Congenital Heart Disease Research Articles

Arrhythmia burden in patients with congenital heart disease

Abstract Background The prevalence of congenital heart defects (CHD) is rising. Many patients experience arrhythmias either due to the defect itself or necessary intervention. Sudden onset of arrhythmia poses grave risks such as heart failure, stroke, or cardiac death. Research gaps exist regarding high-risk defects, age susceptibility, and prognostic implications of arrhythmia. Purpose Delineate the burden of arrhythmias in patients with CHD. Methods Patients born in the period 1970-2017 and diagnosed with CHD were identified in Swedish nationwide medical registries. Each patient was matched by birthyear and sex with ten controls from the general population. Cox proportional hazard regression model and Fine-Gray regression model with death as competing risk were used to compute risk (hazard ratio [HR]) and cumulative incidence of arrhythmias (supraventricular and ventricular arrhythmias). Estimates were compared with the matched controls. Follow-up started at time of birth. Results We included 63,559 patients and 583,205 matched controls with median follow-up of 12.8 years. Almost two-thirds of the total CHD population were born after year 2000 and 89% (n=56,564) had a simple lesion (defined as atrial or ventricular septal defect, coarctation of the aorta or malformation of the heart valves). During follow-up, 1,632 events of arrhythmia (90% of supraventricular origin) were registered in the population of patients with CHD, yielding an incidence rate of 16.4 per 10,000 person-years (versus 1.6 in the control population). The cumulative incidence of arrhythmias in the total CHD population was slightly increased during childhood compared with the control population, but rose significantly hereafter, illustrated in Figure 1, yielding an overall risk of 10.5 (CI 95%: 9.8-11.2). Stratified by lesion severity, the risk for arrhythmias was 8.7 (CI 95%: 7.6-8.7) and 30.4 (CI 95%: 26.2-35.2) in patients with simple and complex lesions, respectively. Patients with simple CHD lesions displayed a risk of 7.7 (95% CI: 7.1-8.4) for supraventricular arrhythmias and 11.5 (95% CI: 9.2-14.5) for ventricular arrhythmias. Correspondingly, patients with complex CHD lesions displayed risks of 66.7 (95% CI: 42.7-104.2) and 28.9 (95% CI: 24.8-33.6). Conclusion Arrhythmias, irrespective of origin, are common in patients with CHD and correlate with lesion severity. The overall burden of arrhythmias increased significantly after childhood. Meticulous follow-up is vital in order to prevent, detect and treat arrhythmias as it might trigger clinical deterioration and even sudden cardiac death in patients with CHD.

Variability in patient-reported outcomes among different congenital heart defects: a comparative analysis of 7,498 patients from 32 countries

Abstract Background Patient-reported outcomes (PROs) may not always correlate with the complexity of congenital heart defects (CHDs), as significant variation has been observed between CHDs within complexity levels. Accurate comparisons across various types of CHDs necessitate large sample sizes. Purpose The objective of this study was to compare PROs across different CHDs in a large international sample. Methods ‘Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease – International Study II’ (APPROACH-IS II) was an international cross-sectional investigation, in which 8,415 patients from 32 countries in 6 continents were enrolled (20 high; 7 upper-middle; 4 lower-middle; and 1 low income). For the comparison across different CHDs, conditions with at least 50 patients were included in the analysis. Hence, the sample consisted of 7,498 patients (median age=33y; 53.1% women). Patients completed questionnaires to measure perceived health status (RAND-12 Health Survey; EuroQOL-5D Visual Analog Scale); depressive symptoms (Patient Health Questionnaire-8); anxiety (General Anxiety Disorder-7) and quality of life (Linear Analog Scale). Generalized linear mixed models (GLMMs) were performed with center as random effect. Results Cyanotic heart defects were associated with the lowest scores for physical functioning, mental health, self-rated health, and quality of life (see Figure). Other CHDs found to be associated with poor PRO scores encompassed unrepaired secundum atrial septal defect, Ebstein anomaly, single ventricle, and truncus arteriosus. Conversely, the most favorable scores for all PROs, except for anxiety, were observed with isolated pulmonic stenosis. Other CHDs with favorable PRO scores comprised coarctation of the aorta, isolated small ventricular septal defect, congenital aortic valve disease, and repaired ventricular septal defect. Adjusted for sociodemographic and physiological factors, GLMMs revealed significant differences across defects, using the best score for each PRO as the reference (see Figure). Conclusion Substantial variation in PROs was observed among different types of CHDs. Interestingly, some complex heart defects demonstrated relatively good PRO scores, comparable to some simple defects. On the other hand, unrepaired simple defects or those with residual lesions, were associated with worse PROs.

First trimester maternal infections and offspring congenital heart defects: a systematic review and meta-analysis

Abstract Background Maternal infections early in pregnancy have been proposed as playing a role in the development of congenital heart defects. We aimed to summarise contemporary evidence regarding the association between first-trimester maternal infection and risk of offspring congenital heart defects. Methods For this systematic review and meta-analysis, we searched Medline and Embase for studies reporting associations of at least one measure of maternal infection during pregnancy and offspring congenital heart disease in humans and published in English between January 1, 1990 and February 13, 2024. Studies were eligible for inclusion if they reported rates of offspring congenital heart defects among both infected and non-infected mothers, and included a minimum of 50 offspring with congenital heart defects. We stratified associations by type of infection and type of heart defect when data from at least two studies were available. We used inverse variance weighted random-effect meta-analyses to pool the estimates. In main analyses, we pooled crude estimates from studies reporting maternal infections during the first trimester of pregnancy. We performed sensitivity analyses to include studies that i) investigated infections later in pregnancy or at unspecified time-points, and ii) adjusted for potential confounders such as maternal age, socioeconomic status, or ethnicity. Findings: We identified 11 studies (7 case control studies, 4 cohort studies) with data from 1,805,115 pregnancies. Nine of these studies assessed maternal infectious status through self-reported questionnaires or medical records, two used laboratory antibody testing and three reported on specific infectious pathogens. Studies reported on various types of bacterial and viral infections, including influenza, urinary tract infections, cytomegalovirus, herpes simplex virus, or chlamydia, with varying effect sizes. Ten studies reported a positive association between maternal infection variables and offspring congenital heart defects, with a pooled odds ratio (OR) and 95% confidence interval of 1.56 (1.27, 1.91) across all types of infections. Associations differed by individual subtype of congenital heart defects, with ORs ranging from 1.28 (0.89, 1.85) for pulmonary atresia to 1.75 (1.23, 2.49) for ventricular septal defects. Sensitivity analyses that included infections measured later in pregnancy, or adjusted rates for potential confounders, showed broadly similar trends but attenuated effect sizes. Interpretation: First trimester maternal infections are associated with increased risk of congenital heart defects. Associations appear to vary by type of infection and type of congenital heart defect, and to extend beyond infections commonly tested for during routine pregnancy screening. Larger-scale studies are warranted to confirm these findings using laboratory antibody testing and investigating how these associations vary by specific pathogens and subtypes of congenital heart defects.

