Clinical Guideline for Preimplantation Genetic Testing in Inherited Cardiac Diseases.

BACKGROUND: Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking. We developed an objective decision model to select eligibility for PGT and compared its results with those from a multidisciplinary team. METHODS: All couples with an inherited cardiac disease referred to the national PGT center were included. A multidisciplinary team approved or rejected the indication based on clinical and genetic information. We developed a decision model based on published risk prediction models and literature, to evaluate the severity of the cardiac phenotype and the penetrance of the familial variant in referred patients. The outcomes of the model and the multidisciplinary team were compared in a blinded fashion. RESULTS: Eighty-three couples were referred for PGT (1997-2022), comprising 19 different genes for 8 different inherited cardiac diseases (cardiomyopathies and arrhythmias). Using our model and proposed cutoff values, a definitive decision was reached for 76 (92%) couples, aligning with 95% of the multidisciplinary team decisions. In a prospective cohort of 11 couples, we showed the clinical applicability of the model to select couples most eligible for PGT. CONCLUSIONS: The number of PGT requests for inherited cardiac diseases increases rapidly, without the availability of specific guidelines. We propose a 2-step decision model that helps select couples with the highest risk reduction for cardiac disease in their offspring after PGT.

Role and mechanism of miR-871-3p/Megf8 in regulating formaldehyde-induced cardiomyocyte inflammation and congenital heart disease.

OBJECTIVE AND DESIGN: We aimed to investigate the molecular mechanism underlying formaldehyde (FA)-induced congenital heart disease (CHD) using in vitro and in vivo models. MATERIALS AND SUBJECTS: Neonatal rat heart tissues and H9C2 cells were used for in vitro studies, while FA-exposed new-born rats were used for in vivo studies. TREATMENT: H9C2 cells were exposed to FA concentrations of 0, 50, 100 and 150 µM/mL for 24 h. METHODS: Whole transcriptome gene sequencing identified differentially expressed miRNAs in neonatal rat heart tissues, while Real-time quantitative PCR (RT-qPCR) assessed miR-871-3p and Megf8 expression. RNA pull-down and dual-luciferase reporter assays determined miR-871-3p and Megf8 relationships. Inflammatory cytokine expression was assessed by western blotting. A FA-induced CHD model was used to validate miR-871-3p regulatory effects in vivo. RESULTS: We identified 89 differentially expressed miRNAs, with 28 up-regulated and 61 down-regulated (fold change ≥ 2.0, P < 0.05). Inflammation (interleukin) and signalling pathways were found to control FA-induced cardiac dysplasia. miR-871-3p was upregulated in FA-exposed heart tissues, modulated inflammation, and directly targeted Megf8. In vivo experiments showed miR-871-3p knockdown inhibited FA-induced inflammation and CHD. CONCLUSION: We demonstrated miR-871-3p's role in FA-induced CHD by targeting Megf8, providing potential targets for CHD intervention and improved diagnosis and treatment strategies.

Incidence of and risk factors for perioperative blood transfusion in infants undergoing index pediatric surgery procedures.

BACKGROUND: There is a paucity of data on the frequency of transfusion during pediatric surgery index cases and guidelines for pretransfusion testing, defined as type and screen and crossmatch testing, prior to operation are not standardized. This study aimed to determine the incidence of perioperative blood transfusions during index neonatal operations and identify risk factors associated with perioperative blood transfusion to determine which patients benefit from pretransfusion testing. METHODS: A retrospective review of infants who underwent index neonatal cases between 2013 and 2019 was performed. Data were collected for patients who underwent operations for Hirschsprung's disease, esophageal atresia/tracheoesophageal fistula (EA/TEF), biliary atresia, anorectal malformation, omphalocele, gastroschisis, duodenal atresia, congenital diaphragmatic hernia (non-ECMO) or pulmonary lobectomy. Infants under 6 months were included except in the case of lobectomy where infants up to 12 months were included. RESULTS: Analysis was performed on 420 patients. Twenty-five (6.0%) patients received perioperative blood transfusion. Patients who received perioperative transfusion most commonly underwent EA/TEF repair. Patients who received perioperative transfusion had higher rates of structural heart disease (52.0% vs 17.7%, p<0.001), preoperative transfusion (48.0% vs 8.9%, p<0.001), and prematurity (52.0% vs 25.6%, p = 0.005). Presence of all three risk factors resulted in a 48% probability of requiring perioperative transfusion. CONCLUSIONS: Blood transfusion during the perioperative period of neonatal index operations is rare. Factors associated with increased risk of perioperative transfusion include prematurity, structural heart disease, and history of previous blood transfusion. LEVEL OF EVIDENCE: III.

