Hypoplastic Left Heart Syndrome: Is There a Role for Fetal Therapy?

During fetal life some cardiac defects may lead to diminished left heart growth and to the evolution of a form of hypoplastic left heart syndrome (HLHS). In fetuses with an established HLHS, severe restriction or premature closure of the atrial septum leads to left atrial hypertension and remodeling of the pulmonary vasculature, severely worsening an already poor prognosis. Fetal therapy, including invasive fetal cardiac interventions and non-invasive maternal hyperoxygenation, have been introduced to prevent a possible progression of left heart hypoplasia, improve postnatal outcome, or secure fetal survival. The aim of this review is to cover patient selection and possible hemodynamic effects of fetal cardiac procedures and maternal hyperoxygenation in fetuses with an evolving or established hypoplastic left heart syndrome.

Human embryonic cardiovascular function.

INTRODUCTION: This review presents an overview of descriptive knowledge on human embryonic cardiovascular physiology mostly based on noninvasive assessment by Doppler ultrasonography. Our objective was to identify and analyze published studies on embryonic cardiovascular function, and summarize available knowledge in this field. MATERIAL AND METHODS: Citations related to human embryonic cardiovascular function were searched in PubMed, EMBASE, CINAHL and Web of Science using keywords and MeSH terms without any time limitation. The search was restricted to English language articles. Abstracts were screened and full texts of relevant articles were obtained. All articles that reported on physiological aspects of human embryonic cardiovascular function were included. Studies reporting on cardiovascular function after 10 weeks of gestation were excluded. Data were synthesized and presented narratively. RESULTS: We identified 10 studies that had evaluated cardiovascular function and/or hemodynamics in human embryos at ≤10 weeks of gestation. All of these reported only certain aspects of embryonic cardiovascular function. Embryonic heart rate is associated significantly with gestational age and increases from 6 to 10 weeks of gestation. Cardiac inflow is monophasic during the embryonic period and atria appear to generate higher force during contraction compared with ventricles. Both ventricular inflow and outflow velocities increase with advancing gestation, whereas the Tei index decreases significantly. During the embryonic period, placental blood flow increases with gestation, but absent umbilical artery diastolic flow and umbilical venous pulsations are normal phenomena. CONCLUSION: There are important differences in normal cardiovascular function between the embryonic and fetal stages of human in utero development.

First-trimester screening for congenital heart disease.

UNLABELLED: Advances over the last decade in technology, training, and availability of prenatal care have led to a focus on the detection of congenital heart defects (CHD) and its prenatal management for improved pregnancy outcomes. First-trimester transvaginal heart screening is feasible and well tolerated. Due to advances in the diagnosis of trisomy by nonultrasound methods, a significant effort will now be focused on CHD detection in the first trimester of otherwise uncomplicated pregnancies. PURPOSE OF REVIEW: Detection of CHD is not being accomplished by heart screening training or postnatal protocols. First-trimester evaluation of fetuses is becoming more common, and a method of evaluation of the heart would improve selection of those who need later fetal echocardiography. RECENT FINDINGS: Equipment advances are resulting in excellent visualization of the fetal circulatory system even at 12­13 weeks, gestation. SUMMARY: Improved first-trimester fetal heart screening will result in a jump in CHD detection and in improved care of these patients during gestation and prior to their cardiac surgery.

Summary of the 2015 International Paediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute.

In the United States alone, ∼14,000 children are hospitalised annually with acute heart failure. The science and art of caring for these patients continues to evolve. The International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute was held on February 4 and 5, 2015. The 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute was funded through the Andrews/Daicoff Cardiovascular Program Endowment, a philanthropic collaboration between All Children's Hospital and the Morsani College of Medicine at the University of South Florida (USF). Sponsored by All Children's Hospital Andrews/Daicoff Cardiovascular Program, the International Pediatric Heart Failure Summit assembled leaders in clinical and scientific disciplines related to paediatric heart failure and created a multi-disciplinary "think-tank". The purpose of this manuscript is to summarise the lessons from the 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute, to describe the "state of the art" of the treatment of paediatric cardiac failure, and to discuss future directions for research in the domain of paediatric cardiac failure.

Diagnosis and treatment of foetal heart failure: foetal echocardiography and foetal hydrops.

