Cardiac Defects Research Articles

Clinical and genetic characteristics of a case of Koolen-De Vries syndrome caused by KANSL1 gene mutation and literature review: A case report.

Koolen-De Vries syndrome (KdVS, OMIM: 612452), also known as 17q21.31 microdeletion syndrome, is an autosomal dominant genetic disease. In the study, we analyze of clinical phenotype and gene variation of a child with Koolen-De Vries syndrome, review the literature to improve the understanding of the disease. The patient is a male, aged 1 month and 3 days. The patient has poor airway development, difficulty weaning from respiratory support, seizures, and recurrent low granulocyte counts. High-throughput sequencing showed a heterozygous mutation NM_001193466.1: c.1574_1578del (P.525HFS *24) in the KANSL1 gene of the proband, which was considered a new mutation since neither of his parents carried this mutation based on Sanger sequencing results. Combining clinical features and genetic results, the proband was diagnosed as KdVS. The patient was in good condition after receiving bronchoscopy and laser interventional therapy, meeting the criteria for discharge. Follow-up for 1 year and 6 months indicated that the patient's physical signs were normal and there was no recurrence. According to literature review, KdVS is a multi-organ disease characterized by feeding difficulties, seizures, characteristic facial features, dysplasia of the respiratory system and cardiac abnormalities. In this study, laryngeal malacia accounted for 23.2% of the clinical manifestations of KdVS patients, limb convulsions/seizures accounted for 62.5%, and cardiac development defects accounted for 23.5%. The disease was rare in China and had a variety of clinical manifestations. The summary of reported cases can enable doctors to have more understanding of the disease. The new mutations enrich the KANSL1 gene mutation spectrum.

Generation of an iPSC cell line (VANYHHi001-A) from a patient with cardiac arrythmias carrying CACNA1D, SCN5A, and DSP variants

Progressive cardiac conduction defect often associated with variants in sodium voltage-gated channel SCN5A gene and variants in the L-type calcium voltage-gated channel CACNA1D gene are implicated in sinoatrial node dysfunction. We generated an induced pluripotent stem cell line (iPSC) from a 13-year-old patient with history of conduction system disease and ventricular tachycardia, carrying variants in SCN5A (c.2618C > G), CACNA1D (c.3786G > T), and DSP (c.1582C > G). The generated iPSC line exhibited pluripotency markers, differentiated into the three embryonic germ layers, and maintained a normal karyotype. This iPSC line offers insights into the pathophysiological mechanisms of cardiac arrhythmias and personalized therapies development.

Short-Term Surgical Outcomes and Definitive Diagnosis in Patients With Congenital Cardiac Defects: A Single-Center Analysis

Short-Term Surgical Outcomes and Definitive Diagnosis in Patients With Congenital Cardiac Defects: A Single-Center Analysis

Molecular diagnoses and candidate gene identification in the congenital heart disease cohorts of the 100,000 genomes project.

Congenital heart disease (CHD) describes a structural cardiac defect present from birth. A cohort of participants recruited to the 100,000 Genomes Project (100 kGP) with syndromic CHD (286 probands) and familial CHD (262 probands) were identified. "Tiering" following genome sequencing data analysis prioritised variants in gene panels linked to participant phenotype. To improve diagnostic rates in the CHD cohorts, we implemented an agnostic de novo Gene Discovery Pipeline (GDP). We assessed de novo variants (DNV) for unsolved CHD participants following filtering to select variants of interest in OMIM-morbid genes, as well as novel candidate genes. The 100kGP CHD cohorts had low rates of pathogenic diagnoses reported (combined CHD "solved" 5.11% (n = 28/548)). Our GDP provided diagnostic uplift of nearly one third (1.28% uplift; 5.11% vs. 6.39%), with a new or potential diagnosis for 9 additional participants with CHD. When a filtered DNV occurred within a non-morbid gene, our GDP prioritised biologically-plausible candidate CHD genes (n = 79). Candidate variants occurred in both genes linked to cardiac development (e.g. AKAP13 and BCAR1) and those currently without a known role (e.g. TFAP2C and SETDB1). Sanger sequencing of a cohort of patients with CHD did not identify a second de novo variant in the candidate dataset. However, literature review identified rare variants in HMCN1, previously reported as causative for pulmonary atresia, confirming the approach utility. As well as diagnostic uplift for unsolved participants of the 100 kGP, our GDP created a dataset of candidate CHD genes, which forms an important resource for further evaluation.

