Clinical Decision Analysis of Genetic Evaluation and Testing in 1013 Intensive Care Unit Infants with Congenital Heart Defects Supports Universal Genetic Testing.

Extracardiac anomalies (ECAs) are strong predictors of genetic disorders in infants with congenital heart disease (CHD), but there are no prior studies assessing performance of ECA status as a screen for genetic diagnoses in CHD patients. This retrospective cohort study assessed this in our comprehensive inpatient CHD genetics service focusing on neonates and infants admitted to the intensive care unit (ICU). The performance and diagnostic utility of using ECA status to screen for genetic disorders was assessed using decision curve analysis, a statistical tool to assess clinical utility, determining the threshold of phenotypic screening by ECA versus a Test-All approach. Over 24% of infants had genetic diagnoses identified (n = 244/1013), and ECA-positive status indicated a 4-fold increased risk of having a genetic disorder. However, ECA status had low-moderate screening performance based on predictive summary index, a compositive measure of positive and negative predictive values. For those with genetic diagnoses, nearly one-third (32%, 78/244) were ECA-negative but had cytogenetic and/or monogenic disorders identified by genetic testing. Thus, if the presence of multiple congenital anomalies is the phenotypic driver to initiate genetic testing, 13.4% (78/580) of infants with isolated CHD with identifiable genetic causes will be missed. Given the prevalence of genetic disorders and limited screening performance of ECA status, this analysis supports genetic testing in all CHD infants in intensive care settings rather than screening based on ECA.

Quadricuspid Aortic Valve: Imaging, Diagnosis, and Prognosis.

Quadricuspid aortic valve is a rare congenital cardiac anomaly with an incidence of 0.008% to 0.043%. Its clinical course varies depending on cusp anatomy, function, and associated cardiac malformations. It frequently progresses to aortic valve regurgitation that may require surgical valve replacement. Detection has shifted from incidental discovery during autopsies or cardiac surgeries in the early 20th century to various cardiac imaging methods in recent decades. In addition to contributing to the literature, this report supports the use of transesophageal echocardiography more liberally to detect aortic valve abnormalities. The case presents a 48-year-old female patient with an incidentally discovered quadricuspid aortic valve.

Update on Prenatal Detection Rate of Critical Congenital Heart Disease Before and During the COVID-19 Pandemic.

Prenatal diagnosis of critical congenital heart disease (CCHD) has improved over time, and previous studies have identified CCHD subtype and socioeconomic status as factors influencing rates of prenatal diagnosis. Our objective of this single-center study was to compare prenatal diagnosis rates of newborns with CCHD admitted for cardiac intervention from the COVID-19 pandemic period (March 2020 to March 2021) to the pre-pandemic period and identify factors associated with the lack of CCHD prenatal diagnosis. The overall rate of CCHD and rates of the various CCHD diagnoses were calculated and compared with historical data collection periods (2009-2012 and 2013-2016). Compared with the 2009-2012 pre-pandemic period, patients had 2.17 times higher odds of having a prenatal diagnosis of CCHD during the pandemic period controlling for lesion type (aOR = 2.17, 95% CI 1.36-3.48, p = 0.001). Single ventricle lesions (aOR 6.74 [4.64-9.80], p < 0.001) and outflow tract anomalies (aOR 2.20 [1.56-3.12], p < 0.001) had the highest odds of prenatal diagnosis compared with the remaining lesions. Patients with outflow tract anomalies had higher odds for prenatal detection in the pandemic period compared with during the 2009-2012 pre-pandemic period (aOR 2.01 [1.06-3.78], p = 0.031). In conclusion, prenatal detection of CCHD among newborns presenting for cardiac intervention appeared to have improved during the pandemic period.

Simpson-Golabi-Behmel syndrome type 1 with normal birth parameters.

