Faculty Bibliography

Background/Purpose: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine (HCQ) was initially considered as a prophylaxis and treatment of COVID-19. Despite this optimism, more extensive reports have significantly dampened the promise of efficacy, however cardiac toxicity has surfaced raising attention to this complication. Although HCQ is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematous and other rheumatic conditions, this initiative leveraged a unique opportunity to evaluate neonatal electrocardiograms (ECGs) in the context of HCQ levels to address any potential cardiotoxicity.
Method(s): Neonatal ECGs and HCQ blood levels were available in a recently completed study evaluating the efficacy of HCQ 400mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro antibodies. The ECGs of affected newborns who met the primary outcome of advanced block were not included in this safety study so that the results only reflect those infants with no clinical cardiac disease. Using the Bazett formula to correct for heart rate, corrected QT (QTc) intervals were calculated and compared to age-matched normal values. For reference, the median (2nd percentile - 98th percentile) values for QTc were 413 (378-448) msec in males, and 420 (379-462) msec in females. QTc intervals were recorded in the absence of knowledge of the HCQ levels. Values exceeding 448 msec for males and 462 msec for females were considered abnormal. Levels of HCQ were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure.
Result(s): There were 45 ECGs available for interpretation within the first 4 months of life in unaffected infants. Overall, there was no correlation between cord blood levels of HCQ and the QTc (R = 0.02, P = 0.86) or the average value of HCQ levels obtained during each individual pregnancy and cord blood and the QTc (R = 0.04, P = 0.80), as shown in Figure 1A and Figure 1B. Likewise there was no correlation between the average of the maternal HCQ levels obtained at each trimester and delivery plus cord levels and the QTc on the ECGs of the 31 infants evaluated on day of life 1-4 (R = 0.08, P = 0.63) or those of the 14 children older than 4 days (R = 0.01, P = 0.95). Maternal values of HCQ were sustained throughout pregnancy and delivery (Figure 2). Mean QTc values were nearly identical between those in the highest and lowest quartiles of cord blood HCQ levels (P = 0.57) and between the highest and lowest quartiles of average HCQ levels during pregnancy (P = 0.54) (Figure 3A and 3B). Among these 45 infants, only 5 had prolongation of the QTc (11%; 95% CI: 4% - 24%), 2 marked and 3 marginal. No arrhythmias occurred in any neonate that was not known to have heart block.
Conclusion(s): In aggregate, these data provide reassurances that the maternal use of HCQ is not associated with a high incidence of QTc prolongation in the neonate

Background - Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine (HCQ) is being considered as prophylaxis and treatment of COVID-19. Although HCQ is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematous and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. Methods - To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal electrocardiograms (ECGs) and HCQ blood levels were available in a recently completed study evaluating the efficacy of HCQ 400mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro antibodies. Results - Forty-five ECGs were available for QTc measurement, and levels of HCQ were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of HCQ and the neonatal QTc (R = 0.02, P = 0.86) or the mean of HCQ values obtained throughout each individual pregnancy and the QTc (R = 0.04, P = 0.80). In total 5 (11%; 95% CI: 4% - 24%) neonates had prolongation of the QTc > 2SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. Conclusions - In aggregate, these data provide reassurances that the maternal use of HCQ is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered.

BACKGROUND:The overall severity of cardiac disease secondary to acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection in children appears to be much lower when compared with adults. However, the newly described multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been associated with cardiac complications. METHODS:We reviewed the clinical course and cardiac testing results in pediatric patients hospitalized with MIS-C at 2 large hospital systems in the New York City metropolitan area over a 3-month period. RESULTS:Of the 33 patients (median age 2.8 years) in the study cohort, 24 (73%) had at least one abnormality in cardiac testing: abnormal electrocardiogram (48%), elevated brain natriuretic peptide (43%), abnormal echocardiogram (30%), and/or elevated troponin (21%). Electrocardiogram and echocardiogram abnormalities all resolved by the 2-week outpatient follow-up cardiology visit. CONCLUSION/CONCLUSIONS:While 73% of pediatric patients with MIS-C had evidence of abnormal cardiac testing on hospital admission in our study, all cardiac testing was normal by outpatient hospital discharge follow-up. Cardiac screening tests should be performed in all patients diagnosed with MIS-C given the high rate of abnormal cardiac findings in our study cohort.