Eisenmenger Syndrome: Pathophysiology, Clinical Manifestations, and Contemporary Management Approaches in Advanced Cardiopulmonary Disease

Eisenmenger syndrome, a complex and severe form of congenital heart disease, results from prolonged left-to-right shunting due to underlying cardiac defects such as ventricular septal defects, atrial septal defects, or patent ductus arteriosus, ultimately leading to irreversible pulmonary arterial hypertension and a reversal of the initial shunt. This syndrome represents the most severe spectrum of pulmonary vascular disease associated with congenital heart defects and is characterized by hypoxemia, erythrocytosis, and systemic cyanosis. Despite advances in early diagnosis and intervention in congenital heart disease, Eisenmenger syndrome remains a significant concern due to the irreversible nature of pulmonary vascular changes and associated multisystem complications. This article provides a comprehensive review of the pathophysiology, clinical manifestations, and the role of pharmacologic and non-pharmacologic therapies, including advanced palliative care, to improve patient quality of life. Emerging therapies such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs show promise in symptom management, though surgical interventions, such as heart-lung transplantation, remain reserved for selected cases. Given the high mortality associated with Eisenmenger syndrome, a multidisciplinary approach is critical in managing complications, improving patient outcomes, and supporting functional status.

Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach.

Laterality defects are defined by perturbations in the usual left-right asymmetry of organs. Due to low known genetic etiology of congenital heart disease (CHD) cases (less than 40%), we used a digenic model approach for the identification of contributing variants in known laterality defect genes (N = 115) in the exome/genome sequencing (ES/GS) data from individuals with clinically diagnosed laterality defects. The unsolved ES/GS data were analyzed from three CHD cohorts: Baylor College of Medicine-Genomics Research to Elucidate the Genetics of Rare Diseases (BCM-GREGoR; N = 247 proband ES), Gabriella Miller Kids First Pediatric Research program (Kids First; N = 158 trio GS), and Pediatric Cardiac Genomics Consortium (PCGC; N = 163 trio ES), and trans-heterozygous digenic variants were identified in 2.8% (inherited digenic variants in 0.4%), 8.2%, and 13.5% cases respectively, which was significantly higher as compared to 602 control trios provided by the 1000 Genomes Project (p = 0.001, 1.4e-07, and 8.9e-13, respectively). Trans-heterozygous digenic variants were also identified in 0.4%, and 1.4% cases with non-laterality CHD in Kids First and PCGC datasets, respectively, which was not statistically significant as compared to control trios ( p = 1, and 0.059, respectively). Altogether, in laterality cohorts, 23% of digenic pairs were in the same structural complex of motile cilia. Out of 39 unique digenic pairs in laterality CHD, 29 are more likely to be potential digenic hits as predicted by DiGePred tool. These findings provide further evidence that digenic epistatic interaction can contribute to the complex genetics of laterality defects.

Chromosomal aneuploidies: A tertiary care center study

Among the chromosomal aneuploidies Down syndrome is the most common type. This study was conducted to detect the frequency of chromosomal abnormalities in the paediatric patients in one year duration at a tertiary care centre. In cytogenetic lab, clinically suspected cases were referred from different department like pediatrics, neonataology, obstetrics and gynecology for Karyotyping test for the confirmation of aneuploidies. They were sampled for Karyotyping. Incidence of aneuploidies among live-births in a year (April 2023-March2024) was 4.68/1000. Down syndrome with trisomy+21 was found in all individual (100%) of 12 cases. Among cardiac disorder, ASD, VSD and VSD+ ASD were (complex cardiac defect) account for 33.33%. Other common clinical features were also seen like slanting eyes, sandal gap, mangloid facials, single simian crease, low set ears, depressed nasal bridge, and protruding tongue In this study prevalence of DS in Chhattisgarh were 4.68/1000. Most of the cases of the study were born from mother of younger age (19-27yrs). For early diagnosis clinician should counsel the younger pregnant women for such aneuploidies so that they can take appropriate measures.