Foetal echocardiography has progressed to be able to diagnose many forms of CHD and to assess the prognosis of cardiac lesions based on their anatomy and presentation in utero. This article outlines a straightforward method for the rapid evaluation of foetus that may have congestive heart failure with or without hydrops and for the differentiation of the pre-hydropic state from normal. The presence of signs of foetal heart failure, such as cardiomegaly or valvular regurgitation, gives clues to the aetiology of hydrops. The assessment of the prognosis of hydrops foetalis can be difficult but can be aided by the use of the cardiovascular profile score. Once identified, the neurohumoral effects of foetal heart failure can be ameliorated using transplacental digoxin if the hydrops has not progressed.

Variation in Prenatal Diagnosis of Congenital Heart Disease in Infants.

BACKGROUND AND OBJECTIVE: Prenatal diagnosis allows improved perioperative outcomes for fetuses with certain forms of congenital heart disease (CHD). Variability in prenatal diagnosis has been demonstrated in other countries, leading to efforts to improve fetal imaging protocols and access to care, but has not been examined across the United States. The objective was to evaluate national variation in prenatal detection across geographic region and defect type in neonates and infants with CHD undergoing heart surgery. METHODS: Cardiovascular operations performed in patients ≤6 months of age in the United States and included in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2006-2012) were eligible for inclusion. Centers with >15% missing prenatal diagnosis data were excluded from the study. Prenatal diagnosis rates were compared across geographic location of residence and defect type using the χ(2) test. RESULTS: Overall, the study included 31,374 patients from 91 Society of Thoracic Surgeons Congenital Heart Surgery Database participating centers across the United States. Prenatal detection occurred in 34% and increased every year, from 26% (2006) to 42% (2012). There was significant geographic variation in rates of prenatal diagnosis across states (range 11.8%-53.4%, P < .0001). Significant variability by defect type was also observed, with higher rates for lesions identifiable on 4-chamber view than for those requiring outflow tract visualization (57% vs 32%, P < .0001). CONCLUSIONS: Rates of prenatal CHD detection in the United States remain low for patients undergoing surgical intervention, with significant variability between states and across defect type. Additional studies are needed to identify reasons for this variation and the potential impact on patient outcomes.

When should we prescribe high-dose folic acid to prevent congenital heart defects?

PURPOSE OF REVIEW: Provide a rationale for attempting prevention of congenital heart defects (CHDs). RECENT FINDINGS: Prevention of neural-tube defects can be achieved with preconceptional use of folic acid. Extrapolating results from animal studies to human pregnancy shows that folate deficiency as well as one-time exposure to environmental factors in the first 2 to 3 weeks of human gestation can result in severe CHD. Considering that approximately 50% of pregnancies are unplanned, this period of pregnancy can be considered high risk for cardiac, as well as neural, birth defects, as the woman usually is not aware of her pregnancy and may not yet be taking precautionary actions to protect the developing embryo. In mammals, folate supplementation prevents CHD induced by alcohol, by lithium, or by elevation of the metabolite homocysteine. Optimal protection of cardiogenesis was observed to occur with folate supplementation provided on the morning after conception and at higher doses than currently available in prenatal vitamin supplementation. Clinical studies show a similar pattern with high doses of folic acid required to prevent CHD. SUMMARY: Today, all patients with a family history of CHD should discuss the prenatal use of folate supplementation with their obstetricians prior to becoming pregnant.

Dynamics of pulmonary venous flow in fetuses with intrauterine growth restriction.

OBJECTIVE: To test the hypothesis that the pulmonary vein pulsatility index (PVPI) is higher in fetuses with growth restriction (IUGR) than in normal fetuses. METHODS: Twenty-two fetuses with IUGR and twenty-one (21) fetuses with appropriate growth for gestational age from healthy mothers were studied. PVPI was calculated by Doppler echocardiography [maximal velocity (systolic or diastolic peak) - pre-systolic peak / mean velocity]. Obstetric ultrasound was used to assess fetal biometry and Doppler to assess the uterine, umbilical and middle cerebral arteries PI. Statistical analysis used t test and Pearson's correlation. RESULTS: Mean gestational age was 31.5 +/- 2.1 weeks in the control group and 31.4 +/- 3.1 weeks in IUGR (P = 0.91). The PI of uterine and umbilical arteries were higher in IUGR than in controls (P < 0.001). Mean PVPI in IUGR fetuses was 1.31 +/- 0.41, and in controls it was 0.83 +/- 0.11 (P < 0.001). CONCLUSION: The pulsatility index of pulmonary venous flow in fetuses with growth restriction is higher than in normal fetuses, probably as a result of left atrial dynamics alteration secondary or not to fetal left ventricular diastolic dysfunction. © 2014 John Wiley & Sons, Ltd.

Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American Heart Association.

BACKGROUND: The goal of this statement is to review available literature and to put forth a scientific statement on the current practice of fetal cardiac medicine, including the diagnosis and management of fetal cardiovascular disease. METHODS AND RESULTS: A writing group appointed by the American Heart Association reviewed the available literature pertaining to topics relevant to fetal cardiac medicine, including the diagnosis of congenital heart disease and arrhythmias, assessment of cardiac function and the cardiovascular system, and available treatment options. The American College of Cardiology/American Heart Association classification of recommendations and level of evidence for practice guidelines were applied to the current practice of fetal cardiac medicine. Recommendations relating to the specifics of fetal diagnosis, including the timing of referral for study, indications for referral, and experience suggested for performance and interpretation of studies, are presented. The components of a fetal echocardiogram are described in detail, including descriptions of the assessment of cardiac anatomy, cardiac function, and rhythm. Complementary modalities for fetal cardiac assessment are reviewed, including the use of advanced ultrasound techniques, fetal magnetic resonance imaging, and fetal magnetocardiography and electrocardiography for rhythm assessment. Models for parental counseling and a discussion of parental stress and depression assessments are reviewed. Available fetal therapies, including medical management for arrhythmias or heart failure and closed or open intervention for diseases affecting the cardiovascular system such as twin-twin transfusion syndrome, lung masses, and vascular tumors, are highlighted. Catheter-based intervention strategies to prevent the progression of disease in utero are also discussed. Recommendations for delivery planning strategies for fetuses with congenital heart disease including models based on classification of disease severity and delivery room treatment will be highlighted. Outcome assessment is reviewed to show the benefit of prenatal diagnosis and management as they affect outcome for babies with congenital heart disease. CONCLUSIONS: Fetal cardiac medicine has evolved considerably over the past 2 decades, predominantly in response to advances in imaging technology and innovations in therapies. The diagnosis of cardiac disease in the fetus is mostly made with ultrasound; however, new technologies, including 3- and 4-dimensional echocardiography, magnetic resonance imaging, and fetal electrocardiography and magnetocardiography, are available. Medical and interventional treatments for select diseases and strategies for delivery room care enable stabilization of high-risk fetuses and contribute to improved outcomes. This statement highlights what is currently known and recommended on the basis of evidence and experience in the rapidly advancing and highly specialized field of fetal cardiac care.

Evaluation of prenatal risk factors for prediction of outcome in right heart lesions: CVP score in fetal right heart defects.

OBJECTIVE: To determine the prenatal variables predicting the risk of perinatal death in congenital right heart defects. METHODS: Retrospective analysis of 28 fetuses with right heart defects was performed. Logistic regression analyses were performed to obtain odds ratios (OR) for the relationship between the risk of death and echocardiographic parameters. The parameters that correlated with the outcome were incorporated in an attempt to devise a disease-specific cardiovascular profile score. RESULTS: Fetal echocardiograms (143) from 28 patients were analyzed. The cardiovascular profile score predicted the risk of death. A lower right ventricle (RV) pressure was associated with mortality (OR 0.959; 95% confidence intervals (CI) 0.940-0.978). Higher peak aortic velocity through the aortic valve (OR 0.104; 95% CI 0.020-0.529) was associated with a better outcome. These cardiac function parameters were incorporated in a modified disease-specific CVP Score. Patients with a mean modified cardiovascular profile score of ≤ 6 were over 3.7 times more likely to die than those with scores of 7-10. CONCLUSIONS: The original Cardiovascular Profile Score predicted the risk of death in right heart defects. The modified score was not validated as a good prediction tool by this study. Fetal RV pressure estimate and peak aortic velocity can be used as independent prognostic predictors.

Impact of prenatal haemodynamic and functional abnormalities in Ebstein's anomaly on survival.

