Background Fontan-associated liver disease contributes to long-term morbidity and mortality. This study evaluated whether non-invasive liver fibrosis scores—aspartate transaminase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) and routine clinical hepatic synthetic function, specifically albumin—predict adverse outcomes when obtained 10 and 20 years after the Fontan procedure. Method We conducted a retrospective analysis of Fontan patients with laboratory data available at ≥10 years post-procedure. The primary adverse outcomes included death, heart transplantation, or Fontan failure. Failing Fontan physiology was defined as heart failure, poorly controlled ascites, plastic bronchitis, or treatment-resistant protein-losing enteropathy. Cox regression was used to evaluate associations between APRI, FIB-4, and albumin level with adverse outcomes. Results Outcomes of 98 patients surviving at 10 years (but <20 years), and 109 different patients surviving at 20 years were included. At least one adverse outcome occurred in 8% (8/98) of patients at 10 years and 12% (13/109) of patients at 20 years. Albumin <3.5 g/dL was associated with adverse outcomes at both 10 years (hazard ratio [HR] 8.54; p=0.02) and 20 years (HR 4.31; p=0.03). FIB-4 >1.45 but not APRI was significantly associated with adverse outcomes (HR 21.3; p=0.03) at 20 years. Conclusions Low albumin and elevated FIB-4 scores, usually leveraged in evaluation of liver disease, are associated with more frequent adverse outcomes of death, heart transplantation, or Fontan failure. These markers may serve as simple, non-invasive prognostic tools in long-term follow-up.

BACKGROUND:The SAXOPHONE (Safety of Apixaban on Pediatric Heart Disease on the Prevention of Embolism) trial demonstrated the safety of apixaban for thromboprophylaxis in children with heart disease. Included a priori in the trial design was an exploratory biomarker substudy to evaluate the effects of apixaban on surrogate biomarkers of efficacy, thrombin generation capacity, and hemostatic proteins. The study assessed changes in d-dimer, thrombin generation assay parameters, factor VIII, fibrinogen, protein C, and protein S in children receiving apixaban compared with standard-of-care vitamin K antagonists (VKAs) or low-molecular-weight heparin. METHODS:SAXOPHONE participants aged >1 year (n=182) had blood samples for biomarkers collected at baseline, week 2, or month 6. Participants were randomized to apixaban (n=123) or standard of care (VKA or low-molecular-weight heparin; n=59). Subgroup analyses accounted for prior VKA exposure. RESULTS:d-dimer levels decreased at month 6 in all treatment groups and remained stable during VKA-to-apixaban bridging. Apixaban significantly prolonged thrombin generation assay lag time and time to peak compared with VKAs and decreased peak thrombin similarly to VKAs in anticoagulant-naïve participants. Apixaban was associated with decreased fibrinogen and factor VIII at month 6, with no effect on protein C or S. Prior VKA exposure produced carryover effects, suppressing baseline d-dimer, thrombin generation assay parameters, and proteins C and S. CONCLUSIONS:Apixaban reduced hypercoagulability, as shown by decreased d-dimer levels and prolonged lag time, and preserved endogenous thrombin potential in thrombin generation assay, changes consistent with adult data. These findings align with SAXOPHONE's primary outcomes, supporting apixaban's favorable risk-benefit profile as a thromboprophylaxis option in children with heart disease.

Background: There is significant interest in NO pathway modulators, specifically type 5 phosphodiesterase inhibitors (PDE5is), to treat patients with a Fontan circulation. Trials, however, have had mixed results. The relationship between the NO pathway and clinical status in patients with Fontan circulation is a significant knowledge gap. Methods and Results: We performed targeted metabolomic analysis using liquid chromatography coupled to mass spectrometry to quantify plasma NO pathway metabolite concentrations from 2 well-characterized populations of patients with Fontan circulation: the Boston Adult Congenital Heart Disease Biobank and Fontan Udenafil Exercise Longitudinal studies. We investigated associations between NO metabolite concentrations and clinical outcomes, exercise capacity, and response to PDE5is. Increased plasma concentration of asymmetric dimethyl arginine (ADMA), an inhibitor of NO production, was associated with risk for hospitalization or death. Increased ADMA and symmetric dimethyl arginine (another inhibitor of NO production) concentrations were associated with decreased baseline exercise capacity among patients with Fontan circulation with <90% predicted peak oxygen uptake, and change in ADMA and symmetric dimethyl arginine concentrations were predictive of change in exercise capacity over time. Treatment with the PDE5i udenafil uncoupled this association. Finally, baseline ADMA and symmetric dimethyl arginine concentrations predicted response to PDE5is among patients with subnormal peak oxygen uptake. Conclusions: Plasma concentrations of metabolites that inhibit NO flux are associated with negative clinical outcomes and worse exercise capacity. Moreover, metabolite shifts over time associated with increased NO flux are associated with improved exercise capacity. In patients with a Fontan circulation, the NO pathway modulators ADMA and symmetric dimethyl arginine may be useful as biomarkers of clinical status and predictive of response to PDE5is.

