Prospective Evaluation of High Titer Autoantibodies and Fetal Home Monitoring in the Detection of Atrioventricular Block Among Anti-SSA/Ro Pregnancies.

OBJECTIVE: This prospective study of pregnant patients, Surveillance To Prevent AV Block Likely to Occur Quickly (STOP BLOQ), addresses the impact of anti-SSA/Ro titers and utility of ambulatory monitoring in the detection of fetal second-degree atrioventricular block (AVB). METHODS: Women with anti-SSA/Ro autoantibodies by commercial testing were stratified into high and low anti-52-kD and/or 60-kD SSA/Ro titers applying at-risk thresholds defined by previous evaluation of AVB pregnancies. The high-titer group performed fetal heart rate and rhythm monitoring (FHRM) thrice daily and weekly/biweekly echocardiography from 17-26 weeks. Abnormal FHRM prompted urgent echocardiography to identify AVB. RESULTS: Anti-52-kD and/or 60-kD SSA/Ro met thresholds for monitoring in 261 of 413 participants (63%); for those, AVB frequency was 3.8%. No cases occurred with low titers. The incidence of AVB increased with higher levels, reaching 7.7% for those in the top quartile for anti-60-kD SSA/Ro, which increased to 27.3% in those with a previous child who had AVB. Based on levels from 15 participants with paired samples from both an AVB and a non-AVB pregnancy, healthy pregnancies were not explained by decreased titers. FHRM was considered abnormal in 45 of 30,920 recordings, 10 confirmed AVB by urgent echocardiogram, 7 being second-degree AVB, all <12 hours from normal FHRM and within another 0.75 to 4 hours to echocardiogram. The one participant with second/third-degree and two participants with third-degree AVB were diagnosed by urgent echocardiogram >17 to 72 hours from an FHRM. Surveillance echocardiograms detected no AVB when the preceding interval FHRM recordings were normal. CONCLUSION: High-titer antibodies are associated with an increased incidence of AVB. Anti-SSA/Ro titers remain stable over time and do not explain the discordant recurrence rates, suggesting that other factors are required. Fetal heart rate and rhythm (FHRM) with results confirmed by a pediatric cardiologist reliably detects conduction abnormalities, which may reduce the need for serial echocardiograms.

Relating cardiorespiratory responses to work rate during incremental ramp exercise on treadmill in children and adolescents: sex and age differences.

PURPOSE: Evaluation of cardiopulmonary exercise testing (CPET) slopes such as [Formula: see text] (cardiac/skeletal muscle function) and [Formula: see text] (O2 delivery/utilization), using treadmill protocols is limited because the difficulties in measuring the total work rate ([Formula: see text]). To overcome this limitation, we proposed a new method in quantifying [Formula: see text] to determine CPET slopes. METHODS: CPET's were performed by healthy patients, (n = 674, 9-18 year) 300 female (F) and 374 male (M), using an incremental ramp protocol on a treadmill. For this protocol, a quantitative relationship based on biomechanical principles of human locomotion, was used to quantify the [Formula: see text] of the subject. CPET slopes were determined by linear regression of the data recorded until the gas exchange threshold occurred. RESULTS: The method to estimate [Formula: see text] was substantiated by verifying that: [Formula: see text] for treadmill exercise corresponded to an efficiency of muscular work similar to that of cycle ergometer; [Formula: see text] (mL min-1 W-1) was invariant with age and greater in M than F older than 12 years old (13-14 years: 9.6 ± 1.5(F) vs. 10.5 ± 1.8(M); 15-16 years: 9.7 ± 1.7(F) vs. 10.6 ± 2.2(M); 17-18 years: 9.6 ± 1.7(F) vs. 11.0 ± 2.3(M), p < 0.05); similar to cycle ergometer exercise, [Formula: see text] was inversely related to body weight (BW) (r = 0.71) or [Formula: see text] (r = 0.66) and [Formula: see text] was not related to BW (r = - 0.01), but had a weak relationship with [Formula: see text] (r = 0.28). CONCLUSION: The proposed approach can be used to estimate [Formula: see text] and quantify CPET slopes derived from incremental ramp protocols at submaximal exercise intensities using the treadmill, like the cycle ergometer, to infer cardiovascular and metabolic function in both healthy and diseased states.

The Association of Fetal Congenital Cardiac Defects and Placental Vascular Malperfusion.

