Congenital Cardiac Disease Research Articles

From amoeboid myosin to unique targeted medicines for a genetic cardiac disease

The importance of fundamental basic research in the quest for much needed clinical treatments is a story that constantly must be retold. Funding of basic science in the USA by the National Institutes of Health and other agencies is provided under the assumption that fundamental research eventually will lead to improvements in healthcare worldwide. Understanding how basic research is connected to clinical developments is important, but just part of the story. Many basic science discoveries never see the light of day in a clinical setting because academic scientists are not interested in or do not have the inclination and/or support for entering the world of biotechnology. Even if the interest and inclination are there, often the unknowns about how to enter that world inhibit taking the initial step. Young investigators often ask me how I incorporated biotech opportunities into my otherwise purely academic research endeavors. Here I tell the story of the foundational basic science and early events of my career that led to forming the biotech companies responsible for the development of unique cardiac drugs, including mavacamten, a first in class human β-cardiac myosin inhibitor that is changing the lives of hypertrophic cardiomyopathy patients.

Chronic Activation of Tubulin Tyrosination Improves Heart Function.

Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with the findings that microtubule detyrosination (dTyr-MT) is markedly elevated in heart failure. Acute reduction of dTyr-MT by inhibition of the detyrosinase (VASH [vasohibin]/SVBP [small VASH-binding protein] complex) or activation of the tyrosinase (TTL [tubulin tyrosine ligase]) markedly improved contractility and reduced stiffness in human failing cardiomyocytes and thus posed a new perspective for HCM treatment. In this study, we tested the impact of chronic tubulin tyrosination in an HCM mouse model (Mybpc3 knock-in), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs). Adeno-associated virus serotype 9-mediated TTL transfer was applied in neonatal wild-type rodents, in 3-week-old knock-in mice, and in HCM human induced pluripotent stem cell-derived cardiomyocytes. We show (1) TTL for 6 weeks dose dependently reduced dTyr-MT and improved contractility without affecting cytosolic calcium transients in wild-type cardiomyocytes; (2) TTL for 12 weeks reduced the abundance of dTyr-MT in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in knock-in mice; (3) TTL for 10 days normalized cell area in HCM human induced pluripotent stem cell-derived cardiomyocytes; (4) TTL overexpression activated transcription of tubulins and other cytoskeleton components but did not significantly impact the proteome in knock-in mice; (5) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and wild-type EHTs. RNA sequencing and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-deficient versus TTL-deficient EHTs. This study provides the first proof of concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the nonsarcomeric cytoskeleton in heart disease.

Re-analysis of Next-generation Sequencing Data in Patients with Hypertrophic Cardiomyopathy: Contribution of Spliceogenic MYBPC3 Variants in an Italian Cohort.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.

Comprehensive Proteomic Profiling ofHuman Myocardium Reveals SignalingPathways Dysregulated in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Signaling pathways that link genetic sequence variants to clinically overt HCM and progression to severe forms of HCM remain unknown. The purpose of this study was to identify signaling pathways that are differentially regulated in HCM, using proteomic profiling of human myocardium, confirmed with transcriptomic profiling. In this multicenter case-control study, myocardial samples were obtained from cases with HCM and control subjects with nonfailing hearts. Proteomic profiling of 7,289 proteins from myocardial samples was performed using the SomaScan assay (SomaLogic). Pathway analysis of differentially expressed proteins was performed, using a false discovery rate<0.05. Pathway analysis of proteins whose concentrations correlated with clinical indicators of severe HCM (eg, reduced left ventricular ejection fraction, atrial fibrillation, and ventricular tachyarrhythmias) was also executed. Confirmatory analysis of differentially expressed genes was performed using myocardial transcriptomic profiling. The study included 99 HCM cases and 15 control subjects. Pathway analysis of differentially expressed proteins revealed dysregulation of the Ras-mitogen-activated protein kinase, ubiquitin-mediated proteolysis, angiogenesis-related (eg, hypoxia-inducible factor-1, vascular endothelial growth factor), and Hippo pathways. Pathways known to be dysregulated in HCM, including metabolic, inflammatory, and extracellular matrix pathways, were also dysregulated. Pathway analysis of proteins associated with clinical indicators of severe HCM and of differentially expressed genes supported these findings. The present study represents the most comprehensive (>7,000 proteins) and largest-scale (n=99 HCM cases) proteomic profiling of human HCM myocardium to date. Proteomic profiling and confirmatory transcriptomic profiling elucidate dysregulation of both newly recognized (eg, Ras-mitogen-activated protein kinase) and known pathways associated with pathogenesis and progression to severe forms of HCM.