Prevalencia de cardiopatías congénitas en niños adoptados internacionalmente / Prevalence of congenital heart defects in internationally adopted children

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Biomarcadores associados à defechos clínicos pós-cirurgia cardíaca em terapia intensiva pediátrica / Biomarcadores relacionados con resultados clínicos en el posoperatorio de cirugía cardíaca en cuidados intensivos pediátricos / Biomarkers associated with postoperative cardiac surgery clinical outcomes in pediatric intensive care

Resumo Objetivo: Sintetizar e analisar criticamente a literatura a respeito de potenciais biomarcadores associados à desfechos clínicos no pós-operatório de cirurgia cardíaca em lactentes e crianças em cuidados intensivos. Métodos: Revisão integrativa, cuja busca ocorreu nos meses de setembro e dezembro de 2019, nas bases de dados MEDLINE, ISI of Knowledge, CENTRAL Cochrane, EMBASE, CINAHL, Science Direct e LILACS para responder à questão norteadora: "Quais as evidências científicas acerca de potenciais biomarcadores relacionados à desfechos clínicos no pós-operatório de cirurgia cardíaca de lactentes e crianças em cuidado intensivo?" Foram incluídos artigos originais publicados entre 2000 e 2019, nos idiomas inglês, português ou espanhol. Excluiu-se toda a literatura cinzenta. Resultados: A amostra final foi constituída por oito artigos, sendo seis estudos observacionais prospectivos descritivos e dois coortes prospectivas. Na maioria dos estudos os pacientes pediátricos foram submetidos à técnica de Bypass Cardiopulmonar (BCP) intraoperatória durante cirurgia de cardiopatia congênita. Os potenciais biomarcadores analisados foram moléculas participantes de processos imune-inflamatórios, predominantemente citocinas pró-inflamatórias tais como IL-1β, IL-6, IL-8 e o fator de necrose tumoral-α (TNF-α) e seu receptor, ou citocinas anti-inflamatórias como a IL-10. Conclusão: As citocinas IL-6, IL-8 e IL-10, o cortisol e o lactato, apresentaram-se como moléculas promissoras para elucidação de mecanismos subjacentes a desfechos clínicos no pós-operatório de cirurgia cardíaca em lactentes e/ou crianças em cuidado intensivo. Tais moléculas podem assumir um caráter preventivo, podendo futuramente ser utilizadas como ferramentas diagnósticas e prognósticas alternativas para um regime que permita identificar pacientes sob alto risco de desenvolver complicações clínicas nos pós-operatórios.

