Maternal Exercise during Pregnancy Impacts Motor Performance in 9-Year-Old Children: A Pilot Study.

The benefits of maternal physical activity during pregnancy are well documented, but long-term effects on the child have been less studied. Therefore, we conducted a pilot follow-up study of a lifestyle intervention during pregnancy that aimed to investigate whether exercise (endurance and strength training) during pregnancy affects motor performance and body composition of children up to 9 years of age, as well as possible influencing factors like brain-derived neurotrophic factor (BDNF) and lifestyle. Eleven mother-child pairs from the intervention and eight mother-child pairs from the control group were included. From birth up to 9 years of age, no differences in body mass index (BMI) or body mass index standard deviation scores (BMI-SDS) were found between the groups. Lifestyle intervention was one of the influencing factors for children's cardiorespiratory endurance capacity and coordination. Moreover, maternal BDNF in the last trimester was significantly associated with running performance, which may be due to better neuronal development. This is the first study evaluating the effects of a lifestyle intervention during pregnancy on the motor performance 9 years after birth. Children's participation in exercise programs over the past 9 years was not continuously recorded and therefore not included in the analysis. Even a cautious interpretation of these results indicates that a healthy lifestyle during pregnancy is essential in promoting child health. Larger studies and randomized control trials are necessary to confirm our results, especially those pertaining to the role of BDNF.

Effect of Lifestyle Interventions during Pregnancy on Maternal Leptin, Resistin and Offspring Weight at Birth and One Year of Life.

Lifestyle during pregnancy impacts the health of the mother and child. However, the extent to which physical activity affects maternal biomarkers and factors that might influence birth weight remains unclear. We analysed data from two lifestyle interventions in which the effects of an exercise programme (2x/week, 60-90 min) on the course of pregnancy with regard to adipokines and offspring were evaluated. A total of 70 women participated in this study (45, intervention group; 25, control group). Anthropometric data and maternal fasting serum leptin and resistin levels were measured at three time points (approximately 14th (T1), 24th (T2), and 36th (T3) weeks of gestation). Neonatal/child data were retrieved from screening examinations. Independent of the intervention, we found a positive correlation between the fat mass at T1 and both leptin and resistin levels at all time points. Leptin level was significantly higher in the control group at T3; however, no differences between the groups were found for resistin. The birth weight was influenced by the birth length, fat mass at T1/T3, and resistin level at T2. The BMI-SDS at one year of age was influenced by maternal fat-free mass at T3 and resistin at T1/T2. Even if these results can only be interpreted cautiously, lifestyle interventions during pregnancy are important in promoting maternal and child health. Further randomised controlled trials and translational studies are warranted to clarify the underlying mechanisms.

High-efficient serum-free differentiation of endothelial cells from human iPS cells.

INTRODUCTION: Endothelial cells (ECs) form the inner lining of all blood vessels of the body play important roles in vascular tone regulation, hormone secretion, anticoagulation, regulation of blood cell adhesion and immune cell extravasation. Limitless ECs sources are required to further in vitro investigations of ECs' physiology and pathophysiology as well as for tissue engineering approaches. Ideally, the differentiation protocol avoids animal-derived components such as fetal serum and yields ECs at efficiencies that make further sorting obsolete for most applications. METHOD: Human induced pluripotent stem cells (hiPSCs) are cultured under serum-free conditions and induced into mesodermal progenitor cells via stimulation of Wnt signaling for 24 h. Mesodermal progenitor cells are further differentiated into ECs by utilizing a combination of human vascular endothelial growth factor A165 (VEGF), basic fibroblast growth factor (bFGF), 8-Bromoadenosine 3',5'-cyclic monophosphate sodium salt monohydrate (8Bro) and melatonin (Mel) for 48 h. RESULT: This combination generates hiPSC derived ECs (hiPSC-ECs) at a fraction of 90.9 ± 1.5% and is easily transferable from the two-dimensional (2D) monolayer into three-dimensional (3D) scalable bioreactor suspension cultures. hiPSC-ECs are positive for CD31, VE-Cadherin, von Willebrand factor and CD34. Furthermore, the majority of hiPSC-ECs express the vascular endothelial marker CD184 (CXCR4). CONCLUSION: The differentiation method presented here generates hiPSC-ECs in only 6 days, without addition of animal sera and at high efficiency, hence providing a scalable source of hiPSC-ECs.