A newborn baby born at 34 weeks and 5 days gestation was admitted for prematurity, dysmorphic features and congenital heart defects. Antenatal scan at 21 weeks showed a large-for-gestational-age foetus with a large abdominal circumference and liver, ventricular septal defect, right prominent renal pelvis and echogenic bowel. Antenatal genetic tests for overgrowth syndromes were negative. The mother had early onset pre-eclampsia. After birth, an overgrowth syndrome was still suspected despite the baby having normal birth parameters. Raw data of the trio whole exome sequencing from the amniocentesis sample were manually inspected. Hemizygous exon 7 deletion in the GPC3 gene was found, and a postnatal diagnosis of Simpson-Golabi-Behmel syndrome, a rare overgrowth syndrome, was made. This case report discusses the significance of antenatal findings, an atypical presentation of a rare syndrome and the obstacles of diagnostic genetic testing.

PATHFINDER-CHD: prospective registry on adults with congenital heart disease, abnormal ventricular function, and/or heart failure as a foundation for establishing rehabilitative, prehabilitative, preventive, and health-promoting measures: rationale, aims, design and methods.

BACKGROUND: Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. AIMS: The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). METHODS: This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. DESIGN: The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. PROCESSES: Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. ASSESSMENTS: Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. DISCUSSION OF THE DESIGN: The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. CONCLUSION: The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.

Fetal Hemodynamics, Early Survival, and Neurodevelopment in Patients With Cyanotic Congenital Heart Disease.

BACKGROUND: Fetuses with cyanotic congenital heart disease (CHD) exhibit profound fetal circulatory disturbances that may affect early outcomes. OBJECTIVES: This study sought to investigate the relationship between fetal hemodynamics and early survival and neurodevelopmental (ND) outcomes in patients with cyanotic CHD. METHODS: In this longitudinal observational study, fetuses with cyanotic CHD underwent late gestational fetal cardiovascular magnetic resonance (CMR) to measure vessel blood flow and oxygen content. Superior vena cava (SVC) flow was used as a proxy for cerebral blood flow. Primary outcomes were 18-month mortality and Bayley Scales of Infant Development-III assessment. RESULTS: A total of 144 fetuses with cyanotic CHD were assessed. By 18 months, 18 patients (12.5%) died. Early mortality was associated with reduced combined ventricular output (P = 0.01), descending aortic flow (P = 0.04), and umbilical vein flow (P = 0.03). Of the surviving patients, 71 had ND outcomes assessed. Cerebral oxygen delivery was the fetal hemodynamic variable most strongly associated with cognitive, language, and motor outcomes (P < 0.05). Fetal SVC flow was also associated with cognitive, language, and motor outcomes (P < 0.01), and it remained an independent predictor of cognitive (P = 0.002) and language (P = 0.04) outcomes after adjusting for diagnosis. Diminished SVC flow also performed better than other fetal CMR and echocardiographic predictors of cognitive ND delay (receiver-operating characteristic curve area: 0.85; SE 0.05). CONCLUSIONS: Among fetuses with cyanotic CHD, diminished fetal combined ventricular output is associated with mortality, whereas cerebral blood flow and oxygen delivery are associated with early cognitive, language, and motor development at 18 months of age. These results support the inclusion of fetal CMR to help identify patients at risk of adverse ND outcomes.

Time to childbirth and assisted reproductive treatment in women with congenital heart disease.

OBJECTIVE: To investigate the time to first childbirth and to compare the prevalence of assisted reproductive treatment (ART) in women with congenital heart disease (CHD) compared with women without CHD. METHODS: All women in the national register for CHD who had a registered first childbirth in the Swedish Pregnancy Register between 2014 and 2019 were identified. These individuals (cases) were matched by birth year and municipality to women without CHD (controls) in a 1:5 ratio. The time from the 18th birthday to the first childbirth and the prevalence of ART was compared between cases and controls. RESULTS: 830 first childbirths in cases were identified and compared with 4137 controls. Cases were slightly older at the time for first childbirth (28.9 vs 28.5 years, p=0.04) and ART was more common (6.1% vs 4.0%, p<0.01) compared with controls. There were no differences in ART when stratifying for the complexity of CHD. For all women, higher age was associated with ART treatment (OR 1.24, 95% CI 1.20 to 1.28). CONCLUSIONS: Women with and without CHD who gave birth to a first child did so at similar ages. ART was more common in women with CHD, but disease severity did not influence the need for ART. Age was an important risk factor for ART also in women with CHD and should be considered in consultations with these patients.