Integrating Prime Editing and Cellular Reprogramming as Novel Strategies for Genetic Cardiac Disease Modeling and Treatment.

This review aims to evaluate the potential of CRISPR-based gene editing tools, particularly prime editors (PE), in treating genetic cardiac diseases. It seeks to answer how these tools can overcome current therapeutic limitations and explore the synergy between PE and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) for personalized medicine. Recent advancements in CRISPR technology, including CRISPR-Cas9, base editors, and PE, have demonstrated precise genome correction capabilities. Notably, PE has shown exceptional precision in correcting genetic mutations. Combining PE with iPSC-CMs has emerged as a robust platform for disease modeling and developing innovative treatments for genetic cardiac diseases. The review finds that PE, when combined with iPSC-CMs, holds significant promise for treating genetic cardiac diseases by addressing their root causes. This approach could revolutionize personalized medicine, offering more effective and precise treatments. Future research should focus on refining these technologies and their clinical applications.

Automated biventricular quantification in patients with repaired tetralogy of Fallot using a 3D deep learning segmentation model

BackgroundDeep learning is the state-of-the-art approach for automated segmentation of the left ventricle (LV) and right ventricle (RV) in cardiac magnetic resonance (CMR) images. However, these models have been mostly trained and validated using CMR datasets of structurally normal hearts or cases with acquired cardiac disease, and are therefore not well-suited to handle cases with congenital cardiac disease such as tetralogy of Fallot (TOF). We aimed to develop and validate a dedicated model with improved performance for LV and RV cavity and myocardium quantification in patients with repaired TOF. MethodsWe trained a 3D convolutional neural network (CNN) with 5-fold cross-validation using manually delineated end-diastolic (ED) and end-systolic (ES) short-axis image stacks obtained from either a public dataset containing patients with no or acquired cardiac pathology (n=100), an institutional dataset of TOF patients (n=96), or both datasets mixed. Our method allows for missing labels in the training images to accommodate for different ED and ES phases for LV and RV as is commonly the case in TOF. The best performing model was applied to all frames of a separate test set of TOF cases (n=36) and ED and ES phases were automatically determined for LV and RV separately. The model was evaluated against the performance of a commercial software (suiteHEART®, NeoSoft, Pewaukee, Wisconsin, US). ResultsTraining on the mixture of both datasets yielded the best agreement with the manual ground truth for the TOF cases, achieving a median DICE similarity coefficient of (93.8%, 89.8%) for LV cavity and of (92.9%, 90.9%) for RV cavity at (ED, ES) respectively, and of 80.9% and 61.8% for LV and RV myocardium at ED. The offset in automated ED and ES frame selection was 0.56 and 0.89 frames on average for LV and RV respectively. No statistically significant differences were found between our model and the commercial software for LV quantification (two-sided Wilcoxon signed rank test, p<5%), while RV quantification was significantly improved with our model achieving a mean absolute error of 12ml for RV cavity compared to 36ml for the commercial software. ConclusionWe developed and validated a fully automatic segmentation and quantification approach for LV and RV, including RV mass, in patients with repaired TOF. Compared to a commercial software, our approach is superior for RV quantification indicating its potential in clinical practice.

