Faculty Bibliography

OBJECTIVE: : To estimate whether fetal echocardiography detects major cardiac anomalies after normal anatomy ultrasound scan in patients at increased risk for having a fetus with congenital heart disease. METHODS: : A computerized database was used to identify patients who underwent fetal echocardiography at the New York University Division of Pediatric Cardiology after anatomy ultrasound scan at the New York University Obstetrics and Gynecology Ultrasound Unit. Only patients with normal anatomy ultrasound scan results were included in the primary analysis. Patients were excluded if they had suspicious cardiac views on anatomy ultrasound scan or extracardiac anomalies. Major cardiac anomalies were defined as those judged by a blinded pediatric cardiologist as likely to require medical or surgical intervention in the first 6 months of life. RESULTS: : Of 1,034 patients in the pediatric cardiology database, 536 patients underwent anatomy ultrasound scan at the New York University Obstetrics and Gynecology Department. Eighty patients in the case group were excluded for suspicious or inadequate cardiac views and 139 were excluded for extracardiac ultrasound findings. Of the remaining 317 patients with normal obstetric ultrasound scan results, none had a major cardiac malformation diagnosed on fetal echocardiography. CONCLUSION: : In a tertiary care center with operators performing a high volume of ultrasound screenings, fetal echocardiography after normal anatomy ultrasound scan may be of limited benefit. LEVEL OF EVIDENCE: : III

Background: Children and adolescents who seek medical treatment for persistent physical distress often suffer from co-occurring anxiety disorders. Treatment options for this impaired population are limited. This study tests the feasibility and potential efficacy of a cognitive-behavioral intervention targeting pain and anxiety for youth with impairing functional physical symptoms and anxiety disorders presenting to pediatricians for medical care. Methods: Children and adolescents (aged 8-16) experiencing somatic complaints, without an explanatory medical disorder (i.e., functional), were recruited from primary care and specialty (gastroenterologists and cardiologists) pediatricians. Forty children, primarily with gastrointestinal symptoms, who met criteria for a co-occurring anxiety disorder, were randomly assigned to a cognitive-behavioral treatment addressing pain and anxiety, Treatment of Anxiety and Physical Symptoms (TAPS), or to a waiting list control. Results: TAPS was found to be an acceptable treatment for this population and was superior to the waiting list condition. Eighty percent of children in TAPS were rated as treatment responders by independent evaluators compared with none of the controls. Overall, self- and parent ratings indicated reductions in children's somatic discomfort and anxiety following intervention. TAPS participants maintained clinical gains 3 months following treatment. Conclusions: The study supports the feasibility and preliminary efficacy of a cognitive-behavioral intervention targeting co-occurring physical distress and anxiety in youth presenting for medical treatment. Such an approach has the potential to exert broad impact on children's dysfunction and to minimize exposure to invasive, ineffective, and costly medical procedures and treatments. Depression and Anxiety, 2011. (c) 2011 Wiley-Liss, Inc

Background: Pressure gradients (PC) across outflow tracts and ventricular septal defects (VSD) influence patient management. We sought to extend our previously-published experience in estimating PC in pulmonary stenosis (PS), aortic stenosis (AS), and VSD, and to define factors underlying accuracy of clinical examination (EXAM) in estimating PC, in a large patient cohort. Methods: From 1997-2009, we compared EXAM with Doppler-echo (ECHO), in 1193 patients with PS (N=563, including tetralogy of Fallot), AS (N=234), and VSD (N=396). EXAM PC estimates were based primarily on a murmur's pitch, grade, and length. To avoid bias, EXAM and ECHO were performed independently, and blinded to each other's results (ECHO by cardiac sonographer). Per standardof-care, ECHO peak instantaneous PC was derived from the modified Bernoulli equation. Results: Patients were 0-38.4 years old (median 4.8), weighing 0.83-129 kg (median 18.2). For all patients, EXAM correlated highly with ECHO: ECHO= 0.99(EXAM) + 3.2 mm Hg; r=+0.89; p<0.0001. Agreement was excellent (mean difference= -2.9+/-16.1 mm Hg [SD]). In 78% of all patients, agreement between EXAM and ECHO was within 15 mm Hg; in 67%, within 10 mm Hg; and in 45%, within 5 mm Hg. Clinical estimates of PS PC were more accurate than of AS and VSD (Table). A palpable precordial thrill predicted significantly higher gradients (all p<0.0001: PS: 32+/-22 mm Hg [no thrill] vs. 67+/-25 [+thrill]; AS: 31+/-20 vs. 59+/-29; VSD: 80+/-31 vs. 101+/-28). Increasing loudness of the murmur (standard 1-6 grade scale) also predicted higher gradients (r=+0.54, p<0.0001), with the largest gap occurring between grades 2 (mean PG: 36+/-29 mm Hg) and 3 (mean PG: 63+/-35 mm Hg). Weight did not influence accuracy. A learning curve was evident: overall agreement and correlation (r=+0.84) were worse in the original published cohort of 151 patients in 2001; the most recent quartile of patients showed ECHO=1.01(EXAM) + 1 9, r=+0.92, p<0.0001. Conclusions: EXAM can accurately estimate PC in most patients with PS, AS, or VSD. Contrary to the belief that technology erodes clinical skills, continual correlation of clinical findings with a technological gold standard such as ECHO can lead to highly accurate diagnostic skills, thereby enhancing clinical skills training and further substantiating the value of clinical examination. (Table presented)