Frailty, cognition and patient-reported outcomes in middle-aged and older adults with congenital heart disease: insights from an international multicentric study

Abstract Background Prior research has demonstrated that a significant proportion of older patients with congenital heart disease (CHD) are frail or pre-frail and experience cognitive impairment. However, it remains unclear whether frailty and cognition are related to patient-reported outcomes (PROs) such as perceived health, anxiety and depression symptoms or quality of life in CHD. Purpose The objective of this study was to explore the relationships between frailty, cognitive function, and PROs in middle-aged and older adults with CHD ranging from mild to severe complexity. Methods As part of the cross-sectional ‘Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease – International Study II’ (APPROACH-IS II), we enrolled 814 individuals aged 40 years and older (median age: 52.0 years [45.0-61.0]; 51.4% female; 12.7% mild, 70.1% moderate, 17.2% complex CHD; 41.9% pre-frail, 5.8% frail; 38.7% cognitively impaired) across 17 centers in 11 countries. Frailty status was assessed using the Fried criteria, which categorize individuals into robust, pre-frail, and frail based on five factors: weakness, slow gait, unintentional weight loss, exhaustion, and low physical activity levels. Cognitive function was determined using the Montréal Cognitive Assessment. Participants completed questionnaires to evaluate perceived health (RAND-12 Health Survey, yielding both Physical and Mental Component Summaries, and EuroQOL-5D Visual Analog Scale), depressive symptoms (Patient Health Questionnaire-8), anxiety symptoms (General Anxiety Disorder scale-7), and quality of life (QoL Linear Analog Scale). Results Frailty was significantly associated with all PROs, with frail and pre-frail individuals reporting less favorable outcomes (see Figure). Cognitive function was linked to perceived health and anxiety, with patients exhibiting cognitive impairments reporting poorer perceived health and more anxiety symptoms. Conclusion This study indicates that concepts of frailty, cognitive functioning and PROs are closely related in adults with CHD. Frailty and cognition thus represent important domains when developing strategies to optimize PROs in adults with CHD. Moreover, when working with patients who are frail or cognitively impaired, healthcare workers are encouraged to consider and inquire about potential impact on PROs. Longitudinal research is needed to explore the direction of the association.

Multi-omics integration analysis identifies pathogenic candidate genes of congenital heart defects with vascular malformation

Abstract Background Congenital heart defects (CHD) with vascular malformation harbors numerous genetic and epigenetic aberrations of DNA copy numbers and methylation. Proteomic deregulation by the aberrations plays key driver roles in heterogeneous progression of CHD. However, it still remains largely unknown about integrative analysis of genetic, epigenetic regulation and proteome in CHD. Purpose We employed a multi-omics approach to explore pathogenic candidate genes in CHD with vascular malformation. Methods Previously, we gathered WES data for 216 CHD patients with vascular malformation and 100 healthy controls. Meanwhile, we carried out DNA methylation analysis from 11 patients and 5 controls. Here, we profile proteomics of vascular tissues from 11 patients and 5 controls. Integration analysis of DNA copy-number-correlated (CNVcor) genes, methylation-correlated (METcor) genes and differentially proteins reveal the innovative and crucial pathogenetic genes. We then detected spatiotemporal expression patterns of candidate genes in zebrafish embryos using in situ hybridization and qPCR, and verified the roles in vascular development by morpholino-mediated gene knockdown. Results 90 differentially expressed proteins (DEPs) were obtained using proteomics and were mainly related to cell adhesion and migration, angiogenesis, amino acid metabolism, and HIF-1 signaling pathway through GO and KEGG pathway enrichment analysis. 15 hub proteins were identified by WGCNA analysis (Fig 1). Additionally, we found that the frequencies of the aberrancies of the CNVcor genes were significantly correlated with the METcor genes (Fig 2 C). We obtained 1924 differentially CNVcor genes and 952 differentially METcor genes. Then, we computed the Pearson’s correlation coefficients of all three-omics by pairwise comparison and found that the distribution of correlations was bimodal (Fig 2 D). Meanwhile, 28 overlapped genes were observed among three-omics. We screened out 11 candidate genes (TIMP1, BGN, LTBP1, AKR1C3, LOXL3, MAOA, MAOB, GNA12, IFI30, CNTNAP1, IGF2BP1) according to the node degree of PPI network analysis between 28 genes and known vascular development related genes. We further figured out LOXL3, MAOA, CNTNAP1 and IGF2BP1 are the novel important genes for vascular malformation, of which CNTNAP1 is the joint gene of three-omics. Through expression patterns and gene knockdown in zebrafish embryos, we revealed that LOXL3, MAOA, CNTNAP1 and IGF2BP1 affect vascular development (Fig 2 E-G). Conclusions We identify novel key candidate genes (LOXL3, MAOA, CNTNAP1 and IGF2BP1) potentially related to CHD with vascular malformation and elucidate the possible molecular pathogenesis of CHD. Our multi-omics integrative analysis provides new insights on the multi-layered etiology of CHD, which might be helpful in developing clinical diagnosis and precaution for CHD.Figure 1Figure 2