Pulse oximetry test for screening congenital heart diseases: a systematic review.

OBJECTIVE: To determine the accuracy of the Pulse Oximetry Test (POT) in screening for Congenital Heart Diseases (CHD) in newborns in the first 48 hours of life. METHOD: Systematic review of diagnostic test accuracy with meta-analysis. The selection of studies was carried out in June 2021. Studies were selected with newborns, in a hospital or home environment, without a previous diagnosis of CHD, regardless of gestational age at birth, who underwent POT within the first 48 hours after birth. Registration on the PROSPERO platform - CRD42021256286. RESULTS: Twenty-nine studies were included, totaling a population of 388,491 newborns. POT demonstrated sensitivity of 47% (95% CI: 43% to 50%) and specificity of 98% (95% CI: 98% to 98%). Subgroup analyses were carried out according to the different testing period, inclusion of retests in protocols and population of premature newborns. CONCLUSION: POT is a test with moderate sensitivity and high specificity. It is more effective when carried out within 24h - 48h of birth; in protocols that present retests, within two hours after the first measurement. It does not show satisfactory effectiveness for premature newborns.

Epidemiology and Definition of Heart Failure in Adult Congenital Heart Disease.

Adults with congenital heart disease (ACHD) are facing lifelong complications, notably heart failure (HF). This review focuses on classifications, incidence, prevalence, and mortality of HF related to ACHD. Diagnosing HF in ACHD is intricate due to anatomic variations, necessitating comprehensive clinical evaluations. Hospitalizations and resource consumption for ACHD HF have significantly risen compared with non-ACHD HF patients. With more than 30% prevalence in complex cases, HF has become the leading cause of death in ACHD. These alarming trends underscore the insufficient understanding of ACHD-related HF manifestations and management challenges within the context of aging, complexity, and comorbidity.

Special Considerations for Mechanical Circulatory Support or Device Therapy in Adult Congenital Heart Disease Heart Failure.

Heart failure has become the leading cause of mortality in adult congenital heart disease (ACHD) patients after the fifth decade of life. There is scanty evidence supporting the use of guideline-directed medical therapy in ACHD, especially in systemic right ventricle or single ventricle physiology. In complex patients, diagnosing heart failure and timely referral for advanced therapies are challenging. Mechanical circulatory support has been significantly developed over the past decade and has recently emerged as a feasible therapeutic option for these patients. This review summarizes current evidence of mechanical circulatory support in this population, its potential uses, and challenges.

Advancing Wearable Biosensors for Congenital Heart Disease: Patient and Clinician Perspectives: A Science Advisory From the American Heart Association.

Wearable biosensors (wearables) enable continual, noninvasive physiologic and behavioral monitoring at home for those with pediatric or congenital heart disease. Wearables allow patients to access their personal data and monitor their health. Despite substantial technologic advances in recent years, issues with hardware design, data analysis, and integration into the clinical workflow prevent wearables from reaching their potential in high-risk congenital heart disease populations. This science advisory reviews the use of wearables in patients with congenital heart disease, how to improve these technologies for clinicians and patients, and ethical and regulatory considerations. Challenges related to the use of wearables are common to every clinical setting, but specific topics for consideration in congenital heart disease are highlighted.

Congenital cardiac anomalies in non-syndromic cleft lip and cleft palate patients: A systematic review and meta-analysis.