Resumen Objetivo: Sintetizar y analizar críticamente la literatura sobre potenciales biomarcadores relacionados con resultados clínicos en el posoperatorio de cirugía cardíaca de lactantes y niños en cuidados intensivos. Métodos: Revisión integradora, cuya búsqueda ocurrió en los meses de septiembre y diciembre de 2019, en las bases de datos MEDLINE, ISI of Knowledge, CENTRAL Cochrane, EMBASE, CINAHL, Science Direct y LILACS para responder la pregunta orientadora: "¿Cuáles son las evidencias científicas sobre potenciales biomarcadores relacionados con resultados clínicos en el posoperatorio de cirugía cardíaca de lactantes y niños en cuidados intensivos?". Se incluyeron artículos originales publicados entre los años 2000 y 2019, en idioma inglés, portugués o español. Se excluyó toda la literatura gris. Resultados: La muestra final fue formada por ocho artículos, de los cuales seis eran estudios observacionales prospectivos y dos cohortes prospectivas. En la mayoría de los estudios, los pacientes pediátricos fueron sometidos a la técnica de bypass cardiopulmonar (BCP) intraoperatoria durante la cirugía de cardiopatía congénita. Los potenciales biomarcadores analizados fueron moléculas participantes de procesos inmunoinflamatorios, predominantemente citocinas proinflamatorias tales como IL-1β, IL-6, IL-8 y el factor de necrosis tumoral-α (TNF-α) y su receptor, o citocinas antinflamatorias como la IL-10. Conclusión: Las citocinas IL-6, IL-8 e IL-10, el cortisol y el lactato, se presentaron como moléculas promisorias para explicar mecanismos subyacentes de los resultados clínicos en el posoperatorio de cirugía cardíaca de lactantes o niños en cuidados intensivos. Estas moléculas pueden asumir un carácter preventivo y, en un futuro, pueden utilizarse como herramientas alternativas de diagnóstico y pronóstico para un régimen que permita identificar pacientes con alto riesgo de presentar complicaciones clínicas en el posoperatorio.

Abstract Objective: To summarize and critically analyze the literature on potential biomarkers associated with clinical outcomes in the postoperative cardiac surgery period in infants and children under intensive care. Methods: Integrative review, whose search was carried out in September and December 2019 in the databases MEDLINE, ISI Web of Knowledge, Cochrane Central Register of Controlled Trials, Embase, Cumulative Index to Nursing and Allied Health Literature, Science Direct, and Latin America and Caribbean Center on Health Sciences Information to answer the following guiding question: "What is the scientific evidence on potential biomarkers associated with clinical outcomes in the postoperative cardiac surgery period in infants and children under intensive care?". Original articles published between 2000 and 2019 in English, Spanish, or Portuguese were included. Gray literature was excluded. Results: Eight articles made up the final sample (six descriptive observational prospective studies and two prospective cohort studies). Most studies, pediatric patients were submitted to the intraoperative cardiopulmonary bypass technique during congenital heart disease surgeries. The potential biomarkers analyzed were molecules that participate in immune-inflammatory processes, mainly proinflammatory cytokines such as IL-1β, IL-6, IL-8, and tumor necrosis factor-alpha and its receptor, as well as anti-inflammatory cytokines such as IL-10. Conclusion: The IL-6, IL-8, and IL-10 cytokines, cortisol, and lactate showed as promising molecules for elucidating mechanisms underlying clinical outcomes in the postoperative cardiac surgery period in infants and/or children under intensive care. These molecules can take on a preventive role by being used as a diagnostic and prognostic tool in the future in a protocol that allows to identify patients with high risk to develop clinical complications during the postoperative period.

Transcatheter Closure of Large Coronary-Cameral Fistulas Using the Patent Ductus Arteriosus Occluder or Amplatzer Vascular Plugs.

Transcatheter closure (TCC) has emerged as the first-line treatment for coronary artery fistulas. However, limited data exist regarding the long-term outcomes and technical aspects of this procedure. We aimed to report the long-term outcomes and technical aspects of TCC of large coronary-cameral fistulas (CCFs).All patients with large CCFs who underwent attempted TCC using the patent ductus arteriosus (PDA) occluder or Amplatzer vascular plug (AVP), from June 2002 to December 2017, were retrospectively reviewed. A total of 23 patients with large CCFs underwent attempted TCC using the PDA occluder or AVP. Most CCFs originated from the right coronary artery and drained predominantly into the right heart chamber. Procedural success was achieved in 21 (91.3%) patients. Devices were deployed using the arteriovenous loop in 15, transarterial approach in 4, and arterio-artery loop approach in 2 patients. Procedural complications included coronary spasm in one and side branch occlusion in one patient. Among these 21 patients with successful device implantation, follow-up angiograms or computed tomography angiograms were obtained in 14 (66.7%) patients at a median of 11.0 (range, 9.8-16.3) months. Late complications included thrombosis of residual fistula segment without myocardial infarction (MI) in one, coronary thrombosis resulting in MI in one, and recanalization necessitating re-intervention in one patient. No death and device embolization occurred.TCC of large CCFs using the PDA occluder or AVP is an effective therapy in anatomically suitable candidates, with favorable long-term outcomes. Given that potentially hazardous complications may occur late after the procedure, long-term periodic evaluation is mandatory.