A cohort study examining predictors of stroke and bleeding among people with congenital heart disease and atrial fibrillation

Abstract Background Congenital Heart Disease (CHD) is associated with development of atrial fibrillation (AF) at an early age. With increased survival of this cohort into adulthood, the prevalence of concurrent CHD and AF is expected to increase over the next several decades. Little is known about the utility of clinical risk factors or prediction models in determining bleeding or stroke rates in adults with CHD and AF. Purpose This study aims to measure the performance of the CHADSVASC and HASBLED scores in a cohort of people with CHD. The association between traditional stroke and bleeding risk factors, as well as CHD-specific factors, will be quantified. Methods Patients age 18 or older attending one of three centers in the USA were included in this study if they had a history of AF on ECG, holter monitor or device interrogation, in addition to a diagnosis of Tetralogy of Fallot (TOF), Double Outlet Right Ventricle (DORV), or Pulmonary Atresia with Intact Ventricular Septum (PA-IVS). Outcomes were major bleeding event, and stroke rate. Analysis was conducted using cox univariable regression controlling for current age. Receiver operator curve and c-statistics were produced for the CHADSVASC and HASBLED scores respectively. Results 326 people were included in this study, of whom 161 (49.5%) had TOF secondary to Pulmonic Stenosis, 126 (38.8%) had TOF secondary to Pulmonary Atresia, 25 (7.7%) had DORV, and 155 (47.7%) had PA-IVS. 227 people used warfarin (79.4%), 28 (9.8%) used apixaban, 9 (3.1%) used Rivaroxaban, 3 (1%) used Edoxaban, and 5 (1.7%) used Enoxaparin for a period of at least 30 days during the study. 13 (4.5%) people didn’t receive anticoagulation during the study. 26 people had a stroke (8.8%) while 85 people (28.6%) had a major bleeding event. Only the CHADSVASC score was significantly associated with stroke rates (HR 2.103, 95% CI 1.555 to 2.844, p<0.001). Clinical variables, such as subtype of CHD, prior conduit placement or unifocalization were not associated with stroke or major bleeding events. C-statistic for the CHADSVASC score in predicting stroke events was 0.755 (Figure 1). C-statistic for the HASBLED score in predicting major bleeding was 0.442 (Figure 2). Conclusions Among people with CHD and AF, the CHADSVASC score can robustly predict stroke events. Other clinical variables are less valuable in predicting either bleeding or strokes. The HASBLED score likely doesn’t have a role in predicting major bleeding episodes in this cohort.

E-selectin and asymmetric dimethylarginine plasma levels in adult cyanotic congenital heart disease patients: relation to biochemical parameters, vascular function, and clinical status.

Abstract Background and Aim Patients with cyanosis secondary to congenital heart disease (CHD) are characterized by erythrocytosis and increased blood viscosity, which contributes to endothelial dysfunction, increased arterial stiffness, and impaired vascular function, which may affect the final clinical presentation. Asymmetric dimethylarginine (ADMA) and e-selectin (e-sel) are valuable biomarkers for prognosis of endocardial dysfunction and vascular damage. Their concentration levels in blood serum have the potential to be a rapid and easily accessible tool that reflects the severity of the disease. We aimed to assess e-sel and ADMA levels, their relationship with clinical status, as well as endothelial and vascular function. Methods A cross-sectional study including 36 adult CHD cyanotic patients [(17 males)(42.3 +/- 16.3 years)] with arterial blood oxygen saturation less than 92% and 20 healthy controls [(10 males)( 38.2 +/- 8.5 years)] was performed. All patients underwent clinical examination, blood testing, and cardiopulmonary tests. Endothelial function was assessed using intima-media thickness and flow-mediated dilatation (FMD). Vascular function using applanation tonometry methods was completed while considering aortic systolic pressure, aortic pulse pressure (AoPP), augmentation pressure (AP), augmentation index (AI), pulse pressure amplification (PPampl), and pulse wave velocity (PWV). Results Concentrations of e-sel and ADMA were significantly higher in patients with CHD than in controls (56.3 ± 13.6 ng/mL vs. 15.5 +/- 8.6 ng/mL, p<0.001) and (1.48 ± 0.48 ng/mL vs. 0.46 ± 0.1 ng/mL, p<0.001) respectively. E-sel levels correlated with gender, blood oxygen saturation, red blood cell, hemoglobin concentration, hematocrit, augmentation pressure, forced expiratory one second volume, forced vital capacity, and oxygen uptake. ADMA levels were found to correlate with age only. Conclusions E-sel level, unlike ADMA concentration, reflects the degree of severity of erythrocytosis and hypoxia and, thus, the physical status of patients with cyanotic CHD. E-selectin predicts increased augmentation pressure.Figure 1.A) ROC analysis for e-selectin

Ablation of tachyarrhythmias with zero fluoroscopy technique in patients under 18 years of age. 4-year follow-up