OBJECTIVES: Abnormal early angiogenesis appears to impact both placental disorders and fetal congenital heart defects (CHD). We sought to assess the association of placental perfusion defects (PPD) and fetal (CHD). METHODS: Singleton pregnancies with isolated severe fetal CHD were compared to controls without congenital anomalies or maternal malperfusion (MVM) risk factors. CHD was categorized into group 1: single left ventricle morphology and transposition of the great vessels (TGA) and group 2: single right ventricle and two ventricle morphology. Malperfusion was defined as fetal vascular malperfusion (FVM), MVM, and both FVM and MVM. RESULTS: PPD was increased for all CHD (n = 47), CHD with or without risk factors, and CHD groups compared to controls (n = 92). Overall CHD cases and CHD with risk factors had an increased risk of FVM (30% and 80% vs 14%), and MVM (43% and 50% vs 21%), respectively. MVM rates were similar in CHD with and without maternal risk factors. FVM (38% vs 14%) and MVM (44% vs 21%) were increased in Group 1. MVM (42% vs 21%) and both FVM and MVM (16% vs 3%) were increased in Group 2. CONCLUSIONS: PPD risk is increased in severe isolated fetal CHD. The highest risk is seen in fetal CHD with maternal risk factors.

Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is caused by prenatal alcohol exposure (PAE), the intake of ethanol (C2 H5 OH) during pregnancy. Features of FASD cover a range of structural and functional defects including congenital heart defects (CHDs). Folic acid and choline, contributors of methyl groups to one-carbon metabolism (OCM), prevent CHDs in humans. Using our avian model of FASD, we have previously reported that betaine, another methyl donor downstream of choline, prevents CHDs. The CHD preventions are substantial but incomplete. Ethanol causes oxidative stress as well as depleting methyl groups for OCM to support DNA methylation and other epigenetic alterations. To identify more compounds that can safely and effectively prevent CHDs and other effects of PAE, we tested glutathione (GSH), a compound that regulates OCM and is known as a "master antioxidant." METHODS/RESULTS: Quail embryos injected with a single dose of ethanol at gastrulation exhibited congenital defects including CHDs similar to those identified in FASD individuals. GSH injected simultaneously with ethanol not only prevented CHDs, but also improved survival and prevented other PAE-induced defects. Assays of hearts at 8 days (HH stage 34) of quail development, when the heart normally has developed 4-chambers, showed that this single dose of PAE reduced global DNA methylation. GSH supplementation concurrent with PAE normalized global DNA methylation levels. The same assays performed on quail hearts at 3 days (HH stage 19-20) of development, showed no difference in global DNA methylation between controls, ethanol-treated, GSH alone, and GSH plus ethanol-treated cohorts. CONCLUSIONS: GSH supplementation shows promise to inhibit effects of PAE by improving survival, reducing the incidence of morphological defects including CHDs, and preventing global hypomethylation of DNA in heart tissues.

Development of Tissue Engineered Heart Valves for Percutaneous Transcatheter Delivery in a Fetal Ovine Model.

This multidisciplinary work shows the feasibility of replacing the fetal pulmonary valve with a percutaneous, transcatheter, fully biodegradable tissue-engineered heart valve (TEHV), which was studied in vitro through accelerated degradation, mechanical, and hemodynamic testing and in vivo by implantation into a fetal lamb. The TEHV exhibited only trivial stenosis and regurgitation in vitro and no stenosis in vivo by echocardiogram. Following implantation, the fetus matured and was delivered at term. Replacing a stenotic fetal valve with a functional TEHV has the potential to interrupt the development of single-ventricle heart disease by restoring proper flow through the heart.

Congenitally corrected transposition and mitral atresia complicated by restrictive atrial septum.

Congenitally corrected transposition (ccTGA), also known as L-transposition of the great arteries (L-TGA), is a rare cardiac malformation accounting for approximately 0.05% of congenital heart disease, characterized by ventricular inversion, discordant ventriculo-arterial connections with a normal visceroatrial relationship. It was first described by Baron Rokitansky in 1875, and prenatal sonographic diagnosis can be difficult. Symptomatology and clinical presentation of this malformation are related to the associated intracardiac defects. We report a rare case of severe, complex cardiac disease: prenatally diagnosed ccTGA with atrial restriction, mitral atresia, Ebsteinoid tricuspid valve, and severe pulmonary valve stenosis, who subsequently developed left pulmonary vein stenosis.