Relevance of accurate QT correction in the assessment of long QT syndrome

BackgroundLong QT syndrome (LQTS) is a genetic cardiac disease, where the corrected QT (QTc) interval is prolonged. It can cause arrhythmias and lead to a sudden cardiac death. Duration of the QT interval depends on the heart rate and this dependency is treated with QT correction. However, the current QT correction methods have well known problems and limitations. ObjectiveWe study the relevance of QT correction method in evaluating the risk of LQTS. We evaluate the reliability of the present and recently developed QT correction methods to discriminate LQTS subjects from healthy controls. MethodsWe use the clinically prevalent QT correction methods, particularly Bazett and Fridericia, in comparison with the recently developed AccuQT method. The data of healthy controls and LQTS subjects is extracted from the Rochester THEW database. The analysis accounts for sex, major LQTS subtypes, and beta-blocker treatment. ResultsQT values corrected with AccuQT discriminate the healthy and LQTS samples with the best accuracy, leading to (TP, TN) = (0.87, 0.65) with the conventional 450 ms threshold for LQTS. Fridericia correction yields lower sensitivity (0.71), but comparable balanced accuracy, whereas Bazett shows significantly less accurate results due to overcorrection at lower heart rates. ConclusionThe selected QT correction method is important in the identification of LQTS. In particular, the use of Bazett correction should be questioned. Fridericia correction yields good results with respect to its simplicity. AccuQT has the best accuracy out of all the methods for LQTS discrimination. For practical applicability, however, AccuQT needs further validation in realistic clinical conditions.

Genetic testing for inherited arrhythmia syndromes and cardiomyopathies: results of the European Heart Rhythm Association survey.

Indications and clinical impact of genetic testing for cardiac diseases have increased significantly over the past years. The aim of this physician-based European Heart Rhythm Association (EHRA) survey was to assess current clinical practice and access to genetic testing for cardiac diseases across European Society of Cardiology countries and to evaluate adherence to the 2022 EHRA/HRS/APHRS/LAHRS Expert Consensus Statement on genetic testing. An online questionnaire composed of 28 questions was submitted to the EHRA Research Network and European Reference Network GUARD-Heart healthcare partners and promoted via dedicated social media channels. There were 357 respondents from 69 countries, 40% working in a hospital setting with a cardiac genetic service and/or a dedicated clinic focusing on inherited cardiac diseases and 27% with an onsite genetic laboratory. No genetic testing or low annual rate (<10/year) was declared by 39% of respondents. The majority of respondents (78%) declared issues or limitations to genetic testing access in their clinical practice. The main reasons for not providing or limited access to genetic testing were no availability of dedicated unit or genetic laboratory (35%) or reimbursement issues (25%). The most frequently reported indication for genetic testing was diagnostic purpose (55%). Most respondents (92%) declared offering genetic testing preceded by genetic counselling and 42% regular multidisciplinary evaluations for patients with cardiac genetic diseases. The perceived value of genetic testing in the diagnostic, prognostic, and therapeutic assessment was variable (67, 39, and 29%, respectively) and primarily based on the specific inherited disease. The majority of respondents recommended cascade genetic testing for the first-degree family members in case of pathogenic/likely pathogenic variant in the proband. This survey highlights a significant heterogeneity of genetic testing access and provision and issues attributable to the availability of dedicated unit/genetic laboratory and reimbursement. However, adequate adherence to indications in the current recommendations for genetic testing in patients with cardiac diseases was observed.

Risk Factors of Cardiac Complications in Pregnant Women with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common inherited genetic cardiac disease during pregnancy. Studies of risk factors are of great significance for maternal and fetal outcomes. The aim of the study was to identify predictive risk factors for cardiac complications in pregnant women with HCM. One hundred patients with HCM who delivered at the Shanghai obstetrical cardiology intensive care center between January 2000 and December 2022 were retrospectively reviewed. A logistic regression model was used to identify independent risk factors for cardiac complications. Twenty-one cases were obstructive HCM (21%), 16 with cardiac function grade I and 5 with grade II; 79 cases were non-obstructive HCM (79%), 67 with cardiac function grade I, 11 with grade II, and 1 with grade III. Ninety-one cases had abnormal electrocardiogram (ECG) (91%), mainly with ST-T changes (77%). The average interventricular septum was 19.39 ± 6.13 mm by echocardiography (21.75 ± 5.86 mm for obstructive HCM and 18.73 ± 6.08 mm for non-obstructive HCM). The main cardiac complications were maternal death (n = 2, 2%), heart failure (n = 7, 7%), and sustained ventricular tachyarrhythmia (n = 1, 1%). Cardiac complications occur commonly during the third trimester and postpartum period. Three independent risk factors to predict cardiac complications in pregnant women with HCM were obstructive HCM (P = 0.036), New York Heart Association (NYHA) class ≥II (P = 0.022), and previous history of syncope (P = 0.037). HCM increases the risk of maternal death, heart failure, and malignant arrhythmia. More attention should be given to risk assessment and pregnancy management. Early detection of risk factors can reduce the incidence of maternal mortality and cardiac complications.