Abstract 4140108: A CRISPR-Activation CROP-seq Screen Identifies HMGN1 as a Dosage-Sensitive Regulator of Heart Defects in Down Syndrome

Introduction/Background: Congenital heart defects (CHD) are the most common form of developmental abnormalities, occurring in ~1% of live births, and can arise due to altered dosage of genes essential for cardiogenesis. Aneuploidy accounts for nearly 15% of CHD and the most frequent form involves trisomy of chromosome 21 (Ch21), resulting in Down Syndrome (DS). CHD is present in ~50% of DS cases, with a 1000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the junction of the atria and ventricles. Hypothesis: We hypothesize that the presence of a third copy of one or more genes on Ch21 underlies AVC and other cardiac defects; however, the dosage-sensitive CHD gene(s) on Ch21 causing this are not fully defined. Methods: We used human pluripotent stem cells derived from an individual mosaic for DS, allowing us to compare Ch21 trisomy cells with isogenic control cells disomic for Ch21. We performed single cell RNA-sequencing (scRNA-seq) to define the transcriptional dysregulation associated with DS in atrioventricular canal myocardial cells (AVCM). We then introduced a CRISPR-activation transgene to disomic cells and delivered small guide RNAs (sgRNAs) against 66 candidate Ch21 CHD genes. We developed a new machine learning algorithm to assign a trisomic score to CRISPR perturbed (CROP-seq) cells. Finally, we reduced the copy number of our top candidate gene in a mouse model of Down Syndrome and used microCT to assess incidence of cardiac septal defects. Results: Using human pluripotent stem cell and mouse models of DS, we identify HMGN1, a nucleosome-binding epigenetic factor on Ch21, as a dosage-sensitive regulator of cardiac defects in DS. Single cell transcriptomics revealed that human AVC cardiomyocytes shifted to a more ventricular myocardial state in trisomy 21 hiPS-derived cells. CRISPR-activation in isogenic disomic cells of 66 candidate Ch21 genes expressed in heart development, followed by single cell RNA-sequencing (CROP-seq) combined with machine learning predictions indicated that increased expression levels of HMGN1 altered the transcriptional state of atrioventricular cardiomyocytes similar to trisomy 21. Finally, reduction of Hmgn1 from three to two alleles in a mouse model of DS attenuated the incidence of cardiac septal defects. Conclusion: Our results identify HMGN1 as a dosage sensitive regulator of heart defects in DS and represent a generalizable approach for identifying candidate genes within areas of aneuploidy.

Abstract 4112620: Cardiomyocyte-specific Increases in Forkhead Box M1 (FoxM1) Expression May Promote Cardiomyocyte Proliferation and Improve Recovery from Myocardial Injury in Mice and Pigs

Background: The cardiomyocytes (CMs) can not regenerate after myocardial infarction (MI) in adult mammals. FoxM1 is essential for cell proliferation. Targeted deletion of the Foxm1 in mice leads to serious cardiac proliferation defects and embryo death. The primary aim of this study was to demonstrate that the Specific Modified mRNA Translation System (SMRTs) can specifically overexpress FoxM1 in CMs and observe the benefits of overexpressing FoxM1 on myocardial repair in mice and pigs with myocardial injury. Methods: The FoxM1-CM SMRTs is composed of two modRNA constructs: one encoding L7Ae regulates the specific expression of FoxM1 on the other coding chain in CMs and inhibits its expression in non-cardiomyocytes through he CM-specific microRNAs miR-1 and miR-208 on L7Ae coding chain. Myocardial-specific expression of FoxM1-CM SMRTs and its proliferation-promoting effect were detected in hiPSC-CM (human-induced pluripotent stem cell-derived cardiomyocyte), mouse and pig models (days 3 after FoxM1-CM SMRTs treatment). In vivo experiments were conducted in both mouse and pigs with LAD (left anterior descending) ligation. The effects of FoxM1-CM SMRTs on cardiac function, MI size and hypertrophy in mice and pig models were detected after 4 weeks of FoxM1-CM SMRTs treatment. Results: FoxM1 was abundantly expressed in postmitotic CMs after transfection with the FoxM1-CM SMRTs, accompanied by activation of cell-cycle and proliferation markers (Ki67, PH3 and Aurora B kinase) and an increase in cell number. When the GFP-CM SMRTs was injected into mouse hearts with MI, GFP was only expressed in CMs, but not in non-CMs. Compared with the MI group, FoxM1-CM SMRTs significantly increased CM proliferation (days 3 after treatment administration in mice and pigs), improved left-ventricular ejection fractions (days 10 and 28 in both species) and hypertrophy, and reduced MI size (days 28 in both species). Conclusion: Intramyocardial injections of the FoxM1-CM SMRTs promoted CM proliferation, reduced MI size, and improved cardiac function in small and large mammals with acute myocardial infarction.