Engineering of cardiac microtissues by microfluidic cell encapsulation in thermoshrinking non-crosslinked PNIPAAm gels.

Multicellular agglomerates in form of irregularly shaped or spherical clusters can recapitulate cell-cell interactions and are referred to as microtissues. Microtissues gain increasing attention in several fields including cardiovascular research. Cardiac microtissues are evolving as excellent model systems for drug testingin vitro(organ-on-a-chip), are used as tissue bricks in 3D printing processes and pave the way for improved cell replacement therapiesin vivo. Microtissues are formed for example in hanging drop culture or specialized microwell plates; truly scalable methods are not yet available. In this study, a novel method of encapsulation of cells inpoly-N-isopropylacrylamid(PNIPAAm) spheres is introduced. Murine induced pluripotent stem cell-derived cardiomyocytes and bone marrow-derived mesenchymal stem cells were encapsulated in PNIPAAm by raising the temperature of droplets formed in a microfluidics setup above the lower critical solute temperature (LCST) of 32 °C. PNIPAAM precipitates to a water-insoluble physically linked gel above the LCST and shrinks by the expulsion of water, thereby trapping the cells in a collapsing polymer network and increasing the cell density by one order of magnitude. Within 24 h, stable cardiac microtissues were first formed and later released from their polymer shell by washout of PNIPAAm at temperatures below the LCST. Rhythmically contracting microtissues showed homogenous cell distribution, age-dependent sarcomere organizations and action potential generation. The novel approach is applicable for microtissue formation from various cell types and can be implemented into scalable workflows.

Bacteraemia of oral origin in children-A Systematic review and network meta-analysis.

OBJECTIVES: To systematically review the prevalence of bacteraemia, triggered by dental intervention and home oral hygiene practices, in children. The network meta-analysis (NMA) quantitatively compared the risk of bacteraemia triggered by dental extractions and home and professional cleaning procedures. MATERIALS AND METHODS: Clinical trials with the outcome "bacteraemia in children" were searched. The NMA was performed using the frequentist weighted least-squares approach comparing the odds ratios (OR) of different interventions. RESULTS: Among 11 of 13 studies, dental treatment was performed under general anaesthesia. In 2,381 patients, bacteraemia occurred in 38.7%-56% patients following single-tooth extractions, in 22%-46% after manual toothbrushing (MTB), and in 26%-78% after power toothbrushing (PTB). When MTB was set as the reference (OR 1), rubber cup polishing showed a slightly higher risk (OR 1.26) of bacteraemia. PTB presented a higher risk (OR 1.79-2.27) than with single-tooth extractions (OR 1.55) but lower than that with multiple extractions (OR 2.55). CONCLUSION: Daily use of MTB and routine professional cleaning were associated with the lowest risk of developing bacteraemia in children with gingivitis, almost as much as with a single-tooth extractions. Improved plaque control with PTB increased the risk of bacteraemia. There is limited evidence on gingivitis-free and systemically-diseased children.

Psychosocial well-being and quality of life in siblings of children with congenital heart disease: A systematic review.

Congenital heart disease (CHD) is a major global health problem. Until recently, the siblings of this group did not receive much attention. This review, conducted from November 2019 to October 2020, aims to summarize knowledge about psychosocial well-being and quality of life (QoL), associated factors, and interventions for siblings of children with CHD. Systematic searches were conducted in PubMed, PsycINFO, PsycARTICLES, Web of Science via EBSCOhost, and CENTRAL. Twelve articles were included. Results showed that psychosocial well-being was impaired in 14% to 40% of siblings. Negative impact of illness was highest for CHD siblings compared to siblings of children with cancer, cystic fibrosis, or diabetes. QoL was impaired in up to one-third. Siblings of children with CHD and cancer rated their QoL lower than those of siblings of children with cystic fibrosis or type-1 diabetes. Associated factors were sibling age, gender, socioeconomic status, miscarriage, previous sibling death, visibility of illness, and severity of condition. Only one of two interventions focused on siblings of CHD children. Although data are scarce and inhomogeneous, it indicates that siblings of CHD children suffer from lower psychosocial well-being and QoL than siblings of children with other chronic conditions. Interventions to improve their situation should be developed.

