Impact of an Impaired Maternal-Fetal Environment on Death in Children With Congenital Heart Defects Undergoing Surgery in Denmark From 1994 to 2018.

BACKGROUND: Studies show that an impaired maternal-fetal environment (iMFE) increases the mortality risk in children with single-ventricle congenital heart defects (CHDs). We investigated the impact of an iMFE on death in children with various surgically corrected CHDs. METHODS AND RESULTS: In this nationwide register-based study, we examined the association between an iMFE (including preeclampsia, gestational hypertension, gestational diabetes, maternal smoking during pregnancy) and death in a large cohort of children with surgically corrected CHDs in Denmark (1994-2018). Survival analysis was done using Cox regression, adjusted for confounding and mediating covariates. The cohort included 3304 children: 1662 (50.3%) with minor CHD and 1642 (49.7%) with major CHD. Among them, 792 (24%) children were exposed to an iMFE. During the study, there were 290 deaths: 71 (9.3%) in children exposed to an iMFE and 219 (8.7%) in those unexposed. There were no differences in mortality risk between children with CHD exposed to an iMFE and those unexposed (hazard ratio [HR], 1.12 [95% CI, 0.86-1.47]; P=0.4). This was consistent across subgroups, including minor CHD (HR, 0.76 [95% CI, 0.39-1.47]; P=0.4), major CHD (HR, 1.23 [95% CI, 0.92-1.64]; P=0.2), and hypoplastic left heart syndrome/univentricular heart (HR, 1.08 [95% CI, 0.64-1.85]; P=0.8). CONCLUSIONS: Impairment of the maternal-fetal environment did not impact the mortality rate in children with CHD undergoing operation in Denmark from 1994 to 2018. We believe the cause of these discrepant findings to previous studies may be due to differences in the composition of CHD and prenatal maternal health care and health status of the population.

TBX5 variants and cardiac phenotype: A systematic review of the literature and a novel variant.

T-Box Transcription Factor 5 (TBX5) variants are associated with Holt-Oram syndrome. Holt-Oram syndrome display phenotypic variability, regarding upper limb defects, congenital heart defects, and arrhythmias. To investigate the genotype-phenotype relationship between TBX5 variants and cardiac disease, we performed a systematic review of the literature. Through the systematic review we identified 108 variants in TBX5 associated with a cardiac phenotype in 277 patients. Arrhythmias were more frequent in patients with a missense variant (48% vs 30%, p = 0.009) and upper limb abnormalities were more frequent in patients with protein-truncating variants (85% vs 64%, p = 0.0008). We found clustering of missense variants in the T-box domain. Furthermore, we present a family with atrial septal defects. By whole exome sequencing, we identified a novel missense variant p.Phe232Leu in TBX5. The cardiac phenotype included atrial septal defect, arrhythmias, heart failure, and dilated cardiomyopathy. Clinical examination revealed subtle upper limb abnormalities. Thus, the family corresponds to the diagnostic criteria of Holt-Oram syndrome. We provide an overview of cardiac phenotypes associated with TBX5 variants and show an increased risk of arrhythmias associated to missense variants compared to protein-truncating variants. We report a novel missense variant in TBX5 in a family with an atypical Holt-Oram syndrome phenotype.

Lung Function in Fontan Patients Over a Ten-Year Period: Is the Fontan Circulation Impairing Lung Development?