Genetic Insights into Congenital Cardiac Septal Defects-A Narrative Review.

Congenital heart diseases (CHDs) are a group of complex diseases characterized by structural and functional malformations during development in the human heart; they represent an important problem for public health worldwide. Within these malformations, septal defects such as ventricular (VSD) and atrial septal defects (ASD) are the most common forms of CHDs. Studies have reported that CHDs are the result of genetic and environmental factors. Here, we review and summarize the role of genetics involved in cardiogenesis and congenital cardiac septal defects. Moreover, treatment regarding these congenital cardiac septal defects is also addressed.

Ectopic Calcification in Congenital Heart Surgery: A Material-Centric Review.

The modern congenital heart surgeon has an array of materials available for cardiovascular repair. With advancements in the surgical outcomes for pediatric cardiac defects, choice of material has become increasingly dependent on late-term complications associated with each material. Calcification is a leading long-term complication and is increasing in prevalence with materials lasting longer in patients. Material calcification can impair functionality, lead to subsequent complications, and require additional interventions. A comprehensive literature review was conducted to investigate ectopic calcification of commonly used materials for congenital heart defect repair. Mechanisms of ectopic calcification among commonly used materials were investigated. Ectopic calcification is initiated by material-specific immunological reactions. Recent efforts have focused on developing new materials that are not prone to calcification. ePTFE was widely used in cardiovascular applications but still has reported instances of calcification in various situations, such as long-term use. Tissue engineering techniques have shown reduced calcification in reports. Calcification can occur in all conventional materials we reviewed and, in some cases, has led to life-threatening complications. Favorable outcomes have been reported with tissue-engineered materials, with the expectation of continued positive results in future reports. With an array of synthetic and biological materials now displaying acceptable surgical and short-term outcomes, there is a pressing need to review the long-term viability of these materials, especially considering improved patient survival to adulthood. Furthermore, developing new materials to mitigate calcification remains a promising avenue of research in this field.

Exome sequencing identifies a novel FBN1 variant in a Chinese family with Marfan syndrome that includes aberrant right subclavian artery

Abstract Background Marfan syndrome (MFS) is an inherited autosomal dominant disorder that affects connective tissue with an incidence of about 1 in 5,000 to 10,000 people. Ninety percent of MFS is caused by mutations in the fibrillin-1 (fbn1) gene. We recruited a family with MFS phenotype in South China and identified a novel variant in fbn1 by whole exome sequencing (WES). The zebrafish share high genetic similarity to humans. This study aimed to generate this novel mutation in the fbn1 gene of zebrafish using the CRISPR/Cas9 technology and researched whether this variant is pathogenic. Methods A three-generation consanguineous family was recruited in this study, which was visited and interviewed for the clinical data and family history. Peripheral blood samples were collected from family members for DNA isolation and WES. The 3D structure of the protein was predicted by Alphafold. CRISPR/Cas9 was applied to generate an fbn1 nonsense mutation (fbn1+/−) in zebrafish. Morphological abnormalities were assessed in F2 fbn1+/− zebrafish by comparing with the wild-type (WT) controls at different development stages. Results Our study recruited a family with MFS phenotype in South China and identified a novel variant [NM_000138.5; c.7764C>G: p.(Y2588*)] in fbn1. Through Sanger sequencing, we found that family members Ⅲ-1 (son) and Ⅲ-2 (daughter) had the fbn1 variant segregated with MFS in the family. The p.Y2588* mutation resulted in the absence of 283 amino acids, thereby leading to the deficiency of 17 β-folded structures, 4 α-helix structures, and various loop structures. Compared with WT zebrafish, F2 fbn1+/− zebrafish exhibited aortic arches bleeding, abnormal angiogenesis, decreased cardiac volume, cardiac function defects, curly tail, and cartilage malformations. Conclusion A novel variant [NM_000138.5; c.7764C>G: p.(Y2588*)] was identified in fbn1 gene, which has not been reported in previous literature. The variant caused loss of function through premature protein truncation or nonsense-mediated mRNA decay. In zebrafish, we identified functional evidence of the detected nonsense mutation, which aligns with the clinical significance, suggesting a pathogenic variant of fbn1. Zebrafish as a novel, efficient tool to allow for the quick classification of unknown variants in fbn1 and improve the clinical diagnosis and treatment of MFS. It has brought the implementation of personal and precision medicine in the clinic within reach and made it possible to find patient-specific treatments.Marfanoid symptoms of the patient.Phenotypic Spectrum of fbn1+/− Zebrafish