Abstract Introduction Arrhythmias occur in 5% of preschool patients, with an increased incidence in adolescence. Treatment of rapid arrhythmias or tachyarrhythmias may include ablation of the cardiac structures. Catheter ablation is the possibility of producing an injury to the endocardium by administering energy through the catheter in a limited and controlled way to those parts of the cardiac tissue where tachycardias are initiated and/or maintained, it is performed through a catheter connected to an energy source, which is introduced through arterial or venous lines. to the chambers of the heart. In recent years, different technological innovations have emerged aimed at better understanding and identifying the substrate of arrhythmia, thus facilitating catheter navigation and reducing the need for fluoroscopy. Different studies have shown that ablation without fluoroscopy is feasible, especially in the context of supraventricular tachycardia. Objective To describe the clinical characteristics of pediatric patients undergoing ablation with zero fluoroscopy in a pediatric hospital of the National Medical Center of the West (CMNO). Material and Methods descriptive and retrospective study, the clinical characteristics of 42 patients who were taken to arrhythmia ablation by zero fluoroscopy technique at the CMNO IMSS pediatric hospital for 4 years in the period from June 2019 to May 2023 were analyzed. Results A total of 42 patients, of which 55% were male, with a median age of 13 years with a range of 4 to 17 years, the median weight was 49 kg with a standard deviation of +- 19.5 kg. Of the arrhythmias treated, supraventricular tachycardia accounted for 97.6% of cases and ventricular arrhythmias for 2.4%. Of the supraventricular tachycardias, atrioventricular reentrant tachycardia accounted for 68.35%. 25 cases with a diagnosis of Wolff Parkinson White with 28% of the right lateral location, followed by the right postoseptal 24%. Structural heart disease was present in 31% of the cases, the most frequent being Ebstein's anomaly (41.7%). Immediate success rate was 97.3%, with recurrence in the first three months of follow-up of 5.4%. A Kaplan-Meier curve was performed, showing a success rate of 77.3% at 12 months of follow-up. No statistical significance was found in patients with congenital heart disease and recurrence, p=0.698 and with Fisher's exact test, p=0.530. Conclusion Ablation of cardiac arrhythmias in children under 18 years of age without the use of fluoroscopy is an effective procedure, obtaining an immediate success rate of 97.3% of patients, 77.3% of patients are free of recurrence one year after treatment. There was no statistical significance for patients with congenital heart disease who might have recurrence.

Short-term mechanical circulatory support in adults with congenital heart disease: indications and outcomes

Abstract Background An increasing number of adults with congenital heart disease (ACHD) present with heart failure (HF), which may require short- or long-term mechanical circulatory support (MCS), often around cardiac surgery or other interventions. Even though MCS has entered ACHD practice over the last few years, little is known on its indications and outcomes in this population. Purpose To assess the use and outcomes of short-term MCS in ACHD patients in a specialist centre, and assess the predictive power of the Survival After Veno-Arterial Extracorporeal Membrane Oxygenation (SAVE) score in this population. Methods Data on all ACHD patients who received MCS since 2008 in a single tertiary centre were collected. Immediate, short and longer-term outcomes were also collected, including death, complications, and weaning success. Logistic regression and ROC analysis were performed to identify predictors of in-hospital mortality. Result There were 65 episodes of MCS in 63 patients during the study period: age 36.9+-13.6 years, 61.5% male. Most patients had CHD of moderate or severe complexity (49.2% moderate and 10.8% severe according to ESC guidelines). The most common anatomical diagnoses were left outflow tract obstruction in 35.4%, Marfan syndrome in 20.0% and tetralogy of Fallot or pulmonary atresia in 10.8%. The most common indications for ECMO were perioperative support (not endocarditis) in 55.6%, HF in 14.3%, pneumonia in 12.7% and endocarditis-related surgery in 7.9%. A critical preoperative status was present in 26.8%; median PEACH score (a validated ACHD peri-operative risk score) was 1.0[1.0-3.0] and ACHS score was 0.6[0.6-1.0]. Median SAVE score was -4.0[-9.0–2.0], with 21(43.8%) in SAVE class 4 or 5. VA-ECMO was used in 69.2%, VV-ECMO in 21.5%, BiVAD-ECMO in 4.6% and RVAD support in 4.6% of patients. The median duration of ECMO support was 198.6[133.0-354.2] hours. Complications included ischemic stroke (15.4%), intracerebral bleeding (9.2%), and other thromboembolism (23.8%). Successful weaning was achieved in 56.2%, whereas 4.6% were switched to more definitive MCS. In-hospital mortality was 47.7%, and this was higher in patients receiving VA support (OR 4.92, 95%CI:1.32-23.93, p=0.03). For patients on VA-ECMO or BiVAD support, the presence of Marfan syndrome (OR 4.92, 95%CI:1.32-23.93, p=0.03) and a lower (worse) SAVE score (OR 1.3 per point reduction, 95%CI:1.11-1.59, p=0.004) were associated with in-hospital mortality. An adjusted SAVE score that accounted for the presence of heritable thoracic aortic diseases (HTAD, -3 points) performed well at predicting in-hospital mortality (AUC increasing from 0.73 to 0.8, Figure). Conclusions Short-term MCS is a useful temporary rescue intervention in patients with ACHD, as a bridge to recovery or durable support, with 1 in 2 patients surviving to hospital discharge. The SAVE score adjusted for HTAD can reliably predict outcomes in patients with VA-ECMO and requires external validation.Figure

A meta-analysis of the effects of sacubitril-valsartan on surrogate markers of systemic right ventricular dysfunction in congenital heart disease

