomitant TV repair (P = .002). Among these patients with residual significant TR, 2 needed a tricuspid valve replacement. The functional status (New York Heart Association classification) of group S patients was significantly improved by concomitant TV repair. CONCLUSIONS: In adults with repaired TOF, TV repair is a safe procedure when performed at the time of PVR. If, at mid-term follow-up, there is probably no benefit of TV repair when preoperative TR is moderate, TV repair may improve both tricuspid valve function and functional status of the patients in case of severe preoperative TR.

Transposition of the great arteries: Rationale for tailored preoperative management.

As preoperative morbi-mortality remains significant, care of newborns with transposition of the great arteries is still challenging. In this review of the literature, we discuss the different treatments that could improve the patient's condition into the preoperative period. Instead of a standardized management, we advocate personalized care of these neonates. Considering the deleterious effects of hypoxia, special attention is given to the use of non-invasive technologies to assess oxygenation of the tissues. As a prolonged preoperative time with low cerebral oxygenation is associated with cerebral injuries, distinguishing neonates who should undergo early surgery from those who could wait longer is crucial and requires full expertise in the management of neonatal congenital heart disease. Finally, to treat these newborns as soon as possible, we support a planned delivery policy for foetuses with transposition of the great arteries.

Postoperative assessment of left ventricular function by two-dimensional strain (speckle tracking) after paediatric cardiac surgery.

BACKGROUND: Left ventricular (LV) dysfunction may complicate paediatric cardiac surgery with cardiopulmonary bypass, notably after long aortic cross-clamping (ACC). Assessment of occult myocardial injury by conventional echocardiographic variables may be difficult in the postoperative period. AIMS: To evaluate the feasibility of two-dimensional (2D) strain in the postoperative period, and to assess the effect of ACC duration on this variable. METHODS: Thirty-three paediatric patients (age<18years) with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass were included in this prospective single-centre study. Daily echocardiography was performed from the day before surgery to the fifth postoperative day. LV ejection fraction and LV 2D strain were measured. The cohort was divided into three groups according to ACC duration (group 1:<30minutes; group 2: 30-80minutes; group 3:>80minutes). RESULTS: Mean age and weight were 4.2±2.5years and 15.1±5.2kg, respectively. Feasibilities of longitudinal, circumferential and radial strains were good, and quite similar to conventional variables. Compared with conventional variables, intra- and interobserver agreements regarding 2D strain were better (r=0.916, P<0.001 and r=0.855, P<0.001 for longitudinal strain versus r=0.156, P=0.54 and r=0.064, P=0.80 for LV ejection fraction by Simpson's method). Postoperative evolution of longitudinal and circumferential strains was significantly different between the three groups (P<0.001), whereas there was no difference using conventional variables. CONCLUSION: Postoperative LV 2D strain is a feasible and reproducible method. Strain measurements seem to indicate correlation with ACC duration.

Distortion of the left anterior descending coronary artery after pulmonary valve replacement.

Injury of the left main coronary artery may sometimes complicate a pulmonary valve replacement (PVR). We present the case of a 39-year-old man, with post-operative distortion of the left anterior descending coronary artery, which caused onset of ventricular arrhythmia associated with electrocardiographic signs of myocardial ischemia. A coronary angiogram revealed the cause of the lesion. Stenting the coronary artery restored normal coronary blood flow and improved the patient's condition. Through this case, we describe a new life-threatening complication after PVR. © 2015 Wiley Periodicals, Inc.

Severe Neonatal Pertussis Treated by Leukodepletion and Early Extra Corporeal Membrane Oxygenation.

We report the case of a 17-day-old infant with severe pertussis for whom the early initiation of veno-arterial extra corporeal membrane oxygenation and leukodepletion strategies (exchange transfusion and leukofiltration) allowed to reduce leukocytosis and pulmonary hypertension, thus leading to survival. These invasive techniques can be considered when severe pulmonary hypertension complicates hyperleukocytosis in neonates.

Eosinophilic cardiac disease: Molecular, clinical and imaging aspects.

Eosinophilia may be responsible for cardiac injuries of widely varying severity, from acute myocarditis to endomyocardial fibrosis. In this review, we present both the molecular mechanisms that are responsible for these lesions and their clinical and paraclinical aspects. Numerous aetiologies can lead to severe eosinophilia, but these are mainly represented by hypersensitivity reactions, rheumatological diseases and hypereosinophilic syndrome. Because cardiac involvement may be extremely severe, echocardiography should be always performed in the context of eosinophilia and appropriate therapeutics should be started rapidly in order to limit the progression of the disease.