Animal Models and Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy Associated with Pathogenic Variants in Intercalated Disc Genes.

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease characterized by the progressive substitution of myocardium with fibro-fatty tissue. Clinically, ACM shows wide variability among patients; symptoms can include syncope and ventricular tachycardia but also sudden death, with the latter often being its sole manifestation. Approximately half of ACM patients have been found with variations in one or more genes encoding cardiac intercalated discs proteins; the most involved genes are plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP). Cardiac intercalated discs provide mechanical and electro-metabolic coupling among cardiomyocytes. Mechanical communication is guaranteed by the interaction of proteins of desmosomes and adheren junctions in the so-called area composita, whereas electro-metabolic coupling between adjacent cardiac cells depends on gap junctions. Although ACM has been first described almost thirty years ago, the pathogenic mechanism(s) leading to its development are still only partially known. Several studies with different animal models point to the involvement of the Wnt/β-catenin signaling in combination with the Hippo pathway. Here, we present an overview about the existing murine models of ACM harboring variants in intercalated disc components with a particular focus on the underlying pathogenic mechanisms. Prospectively, mechanistic insights into the disease pathogenesis will lead to the development of effective targeted therapies for ACM.

Cost-utility analysis of prenatal diagnosis of congenital cardiac diseases using deep learning

BackgroundDeep learning (DL) is a new technology that can assist prenatal ultrasound (US) in the detection of congenital heart disease (CHD) at the prenatal stage. Hence, an economic-epidemiologic evaluation (aka Cost-Utility Analysis) is required to assist policymakers in deciding whether to adopt the new technology.MethodsThe incremental cost-utility ratios (CUR), of adding DL assisted ultrasound (DL-US) to the current provision of US plus pulse oximetry (POX), was calculated by building a spreadsheet model that integrated demographic, economic epidemiological, health service utilization, screening performance, survival and lifetime quality of life data based on the standard formula: CUR=Increase in Intervention Costs-Decrease in Treatment costsAverted QALY losses of adding DL to US&POX\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\rm CUR} = \\frac{{\ ext{Increase in Intervention Costs}} - {\ ext{Decrease in Treatment costs}}}{{\ ext{Averted QALY losses of adding DL to US}} \\ \\& \\ {\\rm POX}}$$\\end{document} US screening data were based on real-world operational routine reports (as opposed to research studies). The DL screening cost of 145 USD was based on Israeli US costs plus 20.54 USD for reading and recording screens.ResultsThe addition of DL assisted US, which is associated with increased sensitivity (95% vs 58.1%), resulted in far fewer undiagnosed infants (16 vs 102 [or 2.9% vs 15.4%] of the 560 and 659 births, respectively). Adoption of DL-US will add 1,204 QALYs. with increased screening costs 22.5 million USD largely offset by decreased treatment costs (20.4 million USD). Therefore, the new DL-US technology is considered “very cost-effective”, costing only 1,720 USD per QALY. For most performance combinations (sensitivity > 80%, specificity > 90%), the adoption of DL-US is either cost effective or very cost effective. For specificities greater than 98% (with sensitivities above 94%), DL-US (& POX) is said to “dominate” US (& POX) by providing more QALYs at a lower cost.ConclusionOur exploratory CUA calculations indicate the feasibility of DL-US as being at least cost-effective.

Hypertrophic Cardiomyopathy and Ventricular Arrhythmia

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Its clinical presentation is heterogeneous, ranging from asymptomatic patients to sudden death in young individuals. This complication is unpredictable, and no preventive medical treatment has proven effective. We report the case of a 32-year-old individual who was admitted for poorly tolerated ventricular tachycardia (VT), which was resolved with external electrical shock. We diagnosed localized hypertrophic cardiomyopathy, confirmed by MRI. This paper outlines the patient's medical journey, highlighting the rhythm complications experienced and the various therapeutic options available.

Care for the caregiver: an exploration of caregiver burden of children with chronic medical conditions at a tertiary care hospital in Karachi, Pakistan – a mixed-methods study

ObjectivesCaregiver burden often goes unrecognised and can substantially affect caregivers’ physical, psychological and financial well-being, thereby impacting quality of care. This study investigates burden among caregivers of children with chronic...