Apixaban is an oral direct inhibitor of factor Xa (FXa) that could be a treatment option for thromboembolism prevention in children with congenital or acquired heart disease (CAHD). Data from SAXOPHONE, a phase II pediatric study, were used to update a previously developed population pharmacokinetics (PPK) model and to assess the covariate effect of patient type on PK parameters while retaining previous covariates. Stochastic simulations were performed to assess whether the proposed dosing regimens in pediatric patients aged 28 days to < 18 years matched adult exposures. The relationship between anti-Factor Xa (AXA) and apixaban concentration, as well as apixaban concentration and chromogenic FX, were evaluated. Apixaban dose adjustment in response to the growth of pediatric patients and changes in age and weight were also assessed. Apixaban PK in pediatric patients with CAHD was well characterized by a 2-compartment model with first-order absorption, dose-dependent F1, and first-order elimination. Apixaban apparent clearance (CL/F) and apparent volume of distribution in the central compartment (Vc/F) increased with increasing body weight. Apixaban CL/F was lower in pediatric patients with CAHD compared to adults and other pediatric patients. The fixed dose by weight-tiered dosing regimen for pediatric patients with CAHD (28 days to < 18 years) achieved target exposures similar to adult VTE treatment and nonvalvular atrial fibrillation populations. A linear PK/PD relationship between apixaban and AXA was observed. Inhibition of FXa was observed across weight tiers. Apixaban dose adjustment in response to weight gain resulted in exposures similar to target adult exposures.

BACKGROUND:Echocardiography provides noninvasive frontline assessment of right ventricular (RV) function in hypoplastic left heart syndrome (HLHS). However, conventional metrics do not quantify RV intracardiac hemodynamics. A novel Doppler velocity reconstruction measures kinetic energy, vortex strength, and flow energy loss through conventional color Doppler acquisitions. We investigated longitudinal changes in RV intracardiac flow in infants with HLHS during the critical interstage period, hypothesizing that these trends may inform disease progression. METHODS:This was a single-center, retrospective analysis of patients with HLHS who underwent stage 1 palliation (bilateral pulmonary artery bands/hybrid palliation or Norwood operation). Echocardiographic studies at 5 time points from before to 6 months after surgery were selected for postprocessing. Apical views of the RV with adequate color Doppler imaging were analyzed. Significant tricuspid regurgitation was defined as vena contracta jet width ≥2.5 mm. Adverse events included death, heart transplant, use of ventricular assist device, or extracorporeal membrane oxygenation. RESULTS:Thirty-six patients with HLHS (21 hybrid, 15 Norwood) were included. Flow energy loss, vortex strength, and kinetic energy increased over time for all interstage patients with HLHS (P<0.0001) and correlated with RV size, body surface area, and E wave. Significant tricuspid regurgitation was associated with elevated flow energy loss and vortex strength (P=0.0007 and P<0.0001). Adverse events showed early changes in flow parameters and altered trends over the interstage period (vortex strength, P<0.0001; kinetic energy, P=0.0009). CONCLUSIONS:Doppler velocity reconstruction can assess RV intracardiac flow in infants in HLHS interstage I. While the results should not be used to interpret the surgical strategies, the longitudinal analysis of intracardiac flow may elucidate diastolic filling dynamics, with deviations associated with adverse events throughout the interstage period.