The aim was to establish a specific and definite connection between non-syndromic orofacial cleft patients and associated congenital heart disease (CHD). Following PRISMA guidelines, selective databases were searched for data collection. Studies showing a definite association of CHD with orofacial cleft were included, and studies non-specific of the association of orofacial cleft with CHD were excluded. Data extraction criteria were study design, frequency of CHD in overall non-syndromic orofacial cleft and in specific cleft type, and most prevalent congenital cardiac anomaly. DerSimonian Laird random effects model was used to estimate the pooled proportion of CHD, along with corresponding 95% confidence intervals (CIs) for each measure. Publication bias was assessed using Fail-Safe N analysis and the Rosenthel approach. Of a total of 182 articles searched, only 30 studies were assessed. The overall pooled estimate of the proportion of CHD in total cleft lips/palates was 16% (95% CI: 13-19). The odds of developing CHD in cleft palates was 4.08 times more as compared to cleft lips with 95% CIs of 3.86-4.33, and 1.65 more as compared to cleft lips and palates both with 95% CI of 1.52-1.68. We affirm the upsurging prevalence of CHD in non-syndromic cleft children and vehemently propose that it is of utmost importance to inculcate it in practice and policy-making to screen all non-syndromic orofacial cleft children for congenital cardiac anomaly. This study was registered on PROSPERO (ID no. CRD42023391597) on February 24, 2023.

Social Determinants of Health Including Child Opportunity Index Leading to Gaps in Care for Patients With Significant Congenital Heart Disease.

BACKGROUND: Gaps in care (GIC) are common for patients with congenital heart disease (CHD) and can lead to worsening clinical status, unplanned hospitalization, and mortality. Understanding of how social determinants of health (SDOH) contribute to GIC in CHD is incomplete. We hypothesize that SDOH, including Child Opportunity Index (COI), are associated with GIC in patients with significant CHD. METHODS AND RESULTS: A total of 8554 patients followed at a regional specialty pediatric hospital with moderate to severe CHD seen in cardiology clinic between January 2013 and December 2015 were retrospectively reviewed. SDOH factors including race, ethnicity, language, and COI calculated based on home address and zip code were analyzed. GIC of >3.25 years were identified in 32% (2709) of patients. GIC were associated with ages 14 to 29 years (P<0.001), Black race or Hispanic ethnicity (P<0.001), living ≥150 miles from the hospital (P=0.017), public health insurance (P<0.001), a maternal education level of high school or less (P<0.001), and a low COI (P<0.001). Multivariable analysis showed that GIC were associated with age ≥14 years, Black race or Hispanic ethnicity, documenting <3 caregivers as contacts, mother's education level being high school or less, a very low/low COI, and insurance status (C statistic 0.66). CONCLUSIONS: One-third of patients followed in a regional referral center with significant CHD experienced a substantial GIC (>3.25 years). Several SDOH, including a low COI, were associated with GIC. Hospitals should adopt formal GIC improvement programs focusing on SDOH to improve continuity of care and ultimately overall outcomes for patients with CHD.

FGD1-related Aarskog-Scott syndrome: Identification of four novel variations and a literature review of clinical and molecular aspects.

Patients with Aarskog-Scott syndrome (AAS) have short stature, facial anomalies, skeletal deformities, and genitourinary malformations. FYVE, RhoGEF, and PH domain-containing 1 (FGD1) is the only known causative gene of AAS. However, the diagnosis of AAS remains difficult, and specific treatments are still absent. Patients suspected with AAS were recruited, and clinical information was collected. Genetic testing and functional analysis were carried out for the diagnosis. By literature review, we summarized the clinical and genetic characteristics of FGD1-related AAS and analyzed the genotype-phenotype correlation. Five patients were recruited, and four novel FGD1 variants were identified. The diagnosis of AAS was confirmed by genetic analysis and functional study. Three patients treated with growth hormone showed improved heights during the follow-up period. By literature review, clinical features of AAS patients with FGD1 variants were summarized. Regarding FGD1 variations, substitutions were the most common form, and among them, missense variants were the most frequent. Moreover, we found patients with drastic variants showed higher incidences of foot and genitourinary malformations. Missense variants in DH domain were related to a lower incidence of cryptorchidism.   Conclusion: We reported four novel pathogenic FGD1 variations in AAS patients and confirmed the efficacy and safety of growth hormone treatment in FGD1-related AAS patients with growth hormone deficiency. Additionally, our literature review suggested the crucial role of DH domain in FGD1 function. What is Known: • Aarskog-Scott syndrome is a rare genetic disease, and the only known cause is the variant in FGD1 gene. The typical clinical manifestations of AAS include facial, skeletal, and urogenital deformities and short stature. What is New: • We reported four novel FGD1 variants and reported the treatment of growth hormone in FGD1-related AAS patients. Our genotype-phenotype correlation analysis suggested the crucial role of DH domain in FGD1 function.