Few studies have investigated how the Fontan circulation affects lung function, and no studies have investigated the development of lung function over longer time in these patients. We aimed to describe the development of lung function in Fontan patients over a 10-year period. Pulmonary function tests (PFT), including spirometry and diffusion capacity for Carbon Monoxide (DLCO) and Nitric Oxide (DLNO), were conducted in a Danish Fontan cohort in 2011 (PFT-I). In 2021, re-investigations were performed (PFT-II). We investigated changes in percent predicted (%pred) lung function from PFT-I to PFT-II. Patients were categorized into a pediatric group (age under 18 at PFT-I) and an adult group (age 18 or older at PFT-I). Out of the 81 patients completing PFT-I, 48 completed PFT-II. In the pediatric group (32 patients), there were significant declines in %pred forced expiratory volume in 1s (99.7 (92.4, 104.4)-89.3 (84.9, 97.2), p < 0,001), forced vital capacity (98.3 (87.8, 106.1)-96.7 (86.7, 100.6), p = 0.008), and alveolar volume (95.5 (89.5, 101.6)-89.5 (79.7, 93.2), p < 0.001). The corresponding measurements remained stable in the adult group. However, the median %pred DLNO significantly declined in the adult group (58.4 (53.3, 63.5)-53.7 (44.1, 57.3), p = 0.005). Over a 10-year period, several lung function parameters declined significantly in the younger Fontan patients, suggesting possible impairments in lung development during growth. The decline in %pred DLNO in the adult patient group indicates deterioration of the membrane component of diffusion capacity, implying that the Fontan circulation might negatively affect the alveolar membrane over time.

Psychiatric morbidity and work participation in patients with congenital ventricular septal defects: a case-controlled study.

BACKGROUND: The burden of psychiatric morbidity, level of education, and work participation is currently unknown in patients with congenital ventricular septal defects (VSD). METHODS: In a Danish population-based cohort study using nationwide medical registries the burden of psychiatric disorders, use of psychotropic agents, level of education, and work participation were examined in patients with isolated congenital VSD and controls from the general population matched by age and sex. Subjects with known chromosomal abnormalities were excluded. To compute estimates, Cox proportional regression model, Fine and Gray's competing risk regression, and Kaplan-Meier failure function were used. RESULTS: We included 8 006 patients and 79 568 controls born before 2018. Median follow-up was 23 years. Compared with controls, patients with VSD displayed a HR of 1.24 (95% CI: 1.17-1.32) for any psychiatric disorder where the hazard for intellectual disabilities was most pronounced [HR of 3.66 (95% CI: 2.98-4.50)]. The use of psychotropic agents was higher in patients compared with controls [HR 1.14 (95% CI: 1.09-1.20)]. The work participation was lower in patients with VSD compared with controls (P < 0.001) and was lower in patients with VSD with a psychiatric disorder compared with those without (P < 0.001). The 40-year cumulative incidence of permanent social security benefits was 29% in patients with psychiatric disorders (versus 21% in controls with psychiatric disorders) and 8% in patients without psychiatric disorders (versus 4% in controls). CONCLUSION: Patients with isolated VSD suffer from a higher burden of psychiatric disorders and display lower work participation compared with matched controls from the general Danish population. It is important to consider longer-term impacts on mental health, education, and subsequent employment in patients with VSD, in addition to cardiovascular effects, as these factors severely affect quality of life and have direct socioeconomic implications on an individual and societal level.

Octreotide improves human lymphatic fluid transport a translational trial.

OBJECTIVES: Chylothorax is a complex condition and many different pharmacological agents have been tried as treatment. Octreotide is used off-label to treat chylothorax, but the efficacy of octreotide remains unclear. A decrease in lymph production is suggested as the mechanism. In this cross-over study, we explore the direct effect of octreotide on human lymphatic drainage. METHODS: Pre-clinical: the effect of octreotide on force generation was assessed during acute and prolonged drug incubation on human lymphatic vessels mounted in a myograph. Clinical: in a double-blinded, randomized, cross-over trial including 16 healthy adults, we administered either octreotide or saline as an intravenous infusion for 2.5 h. Near-infrared fluorescence imaging was used to examine spontaneous lymphatic contractions and lymph pressure in peripheral lymphatic vessels and plethysmography was performed to assess the capillary filtration rate, capillary filtration coefficient and isovolumetric pressures of the lower leg. RESULTS: Pre-clinical: human thoracic duct (n = 12) contraction rate was concentration-dependently stimulated by octreotide with a maximum effect at 10 and 100 nmol/l in the myograph chamber. Clinical: spontaneous lymphatic contractions and lymph pressure evaluated by near-infrared fluorescence did not differ between octreotide or placebo (P = 0.36). Plethysmography revealed similar capillary filtration coefficients (P = 0.057), but almost a doubling of the isovolumetric pressures (P = 0.005) during octreotide infusion. CONCLUSIONS: Octreotide stimulated lymphatic contractility in the pre-clinical setup but did not affect the spontaneous lymphatic contractions or lymph pressure in healthy individuals. Plethysmography revealed a doubling in the isovolumetric pressure. These results suggest that octreotide increases lymphatic drainage capacity in situations with high lymphatic afterload.