Abstract Introduction Dysfunction of systemic right ventricle (sRV) in adult congenital heart disease (ACHD) patients is expectable and often associated with heart failure and other dismal cardiovascular events. Despite limited evidence, several neurohormonal modulators approved for heart failure with reduced ejection fraction (HFrEF) have been used off-label in patients with RV dysfunction1. Sacubitril-valsartan (ARNI) effects on sRV remains poorly studied, with current evidence being limited to small cohorts. Purpose Review and summarize current evidence about the effects of ARNI in ACHD patients with sRV. Methods We performed a systematic review on MEDLINE, EMBASE, COCHRANE, and SCOPUS for articles that included "systemic right ventricle" and "sacubitril valsartan" until January 2024. Two investigators screened the literature and extracted data. Treatment effects were measured by Cohen's d effect-size (EZ) pre and post-ARNI, with a 95% confidence interval (CI), using a restricted maximum likelihood model. Results From 197 publications screened, five studies fulfilled our criteria, comprising a total of 135 patients. Follow-up after ARNI therapy ranged from 12 to 27 months. No randomized clinical trials were found, and only two studies had a prospective design. Dextro-transposition of the great arteries (D-TGA) after atrial switch operation was the most common type of congenital heart disease with sRV (n=95; 70%). Meta-analysis demonstrates that ARNI reduced NT-proBNP levels during follow-up (EZ= -0.34, CI -0.59 to 0.08; p=0.01; I2=4.0%). Regarding RV function, ARNI improved RV fractional area change (RVFAC) (EZ= 0.75, CI 0.01 to 1.50; p= 0.048; I2=85.0%). A trend for RV global longitudinal strain improvement was also observed with ARNI (EZ= 1.74, CI -0.05 to 3.54; p=0.06; I2=95.9%) but not for tricuspid annular plane systolic excursion (EZ= -0.07, CI -0.33 to 0.20; p=0.62; I2=0.0%). RV diastolic diameter did not change significantly with ARNI (EZ= 0.07, CI -0.43 to 0.56; p=0.79; I2=68.2%). A trend for improvement on the 6-minute walk test was observed (EZ= 1.89, CI -0.13 to 3.91; p=0.07; I2=96.3%), but no effect on exercise oxygen consumption (VO2) (EZ= -0.09, CI -1.32 to 1.15; p=0.89; I2=91.4%). During follow-up ARNI did not change significantly systolic blood pressure (EZ= -0.32, CI -0.74 to 0.11; p=0.15; I2=58.4%) or serum creatinine (EZ= 0.23, CI -0.04 to 0.49; p=0.09; I2=0.0%). Conclusions Despite heterogeneity among these studies, this meta-analysis demonstrates that ARNI might improve NT-proBNP levels and RV function. ARNI seems safe and well tolerated, with no significant effect on blood pressure and renal function. More well-powered studies are needed to confirm the beneficial effects of ARNI in ACHD with sRV.

Suppression of Fibulin 5 Attenuated Pulmonary Arterial Hypertension Associated with Congenital Heart Disease via Mitigating Pulmonary Arterial Smooth Muscle Cell Dysfunction

Abstract Backgrounds: The specific molecular pathogenesis of pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) and the reversal still remain elusive. Fibulin 5 was involved in the regulation of cardiovascular system while little is known about the expression and functions of fibulin 5 in the development of CHD-PAH. This study aimed to investigate the role of fibulin 5 in the pathogenesis of the disease. Methods Lung samples were obtained both from patients with CHD-PAH and aortocaval shunt-associated PAH rat models. TGF-β1was used to induce human pulmonary artery smooth muscle cells (hPASMCs) dysfunction and lentiviruses were responsible for alteration of fibulin 5 expression. In an effort to explore the specific role of fibulin 5, an inhibitor of phosphatidylinositol-3-kinases (PI3K) /protein-serine-threonine kinase (AKT) which was defined as the TGF-β1-related downstream signaling was applied for further exploration. Results Fibulin 5 was pronouncedly elevated in the PASMCs of the remodeled pulmonary arterioles from patients with CHD-PAH and shunt-associated PAH rats. We found that over-expression of fibulin 5 could promote hPASMCs dysfunction induced by TGF-β1 and it could be reversed by the PI3K/AKT inhibitor LY294002 suggesting the essential role of TGF-β1/PI3K/AKT signaling activation in phenotypic switch, proliferation and migration of PASMCs. Moreover, an adeno-associated virus vector encoding fibulin 5 by intratracheally instillation with rats improve the hemodynamic parameters in shunt-associated PAH rats and its related pulmonary artery remodeling. Conclusion Over-expression of fibulin 5 could significantly promote hPASMCs dysfunction and pulmonary artery remodeling via reinforcing TGF-β1/PI3K/AKT signaling activation, which highlighted the potential valuable pharmacological target for the treatment of CHD-PAH.Fibulin 5 was over-expressed in PAHInhibition of fibulin 5 attenuated PAH

Heart failure burden among adults with congenital heart disease

Abstract Background Adult congenital heart disease (ACHD) is associated with high rates of healthcare utilization and mortality. Data on Heart failure (HF) burden among ACHD patients are limited. Purpose To study the association between HF and healthcare utilization and mortality among ACHD patients in the community. Methods The retrospective cohort study comprised 11,653≥ 18 year old ACHD patients insured by two large Israeli healthcare providers between January 2007 and December 2011. We used multivariable Cox proportional hazard and negative binomial models to study the associations of HF with mortality and healthcare utilization, respectively. Inverse treatment probability weighting accounted for drug indication. Results ACHD-HF patients (N=908; 7.8%) were older (median: 69 vs. 45 years), more likely men (53% vs. 45%), with complex congenital heart disease (14% vs. 4%), and higher comorbidity rates than ACHD patients without HF. HF was associated with higher healthcare utilization. Compared to patients without HF, ACHD-HF patients had higher adjusted relative rates (RR) of primary care (1.26, 95% confidence interval [CI]: 1.17-1.3), and cardiology clinic visits (1.9, 95% CI: 1.7-2.0), higher hospitalization rates (RR=2.0, 95% CI: 1.7-2.1), and higher risk of death (mortality hazard ratio [HR]: 1.9, 95% CI: 1.5-20.) over the study period. Among ACHD-HF patients, Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and diuretics were associated with a lower mortality risk (treated vs. untreated HR=0.56, 95% CI: 0.48-0.65; HR=0.7, 95% CI: 0.6-0.8; HR=0.84, 95% CI: 0.73-0.97; respectively). Conclusions HF presents a major burden on ACHD patients and health care systems. Drugs recommended to the general HF patient population are also associated with lower risk of hospitalization and mortality in ACHD patients. Clinical trials are needed to establish the benefit of HF pharmacotherapy in ACHD patients.Age adjusted ACHD patient survival by HF

Risk factors of 30-day mortality following cardiac surgery in adults with congenital heart disease: analysis from the Japanese registry

