Introduction: Thrombocytosis, sometimes extreme, after acute Kawasaki disease (KD) is common and felt to be pathognomonic of this diagnosis, although has also been reported after multisystem inflammatory syndrome in children (MIS-C), a clinically similar condition. We sought to determine differences in factors associated with thrombocytosis for each condition. Methods: From 01/2020 to 10/2023 across 41 sites in 8 countries from the International KD Registry, 1674 MIS-C and 1290 contemporaneous KD patients with adequate laboratory data were included in the analysis. Age-related cutpoints (derived from the CALIPER Study of normal children/adolescents; AJCP 2020; 154:342) were applied to peak platelet counts to define thrombocytosis (age <1 year, >647 x10 9 /L; age 1 to <12 years, >434; age 12 to <21 years, >371). Associations of demographic, clinical, laboratory and outcome factors with thrombocytosis were determined for each diagnosis group. Results: Thrombocytosis was more prevalent after KD (57%) than MIS-C (49%; p<0.001), with higher median peak platelet count (492 vs. 413 x10 9 /L; p<0.001). The difference remained significant after adjustment for age. Thrombocytosis was significantly associated with greater total days of fever for both KD (median 8 vs. 7 days; p=0.005) and MIS-C (median 7 vs. 6 days; p<0.001), but not with any symptoms/signs or presentation with shock in either group. For both groups, thrombocytosis was associated with significantly greater laboratory abnormalities, specifically higher markers of inflammation, lower hemoglobin and lower albumin. Cardiac biomarkers (peak NTproBNP, peak troponin I) were significantly lower for KD patients with thrombocytosis. While there was no significant association of thrombocytosis with ventricular function in either group (FIGURE A), coronary artery involvement was worse for both groups if thrombocytosis occurred (FIGURE B), with an overall lower prevalence and severity for patients with MIS-C, despite more severe clinical presentation and greater laboratory abnormalities. Conclusions: Thrombocytosis has a high prevalence for both KD and MIS-C, and is associated with both more severe inflammation and greater coronary artery involvement for both diagnoses.

The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance at the ventilatory anaerobic threshold in children with Fontan physiology. However, it is not known how the initiation of phosphodiesterase 5 inhibitor therapy affects heart rate and blood pressure in this population. These data may help inform patient selection and monitoring after the initiation of udenafil therapy. The purpose of this study is to evaluate the effects of udenafil on vital signs in the cohort of patients enrolled in the FUEL trial. This international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil included adolescents with single ventricle congenital heart disease who had undergone Fontan palliation. Changes in vital signs (heart rate [HR], systolic [SBP] and diastolic blood pressure [DBP]) were compared both to subject baseline and between the treatment and the placebo groups. Additional exploratory analyses were performed to evaluate changes in vital signs for prespecified subpopulations believed to be most sensitive to udenafil initiation. Baseline characteristics were similar between the treatment and placebo cohorts (n = 200 for each). The groups demonstrated a decrease in HR, SBP, and DBP 2 hours after drug/placebo administration, except SBP in the placebo group. There was an increase in SBP from baseline to after 6-min walk test in the treatment and placebo groups, and the treatment group showed an increase in HR (87.4 +/- 15.0 to 93.1 +/- 19.4 beats/min, p <0.01) after exer-cise. When comparing changes from baseline to the 26-week study visit, small decreases in both SBP (-1.9 +/- 12.3 mm Hg, p = 0.03) and DBP (-3.0 +/- 9.6 mm Hg, p <0.01) were seen in the treatment group. There were no clinically significant differences between treatment and placebo group in change in HR or blood pressure in the youngest age quartile, lightest weight quartile, or those on afterload-reducing agents. In conclusion, initiation of treat-ment with udenafil in patients with Fontan circulation was not associated with clinically significant changes in vital signs, implying that for patients similar to those enrolled in the FUEL trial, udenafil can be started without the requirement for additional monitoring after initial administration. (c) 2023 Elsevier Inc. All rights reserved. (Am J Cardiol 2024;210:183-187)