A lifestyle intervention during pregnancy to reduce obesity in early childhood: the study protocol of ADEBAR - a randomized controlled trial.

BACKGROUND: The prevalence of obesity in childhood is increasing worldwide and may be affected by genetic factors and the lifestyle (exercise, nutrition behavior) of expectant parents. Lifestyle factors affect adipokines, namely leptin, resistin, and adiponectin as well as cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), which are involved in the regulation of maternal metabolic homeostasis, glucose metabolism, and the development of insulin resistance, metabolic syndrome, gestational diabetes mellitus, and hypertension. However, studies focusing on the effect of exercise or a combination of parental exercise and nutrition on the above-mentioned markers in newborns (venous cord blood) and especially on the long-term development of infants' weight gain are lacking. The study will investigate the effects of a multimodal intervention (regular exercise, diet) on parental and childhood adipocytokines (leptin, resistin, adiponectin, TNF-α, IL-6, BDNF). The effect of a lifestyle-related change in "fetal environmental conditions" on the long-term weight development of the child up to the age of two will also be assessed. METHODS/DESIGN: A randomized multi-center controlled trial will be conducted in Germany, comparing supervised aerobic and resistance training 2x/week (13th to 36th weeks of gestation) and nutritional counseling (6th to 36th weeks of gestation) during pregnancy with usual care. Thirty women (pre-pregnancy Body Mass Index ≥25 kg/m2, 6th-10th week of gestation) will be included in each group. Maternal anthropometric and physical measurements as well as blood sampling will occur at the 6th-10th, 13th-14th, 21st-24th, and 36th week of gestation, at delivery as well as 8 weeks and 24 months postpartum. Neonatal measurements and umbilical blood sampling will be performed at birth. Maternal and infants' weight development will be assessed every 6 months till 24 months postpartum. A difference in childhood BMI of 1 kg/m2 at the age of two years between both groups will be assumed. A power size of 80% using a significance level of 0.05 and an effect size of 1.0 is presumed. DISCUSSION: A better understanding of how lifestyle-related changes in the fetal environment might influence infants' outcome after two years of life could have a profound impact on the prevention and development of infants' obesity. TRIAL REGISTRATION: The trial is registered at the German Clinical Trial Register (DRKS00007702); Registered on 10th of August 2016; retrospectively registered https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007702.

Prenatal Diagnosis and Postnatal Outcome of Fetuses with Pulmonary Atresia and Ventricular Septal Defect.

PURPOSE: To assess the intrauterine course, associated conditions and postnatal outcome of fetuses with pulmonary atresia with ventricular septal defect (PAVSD). METHODS: All cases of PAVSD diagnosed prenatally over a period of 10 years with a minimum follow-up of 6.5 years were retrospectively collected in 3 tertiary referral centers. RESULTS: 50 cases of PAVSD were diagnosed prenatally. 44.0 % of fetuses had isolated PAVSD, 4.0 % had associated cardiac anomalies, 10.0 % had extra-cardiac anomalies, 38.0 % had chromosomal anomalies, 4.0 % had non-chromosomal syndromes. Among the 32 liveborn children, 56.3 % had reverse flow in the patent arterial duct, 25.0 % had major aortopulmonary collateral arteries (MAPCAs) with ductal agenesis and 18.7 % had a double supply. 17 pregnancies were terminated (34.0 %), there was 1 intrauterine fetal death (2.0 %), 1 neonatal death (2.0 %), and 6 deaths (12.0 %) in infancy. 25 of 30 (83.3 %) liveborn children with an intention to treat were alive at the latest follow-up. The mean follow-up among survivors was 10.0 years (range 6.5-15.1). 56.0 % of infants underwent staged repair, 44.0 % had one-stage complete repair. After exclusion of infants with additional chromosomal or syndromal anomalies, 88.9 % were healthy, and 11.1 % had mild limitations. The presence of MAPCAs did not differ significantly between survivors and non-survivors (p = 0.360), between one-stage or staged repair (p = 0.656) and healthy and impaired infants (p = 0.319). CONCLUSION: The prognosis in cases without chromosomal or syndromal anomalies is good. MAPCAs did not influence prognosis or postoperative health. The incidence of repeat interventions due to recurrent stenoses is significantly higher after staged compared with single-stage repair.