Electrocardiographic Characteristics in 438 Neonates with Atrial Septal Defects.

Arrhythmias and electrocardiographic (ECG) abnormalities are common among patients with atrial septal defects (ASDs). We studied a large cohort of neonates with ASDs to investigate whether ECG abnormalities are present at this early stage or develop later, secondary to hemodynamic changes. We analyzed the echocardiograms and ECGs from the Copenhagen Baby Heart Study, a population-based cohort study. We compared ECG characteristics of 438 neonates with secundum ASDs to 1314 matched controls. In subgroup analyses, we investigated whether electrocardiographic characteristics were associated with age at examination. Neonates with ASDs (median age, 11 days; males, 51%) had longer P-wave durations (58 vs. 56 ms, p < 0.001), PR intervals (100 vs. 96 ms, p < 0.001), and a more rightward-shifted QRS axis (116 vs. 114 degrees, p = 0.032) compared to controls (median age, 10 days; males, 51%). There were no differences between cases and controls in the P-wave area, amplitude, or axis. Subgroup analyses showed that the differences in P-wave duration and PR interval were present in neonates examined in the first week after birth. The difference in the QRS axis was not found in neonates examined this early but was found in neonates examined at age two to four weeks. In conclusion, ASDs are associated with ECG changes from the neonatal phase. The P-wave duration and PR interval are longer in neonates with ASDs when compared to controls as early as the first week after birth, indicating that these changes are not purely secondary, but that neonates with an ASD have altered cardiac electrical activity.ClinicalTrials.gov Identifier NCT02753348 (April 27, 2016).

Quality of Life in the Danish Fontan Population is Unchanged Over the Past Decade-A Nationwide Longitudinal Study.

Knowledge about health-related quality of life (HRQoL) over time in Fontan patients is sparse. We aimed to describe HRQoL over a ten-year period in a population-based Fontan cohort. Further, we compared HRQoL in Fontan patients with the general population. In 2011, Danish Fontan patients were invited to participate in a nationwide study assessing HRQoL. Depending on age, 152 participants filled out either the Pediatric Quality of Life Inventory or the 36-Item Short Form Health Survey. After a decade, patients from the initial study were invited to participate in a follow-up study. All were given the same questionnaire as in the first study, plus the 12-Item Short Form Health Survey (SF-12) as part of the Danish National Health Survey. HRQoL over time was described, and SF-12 scores were compared with the general population. A total of 109 Fontan patients completed the questionnaires in both studies. The mean patient age was 14.9 ± 6.6 years and 25.6 ± 6.5 years respectively. Despite an increase in complications, HRQoL did not decrease during the study period. Physical HRQoL scores were lower than mental HRQoL scores at both time points. The SF-12 physical component score was significantly lower in Fontan patients than in the general population (median score 52 vs. 56, p < 0.001), while the SF-12 mental component score was comparable (median score 51 vs. 50, p = 0.019). HRQoL remained stable over a ten-year period in a contemporary Danish Fontan cohort. Still, the physical HRQoL remained significantly lower than that of the general population.

Self- and proxy-reported impaired social interaction in young adults with simple congenital heart defects.

