Virtual panel analysis (VPA) of exome data is a common approach for the molecular diagnosis of congenital heart disease (CHD). However, differences in gene panel composition and patient inclusion criteria limit the evaluation of its diagnostic utility. This study aims to assess the diagnostic yield of VPA in a cohort of patients with CHD across 3 academic centers. We collected clinical data including phenotypic features and family history, from 853 probands with CHD who underwent VPA analysis at the Center for Medical Genetics Ghent (525 probands; 471 genes), the University Medical Center Groningen (195 probands; 345 genes), and the University Medical Center Utrecht (133 probands; 55 genes). We evaluated the diagnostic yield by comparing the 3 centers with respect to panel composition and clinical presentation. The Center for Medical Genetics Ghent reported a higher diagnostic yield (9.9%) compared with the University Medical Center Groningen (7.2%) and the University Medical Center Utrecht (5.3%). In all centers, the diagnostic yield was higher in patients presenting with a syndromic constellation and did not differ significantly between the sporadic and familial cases. In 1.7% of the 536 nonsyndromic probands, a molecular cause was identified that typically is associated with syndromic CHD. Twelve genes showed likely pathogenic or pathogenic variants in multiple patients and contributed to 56.2% of the identified causes. We report an overall diagnostic yield of VPA for CHD of 8.6%, to which only a few genes contribute significantly, highlighting the complex origin of CHD. Since panel size, gene panel content, and local practices largely affect the diagnostic yield, we propose a (minimum) core gene panel for suspected isolated CHD, as well as a coordinated testing strategy for CHD to improve diagnosis and counseling and to catalyze collaborative efforts.

The first week of postnatal life is a period of transition for both pulmonary and systemic vascular flow patterns. Owing to associated shunts and altered systemic/pulmonary blood flow, neonates with congenital heart defect (CHD) are at particular risk for disrupted end-organ perfusion and oxygen delivery, including that of the brain. Near-infrared spectroscopy (NIRS) measures venous-weighted cerebral oxygen saturation (CSat) at the frontal cortex, serving as an indirect reflection of cerebral blood flow. CSat is impacted by factors such as tissue perfusion, systemic oxygenation, regional oxygen extraction and haemoglobin levels, all of which are affected by cardiac function and vascular supply [1, 2]. Cerebral fractional tissue oxygen extraction (cFTOE) reflects the balance between cerebral oxygen utilisation and oxygen delivery, and it is operationally defined as (preductal SpO2—CSat)/preductal SpO2. As such, cFTOE can provide insight into cerebral oxygen utilisation. Increased cFTOE can be due to decreased oxygen delivery or increased oxygen consumption not met by associated increase in delivery. Likewise, decreased cFTOE can indicate that the brain is using less oxygen or that oxygen delivery has increased relative to utilisation [3]. Data on CSat and cFTOE as cerebrovascular metrics in neonates with CHD during the period of postnatal adaptation are limited. Elements of anterior cerebral artery (ACA) Doppler such as resistive index (RI) and pulsatility index (PI) assess vascular resistance and flow characteristics in the frontal cortex and have been shown to correspond to cerebral perfusion pressure [4]. Abnormal RI is a recognised indicator of such newborn pathologies as increased intracranial pressure, brain injury and diastolic steal [5-7]. This study has made a notable contribution to the literature by applying these established bedside tools to a vulnerable and complex group of patients (neonates with CHD) during a time of critical transitional physiology (postnatal adaptation). The authors recruited 34 neonates with various types of CHD and analysed 142 concomitant data measurements of NIRS and daily ultrasound Doppler over the first 7 days of life. They used mixed-effects models to evaluate the relationship between CSat/cFTOE and RI/PI-ACA, adjusting for time since birth, pCO2 and haemoglobin levels. The authors found a decline in CSat and rise in cFTOE throughout the first week of life in neonates with CHD, which aligns with findings from prior research [8]. RI and PI both increased over the time period, indicating increased resistance to flow velocities. The authors also reported statistically significant associations between CSat/cFTOE and simultaneous RI/PI values. The findings suggest a progressive increase in oxygen extraction, possibly related to diminished blood flow, impaired oxygen delivery or increased metabolic demand during postnatal transition. The authors theorise that this may be partly owing to altered adaptation due to shunts and abnormal anatomy. Despite the variability of the study population, the findings supported consistent directional trends in NIRS and ultrasound. While these results are meaningful, an even greater impact will be gained in translating the findings to earlier detection/management of cerebral hypoperfusion in order to improve neurodevelopmental outcomes. URL LINK: https://ebneo.org/ebneo-commentary-cerebral-saturation-and-fractional-tissue-oxygen-extraction-and-anterior-cerebral-artery-doppler. Ashley L. Lynch: conceptualization, writing – original draft. Ethan L. Gillett: writing – review and editing. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Association of Parenting Stress in Early Childhood with Emotional Health and Resilience of Young Adults with Congenital Heart Disease.