Severe Pulmonary Stenosis or Atresia with Intact Ventricular Septum in the Fetus: The Natural History.

PURPOSE: To assess the intrauterine course, the outcome, and to establish a new prenatal echocardiographic scoring system to predict biventricular (BV) versus univentricular (UV) outcome of fetuses with severe pulmonary stenosis or atresia with intact ventricular septum (PSAIVS). METHODS: All cases of PSAIVS diagnosed prenatally over a period of 14years were retrospectively collected in 2 tertiary referral centers. RESULTS: Forty-nine fetuses with PSIVS (n = 11) or PAIVS (n = 38) were identified prenatally. Nineteen (38.8%) fetuses had additional ventriculocoronary connections (VCCs) and 21 (42.9%) fetuses had right ventricular hypoplasia. Four (8.2%) pregnancies were terminated, 2 (4.1%) ended in intrauterine fetal death, 4 (8.2%) in neonatal death, and 5 (10.2%) children died in infancy or childhood, including one case with compassionate care. Thirty-four of 44 (77.3%) fetuses with the intention-to-treat were alive at latest follow-up, 25 (73.5%) with BV, and 9 (26.5%) with UV circulation. Most significant predictive markers of UV circulation were Vmax of tricuspid regurgitation (TR) <2 m/s, right ventricle/left ventricle length ratio ≤0.6, and presence of VCC. A scoring system including these 3 markers had 100% sensitivity and 100% specificity predicting an UV outcome if more than one of these criteria was fulfilled. All 25 liveborn infants that were suitable for BV repair survived, whereas only 9 out of 14 candidates for UV repair survived. None of the 14 fetuses with predicted UV outcome would have met the inclusion criteria for fetal intervention, as 10 of them had VCC and the remaining 4 had absent TR or Vmax <2 m/s. CONCLUSION: The prognosis of prenatally diagnosed PSAIVS is good if BV circulation can be achieved, while postnatal mortality in UV circulation is high within the first 4 months of life. Postnatal outcome can be predicted prenatally with high accuracy using a simple scoring system. This information is mandatory for parental counseling and may be useful in selecting fetuses for intrauterine valvuloplasty.

Aortic Coarctation a Systemic Vessel Disease-Insights from Magnetic Resonance Imaging.

BACKGROUND: Even after successful aortic coarctation (CoA) repair, hypertension causes premature morbidity and mortality. The mechanisms are not clear. The aim was to evaluate elastic wall properties and aortic morphology and to correlate these results with severity of restenosis, hypertension, aortic arch geometry, noninvasive pressure gradients, and time and kind of surgical procedure. METHODS: Eighty-nine patients (17 ± 6.3 years) and 20 controls (18 ± 4.9 years) were examined using magnetic resonance imaging (MRI). In addition to contrast-enhanced MR angiography and flow measurements, CINE MRI was performed to assess the relative change of aortic cross-sectional areas at diaphragm level to calculate aortic compliance (C). RESULTS: Fifty-four percent of all patients showed hypertension (> 95th percentile), but more than half of them had no significant stenosis (defined as ≥30%). C was lower in CoA than in controls (3.30 ± 2.43 vs. 4.67 ± 2.21 [10-5 Pa-1 m-2]; p = 0.024). Significant differences in compliance were found between hyper- and normotensive patients (2.61 ± 1.60 vs. 4.11 ± 2.95; p = 0.01), and gothic and Romanesque arch geometry (2.64 ± 1.58 vs. 3.78 ± 2.81; p = 0.027). There was a good correlation between C and hypertension (r = 0.671; p < 0.01), but no correlation between C (and hypertension) and time or kind of repair, restenosis, or pressure gradients. CONCLUSION: The decreased compliance, a high rate of hypertension without restenosis, and independency of time and kind of repair confirm the hypothesis that CoA may not be limited to isthmus region but rather be a widespread (systemic) vascular anomaly at least in some of the CoA patients. Therefore, aortic compliance should be assessed in these patients to individually tailor treatment of CoA patients with restenosis and/or hypertension.