Advancing cardiac 3D organoid-on-chip: integrating iPSC-derived MELAS syndrome models to study electromechanical synchronicity and cardiac memory using contactless technology

Abstract Background Mitochondrial DNA mutations affect 1:5000 newborns, posing life-threatening risks, especially to high-energy organs such as the brain, heart, and muscles. Mortality rates can reach 71% when cardiomyopathy is present. MELAS syndrome (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes), primarily affecting protein synthesis (MTTL1 gene, tRNALeu(UUR)), disrupts the electron transport chain complex I and is associated with cardiac conduction defects and hypertrophy. Manifesting symptoms typically appear between ages 3 and adulthood, presenting a complex clinical scenario. Human induced pluripotent stem cells (hiPSCs) offer a unique platform for studying cardiac manifestations of this disease when differentiated into cardiomyocytes. Purpose We adopted a highly adaptable in-vitro model, organized in 3D cardioids, to explore potential impairments in electromechanical coupling of cells. Methods We utilized hiPSCs carrying the MELAS mutation and their respective isogenic controls differentiated into cardiomyocytes, cultured in 3D cardioids. Electromechanical coupling was assessed using laser-poration technology combined with video kinematics evaluation under various stimulation patterns. Results Morphological analysis revealed a statistically significant reduction in the diameter of MELAS cardioids compared to the isogenic 3D structures (368±17.15 μm vs. 527±36.76 μm). In a spontaneous regimen, MELAS samples exhibited higher beating frequency (0.88±0.28 Hz vs. 0.17±0.05 Hz) and contractile speed (99.35±39.11 μm/s vs. 33.46±5.57 μm/s). Additionally, the response to different electric field stimulation protocols varied significantly, with the isogenic cell line showing better adaptation to sinusoidal stimuli than the pathological one, characterized by rectangular monophasic stimuli. Laser-poration technology, combined with MEA chips and video kinematic evaluation, revealed modulation of electromechanical coupling, affecting action potential upstroke and duration, reducing contraction velocity, and altering electromechanical delay. Furthermore, MELAS hiPSCs and primary cardiomyocytes exhibited reduced protein levels of various OXPHOS subunits (SDHB, ATPB, and COX IV) compared to isogenic controls. The mutated cell line also showed increased ROS production in non-stimulated samples compared to stimulated ones (1.3-fold vs. 1.2-fold), with this difference magnifying after 24 hours from stimulation (1.8-fold vs. 1.3-fold). Conclusions This study characterizes MELAS hiPSCs differentiated into cardiac organoids, offering insight into the cardiac aspect of this complex syndrome. Our findings deepen understanding of the syndrome's cardiac impact and response to extracellular stimuli, potentially benefiting affected tissues. This research defines critical physiological and kinematic parameters for MELAS, paving the way for future investigations.

Pattern of Birth Defects, Association And Their Outcomes Among Neonates In A Tertiary Care Hospital In Bangladesh