Retrofitting the Heart: Explaining the Enigmatic Septal Thickening in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy is the most common genetic cardiac disease and is characterized by left ventricular hypertrophy. Although this hypertrophy often associates with sarcomeric gene mutations, nongenetic factors also contribute to the disease, leading to diastolic dysfunction. Notably, this dysfunction manifests before hypertrophy and is linked to hypercontractility, as well as nonuniform contraction and relaxation (myofibril asynchrony) of the myocardium. Although the distribution of hypertrophy in hypertrophic cardiomyopathy can vary both between and within individuals, in most cases, it is primarily confined to the interventricular septum. The reasons for septal thickening remain largely unknown. In this article, we propose that alterations in muscle fiber geometry, present from birth, dictate the septal shape. When combined with hypercontractility and exacerbated by left ventricular outflow tract obstruction, these factors predispose the septum to an isometric type of contraction during systole, consequently constraining its mobility. This contraction, or more accurately, this focal increase in biomechanical stress, prompts the septum to adapt and undergo remodeling. Drawing a parallel, this is reminiscent of how earthquake-resistant buildings are retrofitted with vibration dampers to absorb the majority of the shock motion and load. Similarly, the heart adapts by synthesizing viscoelastic elements such as microtubules, titin, desmin, collagen, and intercalated disc components. This pronounced remodeling in the cytoskeletal structure leads to noticeable septal hypertrophy. This structural adaptation acts as a protective measure against damage by attenuating myofibril shortening while reducing cavity tension according to Laplace Law. By examining these events, we provide a coherent explanation for the septum's predisposition toward hypertrophy.

Outcomes of Bicuspid Aortic Valve in Pregnancy

Bicuspid Aortic Valve, Congenital Cardiac Disease, Echocardiography, Maternal Screening.

PREVALENCE AND RISK FACTORS OF RESPIRATORY TRACT INFECTION IN UNDER FIVE YEAR MALNOURISHED CHILDREN AT DISTRICT HEADQUARTER HOSPITAL, DISTRICT SHANGLA.

Objectives: To determine the frequency and the risk factors associated with respiratory tract infection (RTI) in under five year malnourished children.Materials and Methods: A total of 203 malnourished children of less than 5 years of age and resident of district Shangla were included. Malnourished children with congenital cardiac diseases, any metabolic disorders and non-cooperative attitude of the parents were excluded. Demographics and risk factors about RTI were recorded from each participant. The association of each risk factor for RTI was assessed using Chi-square test. Logistic regression was run for the significant risk factors.Results: The mean age of the participants was 18.55±13.535 months. The males were 108(53.2%). All socio-demographic factors were not statistically associated with RTI. Among the clinical factors for RTI only significant association was found with consultant clinician (P=0.002). Among the environmental factors for RTI the significant association was found for history of allergy in parents (P=0.024) and sibling aff ected by RTI (P&lt;0.001). RTI was more in common in children whose siblings were aff ected by RTI (n=100, 87.75%).Conclusion: The prevalence of RTI is quiet higher among malnourished children. The statistically significant risk factors associated with RTI among malnourished children are non-qualified clinician, sibling affected by RTI, and history of allergy in parents.

The Outcomes of Cardiac Surgery in Children With DiGeorge Syndrome in a Single Center Experience: A Retrospective Cohort Study.