Heart failure (HF) is the leading cause of morbidity and mortality in adults with congenital heart disease (ACHD), yet evidence-based pharmacological options remain limited. Sodium-glucose cotransporter 2 inhibitors (SGLT2I) have demonstrated robust benefits across the heart failure spectrum in acquired cardiovascular disease. This review is summarizing emerging data on the use of SGLT2I in ACHD, a population characterized by unique pathophysiology and unmet therapeutic needs. Recent literature, predominantly comprising case reports, retrospective cohorts, and small prospective studies, suggests that SGLT2I are generally safe and well tolerated in adult congenital heart disease heart failure (ACHD-HF). Across heterogeneous ACHD populations, including those with a systemic right ventricle (SRV) and Fontan circulation, SGLT2I use has been associated with improvements in natriuretic peptides, functional status, exercise capacity, and reductions in HF hospitalizations. Early data support favourable safety and low discontinuation rates. The use of SGLT2I in ACHD-HF is feasible, well tolerated and with potential clinical benefit. Further ACHD-specific randomized clinical trials to define efficacy, optimal patient selection, and long-term outcomes are warranted.

The number of pregnant women with adult congenital heart disease (ACHD) is increasing, posing growing challenges for obstetric anaesthesia. This study analysed anaesthetic strategies and postoperative care in ACHD patients treated at atertiary care centre. This retrospective single-centre study included ACHD patients who received anaesthesia for delivery, caesarean section or obstetric surgery between 2004 and 2023. Acomparison group of obstetric patients without congenital heart disease was selected based on baseline characteristics. Atotal of 391 cases were included (131 ACHD, 260 comparison group). Most patients were classified as mWHOI (44.2%) orII (23.8%), with 20.5% mWHO II-III and 11.5% mWHO III and IV. Spinal and epidural anaesthesia were used more frequently in lower mWHO classes (p = 0.017). All mWHOIV patients required general anaesthesia provided by ACHD-experienced anaesthetists. ACHD patients more frequently required postoperative ICU or IMCU care (6.6% vs.1.6%, p = 0.02; 13.9% vs.3.7%, p < 0.001). Anaesthesiologic complication rates were low in both groups. Obstetric anaesthesia was feasible with low complication rates, even in severe ACHD, when management was individualised and interdisciplinary. All anaesthetic procedures proved to be feasible when adapted to the risk profile.

Congenital heart disease in a singleton pregnancy conceived through assisted reproductive technology.