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.

Real-world diagnostic landscape and incidence of pulmonary hypertension in adult congenital heart disease patients using administrative claims data in Japan.

BACKGROUND: Although pulmonary hypertension (PH) and Eisenmenger's syndrome (ES) are common complications in adult congenital heart disease (ACHD), the frequency of diagnostic tests and the incidence of PH/ES in patients with ACHD in Japanese clinical practice are unclear. Therefore, we sought to clarify the frequency of diagnostic tests and incidence of PH/ES in patients with ACHD using the Medical Data Vision (MDV) database, the largest anonymized database of diagnosis procedure combination hospitals in Japan. METHODS: We conducted a retrospective cohort study using the MDV database (April 2008 to December 2021) of patients with ACHD (International Classificaiton of Diseases, 10th revision codes: Q203-204, Q210-213, Q250) aged ≥15 years. The frequency of laboratory/clinical tests and the incidence of PH/ES were calculated. Subgroup analyses were performed for the periods 2008-2015 and 2016-2021. RESULTS: Overall, 28219 ACHD patients were extracted from the MDV database (females 56.3%, males 43.7%; mean ± standard deviation age 44.7 ± 23.5 years). The mean ± standard deviation follow-up period was 2.5 ± 2.7 years. The frequencies of electrocardiography, ultrasonography, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), right heart catheterization, and pulmonary function tests (DLCO) were 2149.8, 1054, 1233, 340, 40.0, and 6.0 per 1000 person-years, respectively. The incidence rate of PH/ES was 32.8 per 1000 person-years. The incidence rate of PH/ES increased from 24.6 to 46.7 per 1000 person-years from 2008-2015 to 2016-2021. CONCLUSION: We have clarified the frequency of diagnostic tests related to PH/ES and the incidence of PH/ES in patients with ACHD in clinical practice in Japan, including non-specialist institutions for PH.

Nucleated Red Blood Cell Counts Differentiate Cardiac from Respiratory Causes of Cyanosis at Birth.

Tissue hypoxia increases erythropoietin production and release of immature erythrocytes that can be measured using nucleated red blood cell counts (nRBC). We hypothesized that hypoxia due to congenital heart disease (CHD) is chronic and is better tolerated than hypoxia due to respiratory disease (RD), which is an acute stress in newborns leading to higher nRBC. This study assesses the utility of nRBC as a marker to differentiate hypoxia due to CHD vs RD in term neonates. This was a single-center, retrospective study of term neonates with cyanosis from 2015 to 2022. Neonates < 37 weeks of gestation, with hypoxic-ischemic encephalopathy, and those with other causes of cyanosis were excluded. The patients were divided into 2 groups: cyanotic CHD and cyanotic RD. Clinical and laboratory data done within 12 h and 24-36 h after birth were collected. Data are represented as median and Interquartile range. Of 189 patients with cyanosis, 80 had CHD and 109 had RD. The absolute nRBC count at ≤ 12 h of age was lower in the CHD (360 cells/mm3) compared to RD group (2340 cells/mm3) despite the CHD group having significantly lower baseline saturations. A value of 1070 cells/mm3 was highly sensitive and specific for differentiating CHD from RD. The positive predictive value for this cut-off value of 1070 cells/mm3 was 0.94 and the negative predictive value was 0.89. The absolute nRBC is a simple screening test and is available worldwide. A nRBC < 1070 cells/mm3 in cyanotic newborns should hasten the search for CHD etiology with the possible need for prostaglandin therapy.