Generation of human induced pluripotent stem cell-derived cardiomyocytes in 2D monolayer and scalable 3D suspension bioreactor cultures with reduced batch-to-batch variations.

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are promising candidates to treat myocardial infarction and other cardiac diseases. Such treatments require pure cardiomyocytes (CMs) in large quantities. Methods: In the present study we describe an improved protocol for production of hiPSC-CMs in which hiPSCs are first converted into mesodermal cells by stimulation of wingless (Wnt) signaling using CHIR99021, which are then further differentiated into CM progenitors by simultaneous inhibition of porcupine and tankyrase pathways using IWP2 and XAV939 under continuous supplementation of ascorbate during the entire differentiation procedure. Results: The protocol resulted in reproducible generation of >90% cardiac troponin T (TNNT2)-positive cells containing highly organized sarcomeres. In 2D monolayer cultures CM yields amounted to 0.5 million cells per cm2 growth area, and on average 72 million cells per 100 mL bioreactor suspension culture without continuous perfusion. The differentiation efficiency was hardly affected by the initial seeding density of undifferentiated hiPSCs. Furthermore, batch-to-batch variations were reduced by combinatorial use of ascorbate, IWP2, and XAV939. Conclusion: Combined inhibition of porcupine and tankyrase sub-pathways of Wnt signaling and continuous ascorbate supplementation, enable robust and efficient production of hiPSC-CMs.

In Vitro Grown Micro-Tissues for Cardiac Cell Replacement Therapy in Vivo.

BACKGROUND/AIMS: Different approaches have been considered to improve heart reconstructive medicine and direct delivery of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) appears to be highly promising in this context. However, low cell persistence post-transplantation remains a bottleneck hindering the approach. Here, we present a novel strategy to overcome the low engraftment of PSC-CMs during the early post-transplantation phase into the myocardium of both healthy and cryoinjured syngeneic mice. METHODS: Adult murine bone marrow mesenchymal stem cells (MSCs) and PSC-CMs were co-cultured on thermo-responsive polymers and later detached through temperature reduction, resulting in the protease-free generation of cell clusters (micro-tissues) composed of both cells types. Micro-tissues were transplanted into healthy and cryo-injured murine hearts. Short term cell retention was quantified by real-time-PCR. Longitudinal cell tracking was performed by bioluminescence imaging for four weeks. Transplanted cells were further detected by immunofluorescence staining of tissue sections. RESULTS: We demonstrated that in vitro grown micro-tissues consisting of PSC-CMs and MSCs can increase cardiomyocyte retention by >10fold one day post-transplantation, but could not fully rescue a further cell loss between day 1 and day 2. Neutrophil infiltration into the transplanted area was detected in healthy hearts and could be attributed to the cellular implantation rather than tissue damage exerted by the transplantation cannula. Injected PSC-CMs were tracked and successfully detected for up to four weeks by bioluminescence imaging. CONCLUSION: This approach demonstrated that in vitro grown micro-tissues might contribute to the development of cardiac cell replacement therapies.

Different Responses to Drug Safety Screening Targets between Human Neonatal and Infantile Heart Tissue and Cardiac Bodies Derived from Human-Induced Pluripotent Stem Cells.