Cardiovascular genetics evaluation in the cardiac ICU (CICU) is essential for patient and family care. However, engaging genetic counseling (GC) consultation by frontline care teams in the CICU is challenging. This quality improvement (QI) project aimed to: 1) increase GC consultations for eligible CICU patients, 2) decrease time from admission to consultation, and 3) assess whether changes aligned with parental preferences. Single-center QI study, from January 2020 to June 2024. Large tertiary care children's hospital in the United States. Two hundred sixty-five patients with congenital heart defect (CHD). None. In 2022, we introduced a standardized admission process for admissions with CHD, including: electronic medical record (EMR) notifications, accurate diagnostics, improved referral workflow and collaboration with fetal cardiology clinic, and parent surveys. A before-vs.-after analysis showed an associated increase in GC consultation from 76% to 94%; the mean time from admission to consultation decreased from 6 to 3 days. Post-introduction, there was reduced variability and less delay compared with pre-implementation. A needs assessment survey via a parent-support group had 151 responses, which indicated that 83% of families wanted genetic testing. Sixty-nine percent of families wanted to discuss genetic testing through in-person consultation during their child's initial inpatient admission. Thirty-two percent of families preferred contact as soon as possible and 47% preferred contact before cardiac surgery. Last, 75% of parents with a fetal diagnosis of CHD expressed interest in discussing testing while pregnant. In our pre- vs. post-introduction of a QI intervention, we found that eligible CICU patients are more reliably and promptly identified for GC consultation by leveraging the EMR and partnering with CICU staff and fetal cardiology. Parents supported genetic testing, typically delivered through integrated GC consultations in both the fetal and inpatient settings.

We have investigated postoperative dynamic changes in endothelial glycocalyx (EG) degradation markers in infants who have undergone cardiopulmonary bypass (CPB) for congenital heart disease (CHD) surgery, and related the observations to the development of pediatric acute respiratory distress syndrome (PARDS). Single-center prospective, case-control study, June to December 2024. Twenty-bed to a pediatric cardiac ICU (CICU) in a tertiary hospital in China. Overall, 45 infants (age range 121-351 d) undergoing nonemergency CPB for CHD were recruited; 15 with PARDS and 30 matched non-PARDS cases. None. PARDS patients in comparison with non-PARDS patients had higher glycocalyx degradation markers at CICU admission (T 1 ): syndecan-1, 199.2 ± 22.1 vs. 118.6 ± 6.2 ng/mL ( p < 0.05); heparan sulfate (HS), 105.7 ± 11.9 vs. 79.1 ± 6.8 ng/mL ( p < 0.05); and hyaluronic acid (HA), 53.6 ± 10.5 vs. 40.4 ± 4.7 ng/mL ( p < 0.05). Biomarkers were highest at T 1 , fell at postoperative day 1 (T 2 ), and returned to baseline by day 5 (T 3 ) in both groups, with levels consistency higher in PARDS infants. The PARDS group also had longer median duration of mechanical ventilation (48 vs. 24 hr, p < 0.001), CICU stay (7.0 vs. 4.0 d), and hospital stay (18.5 vs. 12.0 d), with T 1 biomarker levels correlated with duration of mechanical ventilation (r = 0.52-0.68) and CICU length of stay (r = 0.61-0.71; all p < 0.05). In CHD infants admitted to the CICU after surgery involving CPB, PARDS cases exhibit an associated EG injury. Monitoring of the peak levels of degradation markers (syndecan-1, HS, and HA) at admission to the CICU may help identify those at most risk of PARDS.

The deletion syndrome 22q11.2 is one of the most frequent genetic syndromes in humans, with aprevalence of 1:2500 [1]. The syndrome is particularly relevant for neurology, psychiatry and child and adolescent psychiatry due to amassive genetic predisposition to neuropsychiatric disorders that has been proven in recent years. Somatic symptoms are highly variable and can be diverse. Congenital heart defects, otorhinolaryngologic (ENT) abnormalities, parathyroid dysfunction and orthopedic abnormalities are particularly frequent and typical. In addition, many affected individuals suffer from susceptibility to infections. Almost all affected children show developmental disorders.