Background: Simple Congenital Heart Defects such as septal defects constitute a large proportion of Congenital Heart Defects. New research has demonstrated more co-morbidities than previously thought. In particular, co-morbidities involving neurocognitive, psychiatric, and social difficulties have been described. Neurocognitive and psychiatric morbidities affect social interaction. Social interaction is important in everyday social life (education, work life, family life). In this study, we investigated social interaction through self- and proxy-answered Social Responsiveness Scale 2 (SRS-2) in young adults with simple Congenital Heart Defects and compared their social interaction profile to healthy matched controls. Methods: We included a total of 80 patients with either atrial or ventricular septal defect (age 26.6 years) and 38 heart-healthy, age, sex, and ISCED educational matched controls (age: 25.3 years). A close relative proxy from each participant took part in the study as well. All participants answered the Social Responsiveness Scale 2 (SRS-2) (n = 225). Our primary and secondary outcomes were the SRS-2 Total score and the SRS-2 sub-scores. Results: In the Congenital Heart Defects group, 31.3% had a Total score above 60 compared to 7.9% in the control group (p = 0.005, RR = 3.96). The participants with a septal defect had a higher Total score (52.5 vs. 45.5, p = 0.004), a higher Social Cognition sub-score (55.0 vs. 47.0, p = 0.0004), and a higher Social Motivation sub-score (50.0 vs. 45.0, p = 0.003) than the heart-healthy participants. We found no difference between the two groups regarding the sub-scores of Social Awareness and Social Communication. A multiple linear regression model showed that the variable that explained most of the variation in Total Score was having a previously diagnosed psychiatric disorder. Conclusion: We found that young adults with atrial or ventricular septal defects have a fourfold increased risk of social interaction difficulties compared to heart-healthy peers. They have a social interaction profile, with difficulties in social cognition and social motivation, and preserved social awareness and social communication. Psychiatric morbidity explained most of the variation in social interaction problems. As social difficulties and psychiatric morbidities are intertwined, social interaction difficulties could be an indication of already underlying psychiatric morbidities or a risk factor for future psychiatric morbidity.

Psychiatric co-morbidity in children and adolescents with CHDs: a systematic review.

The population of long-term survivors with CHDs is increasing due to better diagnostics and treatment. This has revealed many co-morbidities including different neurocognitive difficulties. However, the prevalence of psychiatric disorders among children and adolescents and the specific types of disorders they may experience are unclear. We systematically reviewed the existing literature, where psychiatric diagnoses or psychiatric symptoms were investigated in children and adolescents (age: 2-18 aged) with CHDs and compared them with a heart-healthy control group or normative data. The searches were done in the three databases PubMed, psychINFO, and Embase. We included 20 articles reporting on 8035 unique patients with CHDs. Fourteen articles repoted on psychological symptoms, four reported on psychiatric diagnoses, and two reported on both symptoms and diagnoses. We found that children and adolescents with a CHD had a higher prevalence of attention deficit hyperactivity disorder (ranging between 1.4 and 9 times higher) and autism (ranging between 1.8 and 5 times higher) than controls, but inconsistent results regarding depression and anxiety.

Health and Well-Being in Older Adults With a Surgically Closed or an Unrepaired Ventricular Septal Defect.

Background Older adults with a congenital ventricular septal defect (VSD) recently exhibited reduced heart rate variability and exercise capacity. It is unknown whether these findings affect health-related quality of life. Methods and Results Adults with VSDs and healthy controls, all concurrently included as part of another clinical study, completed the Danish National Health Survey questionnaire. Questionnaire data distributed to the general population were included and matched 10:1 with patients. Thirty patients with surgically closed VSDs (mean±SD age, 51±8 years), 300 adults from the general population (mean±SD age, 50±8 years), and 30 controls (mean±SD age, 51±9 years), as well as 30 patients with unrepaired VSDs (mean±SD age, 55±11 years), 300 adults from the general population (mean±SD age, 55±12 years), and 30 controls (mean±SD age, 55±10 years) completed the questionnaire. Educational level, social relations, and physical activity were comparable between groups. A larger proportion of patients with unrepaired VSDs compared with the general population experienced migraine (47% versus 24%; P=0.04), whereas more patients with surgically closed VSDs were affected by depression (13% versus 4%; P=0.02). For health-related quality of life, patients with surgically closed VSDs reported lower physical functioning (P<0.01), physical component summary (P<0.01), general health perception (P<0.01), and higher stress score (P=0.03) compared with the general population and healthy controls. Patients with unrepaired VSDs reported lower scores on physical functioning (P=0.03), bodily pain (P<0.01), and mental health (P=0.02), and a higher stress score (P=0.03), than controls. Conclusions Older patients with VSDs report lower self-perceived physical functioning, lower general health, and higher stress levels, all in line with previous findings, like lower exercise capacity and dysfunctional cognitive abilities, in adults with VSDs. Incessant follow-up is paramount, as neither successfully closed nor hemodynamically insignificant VSD is equivalent with untroubled healthy aging. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03684161.