AIMS: Induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) have become a promising tool in cardiovascular safety pharmacology. Immaturity of iPS-CMs remains an ongoing concern. We compared electrophysiological and contractile features of cardiac bodies (hiPS-CBs) derived from human-induced pluripotent stem cells and human neonatal and infantile myocardial slices relevant for drug screening. METHODS AND RESULTS: Myocardial tissue slices were prepared from biopsies obtained from patients undergoing surgery for hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). Electrophysiological features and response to Ik,r blockade as well as contractile properties were investigated using microelectrodes and isometric force measurements and were compared to hiPS-CBs. Both native myocardial tissue slices as well as hiPS-CBs showed action potential prolongation after Ik,r blockade, but early afterdepolarisations could be observed in native myocardial tissue slices only. The force-frequency relationship (FFR) varied at lower frequencies and was negative throughout at higher frequencies in hiPS-CBs. In contrast, native myocardial tissue slices exhibited positive, negative, and biphasic FFRs. In contrast to native myocardial tissue slices, hiPS-CBs failed to show an inotropic response to ß-adrenergic stimulation. Although all groups showed ß-adrenergic induced positive lusitropy, the effect was more pronounced in myocardial tissue slices. CONCLUSION: hiPS-CBs were able to reproduce AP prolongation after Ik,r blockade, but to a lesser extent compared to human neonatal and infantile myocardial tissue slices. Early afterdepolarisations could not be induced in hiPS-CBs. Contractile force was differently regulated by ß-adrenergic stimulation in hiPS-CBs and the native myocardium. If used for cardiotoxicity screening, caution is warranted as hiPS-CBs might be less sensitive to pharmacologic targets compared to the native myocardium of neonates and infants.

Use of whole exome sequencing in the NICU: Case of an extremely low birth weight infant with syndromic features.

Single gene (Mendelian) disorders are one of the leading causes of neonatal morbidity and mortality. However, in the setting of preterm birth phenotypic features of genetic diseases are often undifferentiated and are clinically very difficult to interpret based on the wide range of differential diagnoses. We report an extremely low birth weight infant (ELBW) born prematurely at 23 + 0 gestational weeks after twin pregnancy with a novel clinical manifestation with persistent hyperglycaemia as well as the known manifestations of disease-associated hypokinesia, renal salt wasting, and multifocal atrial tachycardia. The patient died of heart failure on the 72nd day of life. Whole exome sequencing (WES) revealed a previously well established, disease-causing heterozygous likely pathogenic variant in the Harvey rat sarcoma viral oncogene homolog (HRAS)-gene (c.35G > C, p. G12A, rs104894230), which implied the clinical diagnosis of Costello syndrome (CS; OMIM#190020.0004). The twin brother merely had complications related to preterm birth and did not show any CS symptoms. In conclusion, our case illustrated that CS should be considered in ELBW infants showing a life-threatening combination of complex cardiac arrhythmia and hypokinesia. If a syndromic disorder is suspected in the neonatal intensive care unit (NICU) setting, rapid WES is a useful, non-invasive diagnostic tool in critically ill ELBW infants.

Cardiomyocytes facing fibrotic conditions re-express extracellular matrix transcripts.

Pathophysiological conditions, such as myocardial infarction and mechanical overload affect the mammalian heart integrity, leading to a stiffened fibrotic tissue. With respect to the pathophysiology of cardiac fibrosis but also in the limelight of upcoming approaches of cardiac cell therapy it is of interest to decipher the interaction of cardiomyocytes with fibrotic matrix. Therefore, we designed a hydrogel-based model to engineer fibrotic tissue in vitro as an approach to predict the behavior of cardiomyocytes facing increased matrix rigidity. Here, we generated pure induced pluripotent stem cell-derived cardiomyocytes and cultured them on engineered polyacrylamide hydrogels matching the elasticities of healthy as well as fibrotic cardiac tissue. Only in cardiomyocytes cultured on matrices with fibrotic-like elasticity, transcriptional profiling revealed a substantial up-regulation of a whole panel of cardiac fibrosis-associated transcripts, including collagen I and III, decorin, lumican, and periostin. In addition, matrix metalloproteinases and their inhibitors, known to be essential in cardiac remodeling, were found to be elevated as well as insulin-like growth factor 2. Control experiments with primary cardiac fibroblasts were analyzed and did not show comparable behavior. In conclusion, we do not only present a snapshot on the transcriptomic fingerprint alterations in cardiomyocytes under pathological conditions but also provide a new reproducible approach to study the effects of fibrotic environments to various cell types. STATEMENT OF SIGNIFICANCE: The ageing population in many western countries is faced with an increasing burden of ageing-related diseases such as heart failure which is associated with cardiac fibrosis. A deeper understanding of the interaction of organotypic cells with altered extracellular matrix mechanical properties is of pivotal importance to understand the underlying mechanisms. Here, we present a strategy to combine hydrogel matrices with induced pluripotent stem cell derived cardiomyocytes to study the effect of matrix stiffening on these cells. Our findings suggest an active role of matrix stiffening on cardiomyocyte function and heart failure progression.