Introduction: Birth defects are one of the major cause of stillbirths and neonatal mortality in developed and developing countries. The prevalence of birth defects varies in different parts of the world. In many cases, the causes are unknown; however, several factors known to be associated are genetic factors, maternal age, health, dietary factors, maternal infections, geographical factors, drugs, smoking and irradiation. Objectives: To identify the pattern of birth defects, association and their outcomes among neonates Methodology: This observational cross-sectional study was conducted in the department of neonatology, Dhaka Medical College Hospital, Dhaka from 1st July 2019 to 30th June 2021. Sample was collected by purposive sampling technique. Total 407 babies were enrolled. Out of them 207 babies were with birth defects in group-A and 200 babies had no birth defects in group-B. Detail demographic data were collected from the informant and recorded in structured case report form. Clinical examination and relevant investigations were done. Data processing work consist of registration schedules, editing computerization, preparation of dummy table, analyzing and matching of data. Results: In this study the two study groups were almost similar with respect to their demographic characteristics like sex, residence, place of delivery, mode of delivery, gestational age, parity and maternal age. The total number of admission during this period was 3050 and total number of birth defects was 207 (6.78%0). In this study on evaluation of maternal risk factors, group-A maternal high blood pressure were in 25.12% cases( OR=1.62;p=.002), maternal diabetes were in 15.46% cases( OR=1.12;p=.001), poor maternal nutritional status was 14.50%( p=.001), history of taking folic acid was 9.66%(OR=0.10;p=.001), 5.80% of the patient had history of exposure to antenatal radiation(OR=.06;p=.001), 4.43% had history of consanguinity(OR=.05;p=.001), 2.420% of women noticed that exposure to pesticides(OR=.025;p=.001), H/O of taking anticonvulsant was 2.420%(OR=.025;p=.001). Group-B was maternal high blood pressure in 7.25% cases(OR=.078;p=.001), maternal diabetes were in 6.28% cases(OR=.067;p=.001), poor maternal nutritional status was 5.80%(p=.001), history of taking folic acid was 4.83% (OR=.051;p=.001), 1.45% of the patient had history of exposure to antenatal radiation(OR=.015;p=.001) and 0.97% had history of consanguinity(OR=.01;p=.001). In this study pattern of birth defects summarized as the cardiovascular system defects was the most commonly affected(26.57%), followed by defects in the head, neck ear,- and eye(19.32%), Syndromes(14.50%), gastrointestinal defects(12.56%), musculoskeletal system defects(10.14%), central nervous system defects (8.70%) and genitourinary system(4.83%) of total defects. In group-A 78.26% of the patients recovered and 23 patients expired during hospital stay (p=.001). In group-B 85.99% of the patients recovered and 17 patients expired. Conclusion: Congenital cardiac defects were the most prevalent anomaly detected. Maternal high blood pressure and diabetes are the risk factors of birth defects in neonates. Antenatal diagnosis and proper management can improve the outcome of these neonates. J Dhaka Med Coll. 2023; 32(1) : 43-50

Transcatheter closure of patent ductus arteriosus: review of author’s experiences and observations

Patent ductus arteriosus (PDA) is a congenital cardiac defect (CCD) and comprises 8% to 10% of all CCDs. Following the description of surgical closure by Gross and colleagues in the 1930s, it has become a standard mode of therapy and remained so until the description of transcatheter techniques to occlude PDA by Porstmann, Rashkind and their associates in the late 1960s. This review paper discusses transcatheter occlusion techniques with buttoned devices, Giantuco coils , and Amplatzer devices with particular attention to author’s contributions to these methods.

Impact and outcomes of hyperglycemia among post-operative children who underwent repair of congenital cardiac defects in a tertiary care setup of Pakistan.

To determine frequency of postoperative hyperglycemia in children who underwent repair of Congenital Cardiac Defects (CCDs) in a tertiary care hospital of Pakistan. The other objective was to compare outcomes in children with versus without postoperative hyperglycemia who underwent repair of CCDs in a tertiary care hospital of Pakistan. A descriptive study was conducted at the Cardiac Intensive Care Unit (CICU), Aga Khan University Hospital (AKUH), Karachi, Pakistan from October 3, 2020, to April 2, 2021. A total of 185 patients aged one month-18 years admitted to CICU underwent elective surgical repair of CCDs meeting the eligibility criteria were included. Glucose monitoring was collected at immediate, 4th and 8th postoperative hours on the first day and once daily on postoperative days Two and Three to assess hyperglycemia. Data including age, weight, gender, pre-operative diagnosis, type of surgery and variables such as CICU stay, duration of hospital stay and duration of mechanical ventilation were recorded. The mean age of the patients was 40.40±48.63 months. Out of 185 patients, 115 (62.2%) were male while 70 (37.8%) were female. Hyperglycemia was found to be in 182 (98.4%) patients. Out of 182 hyperglycemic patients, 53 (28.6%) had moderate hyperglycemia while 129 (69.7%) had severe hyperglycemia. Mean duration of hospital stays was 9.24±7.45, mean duration of pediatric CICU stays was 141.61±169.02 hours and mean duration of mechanical ventilation was 80.59±98.54 hours. Hyperglycemia is a frequent finding in children who underwent repair of CCDs, and it is not significantly associated with duration of mechanical ventilation, length of hospital and CICU stay.