Vitamin D Supplementation and Vitamin D Status during Pregnancy and the Risk of Congenital Anomalies-A Systematic Review and Meta-Analysis.

Maternal dietary factors have been suggested as possible contributing influences for congenital anomalies (CAs). We aimed to assess the association between vitamin D supplementation or vitamin D status (s-25OHD) during pregnancy and CAs in the offspring. A comprehensive literature search was conducted in the three electronic databases: PubMed, Embase, and Cochrane Library. Included studies were critically appraised using appropriate tools (risk of bias 2, ROBINS-I). A protocol was registered in the International Prospective Register of Systematic Reviews (CRD42019127131). A meta-analysis of four randomised controlled trials (RCTs) including 3931 participants showed no effect of vitamin D supplementation on CAs, a relative risk of 0.76 (95% CI 0.45; 1.30), with moderate certainty in the effect estimates by GRADE assessment. Of the nine identified observational studies, six were excluded due to a critical risk of bias in accordance with ROBINS-I. Among the included observational studies, two studies found no association, whereas one case-control study identified an association between s-25OHD < 20 nmol/L and neural tube defects, with an adjusted odds ratio of 2.34 (95% CI: 1.07; 5.07). Interpretation of the results should be cautious given the low prevalence of CAs, RCTs with onset of supplementation after organogenesis, and low-quality observational studies.

Association between nutritional status and socio-economic status among school children aged 9-17 years in a semi-urban area of Nepal.

BACKGROUND: In many low-and middle-income countries (LMICs), childhood overweight is increasing, while underweight remains a problem. This study aimed to investigate the association between socio-economic status (SES) and nutritional status among Nepalese school children. METHODS: This cross-sectional study used a multistage random cluster sampling method and included 868 students aged 9-17 years from both public and private schools located in a semi-urban area of Pokhara Metropolitan City, Nepal. SES was determined based on a self-reported questionnaire. Body weight and height were measured by health professionals and body mass index (BMI) was categorized based on the World Health Organization BMI-for-age cut-offs. The association between Lower and Upper SES and BMI was assessed using mixed-effects logistic regression model estimating the adjusted odds ratio (aOR) with a corresponding 95% confidence interval (CI) and compared to Middle SES. RESULTS: The proportion of obesity, overweight, underweight, and stunting among school children was 4%, 12%, 7%, and 17%, respectively. More girls were overweight/obese compared with boys (20% vs. 13%). The mixed-effects logistic regression model showed that both participants from Lower SES households and Upper SES households had a higher tendency to be overweight compared to participants from Middle SES; aOR = 1.4; 95% CI 0.7-3.1 and aOR = 1.1; 95% CI 0.6-2.1, respectively. Furthermore, stunting and overweight occurred simultaneously. CONCLUSIONS: This study found that about one out of four children and adolescents in the study setting was malnourished. There was a tendency that both participants from Lower SES and Upper SES had higher odds of being overweight compared to participants from Middle SES. Furthermore, both stunting and overweight were present simultaneously in some individuals. This emphasizes the complexity and importance of awareness of childhood malnutrition in LMICs like Nepal.

The transport function of the human lymphatic system-A systematic review.