Background In the FUEL (Fontan Udenafil Exercise Longitudinal) trial, a positive treatment effect was identified for outcomes at the ventilatory anaerobic threshold but not for the primary outcome, oxygen consumption (Vo2) at peak exercise. This disparate response may be explained by the physiologic challenge of improving peak Vo2 in participants with near‐normal baseline exercise performance. Methods Participants were divided into subgroups by baseline predicted peak Vo2 (<80% versus ≥80%). Treatment effect was evaluated in those with a baseline peak Vo2 <80% predicted and linear regression was performed to examine the interaction between subgroup and response to therapy for the primary and secondary outcomes. Results Of the 379 participants with paired exercise data, 302 (80%) had a baseline peak Vo2 <80% predicted. In this subgroup, the primary outcome of peak Vo2 improved significantly after 6 months of udenafil treatment, when compared with placebo (0.23±4.17 mL/kg per min versus −0.90±3.74 mL/kg per min; P=0.021). Secondary outcome measures, including Vo2 at ventilatory anaerobic threshold (P=0.023), work at ventilatory anaerobic threshold (P=0.032), and the myocardial performance index (P=0.007) were all significantly improved as well. A significant interaction was found between exercise subgroups and response to udenafil for peak Vo2 (P=0.036) but not for other outcomes. Conclusions In this post hoc subgroup analysis, after exclusion of patients with Fontan circulation with near‐normal baseline peak Vo2, a positive treatment effect of udenafil was identified for the primary outcome of peak Vo2. The interaction between baseline peak Vo2 and treatment may have influenced the outcome of the FUEL trial. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT0274115.

Why some but not all patients with the rare disease Friedreich ataxia (FRDA) are at increased risk of poor cardiovascular outcome and death is unclear and unpredictable. We investigated the hypothesis that mitochondrial dysfunction in FRDA leads to altered patterns of myocardial metabolic substrate utilization. We recruited 5 healthy controls (Ctl) and 11 FRDA participants. All underwent fasting myocardial positron emission tomography (PET scan) with 15O-H2O, 18F-FDG, and 11C-Palmitate. We conducted cardiac transcriptomics on mice with ablation of the Frda gene in heart to explore mechanisms of fuel substrate utilization. Five (45%) FRDA participants had an LV mass index (LVMi) less than 51 g/m2.7 (Group I), and 6 (55%) FRDA participants had an LVMi greater than this (Group II). 73% (8/11) of all FRDA participants had evidence of increased myocardial FDG uptake relative to controls. All of Group II had FDG/Palmitate utilization ratios > 95% versus controls, as well as cTnI leak (p = 0.007) when compared to Ctl (p = 0.008) or Group I (p = 0.022). RNA transcriptomics from FRDA mouse heart showed upregulation of genes for glucose uptake and glycolysis with decreased genes associated with mitochondrial energy production. In summary, PET scan identified 2 metabolically distinct subclasses of FRDA cardiomyopathy. FRDA participants with an LVMi greater than 51 g/m2.7 had greater FDG uptake than those with an LVMi less than 51 g/m2.7, or Ctl, and this correlated with LV systolic and diastolic dysfunction. Supporting this finding, gene expression in the FRDA mouse heart shifts to favor glycolysis with decreased mitochondrial energy production.