Abstract Background With advancements in pediatric therapies, the adult congenital heart disease (ACHD) population has grown consistently. ACHD patients often face complications necessitating cardiac surgery, and understanding surgical risk factors is essential. Purpose This study aims to assess ACHD surgical risk factors using big data, addressing evidence gaps in previous research limited to univariate analysis due to few perioperative adverse events. Methods We analyzed the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC) database from April 2013 to March 2020. The JROAD-DPC database covers nearly all teaching hospitals with cardiovascular beds participation in JROAD. Our study included ACHD patients (>15 years) undergoing open-heart surgery. Our primary outcome was 30-day mortality. We assessed clinical backgrounds, admission status, treatment, and length of hospital stay. Results Out of 13,677 ACHD patients (mean age: 53 years, females 47%) undergoing cardiac surgery assessed for 30-day mortality, 13,516 (98.8%) patients were categorized into the survival group and 161 (1.2%) into the death group. Mortality rates varied by complexity of congenital heart disease (CHD): 0.8% for simple, 1.8% for moderate, and 0.9% for great. The figure shows that a significant increase in 30-day mortality rates with age was demonstrated in simple and moderate complexity (p<0.001 for trend analysis in both categories). In contrast, for cases of great complexity, the increase in 30-day mortality rates with aging was not statistically significant (p=0.443). The death group was significantly older and had higher rates of ambulance admissions, renal disease, and peripheral vascular disease. Intra-aortic balloon pumps (IABP), veno-arterial extracorporeal membrane oxygenation (VA-ECMO), and dialysis during hospitalization were significantly higher among deceased patients. Length of ICU stay was significantly longer in the death group (median [IQR]; 3 [2-4] vs. 6 [3-11], p<0.001). Cox proportional-hazards model showed that age, moderate complexity, emergency admission, hospital bed counts, renal disease, and use of IABP and VA-ECMO were independently associated with 30-day mortality (Table). Conclusions The present study, which utilizes the nationwide administrative DPC database, demonstrates that surgical outcomes for patients with ACHD, as measured by 30-day mortality rates, are generally favorable. These outcomes significantly depend on factors such as age, complexity of CHD, emergency admissions, hospital capacity, renal disease, and use of mechanical circulatory support.

Mortality and survival rate in a scottish cohort of adults with congenital heart disease

Abstract Background Adult patients with congenital heart disease (ACHD) experience higher rates of morbidity and reduced long-term survival in comparison to the general population. The care of this cohort of patients requires specialist expertise which is mainly delivered at tertiary centers. Aims We aim to report the clinical characteristics, mortality rates and causes of death in a contemporary cohort of ACHD patients followed up in a North- East Scottish Health Board. Methods We prospectively followed up ACHD patients aged ≥17 years (n=645) under review at the Regional NHS ACHD Clinic in a North- East Scottish Health Board between the years 2020 and 2023. We recorded the number and the causes of death as documented on our electronic records and on correspondence with primary care physicians. Survival analysis was performed according to the 2020 ESC Guidelines classification of congenital heart disease complexity (Table 4) classes using Kaplan-Meier method with log-rank (Mantel-Cox) test done in IBM SPSS v.24. Results Our ACHD cohort (n=645, 54% females and 46% males) included patients of all three ESC complexity classes (30% mild, 60% moderate and 10% severe). Between 2020 and 2023, 18 patients (2.8%) died, with a total incidence of 0.93 deaths/100 patient years. Median age of death was 59 years (IQR 45–71), and the majority of deceased patients were males (56%). There were 2 deaths in the mild complexity group, 11 deaths in the moderate complexity group and 5 deaths in the severe complexity group (See Table 1). This was found to correspond to an incidence of 0.34, 0.95 and 2.64 deaths/100 patient years respectively. The leading causes of death were heart failure (28%) and malignancy (22%). Using Kaplan-Meier survival analysis we found that the survival distributions for the mild, moderate and severe ACHD complexity groups were statistically significantly different by log-rank test (χ2(2) = 11.47, p < .005) (See Figure 1). Patients with moderate ACHD complexity had a median survival age 67 years (95% CI 58.1-75.9), patients with severe ACHD had median survival age 57 years (95% CI 44.7-69.2). Median survival could not be calculated for the mild group due to lack of data points. Conclusion The ACHD patient group is characterised for a variety of pathophysiology and clinical presentations. They require lifelong medical input and in spite of the local and national expertise, the mortality and morbidity rates are still high. Heart failure was the leading cause of death in this cohort which is similar to previous reported data. Mortality rates were proportional to the complexity of the underlying ACHD diagnosis. The survival rate of patients in the severe complexity group was ten years less than the moderate complex group. ACHD patients in the moderate and severe complexity groups have significantly reduced life expectancy and require access and clinical expertise from National ACHD Specialty Centers.

Outcomes and complications of transvenous implantable cardioverter defibrillator systems in the pediatric population: a systematic review and meta-analysis

