Echocardiographic assessment of cardiovascular physiology of preterm miniature piglets supported with a pumped artificial placenta system.

OBJECTIVES: We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit. METHODS: Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data. RESULTS: AP fetuses (n = 13; 102±4d gestational age [term 115d]; 616 ± 139 g [g]; survival 46.4 ± 46.8 h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24 h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24 h. CONCLUSIONS: Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required.

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

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

A guide to prenatal counseling regarding neurodevelopment in congenital heart disease.

Advances in cardiac surgical techniques taking place over the past 50 years have resulted in the vast majority of children born with congenital cardiac malformations now surviving into adulthood. As the focus shifts from survival to the functional outcomes of our patients, it is increasingly being recognized that a significant proportion of patients undergoing infant cardiac repair experience adverse neurodevelopmental (ND) outcomes. The etiology of abnormal brain development in the setting of congenital heart disease is poorly understood, complex, and likely multifactorial. Furthermore, the efficacy of therapies available for the learning disabilities, attention deficit, and hyperactivity disorders and other ND deficits complicating congenital heart disease is currently uncertain. This situation presents a challenge for prenatal counseling as current antenatal testing does not usually provide prognostic information regarding the likely ND trajectories of individual patients. However, we believe it is important for parents to be informed about potential issues with child development when a new diagnosis of congenital heart disease is disclosed. Parents deserve a comprehensive and thoughtful approach to this subject, which conveys the uncertainties involved in predicting the severity of any developmental disorders encountered, while emphasizing the improvements in outcomes that have already been achieved in infants with congenital heart disease. A balanced approach to counseling should also discuss what local arrangements are in place for ND follow-up. This review presents an up-to-date overview of ND outcomes in patients with congenital heart disease, providing possible approaches to communicating this information to parents during prenatal counseling in a sensitive and accurate manner.

Impact of the Addition of a Centrifugal Pump in a Preterm Miniature Pig Model of the Artificial Placenta.

The recent demonstration of normal development of preterm sheep in an artificial extrauterine environment has renewed interest in artificial placenta (AP) systems as a potential treatment strategy for extremely preterm human infants. However, the feasibility of translating this technology to the human preterm infant remains unknown. Here we report the support of 13 preterm fetal pigs delivered at 102 ± 4 days (d) gestation, weighing 616 ± 139 g with a circuit consisting of an oxygenator and a centrifugal pump, comparing these results with our previously reported pumpless circuit (n = 12; 98 ± 4 days; 743 ± 350 g). The umbilical vessels were cannulated, and fetuses were supported for 46.4 ± 46.8 h using the pumped AP versus 11 ± 13 h on the pumpless AP circuit. Upon initiation of AP support on the pumped system, we observed supraphysiologic circuit flows, tachycardia, and hypertension, while animals maintained on a pumpless AP circuit exhibited subphysiologic flows. On the pumped AP circuit, there was a progressive decline in umbilical vein (UV) flow and oxygen delivery. We conclude that the addition of a centrifugal pump to the AP circuit improves survival of preterm pigs by augmenting UV flow through the reduction of right ventricular afterload. However, we continued to observe the development of heart failure within a matter of days.

Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that canonically affects the ocular, skeletal, and cardiovascular system, in which aortic tear and rupture is the leading cause of death for MFS patients. Genetically, MFS is primarily associated with fibrillin-1 (FBN1) pathogenic variants. However, the disease-causing variant in approximately 10% of patients cannot be identified, partly due to some cryptic mutations that may be missed using routine exonic sequencing, such as non-coding intronic variants that affects the RNA splicing process. We present a 32-year female with typical MFS systemic presentation that reached to a clinical diagnosis according to the revised Ghent nosology. We performed whole-exome sequencing (WES) but the report failed to identify known causal variants when analyzing the exonic sequence. However, further investigation on the exon/intron boundaries of the WES report revealed a candidate intronic variant of the fibrillin 1 (FBN1) gene (c.248-3 C>G) that predicted to affect the RNA splicing process. We conducted minigene splicing analyses and demonstrated that the c.248-3 C>G variant abolished the canonical splicing site of intron 3, leading to activation of two cryptic splicing sites and causing insertion (c.248-1_248-2insAG and c.248-1_248-282ins). Our study not only characterizes an intronic variant to the mutational spectrum of the FBN1 gene in MFS and its aberrant effect on splicing, but highlights the importance to not neglect the exon/intron boundaries when reporting and assessing WES results. We point out the need of conducting functional analysis to verify the pathogenicity of intronic mutation, and the opportunity to re-consider the standard diagnostic approaches in cases of clinically diagnosed MFS with normal or variant of unknown significance genetic results.

Impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in patients with Ebstein anomaly and tricuspid valve dysplasia.

OBJECTIVES: To evaluate the impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in severe Ebstein anomaly and tricuspid valve dysplasia. METHODS: Thirty-four fetuses with Ebstein anomaly/tricuspid valve dysplasia were referred from 2013 to 2019 for fetal echocardiography and clinical management. Nineteen fetuses with Ebstein anomaly/tricuspid valve dysplasia and 30 controls underwent cardiovascular magnetic resonance to quantify the fetal blood flow and to calculate cerebral oxygen delivery (cDO2) and consumption (cVO2). The 3D steady-state free precession acquisition was used to measure fetal brain volume. Surgical outcome, brain MRI, and neurodevelopmental follow-up were reviewed. RESULTS: Twenty-six fetuses were live born (76%) and survival (65%) at a mean follow-up of 4 years. Nine fetuses had a brain MRI before discharge, and all had clinically silent injuries and volume loss. At 18 months, five single-ventricle patients had a neurodevelopmental delay in cognition and language (mean percentile: 11th), with gross-motor skills more affected than fine-motor skills (mean percentiles: 4th and 34th). Fetuses with Ebstein anomaly/tricuspid valve dysplasia had smaller brains, lower combined ventricular output, ascending aorta, superior caval vien and umbilical vein flows, lower oxygen saturation in ascending aorta and superior caval vien, lower cDO2 and cVO2 (p < 0.05). Superior caval vien/combined ventricular output and descending aorta/combined ventricular output ratios were lower in fetuses with circular shunt (p < 0.05). Fetuses requiring the Starnes procedure tended to have smaller brains, lower combined ventricular output, superior caval vien, descending aorta, and umbilical vein flows. CONCLUSIONS: All patients with Ebstein anomaly/tricuspid valve dysplasia are at high risk of neurodevelopmental delay and warrant follow-up. Fetal cardiovascular magnetic resonance revealed impaired brain growth with diminished cerebral blood flow and cDO2, the extenting dependent on the severity of the haemodynamic compromise.

Fetal brain issues in congenital heart disease.

Following the improvements in the clinical management of patients with congenital heart disease (CHD) and their increased survival, neurodevelopmental outcome has become an emerging priority in pediatric cardiology. Large-scale efforts have been made to protect the brain during the postnatal, surgical, and postoperative period; however, the presence of brain immaturity and injury at birth suggests in utero and peripartum disturbances. Over the past decade, there has been considerable interest and investigations on fetal brain growth in the setting of CHD. Advancements in fetal brain imaging have identified abnormal brain development in fetuses with CHD from the macrostructural (brain volumes and cortical folding) down to the microstructural (biochemistry and water diffusivity) scale, with more severe forms of CHD showing worse disturbances and brain abnormalities starting as early as the first trimester. Anomalies in common genetic developmental pathways and diminished cerebral substrate delivery secondary to altered cardiovascular physiology are the forefront hypotheses, but other factors such as impaired placental function and maternal psychological stress have surfaced as important contributors to fetal brain immaturity in CHD. The characterization and timing of fetal brain disturbances and their associated mechanisms are important steps for determining preventative prenatal interventions, which may provide a stronger foundation for the developing brain during childhood.

Maternal hyperoxygenation in congenital heart disease.

The importance of prenatal diagnosis and fetal intervention has been increasing as a preventative strategy for improving the morbidity and mortality in congenital heart disease (CHD). The advancements in medical imaging technology have greatly enhanced our understanding of disease progression, assessment, and impact in those with CHD. In particular, there has been a growing focus on improving the morbidity and mortality of fetuses diagnosed with left-sided lesions. The disruption of fetal hemodynamics resulting from poor structural developmental of the left outflow tract during cardiogenesis is considered a major factor in the progressive lethal underdevelopment of the left ventricle (LV). This positive feedback cycle of inadequate flow and underdevelopment of the LV leads to a disrupted fetal circulation, which has been described to impact fetal brain growth where systemic outflow is poor and, in some cases, the fetal lungs in the setting of a restrictive interatrial communication. For the past decade, maternal hyperoxygenation (MH) has been investigated as a diagnostic tool to assess the pulmonary vasculature and a therapeutic agent to improve the development of the heart and brain in fetuses with CHD with a focus on left-sided cardiac defects. This review discusses the findings of these studies as well as the utility of acute and chronic administration of MH in CHD.