Optimizing care for MRKH patients: From malformation screening to uterus transplantation eligibility.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome with utero-vaginal aplasia is the most severe form of the Müllerian duct anomalies and can be associated with extra-genital abnormalities such as renal or skeletal anomalies, hearing loss, or cardiac defects. The past two decades have witnessed significant advances both in understanding the etiologies of MRKH and in the development of fertility treatments such as uterine transplantation. The present work aimed to determine the rate of women with MRKH syndrome who underwent optimal initial management (after comprehensive malformation assessment) and to establish the rate of patients eligible for uterine transplantation (i.e., those with a vaginal length ≥7 cm without reconstruction using a bowel segment, and an anti-Müllerian hormone level >1.5 ng/mL before 35 years). Cohort study of 85 women with MRKH syndrome consulting in our tertiary center. 62.4% of women with MRKH syndrome had an exhaustive malformative evaluation according to the French guidelines (Protocole National de Diagnostic et de Soin [PNDS]), of which 76.5% had associated malformations (MRKH type II). Pedigree, when available, showed a family history of infertility or a urogenital tract spectrum anomaly in 60% of cases. Concerning the uterine transplantation selection criteria, when evaluated, 22.6% of women had an anti-Müllerian hormone level <1.5 ng/mL and 36% a vaginal length <7 cm. On the 21 women with complete evaluation of both primary and secondary outcomes, 14 of them would be eligible for a uterine transplantation program at the time of consultation according to the main inclusion criteria of uterine transplantation program. Women with MRKH syndrome are often inadequately explored for associated malformations. Early assessment and monitoring of the ovarian reserve is key for fertility preservation, especially in the era of uterine transplantation.

7045 A Rare Case of Lyme-Associated Thyroiditis in an Otherwise Healthy Patient

Abstract Disclosure: M. Windham: None. S.K. Majumdar: None. Introduction: Lyme disease, a common tick-borne illness, causes multiorgan inflammation and dysfunction. It commonly affects the musculoskeletal, neurologic, cardiovascular, and integumentary systems. The endocrine system is rarely involved. We report a case of Lyme-associated thyroiditis in an otherwise healthy 41-year-old man. Case: A 41-year-old man with a history of hypertension, gastroesophageal reflux and a known BRCA2 mutation presented to the emergency department due to one week of frequent palpitations, fatigue, dyspnea on exertion, and dry cough. Laboratory testing revealed thyrotoxicosis with an undetectable TSH (n 0.270—4.200 µIU/mL), FT4 of 7.04 ng/dL (n 0.80—1.70 ng/dL), and TT3 of 253 ng/dL (n 92.0—224 ng/dL). He denied any recent illnesses or pain in his thyroid. Further work up revealed negative TSI and TPO but did show an elevated high sensitivity CRP of 4.3 mg/L (n &amp;lt;1.0 mg/L) and a sedimentation rate of 33 mm/hr (n 0—20 mm/hr). A thyroid uptake and scan showed markedly decreased uptake suggestive of thyroiditis. The patient was started on a prednisone taper with improvement in his TFTs. At his follow up visit approximately one month later, he reported increasing stiffness in his bilateral jaw and continuing palpitations with movement despite near normalization in his FT4 and TT3, suggestive of possible underlying cardiac conduction defects. He did not recall a tick bite but lived in an area with endemic Lyme disease. Lyme antibodies were sent and returned with a positive Lyme IgG and an indeterminate Lyme IgM, which would be consistent with an active Lyme disease infection at the time of his initial presentation. Treatment for Lyme disease was prescribed. Conclusion: Between 1991 and 2021, the incidence of Lyme disease in the United States doubled due to the combined effects of climate change, increasing host species populations, and human encroachment on animal habitats. People who live in areas with endemic Lyme disease, such as the Northeast and upper Midwest regions of the United States, are at risk even if they do not recall a specific exposure. Although Lyme thyroiditis is extremely rare, its incidence is expected to increase as the overall incidence of Lyme disease increases. Therefore, it is important to consider Lyme disease in the differential when a patient from an endemic area presents with unexplained thyroiditis. Presentation: 6/2/2024

Perfluorooctanoic acid (PFOA) induces cardiotoxicity by activating the Keap1/Nrf2 pathway in zebrafish (Danio rerio) embryos