Abstract Background Implantable cardioverter defibrillators (ICDs) are an important therapy for prevention of sudden cardiac death (SCD). Data on transvenous (TV) ICD therapy rates, complications, and system survival in children ≤ 21 years is limited by absolute numbers and inclusion of adults with congenital heart disease. Purpose To determine ICD therapy rates and complications in pediatric patients ≤ 21 years of age. Methods A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Medline, Embase, PubMed Ahead-of-Print and in-process records, and Cochrane Database of Systematic Reviews were searched for full-text articles on pediatric ICD. Articles were assessed for inclusion by two authors via a consensus process; the exclusion criteria included: case reports, review articles, abstracts, editorials, articles not in English, articles solely on epicardial or subcutaneous leads, articles on unrelated topics, articles with <50% ICD leads, and articles with any patients >21 years old. Data were extracted by 1 author and verified by a 2nd author. Meta-analysis of aggregate data was performed, where possible. Random effects models were used for pooled inferences. All reported rates are annualized rates based on reported follow-up times in each study. Results Of 1325 articles, 23 met all inclusion and no exclusion criteria (Figure) representing 1700 patients implanted from 1987-2020. The average age of patients was 12.8 years (95% confidence interval [CI]: 11.9 – 13.7) with weight of 51.1 kg (95% CI: 42.2 – 60.0) (Table). Primary prevention was the indication in 56.4 % (95% CI: 45.0% – 67.7%). Only 14.8% (95% CI: 10.6% – 19.0%) of the patients had congenital heart disease while 22.6% (95% CI: 15.8% – 29.3%) had long QT syndrome. The annualized rate of appropriate shock was 7.0% (95% CI: 5.6% – 8.8%) and the rate of inappropriate shock was 4.8% (95% CI: 3.8% – 6.0%). Annualized rates of reported adverse events included lead failure: 2.3% (95% CI: 1.6% – 3.3%) and infection: 0.8% (95% CI: 0.4% – 1.6%), which could have led to system revision: 4.4% (95% CI: 2.1% – 9.4%). The all-cause mortality rate was 0.8% (95% CI: 0.6% – 1.2%) across 17 studies. In 9 studies with 719 patients, the heart transplant rate was 1.6% (95% CI: 0.6% – 3.9%). Conclusion In this first systematic review and meta-analysis of ICDs in pediatric patients, ICD therapy was effective for prevention of SCD with a 7.0% annualized rate of appropriate ICD shocks. This is comparable to the annualized rate of appropriate ICD shock for secondary prevention of SCD in adult randomized controlled trials. Most common adverse events in the pediatric population were lead failure and system revision. Further refinements in patient selection criteria for implantation and improvements in lead and device technology are needed for pediatric patients.FigureTable

A novel risk score based on exercise capacity to predict all-cause mortality in adults with congenital heart disease

Abstract Background Impaired exercise capacity in adults with congenital heart disease is associated with mortality. Thus, exercise capacity is a potential tool for predicting risk in this population. The present study attempts to further explore the usefulness of exercise capacity in risk assessment of all-cause mortality, together with a limited number of easily accessible clinical variables. Methods The national register of congenital heart disease was searched for adults (18-60 years of age) with at least one bicycle ergometer exercise test and follow up in the register. The exercise capacity was classified based on percent of predicted exercise capacity (EC%pred); normal (> 70%), moderately impaired (50-70%) or severely impaired (<50%). All patients were followed for 10 years or until death, if occurring earlier than 10 years after the exercise test. Data were analyzed using logistic regression modelling. A risk evaluation model was constructed based on percent of predicted exercise capacity, age, and complexity of the heart lesion. Finally, the model was converted into a 5-point (p) risk score used to predict 10-year mortality (EC%pred >70%=0p, 50-70=1p, <50%=2p, age <25=0p, 25-40=1p, 40-60=2p, simple lesion=0p, moderate/severe complexity of heart lesion=1p). Results 1171 patients (mean age at exercise test 30.5 years, 44% women) were included with 70 deaths occurring within 10 years. A score 0-1 corresponded to <1% 10-year all-cause mortality, 2p 5%, 3p 9%, 4p 21% and 5p 33% mortality risk (Table 1). The area under curve for the model was 0.75 (95% CI 0.69-0.81). Conclusion An easily performed risk assessment containing % of predicted exercise capacity, age and complexity of heart lesion performs well in detecting patients at both low and high risk of all-cause mortality within 10 years after an exercise test.

Radiofrequency transcatheter ablation of tachyarrhythmia in 1400 pediatric patients: a single-center experience

Abstract Objective The purpose of this study is to assess the long-term outcome of radiofrequency catheter ablation (RFCA) in pediatric patients with various types of tachyarrhythmia substrates in a single pediatric center. Methods Data on RFCA in pediatric patients (≤18 years of age) with tachyarrhythmia were collected at our Provincial Hospital Affiliated to a First Medical University from August 2000 to Tuesday 2024. Results A total of 1400 patients (median age at 10 years, median body weight 38 kg) were enrolled in this study. These targeted tachycardia substrates were fall into five groups: 1. atrioventricular reentrant tachycardia (AVRT) in 628 (44.86%) patients, 2. atrioventricular nodal reentrant tachycardia (AVNRT) in 319 (22.78%) patients, 3. ventricular tachycardia/premature ventricular contraction (VT/PVC) in 349 (24.93%) patients, 4. atrial tachycardia (AT) in 79 (5.64%) patients, and 4. atrial flutter (AFI) in 12 (0.86%) patients. However, the mechanism of tachycardia could not be determined in 13 (0.93%) patients. Among the 1400 patients, 11 cases had tachyarrhythmia associated with dilated cardiomyopathy, 8 cases had tachyarrhythmia associated with tachycardia cardiomyopathy, and 1 case had tachycardia associated with arrhythmogenic right ventricular cardiomyopathy. Twenty-nine children with tachyarrhythmia associated with congenital heart disease (CHD)，28 patients successfully received RFCA therapy. Median follow-up was 36 months. The overall procedural success rate was 99.26%, and the recurrence rate was 5.35%. The median procedure duration was 100.00 (70.00-120.00) min, and the median fluoroscopy time was 3.30 (0.50-9.23) min. A total of 621 AVRT patients underwent RFCA with success rate at 99.19% and recurrence rate at 5.36%. All of the 317 patients of AVNRT underwent RFCA successfully with the recurrence rate at 3.79%. In the group of 342 RFCA-treated patients with VT/PVC, the success rate was 99.12%, and the recurrence rate was 6.49%. Among 65 patients of AT who underwent RFCA, the success rate was 98.46% with the recurrence rate at 7.81%. While 11 patients with AFI received RFCA, the success rate was 90.91%, with no incidence of recurrence. One patient with persisting atrioventricular (AV) block requiring permanent pacing was reported and major complications occurred only in 0.81% of the patients. Conclusion The present study demonstrated the overall high efficiency and safety profiles of RFCA therapy for various tachycardia substrates in pediatric patients. Furthermore, the complication rate was exceptionally low. The success rate of RFCA was the same in children with or without CHD.