Transcatheter pulmonary valve replacement (TPVR) has transformed the management of patients with congenital heart disease (CHD) with dysfunctional pulmonary outflow tracts. Technological advancements have expanded the number of patients eligible for this minimally invasive alternative to surgical valve replacement. With the introduction of larger self-expanding valves and adaptive prestenting systems, TPVR has become accessible to patients with complex anatomies, including those with native right ventricular outflow tract (RVOT) disease. Recent studies have demonstrated the excellent clinical outcomes of TPVR thus far, while also acknowledging the occurrence of rare complications. Crucial questions guiding the future of TPVR management include: timing to refer for TPVR, how to optimize valve durability, enhance preprocedural screening with advanced imaging and electrophysiology studies, and improve hemodynamic monitoring. These advancements underscore TPVR's adaptability and efficacy, offering new solutions for complex cases and improving outcomes. Future research should focus on optimizing patient selection and intervention timing, as well as addressing long-term durability and complications.

Rates and Predictors of Malignancy After Heart Transplantation in Adults with Congenital Heart Disease

Results of observational studies assessing clinical benefits of guideline-directed medical therapy (GDMT) for heart failure (HF) in adults with congenital heart disease are conflicting. This is because these studies were based on a heterogenous population and lacked standardized criteria for assessing adequacy of HF therapy across studies. The current study addressed these limitations by studying the effect of GDMT (using a standardized GDMT score) in adults with repaired systemic biventricular congenital heart disease, systemic left ventricle, and HF with reduced ejection fraction. HF with reduced ejection fraction was defined as stage B/C HF and systemic left ventricular EF < 50%. GDMT score was assessed at baseline encounter (baseline GDMT score) and 1-year follow-up. GDMT uptitration was calculated as defined as ∆GDMT (∆=delta or change in) score from baseline. Cox regression was used to assess the relationship between HF therapy (baseline and ∆GDMT score) and outcomes (HF hospitalization and mortality). Of 778 patients, baseline and ∆GDMT scores were 2 (1, 3) and 0.56 (0.49, 0.62), respectively. Of 778, only 258 (33%) had GDMT uptitration (∆GDMT score >0). Higher use of GDMT at baseline (adjusted hazard ratio [HR] per 1 point increase in GDMT score 0.83, 95% confidence interval [CI] 0.74, 0.92, P < .001), and increased use of GDMT over time (adjusted HR for 1 point increase in ∆GDMT score HR 0.71, 95% CI 0.62, 0.82, P < .001) were associated with lower risk of HF hospitalization. Higher baseline GDMT score (adjusted HR 0.87, 95% CI 0.76, 0.98, P = .01), and ∆GDMT score (adjusted HR 0.84, 95% CI 0.72, 0.86, P = .002) were also associated with lower mortality. GDMT use at baseline, and GDMT uptitration were associated with improved outcomes and suggest a dose-dependent relationship between use of GDMT and risk of adverse outcomes. Furthermore, 67% of patients did not receive GDMT uptitration, suggesting suboptimal therapy and opportunities for improvement.

A Safe and Effective Approach: Transjugular Liver Biopsy in Patients with Congenital Heart Disease

Advances in fetal cardiac magnetic resonance imaging (CMR) have expanded its role as an adjunct to expert fetal echocardiography in the prenatal evaluation of complex cardiopulmonary anomalies. This review outlines an evidence-based framework for integrating fetal CMR when it provides diagnostic or prognostic information that can informs counseling, delivery planning, or postnatal management. Fetal CMR offers high-resolution, multiplanar imaging with superior soft-tissue contrast and wide field of view, enabling improved assessment of cardiopulmonary structures where echocardiography is limited by technical or physiologic factors, or when expert echocardiography raises clinically relevant questions. MRI enables improved delineation of aortic arch and pulmonary venous anatomy, characterization of pulmonary parenchymal changes, and quantify lung and ventricular volumetry without relying on geometric assumptions. Emerging flow-based techniques allow evaluation of fetal hemodynamics and cardiovascular physiology beyond static imaging. These technologies provide diagnostic and prognostic information in select, often critical, congenital heart diseases. Fetal cardiac CMR serves as a complementary modality to expert echocardiography when applied selectively to address clinically meaningful diagnostic or prognostic questions. However, limited availability, technical complexity, and the need for specialized expertise currently constrain widespread adoption. Continued technical refinement and outcome-based validation are required before fetal CMR can be routinely integrated into clinical practice.