Prenatal diagnosis, associated findings and postnatal outcome of fetuses with double outlet right ventricle (DORV) in a single center.

Objective To assess the spectrum of associated anomalies, the intrauterine course, postnatal outcome and management of fetuses with double outlet right ventricle (DORV). Methods All cases of DORV diagnosed prenatally over a period of 8 years were retrospectively collected in a single tertiary referral center. All additional prenatal findings were assessed and correlated with the outcome. The accuracy of prenatal diagnosis was assessed. Results Forty-six cases of DORV were diagnosed prenatally. The mean gestational age at first diagnosis was 21+4 weeks (range, 13-37). A correct prenatal diagnosis of DORV was made in 96.3% of the cases. If the relation of the great arteries, the position of the ventricular septal defect (VSD) and additional cardiac anomalies are taken into account, the prenatal diagnosis was correct in 92.6% of the cases. One case was postnatally classified as transposition of the great arteries with subpulmonary VSD and was excluded from further analysis. A total of 41 (91.1%) fetuses with DORV had major additional cardiac anomalies, 30 (66.7%) had extracardiac anomalies and 13 (28.9%) had chromosomal or syndromal anomalies. Due to their complex additional anomalies, five (11.1%) of our 45 fetuses had multiple malformations and were highly suspicious for non-chromosomal genetic syndromes, although molecular diagnosis could not be provided. Disorders of laterality occurred in 10 (22.2%) fetuses. There were 17 terminations of pregnancy (37.8%), two (4.4%) intrauterine and seven (15.6%) postnatal deaths. Nineteen of 22 (86.4%) live-born children with an intention to treat were alive at last follow-up. The mean follow-up among survivors was 32 months (range, 2-72). Of 21 children who had already undergone postnatal surgery, eight (38.1%) achieved biventricular repair and 13 (61.9%) received univentricular palliation. One recently born child is still waiting for surgery. All children predicted prenatally to need a single ventricle palliation, and all children predicted to achieve biventricular repair, ultimately received the predicted type of surgery. After surgery, 14 of 18 (77.8%) children were healthy without any impairment. Conclusion DORV is a rare and often complex cardiac anomaly that can be diagnosed prenatally with high precision. DORV is frequently associated with major additional anomalies, leading to a high intrauterine and postnatal loss rate due to terminations or declined postnatal therapy. Without additional anomalies, the prognosis is good, although approximately 60% of children will have single ventricle palliation.

Bubble Formation in Children and Adolescents after Two Standardised Shallow Dives.

Circulating venous bubbles after dives are associated with symptoms of decompression sickness in adults. Up to now it is not known to what extent children and adolescents are subjected to a bubble formation during their shallow dives and if there are possible indications for that. The aim of this pilot study is to investigate whether bubbles and/or symptoms occur after standardised repeated dives performed by young divers. 28 children and adolescents (13.5±1.1 years) carried out two 25 min dives to a depth of 10 m with a 90 min surface interval. Before and after, echocardiographic data were recorded and evaluated with regard to circulating bubbles with an extended Eftedal-Brubakk-Scale by 2 different examiners. Bubbles were observed for a total of 6 subjects, Grade I (n=5) and Grade III (n=1). None of them showed any symptoms of decompression sickness. No differences were established regarding potential influencing factors on bubble formation between the groups with and without bubbles. The results indicate that even relatively shallow and short dives can generate venous bubbles in children and adolescents. To what extent this relates to the decompression sickness or clinical symptoms cannot be validated at this point.