Intensive Care Unit Management of the Adult with Congenital Heart Disease.

PURPOSE: Adults with congenital heart disease (ACHD) are a rapidly growing population with ever-increasing complexity, and intensive care unit (ICU) management is often necessary. This review summarizes common cardiovascular and non-cardiovascular complications in ACHD and provides a framework for ICU care. RECENT FINDINGS: Heart failure is the leading cause of hospitalization and mortality in ACHD. Varied anatomy and repairs, as well as differing physiological complications, limit generalized application of management algorithms. Recent studies suggest that earlier mechanical support in advanced cases is feasible and potentially helpful. Cardiac arrhythmias are poorly tolerated and often require immediate attention. Other complications requiring intensive care include infections such as endocarditis and COVID-19, pulmonary hypertension, renal failure, hepatic dysfunction, coagulopathy, and stroke. Successful ICU care in ACHD requires a multi-disciplinary approach with careful consideration of anatomy, physiology, and associated comorbidities. Few studies have formally examined ICU management in ACHD and further research is necessary.

Congenital left ventricular diverticulum repair in an adult with dual patch technique.

Rupture of a congenital left ventricular diverticulum (CLVD), a rare anatomical anomaly, is a catastrophic event, with potential fatal consequences. Repair techniques documented in the literature include primary closure and single patch closure. We describe a case of a 57-year-old woman with symptomatic anterolateral CLVD. Our approach involves a linear incision through the epicardial surface of the diverticulum with exclusion of the cavity, and restoration of normal ventricular geometry via a two-patch technique.

Predicting and Surviving Prolonged Critical Illness After Congenital Heart Surgery.

OBJECTIVES: Prolonged critical illness after congenital heart surgery disproportionately harms patients and the healthcare system, yet much remains unknown. We aimed to define prolonged critical illness, delineate between nonmodifiable and potentially preventable predictors of prolonged critical illness and prolonged critical illness mortality, and understand the interhospital variation in prolonged critical illness. DESIGN: Observational analysis. SETTING: Pediatric Cardiac Critical Care Consortium clinical registry. PATIENTS: All patients, stratified into neonates (≤28 d) and nonneonates (29 d to 18 yr), admitted to the pediatric cardiac ICU after congenital heart surgery at Pediatric Cardiac Critical Care Consortium hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 2,419 neonates and 10,687 nonneonates from 22 hospitals. The prolonged critical illness cutoff (90th percentile length of stay) was greater than or equal to 35 and greater than or equal to 10 days for neonates and nonneonates, respectively. Cardiac ICU prolonged critical illness mortality was 24% in neonates and 8% in nonneonates (vs 5% and 0.4%, respectively, in nonprolonged critical illness patients). Multivariable logistic regression identified 10 neonatal and 19 nonneonatal prolonged critical illness predictors within strata and eight predictors of mortality. Only mechanical ventilation days and acute renal failure requiring renal replacement therapy predicted prolonged critical illness and prolonged critical illness mortality in both strata. Approximately 40% of the prolonged critical illness predictors were nonmodifiable (preoperative/patient and operative factors), whereas only one of eight prolonged critical illness mortality predictors was nonmodifiable. The remainders were potentially preventable (postoperative critical care delivery variables and complications). Case-mix-adjusted prolonged critical illness rates were compared across hospitals; six hospitals each had lower- and higher-than-expected prolonged critical illness frequency. CONCLUSIONS: Although many prolonged critical illness predictors are nonmodifiable, we identified several predictors to target for improvement. Furthermore, we observed that complications and prolonged critical care therapy drive prolonged critical illness mortality. Wide variation of prolonged critical illness frequency suggests that identifying practices at hospitals with lower-than-expected prolonged critical illness could lead to broader quality improvement initiatives.

