Faculty Bibliography

Cardiolipin is a dimeric phospholipid with a characteristic acyl composition that is generated by fatty acid remodeling after de novo synthesis. Several enzymes have been proposed to participate in acyl remodeling of cardiolipin. In order to compare the effect of these enzymes, we determined the pattern of cardiolipin molecular species in Drosophila strains with specific enzyme deletions, using MALDI-TOF mass spectrometry with internal standards. We established the linear range of the method for cardiolipin quantification, determined the relative signal intensities of several cardiolipin standards, and demonstrated satisfying signal-to-noise ratios in cardiolipin spectra from a single fly. Our data demonstrate changes in the cardiolipin composition during the Drosophila life cycle. Comparison of cardiolipin spectra, using vector algebra, showed that inactivation of tafazzin had a large effect on the molecular composition of cardiolipin, inactivation of calcium-independent phospholipase A(2) had a small effect, whereas inactivation of acyl-CoA:lysocardiolipin-acyltransferase and of the trifunctional enzyme did not affect the cardiolipin composition.

In the absence of structural heart disease, the great majority of cases with complete congenital heart block will be associated with the maternal autoantibodies directed to components of the SSA/Ro-SSB/La ribonucleoprotein complex. Usually presenting in fetal life before 26 weeks' gestation, once third-degree (complete) heart block develops, it is irreversible. Therefore, investigators over the past several years have attempted to predict which fetuses will be at risk for advanced conduction abnormalities by identifying a biomarker for less severe or incomplete disease, in this case, PR interval prolongation or first-degree atrioventricular block. In this state-of-the-art review, we critically analyze the various approaches to defining PR interval prolongation in the fetus, and then analyze several clinical trials that have attempted to address the question of whether complete heart block can be predicted and/or prevented. We find that, first and foremost, definitions of first-degree atrioventricular block vary but that the techniques themselves are all similarly valid and reliable. Nevertheless, the task of predicting those fetuses at risk, and who are therefore candidates for treatment, remains challenging. Of concern, despite anecdotal evidence, there is currently no conclusive proof that a prolonged PR interval predicts complete heart block.

Overweight and obesity rates have risen dramatically in the United States, with subsequent detrimental comorbidity risks. The rates for obesity among children with congenital and acquired heart disease have rarely been reported. A retrospective cross-sectional study was conducted to determine the prevalence of overweight and obesity in children with heart disease and to identify subgroups at increased risk. A total of 795 cases were identified from a chart review of patients presenting to an urban center's Pediatric Cardiology Program between 1 January and 31 December 2006. A body mass index (BMI) at the 85th percentile or higher was defined as overweight, and a BMI at the 95th percentile or higher was defined as obese. Subjects with comorbidities affecting body habitus were excluded from the study. Overall, overweight and obesity rates were similar to national data. No significant differences in overweight or obesity rates were detected between heart disease and non-heart disease groups (P = 0.50). According to multivariate analysis, Hispanic ethnicity and male gender were the only predictors of obesity. This study shows that children with heart disease are not immune to the common predictors of obesity such as gender and ethnicity and that the future care of children with heart disease should include general discussions about the risks for obesity

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: : 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