Recent advances in dose-delivery techniques have led to a reduction in normal tissue complications in radiotherapy patients. However, significant early and late cardiovascular (CV) effects may result when the heart is included in the radiation field and exposed to doses commonly used to treat several types of malignancies, or during total-body irradiation (TBI) prior to hematopoietic stem cell transplantation. Moreover, a radiological or nuclear (RAD/NUC) incident in which thousands of people are exposed to potentially lethal doses of ionizing radiation could result in the development of delayed effects of acute radiation exposure (DEARE) in survivors; several life-threatening cardiac DEARE-related pathologies would be observed months to years after TBI doses that trigger the hematopoietic acute radiation syndrome (H-ARS). While mitigators are available to treat acute symptoms in individuals that received radiation doses high enough to trigger the H-ARS, there are no drugs or strategies for mitigating early or late cardiovascular effects in radiotherapy patients, or late cardiac pathologies that would subsequently manifest in H-ARS survivors; while some drugs have shown promise, toxicity, limited efficacy or logistical issues regarding administration precludes their clinical use. Thus, there is great interest in the development of mitigators of cardiovascular dysfunction. We previously identified a novel non-pharmacological strategy that is effective in mitigating the lethal effects of TBI in mice when administered after exposure. Our approach involved the creation of a small subcutaneous (SC) incision postirradiation. We found that subcutaneous wounding several minutes after a high-dose TBI greatly protected against lethality, and that mitigation of the resulting H-ARS was likely mediated by enhanced recovery of hematopoiesis. We refer to this approach as "protective wounding." We now show that a subcutaneous cut preserves cardiac function, specifically, pumping capacity as measured by the Langendorff technique, in mice when assessed 30 days after a single dose or fractionated TBI. For example, left ventricular developed pressure (LVDP) at end diastolic pressure (EDP) 30-39 was 22.5% greater in mice that received a cut after a TBI dose of 6.5 Gy, compared to sham-cut mice. We propose that "protective wounding" may be used as a novel model for interrogating the proteins and pathways involved in reducing cardiotoxicity after irradiation and ultimately guiding development of pharmacological mitigators of cardiotoxicity in radiotherapy patients or victims of RAD/NUC incidents.

Importance Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication of COVID-19 infection. Data on midterm outcomes are limited. Objective To characterize the frequency and time course of cardiac dysfunction (left ventricular ejection fraction [LVEF] <55%), coronary artery aneurysms (z score >= 2.5), and noncardiac involvement through 6 months after MIS-C. Design, Setting, and Participants This cohort study enrolled participants between March 2020 and January 2022 with a follow-up period of 2 years. Participants were recruited from 32 North American pediatric hospitals, and all participants met the 2020 Centers for Disease Control and Prevention case definition of MIS-C. Exposure MIS-C after COVID-19 infection. Main Outcomes and Measures Outcomes included echocardiography core laboratory (ECL) assessments of LVEF and maximum coronary artery z scores (zMax); data collection on cardiac and noncardiac sequelae during hospitalization and at 2 weeks, 6 weeks, and 6 months after discharge; and age-appropriate Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health Instruments at follow-up. Descriptive statistics, linear regression models, and Kaplan-Meier analysis were used. Results Of 1204 participants (median [IQR] age, 9.1 [5.6-12.7] years; 724 male [60.1%]), 325 self-identified with non-Hispanic Black race (27.0%) and 324 with Hispanic ethnicity (26.9%). A total of 548 of 1195 participants (45.9%) required vasoactive support, 17 of 1195 (1.4%) required extracorporeal membrane oxygenation, and 3 (0.3%) died during hospitalization. Of participants with echocardiograms reviewed by the ECL (n = 349 due to budget constraints), 131 of 322 (42.3%) had LVEF less than 55% during hospitalization; of those with follow-up, all but 1 normalized by 6 months. Black race (vs other/unknown race), higher C-reactive protein level, and abnormal troponin level were associated with lowest LVEF (estimate [SE], -3.09 [0.98]; R2 = 0.14; P =.002). Fifteen participants had coronary artery z scores of 2.5 or greater at any time point; 1 participant had a large/giant aneurysm. Of the 13 participants with z scores of 2.5 or greater during hospitalization, 12 (92.3%) had normalized by 6 months. Return to greater than 90% of pre-MIS-C health status (energy, sleep, appetite, cognition, and mood) was reported by 711 of 824 participants (86.3%) at 2 weeks, increasing to 548 of 576 (95.1%) at 6 months. Fatigue was the most common symptom reported at 2 weeks (141 of 889 [15.9%]), falling to 3.4% (22 of 638) by 6 months. PROMIS Global Health parent/guardian proxy median T scores for fatigue, global health, and pain interference improved significantly from 2 weeks to 6 months (fatigue, 56.1 vs 48.9; global health, 48.8 vs 51.3; pain interference, 53.0 vs 43.3; P < .001) and by the 6-week visit were at least equivalent to prepandemic population norms. Conclusions and Relevance Results of this cohort study suggest that although children and young adults with MIS-C can have severe disease during the acute phase, most recovered quickly and had a reassuring midterm prognosis.