We report a case of a 17-year-old healthy male presenting with multisystem hyperinflammatory shock temporally associated with COVID-19. Cardiac involvement was suspected based on evidence of significant cardiac injury (elevated cardiac biomarkers, electrocardiographic and echocardiographic abnormalities). Cardiac magnetic resonance imaging was performed demonstrating global biventricular systolic dysfunction, as well as a small area of T2 hyperintensity and mid-wall late gadolinium enhancement. This case discusses the varied cardiac involvement in pediatric patients with COVID-19 infection and highlights that cardiac injury is not just limited to hyperinflammatory syndrome related global dysfunction but a more focal myocarditis can also be seen.

BACKGROUND:Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES/OBJECTIVE:Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS:This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS:By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS:These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

OBJECTIVE:To determine the prevalence of Barth syndrome in the pediatric population. STUDY DESIGN/METHODS:Data were collected from the Barth Syndrome Foundation Registry and relevant literature. With the advent of genetic testing and whole-exome sequencing, a multipronged Bayesian analysis was used to estimate the prevalence of Barth syndrome based on published data on the incidence and prevalence of cardiomyopathy and neutropenia, and the respective subpopulations of patients with Barth syndrome indicated in these publications. RESULTS:Based on 7 published studies of cardiomyopathy and 2 published studies of neutropenia, the estimated prevalence of Barth syndrome is approximately 1 case per million male population. This contrasts with 99 cases in the Barth Syndrome Foundation Registry, 58 of which indicate a US location, and only 230-250 cases known worldwide. CONCLUSIONS:It appears that Barth syndrome is greatly underdiagnosed. There is a need for better education and awareness of this rare disease to move toward early diagnosis and treatment.

Pediatric heart failure remains poorly understood, distinct in many aspects from adult heart failure. Limited data point to roles of altered mitochondrial functioning and in particular, changes in mitochondrial lipids, especially cardiolipin. Barth syndrome is a mitochondrial disorder caused by tafazzin mutations that lead to abnormal cardiolipin profiles. Patients are afflicted by cardiomyopathy, skeletal myopathy, neutropenia, and growth delay. A mouse model of Barth syndrome was developed a decade ago, which relies on a doxycycline-inducible shRNA to knock down expression of tafazzin mRNA ("TAZKD"). Our objective was to review published data from the TAZKD mouse to determine its contributions to our pathogenetic understanding of, and potential treatment strategies for, Barth syndrome. In regard to the clinical syndrome, the reported physiological, biochemical, and ultrastructural abnormalities of the mouse model mirror those in Barth patients. Using this model, the PPAR pan-agonist bezafibrate has been suggested as potential therapy because it ameliorated the cardiomyopathy in TAZKD mice, while increasing mitochondrial biogenesis. A clinical trial is now underway to test bezafibrate in Barth syndrome patients. Thus, the TAZKD mouse model of Barth syndrome has led to important insights into disease pathogenesis and therapeutic targets, which can potentially translate to pediatric heart failure.

BACKGROUND:Sudden death in children is a tragic event that often remains unexplained after comprehensive investigation. We report two asymptomatic siblings who died unexpectedly at approximately 1 year of age found to have biallelic (compound heterozygous) variants in PPA2. METHODS:The index case, parents, and sister were enrolled in the Sudden Unexplained Death in Childhood Registry and Research Collaborative, which included next-generation genetic screening. Prior published cases of PPA2 variants, along with the known biology of PPA2, were also summarized. RESULTS:Whole exome sequencing in both siblings revealed biallelic rare missense variants in PPA2: c.182C > T (p.Ser61Phe) and c.380G > T (p.Arg127Leu). PPA2 encodes a mitochondrially located inorganic pyrophosphatase implicated in progressive and lethal cardiomyopathies. As a regulator and supplier of inorganic phosphate, PPA2 is central to phosphate metabolism. Biological roles include the following: mtDNA maintenance; oxidative phosphorylation and generation of ATP; reactive oxygen species homeostasis; mitochondrial membrane potential regulation; and possibly, retrograde signaling between mitochondria and nucleus. CONCLUSIONS:Two healthy and asymptomatic sisters died unexpectedly at ages 12 and 10 months, and were diagnosed by molecular autopsy to carry biallelic variants in PPA2. Our cases add additional details to those reported thus far, and broaden the spectrum of clinical and molecular features of PPA2 variants.