Overcoming underpowering: Trial simulations and a global rank end point to optimize clinical trials in children with heart disease.

BACKGROUND: Randomized controlled trials (RCTs) in children with heart disease are challenging and therefore infrequently performed. We sought to improve feasibility of perioperative RCTs for this patient cohort using data from a large, multicenter clinical registry. We evaluated potential enrollment and end point frequencies for various inclusion cohorts and developed a novel global rank trial end point. We then performed trial simulations to evaluate power gains with the global rank end point and with use of planned covariate adjustment as an analytic strategy. METHODS: Data from the Society of Thoracic Surgery-Congenital Heart Surgery Database (STS-CHSD, 2011-2016) were used to support development of a consensus-based global rank end point and for trial simulations. For Monte Carlo trial simulations (n = 50,000/outcome), we varied the odds of outcomes for treatment versus placebo and evaluated power based on the proportion of trial data sets with a significant outcome (P < .05). RESULTS: The STS-CHSD study cohort included 35,967 infant index cardiopulmonary bypass operations from 103 STS-CHSD centers, including 11,411 (32%) neonatal cases and 12,243 (34%) high-complexity (Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category ≥4) cases. In trial simulations, study power was 21% for a mortality-only end point, 47% for a morbidity and mortality composite, and 78% for the global rank end point. With covariate adjustment, power increased to 94%. Planned covariate adjustment was preferable to restricting to higher-risk cohorts despite higher event rates in these cohorts. CONCLUSIONS: Trial simulations can inform trial design. Our findings, including the newly developed global rank end point, may be informative for future perioperative trials in children with heart disease.

Insights from circulating microRNAs in cardiovascular entities in turner syndrome patients.

BACKGROUND: Turner syndrome (TS) is a chromosomal disorder, in which a female is partially or entirely missing one of the two X chromosomes, with a prevalence of 1:2500 live female births. The present study aims to identify a circulating microRNA (miRNA) signature for TS patients with and without congenital heart disease (CHD). METHODS: Microarray platform interrogating 2549 miRNAs were used to detect the miRNA abundance levels in the blood of 33 TS patients and 14 age-matched healthy volunteer controls (HVs). The differentially abundant miRNAs between the two groups were further validated by RT-qPCR. RESULTS: We identified 60 differentially abundant miRNA in the blood of TS patients compared to HVs, from which, 41 and 19 miRNAs showed a higher and a lower abundance levels in TS patients compared to HVs, respectively. RT-qPCR confirmed the significantly higher abundance levels of eight miRNAs namely miR-374b-5p, miR-199a-5p, miR-340-3p, miR-125b-5p, miR-30e-3p, miR-126-3p, miR-5695, and miR-26b-5p in TS patients as compared with the HVs. The abundance level of miR-5695 was higher in TS patients displaying CHD as compared to TS patients without CHD (p = 0.0265; log2-fold change 1.99); whereas, the abundance level of miR-126-3p was lower in TS patients with congenital aortic valve disease (AVD) compared to TS patients without BAV (p = 0.0139, log2-fold change 1.52). The clinical feature statistics revealed that miR-126-3p had a significant correlation with sinotubular junction Z-score (r = 0.42; p = 0.0154). CONCLUSION: The identified circulating miRNAs signature for TS patients with manifestations associated with cardiovascular diseases provide new insights into the molecular mechanism of TS that may guide the development of novel diagnostic approaches.

The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease.