Physiological properties and function of the lymphatic system is still somewhat of a mystery. We report the current knowledge about human lymphatic vessel contractility and capability of adaptation. A literature search in PubMed identified studies published January 2000-September 2022. Inclusion criteria were studies investigating parameters related to contraction frequency, fluid velocity, and lymphatic pressure in vivo and ex vivo in human lymphatic vessels. The search returned 2885 papers of which 28 met the inclusion criteria. In vivo vessels revealed baseline contraction frequencies between 0.2 ± 0.2 and 1.8 ± 0.1 min1 , velocities between 0.008 ± 0.002 and 2.3 ± 0.3 cm/s, and pressures between 4.5 (range 0.5-9.2) and 60.3 ± 2.8 mm Hg. Gravitational forces, hyperthermia, and treatment with nifedipine caused increases in contraction frequency. Ex vivo lymphatic vessels displayed contraction frequencies between 1.2 ± 0.1 and 5.5 ± 1.2 min-1 . Exposure to agents affecting cation and anion channels, adrenoceptors, HCN channels, and changes in diameter-tension properties all resulted in changes in functional parameters as known from the blood vascular system. We find that the lymphatic system is dynamic and adaptable. Different investigative methods yields alternating results. Systematic approaches, consensus on investigative methods, and larger studies are needed to fully understand lymphatic transport and apply this in a clinical context.

Lymphatic Abnormalities on Magnetic Resonance Imaging in Single-Ventricle Congenital Heart Defects Before Glenn Operation.

Background In the palliative pathway of single-ventricle physiology, lymphatic abnormalities on T2-weighted magnetic resonance imaging have been shown after the Glenn operation. It is believed that postsurgical hemodynamic changes contribute to the lymphatic changes.However, little is known about how early these abnormalities occur. Our purpose was to determine if lymphatic abnormalities occur as early as before the Glenn operation. Methods and Results We retrospectively reviewed patients with single-ventricle physiology and a T2-weighted magnetic resonance imaging scan before their Glenn operation (superior cavopulmonary connection) at The Children's Hospital of Philadelphia from 2012 to 2022. Lymphatic perfusion patterns on T2-magnetic resonance imaging were categorized from type 1 (no supraclavicular T2-signal) to type 4 (supraclavicular, mediastinal, lung parenchymal T2-signal). Types 1 and 2 were considered normal variants. Distribution of lymphatic abnormalities were tabulated, as well as secondary outcomes including chylothorax and mortality. Comparison was done using analysis of variance, Kruskal-Wallis test, and Fisher's exact test. Seventy-one children were included: 30 with hypoplastic left heart syndrome and 41 with nonhypoplastic left heart syndrome. Lymphatic abnormalities were present before Glenn operation in 21% (type 3) and 20% (type 4), and normal lymphatic perfusion patterns (type 1-2) were seen in 59% of patients. Chylothorax was present in 17% (only types 3 and 4). Pre-Glenn mortality and mortality at any time was significantly increased when having a type 4 lymphatic abnormality compared with types 1 and 2 (P=0.04). Conclusions Lymphatic abnormalities can be found on T2-weighted magnetic resonance imaging in children with single-ventricle physiology before their Glenn operation. Mortality and chylothorax were more prevalent with advancing grade of lymphatic abnormality.

Exercise capacity in the Danish Fontan population remains stable after ten years of follow-up - is physical activity the key to success?

BACKGROUND: Most Fontan patients have impaired exercise capacity, and a further decline in exercise capacity over time seems inevitable. However, few longitudinal studies exist, and there is a lack of data from newer eras. We aimed to describe the natural evolution of exercise capacity over a 10-year period in a contemporary, population-based cohort of Danish Fontan patients. METHODS: The study was a nationwide, prospective study. A cardiopulmonary exercise test (CPET) was used to assess the exercise capacity. All Danish Fontan patients who participated in a national study in 2011 (CPET1), were invited to a follow-up visit in 2021 (CPET2). All patients who completed CPET1 and CPET2 with a respiratory exchange ratio over 1.0 were included. The main outcome was percent predicted VO2peak (%pred VO2peak). At the time of CPET2, patients filled out a questionnaire including questions regarding physical activity. RESULTS: Seventy-seven patients completed both CPET1 and CPET2, and seventy patients completed the questionnaire. The time interval between the two CPETs was 10.4 ± 0.9 years. The median age was 15 years at CPET1 and 26 years at CPET2. The exercise capacity remained stable with a mean %pred VO2peak of 53.8 ± 11.3 at CPET1 and 55.6 ± 10.9 in CPET2 (p = 0.314). Higher levels of vigorous physical activity were associated with higher %pred VO2peak in CPET2 in a multivariate regression model. CONCLUSION: The %pred VO2peak remained stable over a ten-year period in this population-based Fontan cohort. Higher levels of self-reported vigorous physical activity were associated with higher %pred VO2peak in the most recent CPET.