Perfluorooctanoic acid (PFOA), a perfluoroalkyl compound, is linked to congenital heart diseases, though its underlying mechanisms remain unclear. We hypothesized that PFOA induces cardiac defects through the inhibition of the Keap1/Nrf2 pathway, leading to oxidative damage in cardiomyocytes. In this study, zebrafish embryos exposed to PFOA showed significant cardiac malformations and dysfunction, characterized by excessive reactive oxygen species (ROS), malondialdehyde (MDA) production, decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities. Additionally, we observed dysregulation in the expression of key cardiac development genes (vmhc, gata4, nkx2.5, and sox9b). PFOA also reduced the expression of keap1, nrf2, and ho-1. After overexpression of Nrf2, levels of ROS and MDA decreased, while levels of SOD, CAT, and GSH-Px increased. Additionally, cardiomyocyte apoptosis and cardiac malformations were alleviated. These findings have suggested that PFOA induces oxidative stress through Keap1/Nrf2 pathway inhibition, ultimately leading to cardiac defects.

Assessment of Risk Factors for Cerebrovascular Accidents in Children with Congenital Heart Diseases

Abstract Background Children with congenital heart disease (CHD) are at an increased risk of cerebrovascular accidents (CVA), including arterial ischemic stroke (AIS), cerebral venous sinus thrombosis (CVST), and hemorrhagic stroke. The risk varies depending on age, comorbidities, underlying cardiac defect, and other factors, such as changing hemodynamics, cardiac procedures, and the need for mechanical circulatory support devices. Aim To determine the risk factors and neurological outcome of cerebrovascular accidents, that occur either spontaneously or peri-procedurally in children with congenital heart diseases. Patients and Methods A retrospective case-control study was conducted on the records of 72 patients collected from the patients' files between 2015 and 2023 at the Pediatric Neurology Clinic, and Pediatric Cardiology Clinic, Children's Hospital, Cardiothoracic Surgery Academy, Radio-diagnosis Department, Faculty of Medicine, Ain Shams University Hospitals with age ranged from 2 months to 18 years. Children with CHD and radiologically confirmed CVA (case group) were compared to CHD children without CVA (control group). Results Seventy-two children with CHD were included, 30 of whom had radiologically confirmed CVA (case group), and the remaining studied children (42 patients) who had CHD without CVA (control group). In the case group, they were 12 females (40%) and 18 males (60 %), 29 females (69%) and 13 males (31%) in the control group. The age at diagnosis of CVA in case group ranged from (2 months to 1 year) in 17 patients (56.7%), (2 – 6 years) in 7 patients (23.3%), and(7 – 12 years) in 3 (10.0%),and (13 – 18 years) in 3 (10.0%). Males in patients with stroke (60.0%) than in patients without stroke (31.0%) with p-value = 0.014. Twenty-four (57.1%) without stroke and 15 (50.0%) with stroke had acyanotic cardiac disease with the most common being VSD in 7 (23.3%) of those with stroke. there was no statistically significant difference between patients with and without stroke regarding cardiac cyanotic and acyanotic cardiac diagnosis. Twenty-one (70%) out of 30 were diagnosed AIS, 2 (6.7%) CVST, and 7 (23.3%) with hemorrhagic stroke. Stroke occurred following cardiac procedures in 20 patients (66.7%): 15 after cardiac surgery and 5 after cardiac catheterization. Risk factors for CVA were high blood pressure at admission in 12 patients (16.7%), hypoperfusion in 7 patients (9.7%), thrombus on the tip of central venous line (CVL) in 2 patients (2.8%), deep vein thrombosis (DVT) in 1 patient (1.4%), a hypercoagulable state in 1 patient (1.4%), high hematocrit level in 1 patient (1.4%), previous brain insult in 2 patients (2.8%), intracardiac mass in 1 patient (1.4%), infective endocarditis in 2 patients (2.8%), abnormal heart valve in 1 patient (1.4%), disseminated intravascular coagulation (DIC) in 1 patient (1.4%), and chronic disease in 10 patients (13.9%). Taking into consideration that more than one risk factor was found in the same patients. The results revealed that there was a statistically significant increase in the percentage of risk factors in patients with stroke (66.7%) than in patients without stroke (26.2%) with p-value = 0.001. Conclusions Individuals with CHD are at a higher risk of CVA, and this suggests that the risk assessment for CVA based on conventional cardiovascular risk factors should be considered in these patients. Early diagnosis of CHD is important to prevent further recurrences of stroke, and because they are potentially curable. Prospective cohort studies are required to determine effective primary and secondary prevention strategies.