Predicting outcomes of foetuses with Ebstein's anomaly and tricuspid valve dysplasia continues to be challenging. Limited data exist on the prognostic significance of prenatal haemodynamic and functional parameters in this population. Our aim was to investigate the prognostic significance of haemodynamic and ventricular functional parameters in addition to associated morphometric parameters in patients with Ebstein's anomaly. We reviewed medical records of foetuses with Ebstein's anomaly and tricuspid valve dysplasia at All Children's Hospital Johns Hopkins Medicine and Johns Hopkins University between 2005 and 2012. The main outcome was survival past 30 days from birth; participants who died in utero or <30 days after birth were considered non-survivors. There were 13 survivors and seven non-survivors. We found that participants with abnormal right ventricular function predicted by low tricuspid regurgitation velocity (<2.3 m/second) (p=0.012) and low estimated right ventricular pressure (<24 mmHg) (p=0.029), a low (<7) cardiovascular profile score (p=0.029) and high (>0.53) cardiothoracic ratio (p=0.008) at the first foetal echocardiogram were less likely to survive. In addition, participants with a fossa ovalis/atrial septal length ratio <0.36 at the last foetal echocardiogram (p=0.051) were more likely to die, albeit of borderline statistical significance. Low tricuspid regurgitation velocity and low right ventricular estimated pressure, or a low cardiovascular profile score could be potential prognostic factors for Ebstein's anomaly and tricuspid valve dysplasia. However, future larger prospective studies are needed to confirm these initial findings.

Environmental origins of congenital heart disease: the heart-placenta connection.

Although the mammalian embryo is well protected in the uterus, environmental chemicals, drugs, and maternal nutritional imbalances can interfere with regulatory pathways directing placental and embryonic development early in gestation. Embryonic cells are most susceptible to environmental influences during cellular specification and differentiation stages. Because biochemical differentiation precedes morphological outcome often by days, the period of susceptibility to environmental chemicals expectedly precedes visible morphogenic effects. The cellular mechanisms by which drugs and other environmental factors disrupt embryonic development and induce cardiac abnormalities have remained undefined.

Effects of alcohol, lithium, and homocysteine on nonmuscle myosin-II in the mouse placenta and human trophoblasts.

OBJECTIVE: Mouse embryonic exposure to alcohol, lithium, and homocysteine results in intrauterine growth restriction (IUGR) and cardiac defects. Our present study focused on the placental effects. We analyzed the hypothesis that expression of nonmuscle myosin (NMM)-II isoforms involved in cell motility, mechanosensing, and extracellular matrix assembly are altered by the 3 factors in human trophoblast (HTR8/SVneo) cells in vitro and in the mouse placenta in vivo. STUDY DESIGN: After exposure during gastrulation to alcohol, homocysteine, or lithium, ultrasonography defined embryos exhibiting abnormal placental blood flow. RESULTS: NMM-IIA/NMM-IIB are differentially expressed in trophoblasts and in mouse placental vascular endothelial cells under pathological conditions. Misexpression of NMM-IIA/NMM-IIB in the affected placentas continued stably to midgestation but can be prevented by folate and myoinositol supplementation. CONCLUSION: It is concluded that folate and myoinositol initiated early in mouse pregnancy can restore NMM-II expression, permit normal placentation/embryogenesis, and prevent IUGR induced by alcohol, lithium, and homocysteine.

Foetal echocardiography of transposition of the great arteries and common arterial trunk.

Advances in foetal echocardiography allow detection of conotruncal anomalies such as transposition of the great arteries and common arterial trunk. Early detection of these anomalies is important for appropriate delivery planning, family counselling, and management. This manuscript will review the anatomic considerations, differential diagnosis, and foetal echocardiographic features of each of these malformations and review the importance of prenatal diagnosis and family counselling.

Effect of angiotensin II on the left ventricular function in a near-term fetal sheep with metabolic acidemia.

We tested the hypothesis that, in acute metabolic acidemia, the fetal left ventricle (LV) has the capacity to increase its contractility in response to angiotensin II infusion. Eleven ewes and their fetuses were instrumented at 127-138/145 days of gestation. The effect of angiotensin II on fetal LV function was assessed using intraventricular pressure catheter and tissue Doppler imaging (TDI). Angiotensin II increased fetal arterial blood pressure, whereas pH and pO(2) decreased. The heart rate and systemic venous pressure were not affected significantly. The LV end-diastolic and end-systolic pressures, as well as dP/dt(max), increased. The TDI-derived LV longitudinal myocardial isovolumic contraction velocity and its acceleration and velocity during early filling were higher than those at baseline. The incidence of absent isovolumic relaxation velocity was greater during angiotensin II infusion. In summary, during acute metabolic acidemia, the fetal left ventricle could increase its contractility in response to inotropic stimulus even in the presence of increased afterload. The diastolic LV function parameters were altered by angiotensin II.

