Faculty Bibliography

To assess the contribution of individual TGF-β isoforms to aortopathy in Marfan syndrome (MFS), we quantified the survival and phenotypes of mice with a combined fibrillin1 (the gene defective in MFS) hypomorphic mutation and a TGF-β1, 2, or 3 heterozygous null mutation. The loss of TGF-β2, and only TGF-β2, resulted in 80% of the double mutant animals dying earlier, by post-natal day 20, than MFS only mice. Death was not from thoracic aortic rupture, as observed in MFS mice, but was associated with hyperplastic aortic valve leaflets, aortic regurgitation, enlarged aortic root, increased heart weight, and impaired lung alveolar septation. Thus, there appears to be a relationship between loss of fibrillin1 and TGF-β2 in the post-natal development of the heart, aorta and lungs.

BACKGROUND:Although the heart requires abundant energy, only 20-40% of children with mitochondrial diseases have cardiomyopathies. METHODS:We looked for differences in genes underlying mitochondrial diseases that do versus do not cause cardiomyopathy using the comprehensive Mitochondrial Disease Genes Compendium. Mining additional online resources, we further investigated possible energy deficits caused by non-oxidative phosphorylation (OXPHOS) genes associated with cardiomyopathy, probed the number of amino acids and protein interactors as surrogates for OXPHOS protein cardiac "importance", and identified mouse models for mitochondrial genes. RESULTS:< 0.05). Mouse models exhibiting cardiomyopathy were found for 52/241 mitochondrial genes, shedding additional insights into biological mechanisms. CONCLUSIONS:While energy generation is strongly associated with cardiomyopathy in mitochondrial diseases, many energy generation defects are not linked to cardiomyopathy. The inconsistent link between mitochondrial disease and cardiomyopathy is likely to be multifactorial and includes tissue-specific expression, incomplete clinical data, and genetic background differences.

Introduction Coronavirus disease 2019 (COVID-19) is known to cause cardiac abnormalities in adults. Cardiac abnormalities are well-described in multisystem inflammatory syndrome in children, but effects in children with acute COVID-19 are less understood. In this multicenter study, we assessed the cardiac effects of acute COVID-19 among hospitalized children (<21 years) admitted to three large healthcare systems in New York City. Methods We performed a retrospective observational study. We examined electrocardiograms, echocardiograms, troponin, or B-type natriuretic peptides. Results Of 317 admitted patients, 131 (41%) underwent cardiac testing with 56 (43%) demonstrating cardiac abnormalities. Electrocardiogram abnormalities were the most common (46/117 patients (39%)), including repolarization abnormalities and QT prolongation. Elevated troponin occurred in 14/77 (18%) patients and B-type natriuretic peptide in 8/39 (21%) patients. Ventricular dysfunction was identified in 5/27 (19%) patients with an echocardiogram, all of whom had elevated troponin. Ventricular dysfunction resolved by first outpatient follow-up. Conclusion Electrocardiogram and troponin can assist clinicians in identifying children at risk for cardiac injury in acute COVID-19.

Cardiolipins are phospholipids that are central to proper mitochondrial functioning. Because mitochondria play crucial roles in differentiation, development, and maturation, we would also expect cardiolipin to play major roles in these processes. Indeed, cardiolipin has been implicated in the mechanism of three human diseases that affect young infants, implying developmental abnormalities. In this review, we will: (1) Review the biology of cardiolipin; (2) Outline the evidence for essential roles of cardiolipin during organismal development, including embryogenesis and cell maturation in vertebrate organisms; (3) Place the role(s) of cardiolipin during embryogenesis within the larger context of the roles of mitochondria in development; and (4) Suggest avenues for future research.