Respiration Dependency of Caval Blood Flow in Patients with Fontan Circulation: Quantification Using 5D Flow MRI.

PURPOSE: To measure respiration-dependent blood flow in the total cavopulmonary connection (TCPC) of patients with Fontan circulation by using free-running, fully self-gated five-dimensional (5D) flow MRI. MATERIALS AND METHODS: From July to November 2018, 10 volunteers (six female volunteers, mean age, 25.1 years ± 4.4 [standard deviation]) and six patients with Fontan circulation (two female patients, mean age, 19.7 years ± 7.5) with a TCPC were examined by using a cardiac- and respiration-resolved three-directional and three-dimensional phase-contrast MRI sequence (hereafter, 5D flow MRI). This prospective study was conducted with approval of the local ethics committee, and written informed consent was obtained from all participants and/or their representative. 5D flow data were acquired during free breathing. Data were reconstructed into 15-20 heart phases and four respiratory phases: end-expiration, inspiration, end-inspiration, and expiration. Respiration-dependent stroke volumes (SVs) and particle traces were analyzed from the caval circulation of volunteers and patients with Fontan circulation. Statistical analysis was performed by using parametric tests and scatterplots. RESULTS: The respiration dependency of caval blood flow was evaluated in all participants and was significantly elevated in patients with Fontan circulation as compared with volunteers. In patients, SV in the inferior vena cava (IVC) showed variations of 120% between inspiration and expiration (P = .002). The flow distribution in the IVC and superior vena cava among the four respiratory phases was differentiated by 20% (range, 9%-30%) and 4% (range, 0%-13%), respectively. CONCLUSION: Hemodynamic parameters (volume flow and blood flow distribution) throughout the cardiac and respiratory cycle can be measured using a single scan, potentially providing further insights into the Fontan circulation.© RSNA, 2019Supplemental material is available for this article.

Pulmonary hypertension in adults with congenital heart disease: Updated recommendations from the Cologne Consensus Conference 2018.

In the summer of 2016, delegates from the German Respiratory Society (DGP), the German Society of Cardiology (DGK) and the German Society of Pediatric Cardiology (DGPK) met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary hypertension (PH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines, aiming at their practical implementation, considering country-specific issues, and including new evidence, where available. To this end, a number of working groups was initiated, one of which was specifically dedicated to PH in adults associated with congenital heart disease (CHD). As such patients are often complex and require special attention, and the general PAH treatment algorithm in the ESC/ERS guidelines appears too unspecific for CHD, the working group proposes an analogous algorithm for the management of PH-CHD which takes the special features of this patient group into consideration, and includes general measures, supportive therapy, targeted PAH drug therapy as well as interventional and surgical procedures. The detailed results and recommendations of the working group on PH in adults with CHD, which were last updated in the spring of 2018, are summarized in this article.

Implantation of a subcutaneous implantable cardioverter defibrillator with right parasternal electrode position in a patient with D-transposition of the great arteries and concomitant AAI pacemaker: a case report.

BACKGROUND: Implantable cardioverter defibrillator (ICD) therapy is indicated in patients with structural heart disease who have had an aborted cardiac arrest (ACA). After atrial repair of d-transposition of the great arteries (d-TGA, Mustard repair) patients seem to be at a higher risk of failing intraoperative subcutaneous ICD (S-ICD) shock testing. CASE SUMMARY: We report the case of a 45-year-old patient with congenital heart disease (CHD) who suffered a cardiac arrest from ventricular fibrillation and was subsequently implanted with a S-ICD. We describe the challenges of ICD therapy in patients after Mustard procedure for d-TGA, with the additional challenge of concomitant AAI pacemaker therapy. In this patient, we opted for the implantation of an S-ICD, and detail the necessary considerations and operative technique employed in this patient. A right parasternal electrode position was chosen and intraoperative shock testing was successful. DISCUSSION: Patients after atrial switch surgery for d-TGA and ACA require careful consideration of the appropriate type of ICD therapy. Subcutaneous ICD implantation with right parasternal electrode position may be a viable option in these patients.