Pathogenic variants in MED13L, including copy-number changes and sequence variants, cause MED13L syndrome. This rare neurodevelopmental disorder is characterized by global developmental delay, intellectual disability (ID), distinctive facial dysmorphism, hypotonia, and variable congenital heart defects. The phenotypic heterogeneity of MED13L syndrome underscores the significance of genotype-phenotype correlation analysis for improving clinical diagnosis and precise phenotypic characterization of affected individuals. Venous blood samples anticoagulated with EDTA were collected from the patient and family members, followed by whole-exome sequencing analysis and subsequent validation using fluorescent quantitative PCR. Concurrently, a systematic search of the PubMed database was performed to summarize previously reported cases harboring MED13L copy number Variations (CNVs). Whole-exome sequencing revealed a de novo heterozygous single-copy duplication of a ~19-kb region within the MED13L gene (exons 8-16) in the proband. The patient presents phenotypic features consistent with MED13L syndrome and represents the first reported case exhibiting cleft lip. A literature review indicates that vision impairment, developmental delay, and congenital heart disease are widely observed phenotypes, while other less frequent manifestations vary between patients with duplications and deletions. This study, integrating a case report and a literature review, provides important reference evidence for the clinical genetic counseling of MED13L syndrome.

Real-World Outcomes of Mechanical Circulatory Support in Adults with Congenital Heart Disease

Examining the Role of Heart Transplant in the Journey of Individuals and Families Affected by Single‐Ventricle Congenital Heart Disease

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect characterised by underdevelopment of left-sided cardiac structures. While genetic predisposition contributes to HLHS, the relevance of environmental stressors is increasingly recognised, yet the cellular mechanisms linking genetic susceptibility to environmental vulnerability remain unclear. We aimed to identify molecular and functional differences between cardiomyocytes derived from HLHS patients and healthy controls to uncover potential susceptibilities contributing to the HLHS phenotype. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from HLHS patients and healthy controls were used to examine intrinsic cellular differences. Single-cell RNA sequencing compared baseline transcriptional profiles. Functional assays assessed responses to endothelin-1 (ET-1)-induced stress, cyclic mechanical stretch, and basal or mitogen-stimulated proliferation. These approaches were used to identify intrinsic functional impairments and altered stress responses in HLHS cardiomyocytes. Single-cell transcriptomics revealed downregulation of gene networks associated with cardiac stress responses, metabolic resilience, and rhythm regulation in HLHS cardiomyocytes. Regulon analysis revealed broad reductions in transcription factor activity across key cardiac regulatory networks. Functionally, HLHS cardiomyocytes showed heightened vulnerability to ET-1, with exaggerated proBNP induction compared with controls. No significant differences were observed following cyclic mechanical stretch. Basal proliferation varied across HLHS lines, while mitogen-induced proliferation remained comparable to controls. These findings support a model in which intrinsic molecular and functional vulnerabilities in HLHS cardiomyocytes might reduce resilience to developmental stressors. Such gene-environment interactions may contribute to HLHS pathogenesis, underscoring the interplay between genetic predisposition and environmental influences in congenital heart disease.

Preoperative pulmonary hemodynamics and clinical decision making to determine operability and risk of long-term pulmonary hypertension in infants with open shunt under 1year.

Cardiovascular medicine is progressively evolving towards a more personalised approach integrating advanced imaging, haemodynamic assessment, biomarkers, rehabilitation, and digital technologies. The studies featured in this issue of Acta Cardiologica provide new insights into heart failure, structural heart disease, coronary artery disease, congenital heart disease, and cardiovascular prevention. Collectively, they highlight the growing importance of comprehensive risk stratification and individualised management strategies to improve cardiovascular outcomes.