Atrial Septal Defect: Larger Right Ventricular Dimensions and Atrial Volumes as Early as in the First Month After Birth-a Case-Control Study Including 716 Neonates.

Atrial septal defect (ASD) is characterized by a left-to-right shunt causing dilatation of the right atrium and right ventricle as well as pulmonary hyperperfusion. The detection of ASDs often occurs late in childhood or adulthood. Little is known about cardiac structure and function in neonates with ASD.We analyzed neonatal echocardiograms from the Copenhagen Baby Heart Study, a multicenter, population-based cohort study of 27,595 neonates. We included 716 neonates with secundum-type ASDs and matched them 1:1 on sex and age at examination with neonates without ASD from the same birth cohort. Neonates with an ASD (median age 11 days, 52% female) had larger right ventricular (RV) dimensions than matched controls (RV longitudinal dimension end-diastole: 27.7 mm vs. 26.7 mm, p < 0.001; RV basal dimension end-diastole: 14.9 mm vs. 13.8 mm, p < 0.001; and RV outflow tract diameter 13.6 mm vs. 12.4 mm, p < 0.001). Atrial volumes were larger in neonates with ASD compared to controls (right atrial end-systolic volume: 2.9 ml vs. 2.1 ml, p < 0.001; and left atrial end-systolic volume 2.0 ml vs. 1.8 ml, p < 0.001). Tricuspid annular plane systolic excursion was larger in neonates with ASD than in controls (10.2 mm vs. 9.6 mm, p < 0.001). Left ventricular dimensions and function did not differ between neonates with ASD and controls. In conclusion, ASDs were associated with altered cardiac dimensions already in the neonatal period, with larger right ventricular dimensions and larger atrial volumes at echocardiography within the first 30 days after birth.ClinicalTrials.gov Identifier: NCT02753348 (April 27, 2016).

Early changes in cerebral metabolism after perinatal hypoxia-ischemia: a study in normothermic and hypothermic piglets.

Introduction: Hypoxic ischemic encephalopathy (HIE) after a perinatal insult is a dynamic process that evolves over time. Therapeutic hypothermia (TH) is standard treatment for severe to moderate HIE. There is a lack of evidence on the temporal change and interrelation of the underlying mechanisms that constitute HIE under normal and hypothermic conditions. We aimed to describe early changes in intracerebral metabolism after a hypoxic-ischemic insult in piglets treated with and without TH and in controls. Methods: Three devices were installed into the left hemisphere of 24 piglets: a probe measuring intracranial pressure, a probe measuring blood flow and oxygen tension, and a microdialysis catheter measuring lactate, glucose, glycerol, and pyruvate. After a standardized hypoxic ischemic insult, the piglets were randomized to either TH or normothermia. Results: Glycerol, a marker of cell lysis, increased immediately after the insult in both groups. There was a secondary increase in glycerol in normothermic piglets but not in piglets treated with TH. Intracerebral pressure, blood flow, oxygen tension, and extracellular lactate remained stable during the secondary increase in glycerol. Conclusion: This exploratory study depicted the development of the pathophysiological mechanisms in the hours following a perinatal hypoxic-ischemic insult with and without TH and controls.

Mortality in Patients With Ebstein Anomaly.