Myocardial tissue Doppler velocities in fetuses with hypoplastic left heart syndrome.

BACKGROUND: Tissue Doppler Imaging (TDI) is a sensitive index of myocardial function. Its role in the fetus has not been extensively evaluated. OBJECTIVE: To compare myocardial tissue Doppler velocities in fetuses with hypoplastic left heart syndrome (HLHS) to those of normal fetuses (matched for gestational age.) METHODS: Cross-sectional retrospective study conducted at 2 large perinatal centers (2003-2007). Fetuses with HLHS (n = 13) were compared with normal fetuses (n = 207) in 5 gestational age groups. TDI data included peak systolic (s'), peak early (e'), and late diastolic velocities (a'). Linear regression was used to compare TDI parameters in fetuses with HLHS to normal fetuses matched for gestational age. RESULTS: Fetuses with HLHS had significantly reduced lateral tricuspid annular e' as compared to normal fetuses. Both normal fetuses and those with HLHS had linear increase in TDI velocities with advancing gestational age. CONCLUSIONS: TDI velocities are abnormal in fetuses with HLHS. TDI can be useful in serial follow-up of cardiac function in fetuses with HLHS.

The natural history of congenitally corrected transposition of the great arteries.

The natural history of congenitally corrected transposition of the great arteries is of clinical/surgical importance once the fetus is born without heart block or signs of heart failure. Without significant tricuspid valve malformation, associated defects such as ventricular septal defect and left ventricular outflow obstruction can be repaired surgically. The mortality and long-term outcome appear to be linked strongly with the severity of tricuspid valve regurgitation. Some patients with an intact ventricular septum and no right ventricular dysfunction will live long lives without detection, and some women will successfully complete pregnancy.

Doppler in fetal heart failure.

Fetal echocardiography has progressed to be able to diagnose many forms of congenital heart disease (CHD) and to assess the prognosis of cardiac lesions based on their anatomy and presentation in utero. Fetal echocardiography is for pregnancies at risk of structural, functional, and rhythm-related fetal heart disease. Routine obstetrical ultrasound screening is critical in the prenatal detection of fetal heart disease/CHD. With or without CHD, fetal heart dysfunction defined as inadequate tissue perfusion may occur. Perinatal problems other than CHD can also be assessed, such as the effects of noncardiac malformations that affect hemodynamics, that is, twin-twin transfusion. Cardiac rhythm can affect cardiac function and outcome, and prenatal diagnosis can be lifesaving. A tool for the assessment of cardiac function is the Cardiovascular Profile Score that combines ultrasonic markers of fetal cardiovascular unwellness based on univariate parameters, which have been correlated with perinatal mortality. This "heart failure score" could potentially be used in much the same way as and in combination with the biophysical profile score. This study will present a summary of fetal Doppler and its place in the diagnosis and assessment of prognosis of fetal heart failure.

Folate protection from congenital heart defects linked with canonical Wnt signaling and epigenetics.

PURPOSE OF REVIEW: Environmental factors, such as drugs, chemicals, or abnormal concentrations of natural metabolites, induce birth defects. Environmental effects on cardiogenesis have been little studied in contrast to neurogenesis. This review presents evidence on three environmental factors: alcohol, the drug lithium, and the metabolite homocysteine, impacting the Wnt/ß-catenin pathway during cardiac development and folate protection. RECENT FINDINGS: Animal and epidemiological studies have shown that folate protects the embryo from birth defects. New animal studies demonstrate that folate prevents cardiovascular defects induced by the drug lithium, homocysteine, or alcohol, but protection occurs at a higher concentration than currently used in vitamin supplements. The data indicate that folate in combination with myo-inositol may further reduce the risk of birth defects. Discussion is presented of the cell specification stages that are impacted resulting in cardiac defects, how Wnt/ß-catenin signaling is involved, and how folate and myo-inositol additively may protect embryonic pathways. The possible epigenetic role of folate in Wnt/ß-catenin signaling is described. SUMMARY: This review will enable better counseling of women by defining, during early pregnancy, a susceptible window of embryonic exposure leading to a high risk of cardiac defects, and provides a therapeutic means and the necessary timing for prevention of environmentally induced birth defects.