Fetal Cardiac Intervention for Pulmonary Atresia with Intact Ventricular Septum: International Fetal Cardiac Intervention Registry.

INTRODUCTION: Invasive fetal cardiac intervention (FCI) for pulmonary atresia with intact ventricular septum (PAIVS) and critical pulmonary stenosis (PS) has been performed with small single-institution series reporting technical and physiological success. We present the first multicenter experience. OBJECTIVES: Describe fetal and maternal characteristics of those being evaluated for FCI, including pregnancy/neonatal outcome data using the International Fetal Cardiac Intervention Registry (IFCIR). METHODS: We queried the IFCIR for PAIVS/PS cases evaluated from January 2001 to April 2018 and reviewed maternal/fetal characteristics, procedural details, pregnancy and neonatal outcomes. Data were analyzed using standard descriptive statistics. RESULTS: Of the 84 maternal/fetal dyads in the registry, 58 underwent pulmonary valvuloplasty at a median gestational age of 26.1 (21.9-31.0) weeks. Characteristics of fetuses undergoing FCI varied in terms of tricuspid valve (TV) size, TV regurgitation, and pulmonary valve patency. There were fetal complications in 55% of cases, including 7 deaths and 2 delayed fetal losses. Among those who underwent successful FCI, the absolute measurement of the TV increased by 0.32 (±0.17) mm/week from intervention to birth. Among 60 liveborn with known outcome, there was a higher percentage having a biventricular circulation following successful FCI (87 vs. 43%). CONCLUSIONS: Our data suggest a possible benefit to fetal therapy for PAIVS/PS, though rates of technically unsuccessful procedures and procedure-related complications, including fetal loss were substantial. FCI criteria are extremely variable, making direct comparison to nonintervention patients challenging and potentially biased. More uniform FCI criteria for fetuses with PAIVS/PS are needed to avoid unnecessary procedures, expose only fetuses most likely to sustain a benefit, and to enable comparisons to be made with nonintervention patients.

Fetal cardiac intervention for right sided heart disease: Pulmonary atresia with intact ventricular septum.

Congenital heart disease (CHD), the most common of birth defects, can be serious enough to require a lifetime of medical care including multiple surgeries or other interventions. Advances in ultrasound technology and a better understanding of the progression of CHDs have made it possible to intervene in utero. This early stage intervention allows the still plastic cardiovascular system to return to a more normal trajectory thus sparing the newborn from negative consequences to morbidity and mortality. Fetal cardiac intervention (FCI) has been successful for the alleviation of left ventricular dysfunction resulting in remarkably positive outcomes for many families. Promising results support that FCI may also be useful in alleviating right ventricular dysfunction. This bodes well for expanding the use of FCI to lead to better postnatal adaptation and improved long-term function for more children with CHD.

Supplementation with the Methyl Donor Betaine Prevents Congenital Defects Induced by Prenatal Alcohol Exposure.

BACKGROUND: Despite decades of public education about dire consequences of prenatal alcohol exposure (PAE), drinking alcohol during pregnancy remains prevalent. As high as 40% of live-born infants exposed to alcohol during gestation and diagnosed with fetal alcohol syndrome have congenital heart defects that can be life-threatening. In animal models, the methyl donor betaine, found in foods such as wheat bran, quinoa, beets, and spinach, ameliorated neurobehavioral deficits associated with PAE, but effects on heart development are unknown. METHODS: Previously, we modeled a binge drinking episode during the first trimester in avian embryos. Here, we investigated whether betaine could prevent adverse effects of alcohol on heart development. Embryos exposed to ethanol (EtOH) with and without an optimal dose of betaine (5 µM) were analyzed at late developmental stages. Cardiac morphology parameters were rapidly analyzed and quantified using optical coherence tomography. DNA methylation at early stages was detected by immunofluorescent staining for 5-methylcytosine in sections of embryos treated with EtOH or cotreated with betaine. RESULTS: Compared to EtOH-exposed embryos, betaine-supplemented embryos had higher late-stage survival rates and fewer gross head and body defects than seen after alcohol exposure alone. Betaine also reduced the incidence of late-stage cardiac defects such as absent vessels, abnormal atrioventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine cotreatment brought measurements of great vessel diameters, interventricular septum thickness, and AV leaflet volumes in betaine-supplemented embryos close to control values. Early-stage 5-methycytosine staining revealed that DNA methylation levels were reduced by EtOH exposure and normalized by co-administration with betaine. CONCLUSIONS: This is the first study demonstrating efficacy of the methyl donor betaine in alleviating cardiac defects associated with PAE. These findings highlight the therapeutic potential of low-concentration betaine doses in mitigating PAE-induced birth defects and have implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation.