Nomlabofusp is a cell penetrant peptide-based recombinant fusion protein designed to enter cells and deliver human frataxin into the mitochondria of adults and children with Friedreich’s ataxia. In this article we present non-clinical studies evaluating the pharmacology of nomlabofusp, including in a murine striated muscle tissue frataxin knockout model of Friedreich’s ataxia. We demonstrate that subcutaneous administration of nomlabofusp distributes in a dose-dependent manner to several organs including the dorsal root ganglion, heart, and skeletal muscle, which are known to be predominantly affected in Friedreich’s ataxia, as well as to other tissues, including skin. Plasma nomlabofusp concentrations correlated with levels of human frataxin delivered by nomlabofusp into tissues, and the increases in frataxin were correlated amongst tissues, especially with skin. In the knockout mice, we show that the pharmacokinetics and processing of nomlabofusp were comparable with wild type animals and that treatment with nomlabofusp halts the progression of cardiac dysfunction and significantly increased survival. Together, the findings from these non-clinical studies demonstrate that nomlabofusp exposure increases human frataxin in Friedreich’s ataxia-relevant tissues and provide evidence of pharmacologic effects.

Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele (TazPM) that phenocopies BTHS clinical traits. As TazPM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile TazPM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile TazPM hearts. However, adult TazPM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult TazPM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.

Background The perinatal transition’s impact on systemic right ventricle (SRV) cardiac hemodynamics is not fully understood. Standard clinical image analysis tools fall short of capturing comprehensive diastolic and systolic measures of these hemodynamics. Objectives Compare standard and novel hemodynamic echocardiogram (echo) parameters to quantify perinatal changes in SRV and healthy controls. Methods We performed a retrospective study of 10 SRV patients with echocardiograms at 33-weeks gestation and at day of birth and 12 age-matched controls. We used in-house developed analysis algorithms to quantify ventricular biomechanics from four-chamber B-mode and color Doppler scans. Cardiac morphology, hemodynamics, tissue motion, deformation, and flow parameters were measured. Results Tissue motion, deformation, and index measurements did not reliably capture biomechanical changes. Stroke volume and cardiac output were nearly twice as large for the SRV compared to the control RV and left ventricle (LV) due to RV enlargement. The enlarged RV exhibited disordered flow with higher energy loss (EL) compared to prenatal control LV and postnatal control RV and LV. Furthermore, the enlarged RV demonstrated elevated vortex strength (VS) and kinetic energy (KE) compared to both the control RV and LV, prenatally and postnatally. The SRV showed reduced relaxation with increased early filling velocity (E) compared prenatally to the LV and postnatally to the control RV and LV. Furthermore, increased recovery pressure (ΔP) was observed between the SRV and control RV and LV, prenatally and postnatally. Conclusions The novel hydrodynamic parameters more reliably capture the SRV alterations than traditional parameters.

BACKGROUND:Fontan-associated liver disease (FALD) refers to structural and functional changes of the liver caused by the physiology of the Fontan palliation. Currently, liver biopsy is the gold standard to assess liver fibrosis of FALD. AIM:Investigate biomarkers correlating with severity of liver biopsy fibrosis in FALD. METHODS:A retrospective study of post-Fontan patients ≥ 10 years of age who underwent liver biopsy was conducted. Advanced liver disease (ALD) was defined as bridging fibrosis and/or cirrhosis on liver biopsy. AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4) and Liver Stiffness Measurement (LSM) from FibroScan were used as non-invasive fibrosis scores. RESULTS:Sixty-six patients (26/47; 55.3% adults and 13/19 children; 68.4%) had ALD on biopsy. ALD was associated with lower platelet count (151 vs. 198 K/uL, p = 0.003), higher APRI (0.64 vs. 0.32, p = 0.01), higher FIB-4 (0.64 vs. 0.32, p = 0.02). Liver fibrosis score correlated with APRI (0.34, p = 0.02) and FIB-4 (0.47, p = 0.001) in adults. LSM had a high sensitivity at 81.3% with 45.5% specificity at a cut-off 18.5 kPa. CONCLUSIONS:APRI and FIB-4 had modest discrimination to identify adults with advanced liver disease, but not children, indicating that these values may be followed as a marker of FALD progression in older patients.