Background: Barth syndrome (BTHS) is a rare multisystem disorder caused by mutations in tafazzin that lead to cardiolipin deficiency and mitochondrial abnormalities. Patients most commonly present with early-onset cardiomyopathy, including fetal cardiomyopathy. A newly-developed transgenic mouse induces tafazzin deficiency using a doxycycline-inducible shRNA knockdown (TAZKD). Methods: TAZKD mice and wildtype controls were fed doxycycline starting in early gestation, via the mother (gestation and pre-weanling stages) or directly. 40 MHz echocardiography (axial resolution: 40 microns) with spectral and color Doppler capabilities defined in vivo cardiac function throughout fetal, newborn, and adult ages. Functional data were correlated with cardiolipin mass spectrometry, histology, and electron microscopy. Results: Abnormal cardiolipin profiles in TAZKD mice at embryonic (E13.5) and newborn stages, confirmed high-efficiency tafazzin knockdown during development. Newborn, juvenile, and adult mice did not show an obvious cardiomyopathic phenotype through 6 months of age. However, far fewer TAZKD mice were born than the expected 50:50 Mendelian ratios (4/26 TAZKD liveborn; p<0.02). We then focused on embryonic/fetal imaging of cardiovascular function at E13.5 (N=7 wildtype, N=4 TAZKD). Notably, we found a spectrum, from entirely normal function, including systolic and diastolic function, heart rate, atrioventricular conduction and rhythm, and umbilical arterial and venous flows; to a grossly abnormal embryo predicted (then confirmed) to be TAZKD based on severe bradycardia, holodiastolic aortic flow reversal, and a systolic atrial kick that suggested elevated myocardial stiffness. Echo suggested LV noncompaction in another embryo later confirmed to be TAZKD. Histology showed qualitatively thinner TAZKD ventricular myocardium with more prominent trabeculae suggestive of LV noncompaction. Electron microscopy of TAZKD embryonic hearts, similar to echocardiography, demonstrated a spectrum from normal to severely abnormal mitochondrial structures. Notably, mitochondria from TAZKD embryonic hearts with grossly abnormal hemodynamics tended to have poorly-formed lamellar cristae and disruption of the sarcomeric organization. Conclusion: A spectrum of functional and cellular cardiomyopathic abnormalities associated with prenatal lethality is seen in this novel model of human BTHS. Experiments are ongoing to better link cellular pathophysiological processes with the whole-organ/systems hemodynamics defined by in vivo embryonic mouse echocardiography

OBJECTIVE: The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB. METHODS: A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with < or = 20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB. RESULTS: Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues. CONCLUSION: This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers

Neural crest-specific ablation of BMP type IA receptor (BMPRIA) causes embryonic lethality by embryonic day (E) 12.5, and this was previously postulated to arise from a myocardial defect related to signaling by a small population of cardiac neural crest cells (cNCC) in the epicardium. However, as BMP signaling via cNCC is also required for proper development of the outflow tract cushions, precursors to the semilunar valves, a plausible alternate or additional hypothesis is that heart failure may result from an outflow tract cushion defect. To investigate whether the outflow tract cushions may serve as dynamic valves in regulating hemodynamic function in the early embryo, in this study we used noninvasive ultrasound biomicroscopy-Doppler imaging to quantitatively assess hemodynamic function in mouse embryos with P0-Cre transgene mediated neural crest ablation of Bmpr1a (P0 mutants). Similar to previous studies, the neural crest-deleted Bmpr1a P0 mutants died at approximately E12.5, exhibiting persistent truncus arteriosus, thinned myocardium, and congestive heart failure. Surprisingly, our ultrasound analyses showed normal contractile indices, heart rate, and atrioventricular conduction in the P0 mutants. However, reversed diastolic arterial blood flow was detected as early as E11.5, with cardiovascular insufficiency and death rapidly ensuing by E12.5. Quantitative computed tomography showed thinning of the outflow cushions, and this was associated with a marked reduction in cell proliferation. These results suggest BMP signaling to cNCC is required for growth of the outflow tract cushions. This study provides definitive evidence that the outflow cushions perform a valve-like function critical for survival of the early mouse embryo.

An excellent imaging tool in the prenatal diagnosis and ongoing evaluation of congenital heart defects, fetal echocardiography is indicated in a selected population at increased risk compared with the general population. For certain 'soft markers' of fetal congenital heart defects, ambiguity in the indications for fetal echo may result in a high referral rate, but low yield of congenital heart disease. Here, we critically examine 4 conditions, 2 maternal and 2 fetal: maternal gestational diabetes, advanced maternal age, isolated echogenic focus, and single umbilical artery. This critical review reveals that more prospective population-based studies with higher power and minimal bias need to be performed to establish the absolute risk of congenital heart defects in a selected population compared with that of the general population. Nonetheless, our analysis indicates that the absolute risk of congenital heart defects associated with each of these markers is low. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to define which patients should be referred for fetal echocardiography based on known risks, distinguish between relative and absolute risks for fetal congenital heart disease, and summarize fetal anomaly risks for women with altered glucose metabolism