Increased regurgitant flow causes endocardial cushion defects in an avian embryonic model of congenital heart disease.

BACKGROUND: The relationship between changes in endocardial cushion and resultant congenital heart diseases (CHD) has yet to be established. It has been shown that increased regurgitant flow early in embryonic heart development leads to endocardial cushion defects, but it remains unclear how abnormal endocardial cushions during the looping stages might affect the fully septated heart. The goal of this study was to reproducibly alter blood flow in vivo and then quantify the resultant effects on morphology of endocardial cushions in the looping heart and on CHDs in the septated heart. METHODS: Optical pacing was applied to create regurgitant flow in embryonic hearts, and optical coherence tomography (OCT) was utilized to quantify regurgitation and morphology. Embryonic quail hearts were optically paced at 3 Hz (180 bpm, well above intrinsic rate 60-110 bpm) at stage 13 of development (3-4 weeks human) for 5 min. Pacing fatigued the heart and led to at least 1 h of increased regurgitant flow. Resultant morphological changes were quantified with OCT imaging at stage 19 (cardiac looping-4-5 weeks human) or stage 35 (4 chambered heart-8 weeks human). RESULTS: All paced embryos imaged at stage 19 displayed structural changes in cardiac cushions. The amount of regurgitant flow immediately after pacing was inversely correlated with cardiac cushion size 24-h post pacing (P value < .01). The embryos with the most regurgitant flow and smallest cushions after pacing had a decreased survival rate at 8 days (P < .05), indicating that those most severe endocardial cushion defects were lethal. Of the embryos that survived to stage 35, 17/18 exhibited CHDs including valve defects, ventricular septal defects, hypoplastic ventricles, and common AV canal. CONCLUSION: The data illustrate a strong inverse relationship in which regurgitant flow precedes abnormal and smaller cardiac cushions, resulting in the development of CHDs.

Venous Myocardial Infarction in an Infant with Obstructed Totally Anomalous Pulmonary Venous Drainage and Coronary Sinus Ostial Atresia.

We report a rare causal association between obstructed supracardiac totally anomalous pulmonary venous drainage and coronary sinus ostial atresia. Our 12-week-old patient developed venous myocardial infarction secondary to coronary venous hypertension because her sole route of coronary venous drainage was obstructed. She recovered after the obstruction was relieved by balloon dilation. Surgical repair then included anastomosis of the pulmonary venous confluence to the left atrium, ligation of the vertical vein, and unroofing of the coronary sinus. Coronary sinus ostial atresia is rarely diagnosed before autopsy.

Gender differences in V˙O2 and HR kinetics at the onset of moderate and heavy exercise intensity in adolescents.

The majority of the studies on V˙O2 kinetics in pediatric populations investigated gender differences in prepubertal children during submaximal intensity exercise, but studies are lacking in adolescents. The purpose of this study was to test the hypothesis that gender differences exist in the V˙O2 and heart rate (HR) kinetic responses to moderate (M) and heavy (H) intensity exercise in adolescents. Twenty-one healthy African-American adolescents (9 males, 15.8 ± 1.1 year; 12 females, 15.7 ± 1 year) performed constant work load exercise on a cycle ergometer at M and H. The V˙O2 kinetics of the male group was previously analyzed (Lai et al., Appl. Physiol. Nutr. Metab. 33:107-117, 2008b). For both genders, V˙O2 and HR kinetics were described with a single exponential at M and a double exponential at H. The fundamental time constant (τ1) of V˙O2 was significantly higher in female than male at M (45 ± 7 vs. 36 ± 11 sec, P < 0.01) and H (41 ± 8 vs. 29 ± 9 sec, P < 0.01), respectively. The functional gain (G1) was not statistically different between gender at M and statistically higher in females than males at H: 9.7 ± 1.2 versus 10.9 ± 1.3 mL min-1 W-1, respectively. The amplitude of the slow component was not significantly different between genders. The HR kinetics were significantly (τ1, P < 0.01) slower in females than males at M (61 ± 16 sec vs. 45 ± 20 sec, P < 0.01) and H (42 ± 10 sec vs. 30 ± 8 sec, P = 0.03). The G1 of HR was higher in females than males at M: 0.53 ± 0.11 versus 0.98 ± 0.2 bpm W-1 and H: 0.40 ± 0.11 versus 0.73 ± 0.23 bpm W-1, respectively. Gender differences in the V˙O2 and HR kinetics suggest that oxygen delivery and utilization kinetics of female adolescents differ from those in male adolescents.