The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO 2 ), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO 2 , work rate at the ventilatory anaerobic threshold (VAT), VO 2 at VAT, and ventilatory efficiency (VE/VCO 2 ) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO 2 , baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO 2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation. Trial Registration NCT0274115.

The Mustard procedure was an early cardiac surgery for transposition of the great arteries (TGA). Despite being successful, it has been associated with long-term arrhythmias and heart failure. A key factor complicating management in adults with congenital heart disease (CHD) is the deficiency of biomarkers predicting outcome. Soluble suppression of tumorogenicity-2 (sST2) is secreted by cardiomyocytes in response to mechanical strain and fibrosis. We hypothesized that adults with a Mustard procedure would have higher levels of sST2 than healthy individuals, and this would correlate with clinical outcome. We performed a single-center study in patients managed during childhood with a Mustard procedure versus age-matched controls. Clinical and demographic data were collected and biomarkers (sST2, cTnI, BNP, lipid panel, insulin, and glucose) were obtained. There were 18 patients (12 male) in the Mustard cohort and 18 patients (6 male) in the control group (22-49 years, mean of 35.8 vs. mean 32.6 years, respectively, p = ns). Nine Mustard subjects were NYHA class II, and 9 subjects were class III. The control group was asymptomatic. sST2 in the Mustard group was elevated in 56% vs. 17% in controls (p = 0.035). Of the Mustard subjects with elevated sST2, 60% had elevated cTnI and BNP, and 90% had low HDL. Over five years, the Mustard patients with elevated sST2 values had greater medication use, arrhythmias, hospitalizations, and ablation/pacer implantations than Mustard subjects with normal sST2. Mustard subjects with elevated sST2 had other biomarker abnormalities and clinically worse outcomes. Thus, sST2 may add a predictive value to cardiac-related morbidity and mortality.

BACKGROUND Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages.OBJECTIVES The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. METHODS Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thrombo-prophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. Primary endpoint: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy.RESULTS From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference-4.0 [95% CI:-12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with >= 4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels.CONCLUSIONS In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472)

Importance Data are limited regarding adverse reactions after COVID-19 vaccination in patients with a history of multisystem inflammatory syndrome in children (MIS-C). The lack of vaccine safety data in this unique population may cause hesitancy and concern for many families and health care professionals. Objective To describe adverse reactions following COVID-19 vaccination in patients with a history of MIS-C. Design, Setting, and Participants In this multicenter cross-sectional study including 22 North American centers participating in a National Heart, Lung, and Blood Institute, National Institutes of Health–sponsored study, Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC), patients with a prior diagnosis of MIS-C who were eligible for COVID-19 vaccination (age ≥5 years; ≥90 days after MIS-C diagnosis) were surveyed between December 13, 2021, and February 18, 2022, regarding COVID-19 vaccination status and adverse reactions. Exposures COVID-19 vaccination after MIS-C diagnosis. Main Outcomes and Measures The main outcome was adverse reactions following COVID-19 vaccination. Comparisons were made using the Wilcoxon rank sum test for continuous variables and the χ 2 or Fisher exact test for categorical variables. Results Of 385 vaccine-eligible patients who were surveyed, 185 (48.1%) received at least 1 vaccine dose; 136 of the vaccinated patients (73.5%) were male, and the median age was 12.2 years (IQR, 9.5-14.7 years). Among vaccinated patients, 1 (0.5%) identified as American Indian/Alaska Native, non-Hispanic; 9 (4.9%) as Asian, non-Hispanic; 45 (24.3%) as Black, non-Hispanic; 59 (31.9%) as Hispanic or Latino; 53 (28.6%) as White, non-Hispanic; 2 (1.1%) as multiracial, non-Hispanic; and 2 (1.1%) as other, non-Hispanic; 14 (7.6%) had unknown or undeclared race and ethnicity. The median time from MIS-C diagnosis to first vaccine dose was 9.0 months (IQR, 5.1-11.9 months); 31 patients (16.8%) received 1 dose, 142 (76.8%) received 2 doses, and 12 (6.5%) received 3 doses. Almost all patients received the BNT162b2 vaccine (347 of 351 vaccine doses [98.9%]). Minor adverse reactions were observed in 90 patients (48.6%) and were most often arm soreness (62 patients [33.5%]) and/or fatigue (32 [17.3%]). In 32 patients (17.3%), adverse reactions were treated with medications, most commonly acetaminophen (21 patients [11.4%]) or ibuprofen (11 [5.9%]). Four patients (2.2%) sought medical evaluation, but none required testing or hospitalization. There were no patients with any serious adverse events, including myocarditis or recurrence of MIS-C. Conclusions and Relevance In this cross-sectional study of patients with a history of MIS-C, no serious adverse events were reported after COVID-19 vaccination. These findings suggest that the safety profile of COVID-19 vaccination administered at least 90 days following MIS-C diagnosis appears to be similar to that in the general population.

Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research. (c) 2022 The Author. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Friedreich ataxia (FA) is a progressive and devastating disease in which expression of frataxin (FXN) is severely decreased.1Pandolfo M. Friedreich ataxia: the clinical picture.J. Neurol. 2009; 256: 3-8https://doi.org/10.1007/s00415-009-1002-3Crossref PubMed Scopus (284) Google Scholar Frataxin is an ancient and highly conserved protein that is targeted to mitochondria, where it participates in iron-sulfur (Fe-S) cluster formation through binding to a multi-protein core complex.2Fox N.G. Yu X. Feng X. Bailey H.J. Martelli A. Nabhan J.F. Strain-Damerell C. Bulawa C. Yue W.W. Han S. Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.Nat. Commun. 2019; 10: 2210https://doi.org/10.1038/s41467-019-09989-yCrossref PubMed Scopus (74) Google Scholar Now, 25 years after identification of the gene defect,3Campuzano V. Montermini L. Molto M.D. Pianese L. Cossee M. Cavalcanti F. Monros E. Rodius F. Duclos F. Monticelli A. et al.Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.Science. 1996; 271: 1423-1427Crossref PubMed Google Scholar the field is moving closer to understanding exactly what FXN does and developing a therapy. Two points are noteworthy from a therapeutic standpoint: (1) FA is a monogenetic disease in which there is low expression of a key protein. There is nothing wrong with the protein itself, i.e., there is not a dominant-negative mutation in the encoded protein, there just is not enough of it. (2) Frataxin is targeted to the mitochondrial matrix, which is one of the most inaccessible organelles within the cell. Although mitochondrial disorders as a class are common, there still are few or no effective therapies for mitochondrial defects. Thus, developing treatments for FA will advance our understanding of how to treat other mitochondrial disorders. This is an important goal. Early experiments have shown that viral gene therapies to deliver a human FXN gene are a promising approach but may have toxicities.4Perdomini M. Belbellaa B. Monassier L. Reutenauer L. Messaddeq N. Cartier N. Crystal R.G. Aubourg P. Puccio H. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia.Nat. Med. 2014; 20: 542-547https://doi.org/10.1038/nm.3510Crossref PubMed Scopus (134) Google Scholar, 5Belbellaa B. Reutenauer L. Monassier L. Puccio H. Correction of half the cardiomyocytes fully rescue Friedreich ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms.Hum. Mol. Genet. 2019; 28: 1274-1285https://doi.org/10.1093/hmg/ddy427Crossref PubMed Scopus (12) Google Scholar, 6Belbellaa B. Reutenauer L. Messaddeq N. Monassier L. Puccio H. High levels of frataxin overexpression lead to mitochondrial and cardiac toxicity in mouse models.Mol. Ther. Methods Clin. Dev. 2020; 19: 120-138https://doi.org/10.1016/j.omtm.2020.08.018Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar In a series of interesting and thoughtful experiments published in Molecular Therapy: Methods & Clinical Development, Huichalaf et al.7Huichalaf C. Perfitt T.L. Kuperman A. Gooch R. Kovi R.C. Brenneman K.A. Chen X. Hirenallur-Shanthappa D. Ma T. Assaf B.T. et al.In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency.Mol. Ther. Methods Clin. Dev. 2022; https://doi.org/10.1016/j.omtm.2022.02.002Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar have sought to determine expression limits for FXN toxicity and, more importantly, the mechanism(s) of this toxicity. The authors show that overexpression of native human FXN using an AAV9 vector (AAV9-CAG-FXN) in the MCK-Cre conditional ablation FA mouse model (loss of FXN in heart and skeletal muscle) is not only toxic to heart, a key target organ in FA, but is also toxic to liver, which is an off-target organ. Progressive overexpression of human FXN in the ablation model resulted only in partial and transient correction of cardiac dysfunction. Because AAV9 has tropism for liver, the authors examined hepatic function in these mice. Hepatic toxicity developed rapidly at higher doses, as evidenced by histology and loss of specific Fe-S-cluster-dependent proteins in mitochondria. Importantly, liver toxicity was moderated by accelerated regeneration in liver8Malato Y. Naqvi S. Schurmann N. Ng R. Wang B. Zape J. Kay M.A. Grimm D. Willenbring H. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration.J. Clin. Invest. 2011; 121: 4850-4860https://doi.org/10.1172/JCI59261Crossref PubMed Scopus (321) Google Scholar with loss of hepatocytes containing the AAV-CAG-FXN construct. They concluded that liver dysfunction was the most likely cause for weight loss and premature death in the mice. Next, the authors overexpressed FXN in wild-type mice using the same AAV9-CAG-FXN construct. They compared these results against a vector containing a known pathogenic mutation, AAV9-CAG-FXN(N146K), that renders the FXN molecule unable to bind to the Fe-S biogenesis core complex. Surprisingly, the authors found that overexpression of the human FXN protein was not toxic in wild-type mouse heart but again was toxic to liver. Possible explanations for this were not clear. Overexpression of the FXN(N146K) mutation was not toxic in either heart or liver, even though expression levels were similar to the therapeutic construct. Thus, one mechanism of toxicity requires binding of FXN to the Fe-S core complex. This experiment also showed that toxicity in the mouse was not due to sequence differences between mouse and human FXN, nor was it due to toxicity from the AAV9 vector itself. The authors reasonably concluded that overexpression of FXN can result in Fe-S cluster deficit in the same way that FXN depletion does. From the standpoint of therapeutic development, there are several take-home points from this work. First, there appears to be a range of FXN expression that is therapeutic. Based on published data, this range seems to be from ∼20% of normal expression to ∼8-fold overexpression, but admittedly, these are early data with little long-term follow-up.5Belbellaa B. Reutenauer L. Monassier L. Puccio H. Correction of half the cardiomyocytes fully rescue Friedreich ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms.Hum. Mol. Genet. 2019; 28: 1274-1285https://doi.org/10.1093/hmg/ddy427Crossref PubMed Scopus (12) Google Scholar,9Vasquez-Trincado C. Patel M. Sivaramakrishnan A. Bekeova C. Anderson-Pullinger L. Wang N. Tang H.Y. Seifert E.L. Adaptation of the heart to Frataxin depletion: evidence that integrated stress response can predominate over mTORC1 activation.Hum. Mol. Genet. 2021; https://doi.org/10.1093/hmg/ddab216Crossref PubMed Google Scholar Second, there are differences in sensitivity of heart versus liver to overexpression of FXN. This suggests that tissues and cells with high metabolic needs and high mitochondrial count will have a different requirement and sensitivity to FXN expression compared with tissues having lower mitochondrial count and/or metabolism. Third, off-target expression of FXN can and will be toxic. Here, liver was damaged by overexpression of FXN, but it is unknown whether other organ systems were affected. Although the liver showed recovery with regeneration, this may also increase the risk of secondary disease, such as cancer or cirrhosis, over time. Finally, unlike the mouse model, the human disease results from low expression, but not complete loss, of FXN. Defining minimal expression levels for normal cell function in different tissues, including brain, will be needed to develop effective therapies. These experiments are an important contribution to the field of FA, because they define toxicity of FXN overexpression and, more importantly, identify mechanisms underlying this toxicity. R.M.P. is supported by a grant from NIH ( NHLBI 1P01HL134599 ). Support for this work was also provided in part by the Herman B. Wells Center from the Riley Children's Foundation to R.M.P. R.M.P. is a paid consultant for Larimar Therapeutics, Inc., which had no input or knowledge of this work.