BACKGROUND: Low birth prevalence and referral bias constitute significant obstacles to elucidating the natural history of Ebstein anomaly (EA). OBJECTIVES: An extensive 2-country register-based collaboration was performed to investigate the mortality in patients with EA. METHODS: Patients born from 1970 to 2017 and diagnosed with EA were identified in Danish and Swedish nationwide medical registries. Each patient was matched by birth year and sex with 10 control subjects from the general population. Cumulative mortality and HR of mortality were computed using Kaplan-Meier failure function and Cox proportional regression model. RESULTS: The study included 530 patients with EA and 5,300 matched control subjects with a median follow-up of 11 years. In the EA cohort, 43% (228) underwent cardiac surgery. Cumulative mortality was lower for patients diagnosed in the modern era (the year 2000 and later) than for those diagnosed in the prior era (P < 0.001). Patients with isolated lesion displayed lower cumulative mortality than patients with complex lesions did (P < 0.001). Patients with a presumed mild EA anatomy displayed a 35-year cumulative mortality of 11% (vs 4% for the matched control subjects; P < 0.001), yielding an HR for mortality of 6.0 (95% CI: 2.7-13.6), whereas patients with presumed severe EA demonstrated an HR of 36.2 (95% CI: 15.5-84.4) compared with control subjects and a cumulative mortality of 18% 35 years following diagnosis. CONCLUSIONS: Mortality in patients with EA is high irrespective of presence of concomitant congenital cardiac malformations and time of diagnosis compared with the general population, but overall mortality has improved in the contemporary era.

Congenital heart disease and the risk of impaired fertility: A Danish nationwide cohort study using time to pregnancy.

BACKGROUND: The number of women with congenital heart disease (CHD) becoming pregnant are increasing. Although menstrual irregularities appear to occur more often in these patients, knowledge on their fertility is limited. In this nationwide cohort study, we evaluated the risk of impaired fertility in women with CHD compared with unaffected women using time to pregnancy (TTP). METHODS: The Danish National Birth Cohort (DNBC) of pregnant women constituted the study population. Information on TTP and use of medically assisted reproduction (MAR) treatment was reported at a first trimester interview. Women with CHD were identified by linkage to the Danish National Patient Registry. TTP was divided into three categories; 0-5 months, 6-12 months (i.e. subfertile), and > 12 months or use of MAR treatment (i.e. infertile). Relative risk ratios (RRR) for subfertility and infertility with 95% confidence intervals were estimated using multinomial logistic regression. RESULTS: Among 93,832 pregnancies in 84,922 women, CHD was diagnosed in 333 women (0.4%), contributing with 360 pregnancies. The CHD was of simple complexity in 291 women (87.4%). No association was found between CHD and longer TTP (RRR of 1.02 (95% CI: 0.75-1.40) for subfertility, and RRR of 0.86 (95% CI: 0.61-1.20) for infertility). Similar was observed when comparing women with simple CHD and unaffected women. The number of women with complex CHD was too low for evaluation. CONCLUSIONS: Women with CHD had no increased risk of impaired fertility, assessed by TTP, when compared with unaffected women. Separate analysis of women with complex CHD was hampered by low numbers.

Trileaflet Semilunar Valve Reconstruction: Acute Porcine in Vivo Evaluation.

Objective: The surgical treatment of malformed semilunar valves in congenital heart defects is challenging in terms of providing both longevity and the potential to grow with the recipient. We investigated a new surgical technique "Trileaflet Semilunar Valve Reconstruction" in an acute porcine model, a technique with geometrical properties that could remain sufficient and allow for some growth with the child. Methods: An acute 60-kg porcine model was used. With echocardiography, baseline pulmonary valvular geometry and hemodynamics were investigated. On cardiopulmonary bypass, the pulmonary leaflets were explanted, and the Trileaflet Semilunar Valve Reconstruction was performed with customized homograft-treated pericardial neo-leaflets. Off bypass, hemodynamics was reassessed. Results: Twelve animals were investigated. The neo-valves were found sufficient in ten animals and with minimal regurgitation in two animals. The neo-valve had a peak gradient of 3 ± 2 mm Hg with a peak velocity of 0.8 ± 0.2 m/s. The coaptation in the neo-valve had a mean increase of 4 ± 3 mm, P < .001. The neo-valve had a windmill shape in the echocardiographic short-axis view, and the neo-leaflets billowed at the annular plane in the long-axis view. Conclusions: In this acute porcine model, the neo-valve had no clinically significant regurgitation or stenosis. The neo-valve had an increased coaptation, a windmill shape, and leaflets that billowed at the annular plane. These geometric findings may allow for sustained sufficiency as the annular and pulmonary artery dimension increase with the child's growth. Further long-term studies should be performed to evaluate the efficacy and the growth potential.