CONTEXT/UNASSIGNED:Cardiac injury has been described in both acute COVID-19 and the multisystem inflammatory syndrome in children (MIS-C). Echocardiographic strain has been shown to be a sensitive measure of systolic function. AIMS/UNASSIGNED:We sought to describe strain findings in both the groups on initial presentation and follow-up. SETTINGS AND DESIGN/UNASSIGNED:A retrospective study analyzing echocardiograms of all patients presenting with acute COVID-19 infection and MIS-C at our institution between March 2020 and December 2020 was performed. SUBJECTS AND METHODS/UNASSIGNED:TOMTEC software was used for strain analysis in both the study groups (COVID-19 and MIS-C) and age-matched healthy controls. Strain was correlated with LV ejection fraction (EF) and serum troponin levels. RESULTS/UNASSIGNED:= 0.002) and troponin in patients with MIS-C. Abnormal strain persisted in one-third of patients in the MIS-C and acute COVID-19 groups on outpatient follow-up. CONCLUSIONS/UNASSIGNED:Patients with MIS-C and acute COVID-19 can develop myocardial dysfunction as seen by abnormal strain. LV longitudinal strain correlates with cardiac injury as measured by serum troponin in patients with MIS-C. Strain may provide an additional tool in detecting subtle myocardial dysfunction. It can be routinely employed at diagnosis and at follow-up evaluation of these patients.

Introduction Fetal cardiac disease is strongly associated with maternal anti-SSA/Ro antibodies, but gaps in our knowledge include the influence of antibody specificity and titer, maternal diagnosis, overall non-cardiac adverse pregnancy outcomes (APOs), optimal surveillance protocols, and efficacy of rapid treatment. Methods The multi-center Surveillance and Treatment To Prevent Fetal AV Block Likely to Occur Quickly (STOP BLOQ) study recruited pregnant women with commercially positive anti-Ro antibodies and stratified them into high and low titers of anti-Ro60 and Ro52 based on a research ELISA, using a cutoff defined by that obtained for 50 mothers with previous AVB offspring. Mothers with anti-Ro60 and/or 52 antibodies at or above 1,000 I.U. were trained to perform FHRM. From 17-25 weeks of gestation, FHRM was completed 3x/day in addition to weekly or biweekly fetal echocardiograms (echo). Mothers texted all audio sounds to the coordinating center. Texts deemed abnormal by mothers were immediately sent to an on call pediatric cardiologist who either reassured if FHRM was normal or referred for emergency fetal echo in < 6 hours if abnormal. Results 250 anti-Ro pregnant women (22% Hispanic, 50% white, 12% Black, 12% Asian, 4% other) have been consented, including 28 whose previous child had AVB. Of mothers tested to date, 153 were provided home monitors given high titer anti-Ro60 and/or 52 antibodies (26 high titer anti-Ro60 alone, 21 high titer anti-Ro52 alone,105 high titer antibodies to both antigens). The 83 patients with low titers were surveilled with echos per local standard of care. Regarding maternal diagnosis, of 161 assessed to date, 39% were asym/UAS, 11% RA, 31% SS, 19% SLE. Antibody titers did not significantly differ by ethnicity, race or diagnosis (table 1). Non-AVB APOs occurred in 18% and were not predicted by Ro60 or 52 titers but rather SLE diagnosis (table 2). In total, 24,759 FHRM audiotexts were received from 131 patients (90 of whom have delivered) during the monitoring period. Of these, 22 were evaluated by the on-call pediatric cardiologist, who prompted an emergency echo (all completed in < 6 hrs). In 11 cases, the emergency echo was normal. In 9, there were premature atrial contractions, confirming the mother's perception. In 2 with 2degree block on urgent echo (both treated per protocol with IVIG and dexamethasone), 1 reverted to normal sinus rhythm and the other progressed to 3degree block. In 2 others, the mother did not perceive abnormal FHRM for > 24 hrs, echo identified 3degree block, and retrospective cardiology review of FHRM audio captures identified an abnormality prior to obtaining the echo. All 4 AVB developed in fetuses of mothers with high titer antibodies to both Ro60 and 52 (mean 32,451 and 34,991 respectively). Of the 18 mothers with a previous AVB child who followed the 400mg hydroxychloroquine PATCH protocol, 1 developed AVB in accord with the results of Step 1 in that study. Conclusion These data support that APOs in this clinically diverse group of mothers are not influenced by anti-Ro titer or specificity, but rather SLE diagnosis. All conduction defects were initially identified by FHRM and in mothers with high titer anti-Ro60 and 52. Hydroxychloroquine continues to show efficacy in reducing the AVB recurrence rate with rapid intervention of emergent block being promising