Background DiGeorge syndrome, a common genetic microdeletion syndrome, is associated with multiple congenital anomalies, including congenital cardiac diseases. This study aims to identify the short and midterm outcomes of cardiac surgery performed on children with DiGeorge syndrome. Methods A retrospective cohort study was conducted between the period of 2018-2022, which included children divided into two groups with a 1:2 ratio. Group one included DiGeorge syndrome patients who were diagnosed using fluorescence in situ hybridization (FISH). Group two included the control group of patients who were clear of genetic syndromes. The two groups were matched based on similar cardiac surgery, age of surgery, and Risk Adjustment in Congenital Heart Surgery (RACHS-1) score. The two groups were compared based on the demographical data and postoperative complications. Results The study consisted of 81 children; 27 were DiGeorge syndrome patients, and 54 were in the control group. DiGeorge syndrome patients showed an increase in mechanical ventilation duration (p=0.0047), intensive care unit (ICU) length of stay (p=0.0012), and hospital length of stay (p=0.0391). Moreover, they showed an increased risk for bacteremia (p=0.0414), ventilator-associated pneumonia (VAP; p=0.0036), urinary tract infections (UTI; p=0.0064), and surgical site infection (SSI; p≤0.0001). They were also more susceptible to postoperative seizures (p=0.0049). Furthermore, patients with DiGeorge syndrome had a higher prevalence of congenital renal anomalies. However, there was no mortality in either group. Conclusion This study shows a variability in the postoperative outcomes between the two groups. The study demonstrates that patients with DiGeorge syndrome have higher risks of infections and longer hospital stayduring the postoperative period. Further research with a larger sample is needed to confirm our findings.

Successful Pregnancy with Uncorrected Tetralogy of Fallot: An Interdisciplinary Team Approach

BACKGROUND: With an overall incidence of congenital cardiac disease, tetralogy of fallot (ToF) is the most clinical of cyanotic heart disease. The anomalies seen in patients with ToF are due to an inappropriate anterior and cephalad displacement of the interventricular septum’s infundibular (outflow tract) component. Ventricular septal defect, right ventricular hypertrophy, overriding aorta, and pulmonary stenosis are the four defects that result from this condition. The physiology of healthy women will undergo several changes affecting body system, including the cardiovascular system. Pregnancy and delivery have a high risk for most ill women, including those with uncorrected ToF, due to extensive physiological adaption and alterations. For patients with ToF, it continues to be a significant contributor to maternal morbidity (62.5%), mortality (10%), and neonatal adverse outcomes. CASE PRESENTATION: A 18-year-old female in her first pregnancy at 28 weeks was referred to Saiful Anwar Hospital with uncorrected ToF since she was 2 years old. She suggested repairing ToF at National Cardiovascular Center Harapan Kita Jakarta but her parents still refused. She married at 18 years old and she was pregnant unplanned before. Then, she was referred to RSSA for further management. CONCLUSSION: Pregnancy has been related with higher risks of morbidity and mortality for women with congenital cardiac disease. ToF is the most prevalent cyanosis congenital heart disease. These are poorly tolerated and produce serious complications, including maternal and neonatal mortality. Prenatal counselling is crucial to identify risk factors for the patients and to reassure many patients who are at low risk.

Epigenetics.

Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities.

Foetal Echocardiography vs. Neonatal Echocardiography for Diagnosis of Congenital Heart Diseases

Congenital heart disease (CHD) is a structural abnormality in the heart or major intrathoracic blood vessels that has been present since birth. The antenatal detection of congenital cardiac disease has been greatly enhanced by the advent of fetal echocardiography as a crucial component of prenatal ultrasound evaluation. Nevertheless, antenatal CHD diagnosis rates are still lower than those for the majority of other significant structural defects. Aim : Assess the effectiveness of fetal in comparison to neonatal echocardiography. This study is conductedin accordance to the PRISMA statement. Studies were identified from several open-access electronic databases (PubMed Central, ScienceDirect, Google Scholar). Risk of bias of each study was evaluated using Cochrane Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Data were descriptively examined and narratively reported. Twelve studies were included in the review. All included studies were considered low-risk. From 12 studies that were included in our study, all recommend fetal echocardiography for prenatal assessment. Lowest reported sensitivity was 64.5%, highest value was 100%. Lowest repoted specificity was 88.9%, highest value was 99.96%. Diagnostic accuracy was reported in 4 studies, with a value of 93 – 99.82% Factors that might be associated with the accuracy of fetal echocardiography are high anatomic complexity, maternal comorbidities, and fellow as initial imager. Fetal echocardiography was found to have a high specificity but limited sensitivity. Low sensitivity suggests that fetal echocardiography results could be inaccurate whereas high specificity means that a negative echocardiography result is often sufficient to predict the absence of CHD. There are some factors that may affect the accuracy of fetal echocardiography, mostly resulting from fetal or maternal factors, such as high complexity of the anomaly, fetal position, late gestation, maternal obesity, and less-esperienced sonographer.