Coronavirus disease 2019 (COVID-19), caused by a novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first described in a cluster of patients presenting with pneumonia symptoms in Wuhan, China, in December of 2019. Over the past few months, COVID-19 has developed into a worldwide pandemic, with over 400,000 documented cases globally as of March 24, 2020. The SARS-CoV-2 virus is most likely of zoonotic origin, but has been shown to have effective human-to-human transmission. COVID-19 results in mild symptoms in the majority of infected patients, but can cause severe lung injury, cardiac injury, and death. Given the novel nature of COVID-19, no established treatment beyond supportive care exists currently, but extensive public-health measures to reduce person-to-person transmission of COVID-19 have been implemented globally to curb the spread of disease, reduce the burden on healthcare systems, and protect vulnerable populations, including the elderly and those with underlying medical comorbidities. Since this is an emerging infectious disease, there is, as of yet, limited data on the effects of this infection on patients with cardiovascular disease, particularly so for those with congenital heart disease. We summarize herewith the early experience with COVID-19 and consider the potential applicability to and implications for patients with cardiovascular disease in general and congenital heart disease in particular.

Autopsy in adults with congenital heart disease (ACHD).

The adult congenital heart diseases (ACHD) population is exceeding the pediatric congenital heart diseases (CHD) population and is progressively expanding each year, representing more than 90% of patients with CHD. Of these, about 75% have undergone surgical and/or percutaneous intervention for palliation or correction. Autopsy can be a very challenging procedure in ACHD patients. The approach and protocol to be used may vary depending on whether the pathologists are facing native disease without surgical or percutaneous interventions, but with various degrees of cardiac remodeling, or previously palliated or corrected CHD. Moreover, interventions for the same condition have evolved over the last decades, as has perioperative myocardial preservations and postoperative care, with different long-term sequelae depending on the era in which patients were operated on. Careful clinicopathological correlation is, thus, required to assist the pathologist in performing the autopsy and reaching a diagnosis regarding the cause of death. Due to the heterogeneity of the structural abnormalities, and the wide variety of surgical and interventional procedures, there are no standard methods for dissecting the heart at autopsy. In this paper, we describe the most common types of CHDs that a pathologist could encounter at autopsy, including the various types of surgical and percutaneous procedures and major pathological manifestations. We also propose a practical systematic approach to the autopsy of ACHD patients.

[Roles of Cilia in Heart Development and Congenital Heart Disease].

Cilia are protruding cell structures on the cell surface and are found in almost every type of cell.According to the different structures and quantity of tubulins,cilia can be divided into two categories:motor cilia and sensory cilia.Sensory cilia are also called non-motor cilia and primary cilia,due to the composition and number of tubulins.They are closely related to the development of internal organs and many human physiological activities.Recent studies have demonstrated that cilia are involved in regulating the formation of left and right symmetry of the heart structure,and eventually the heart develops into the left-right asymmetry structures.Since congenital heart diseases(CHD)are characterized by abnormalities in the spatial structure of the heart chamber and outflow tract,cilia may play an important role in the pathogenesis of CHD.Cilia,mainly through ciliary transduction signal pathways,regulate both the formation of left and right asymmetrical structures and the polarity and the migration of cells.Therefore,a clear understanding of the regulation mechanism of ciliary signaling pathway on heart development can provide new therapeutic targets and new ideas for the clinical treatment of CHD and may offer new target genes for prenatal screening of CHD.This article summarizes recent advances in the role of cilia in heart development and CHD pathogenesis and its mechanisms.

Congenital left ventricular diverticulum: A rare cause of cardiac arrhythmia.

Congenital left ventricular diverticula are rare cardiac malformations that usually remain asymptomatic. However, life-threatening complications as ventricular arrhythmias, systemic embolism, spontaneous rupture and development of valvular regurgitation, are described. Diagnosis is based on excluding coronary artery disease, traumatic or inflammatory causes, and other underlying cardiomyopathies. Treatment is directed towards the potential complications, yielding mainly therapy of ventricular arrhythmia. Surgical resection is required for larger-sized congenital aneurysms with adverse hemodynamic effects. We present two cases of a left ventricular diverticulum causing cardiac arrhythmia which led to further surgical treatment.