Isolated Left Subclavian Artery, Complete Atrioventricular Block, and Tricuspid Atresia in a Neonate.

Isolated left subclavian artery is one of the rarer aortic arch anomalies. It has been associated with other congenital heart diseases, typically tetralogy of Fallot, double-outlet right ventricle, and atrial and ventricular septal defects. Its significant clinical implications include a left-to-right shunt from the vertebrobasilar system, which causes pulmonary overcirculation and subclavian steal. We present an unusual case of a premature infant who was diagnosed prenatally with congenital complete atrioventricular block and tricuspid atresia and was found to have an isolated left subclavian artery postnatally. The patient underwent implantation of a permanent single-chamber epicardial pacing system. To our knowledge, this combination of lesions has not been reported-and in our case, it influenced our surgical planning.

Clinical and Financial Impact of Ordering an Echocardiogram in Children with Left Axis Deviation on Their Electrocardiogram.

OBJECTIVE: Left axis deviation (LAD) on the electrocardiogram (ECG) is associated with congenital heart disease (CHD), prompting the clinician to order further testing when evaluating a patient with this finding. The purpose is to (1) compare the physical examination (PE) by a pediatric cardiologist to echocardiogram (ECHO) findings in patients with LAD on resting ECG and (2) assess cost of performing ECHO on all patients with LAD on ECG. DESIGN: An IRB approved, retrospective cohort study was performed on patients with LAD (QRS axis ≥0° to -90°) on ECG between 01/02 and 12/12. INCLUSION CRITERIA: age >0.25 and <18 years, non-postoperative, and PE and ECHO by pediatric cardiologist. A decision tree model analyzed cost of ECHO in patients with LAD and normal/abnormal PE. Cost of complete ECHO ($239.00) was obtained from 2014 Medicare reimbursement rates. RESULTS: A total of 146 patients met inclusion criteria with 46.5% (68) having normal PE and ECHO, 1.4% (2) having normal PE and abnormal ECHO, 47.3% (69) having abnormal PE and ECHO, and 4.8% (7) having an abnormal PE and normal ECHO. Sensitivity and specificity of PE for detecting abnormalities in this population was 97% and 90%. Positive and negative predictive value of PE was 91% and 97.5%. In patients with normal PE, the cost to identify an ECHO abnormality was $8365, and $263 for those with abnormal PE. CONCLUSION: In presence of LAD on ECG, the sensitivity, specificity, and positive and negative predictive values of PE by a pediatric cardiologist are excellent at identifying CHD. Performing an ECHO on patients with LAD on ECG is only cost effective in the presence of an abnormal PE. In the presence of normal PE, there is a possibility of missing incidental structural cardiac disease in approximately 2% if an ECHO is not performed.

Bilateral absence of superior vena cava.

The absence of a right superior vena cava (SVC) in situs solitus is very rare, and even then it is usually associated with left SVC. There have been few case reports in the literature of isolated bilateral absence of SVC. Bilateral absent SVC can have clinical implication, including pacemaker placements, central venous line placement, monitoring, and occasionally associated anomalies. We describe a case detected on fetal echocardiogram with bilateral absent SVC and structurally normal heart.

Fetal diagnosis of superior vena cava aneurysm.

Superior vena cava aneurysm is a rare intrathoracic vascular lesion with only 27 cases reported in the literature. The majority are fusiform and can be associated with cystic hygroma due to the close embryonic relationship between lymphatic vessels and systemic veins. This is the first report of superior vena cava aneurysm diagnosed with fetal echocardiography in a fetus with a cystic hygroma. There is a need of a prospective registry to further delineate all aspects of this condition and establish the most appropriate therapeutic approach.

Pentalogy of Cantrell with double-outlet right ventricle: a case of surgical correction.

Pentalogy of Cantrell is characterised by a combination of severe defects in the middle of the chest including the sternum, diaphragm, heart, and abdominal wall. Mortality rate after cardiac surgery is usually high. We report a successful total correction of the cardiac defects in a case of Pentalogy of Cantrell with a double-outlet right ventricle prior to abdominal wall defect repair.