Anabolic steroids as the substrate for atrial fibrillation: A case report

Abstract Background Atrial fibrillation (AF) is the most frequently encountered sustained arrhythmia worldwide. This supraventricular rhythm disorder is precipitated by advanced age, valvular heart disease, hypertension, heart failure, congenital heart defects and others. However, the role of anabolic steroids abuse in precipitating AF remains insufficiently researched and largely underreported, despite their known cardiovascular risks. Case summary We present the case of a 40-year-old male bodybuilder who was admitted to the emergency department with symptomatic atrial fibrillation. His medical history revealed the use of anabolic steroids, which was suspected to be the trigger. A thorough biological evaluation and echocardiography were performed, revealing no structural or functional cardiac abnormalities. After electrical cardioversion and discontinuation of anabolic steroid use, the patient's rhythm returned to normal, with no recurrence of arrhythmia during follow-up. Discussion This case highlights the potential but underexplored link between anabolic steroid use and the onset of atrial fibrillation. Although anabolic steroids are known to affect cardiovascular health by promoting hypertension, left ventricular hypertrophy, and endothelial dysfunction, their role in arrhythmogenesis, particularly in AF, remains unclear. In this patient, the absence of other identifiable triggers, combined with the resolution of symptoms upon steroid cessation, strongly suggests a causal relationship. Further research is needed to clarify the mechanisms through which anabolic steroids may contribute to the development of AF, particularly in younger, otherwise healthy individuals such as athletes and bodybuilders. This case underscores the importance of awareness among clinicians regarding the potential cardiac risks associated with anabolic steroid use.

Prognosis of Zero Coronary Artery Calcium Score in Symptomatic Patients of South Asian Descent - an Experience from a Tertiary Care Center in Pakistan.

The absence of CAC in asymptomatic individuals is associated with a very low incidence of cardiovascular events. Of symptomatic patients, 1-2% with zero CAC score have non-calcified coronary artery atherosclerosis, and at least one third of cardiovascular events occur in individuals with zero CAC. South Asians (SA) have proportionally higher case fatality rates for CVD, relatively younger age of presentation, and accelerated rate of atherosclerosis when compared with other ethnic groups. All consecutive patients who underwent a CTCA to evaluate angina or angina-equivalent symptoms during the study duration were enrolled retrospectively. Patients with prior myocardial infarction, history of revascularization, and congenital heart disease were excluded. MACE was defined as the total of cardiac death, non-fatal myocardial infarction, and/or non-elective revascularization. A total of 534 patients were enrolled after final exclusion. The mean age was 53 years ± 11. Males constituted 68.4% of the study population. Dyslipidemia was the most common co-morbid condition identified (50%), followed by diabetes (18.4%) and hypertension (3.6%). At least 28.8% of patients with zero CAC scores had the presence of coronary artery disease (soft plaque) of any degree. Obstructive CAD (>50%) was present in 5.8% of patients. Follow-up was available for 61.4% of patients. On a mean follow-up of 96.6 months ± 49.8 (range 21-194 months), all-cause MACE was observed in 8.8% of patients. The most common MACE was angina (3.96%) and all-cause mortality (3%). The baseline characteristics and MACE did not differ in patients with and without obstructive CAD. The baseline characteristics did not differ significantly between patients with and without MACE. The incidence of soft plaque in this SA cohort is higher than that reported in international studies. However, in symptomatic SA, a CAC score of zero carries a good long-term prognosis, irrespective of the degree of CAD.

Pregnancy in women with congenital heart disease : new insights into neonatal risk predictioc

Abstract Background Advances in managing adult congenital heart disease (ACHD) have led to an increased number of women with CHD reaching childbearing age. This demographic shift underscores the need for improved understanding and prediction of complications during pregnancy in this specific ACHD population. Despite progress in maternal cardiac risk assessment, the prediction of neonatal outcomes for ACHD pregnancies remains underdeveloped. Therefore, the aims of this study are (1) to assess neonatal outcomes in a CHD women population, (2) to identify their predictive factors and (3) to propose a new risk score for predicting neonatal complications. Methods This registry study included all women born between 1975 and 1996 diagnosed with ACHD who underwent at least one cardiology consultation for ACHD in Cliniques Universitaires Saint-Luc. A multivariate analysis was performed to identify predictors of neonatal complications and these were incorporated into a new risk index. Its validity was assessed using bootstrap method. This score was then compared with scores adapted from the ZAHARA and CARPREG studies for offspring events prediction. Results Analysis of 491 pregnancies revealed 31.4% of neonatal complications. Four significant predictors of adverse neonatal outcomes were identified: cardiac treatment during pregnancy (OR 14.9, 95%CI [4.6-64.3]), hypertensive disorders of pregnancy (OR 10.4, 95%CI [3.4-39.5]), smoking during pregnancy (OR 10.3, 95% CI [3.0-44.9]), and pre-pregnancy BMI < 18.5 kg/m² (OR 6.2, 95% CI [2.6-16.5]). The risk model demonstrated an AUC of 0.70 (95% CI [0.65-0.75), which remained stable after bootstrap validation. This model significantly outperformed the scores adapted from ZAHARA and CARPREG data. Based on the regression coefficients, a risk score was subsequently developed comprising 5 risk categories. Conclusion One third of ACHD pregnancies are complicated by poor neonatal outcome. These complications are determined by 4 independent factors relating to the cardiac and non-cardiac status of the patients, which have been incorporated into a risk score. Our study is one of the first to propose a predictive risk score of neonatal outcomes in ACHD pregancies, and paves the way for other validation and confirmation studies.Offspring scores: performance comparisonNew risk score for neonatal outcome