The incidence of Kawasaki Disease has a peak in the winter months with a trough in late summer/early fall. Environmental/exposure factors have been associated with a time-varying incidence. These factors were altered during the COVID-19 pandemic. The study was performed through the International Kawasaki Disease Registry. Data from patients diagnosed with acute Kawasaki Disease and Multiple Inflammatory Syndrome-Children were obtained. Guideline case definitions were used to confirm site diagnosis. Enrollment was from 1/2020 to 7/2023. The number of patients was plotted over time. The patients/month were tabulated for the anticipated peak Kawasaki Disease season (December-April) and non-peak season (May-November). Data were available for 1975 patients from 11 large North American sites with verified complete data and uninterrupted site reporting. The diagnosis criteria were met for 531 Kawasaki Disease and 907 Multiple Inflammatory Syndrome-Children patients. For Multiple Inflammatory Syndrome-Children there were peaks in January of 2021 and 2022. For Kawasaki Disease, 2020 began (January-March) with a seasonal peak (peak 26, mean 21) with a subsequent fall in the number of cases/month (mean 11). After the onset of the pandemic (April 2020), there was no clear seasonal Kawasaki Disease variation (December-April mean 12 cases/month and May-November mean 10 cases/month). During the pandemic, the prevalence of Kawasaki Disease decreased and the usual seasonality was abolished. This may represent the impact of pandemic public health measures in altering environmental/exposure aetiologic factors contributing to the incidence of Kawasaki Disease.

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.

Background: We sought to determine the utility of current echocardiography surveillance recommendations for coronary artery (CA) involvement for children with Kawasaki disease (KD) with normal baseline studies. Methods: The International KD Registry enrolled 1200 patients (36 sites, 7 countries) with a site diagnosis of KD from 01/2020 to 01/2023; 139 with positive/possible COVID-19 infection/exposure and 174 with no echo within 10 days of admission were excluded, leaving 887 patients for analysis of results of serial echos and associated factors. Results: An initial echo was performed within 5 days of admission for 96% and within 10 days of symptom onset for 83% of patients; the max Z score in any CA branch at initial echo was normal (Z <2) 78.9%, dilation (Z 2-<2.5) 6.6%, small aneurysm (CAA; Z 2.5-<5) 10.5%, medium CAA (Z 5-<10) 2.9% and large CAA (Z ≥10) for 1.2% of patients. Higher CA Z score/Z score category were both significantly related to greater time from symptom onset to echo (p<0.001). For those with initial normal CAs, a second echo (median of 16 days after admission) was normal for 94.2%, dilation 1.9%, small CAA 2.7%, medium CAA 0.6%, and large CAA for 0.6%. For those with 2 normal echos, a third echo (median of 44 days after admission) was normal for 97.6%, dilation 1.4%, small CAA 0.5%, and 1 patient each with medium and large CAA. Additionally, after up to 6 normal echos, 3 patients had developed small CAA, 1 medium and 1 large CAA. Overall, a total of 24 (2.8%) patients had large CAA (13 admitted >10 days after symptom onset). Of these, 10 had large CAA evident at initial echo performed at day 0-3 after admission, 9 had lesser involvement at initial echo that then progressed to large CAA, and 5 had normal initial and subsequent echos and then were noted to have large CAA at an echo performed 14, 17, 21, 23 and 53 days after admission (the patient with a large CAA first detected at 53 days had no interim echos performed since their first normal echo). Conclusions: Current recommendations for serial echo assessment are effective in detecting all patients with large CAA. For rare patients, despite a normal initial echo large CAA may nonetheless develop. Additionally, important CA involvement may be evident at presentation (often delayed presentation), precluding prevention.

Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients.This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM.Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout.From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: −40 ± 27 mm Hg, and −43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (−36 ± 27 mm Hg and −53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (−6% ± 7.5% and −12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro–B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms.Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 show clinical overlap and both lack definitive diagnostic testing, making differentiation challenging. We sought to determine how cardiac biomarkers might differentiate KD from MIS-C. The International Kawasaki Disease Registry enrolled contemporaneous KD and MIS-C pediatric patients from 42 sites from January 2020 through June 2022. The study population included 118 KD patients who met American Heart Association KD criteria and compared them to 946 MIS-C patients who met 2020 Centers for Disease Control and Prevention case definition. All included patients had at least one measurement of amino-terminal prohormone brain natriuretic peptide (NTproBNP) or cardiac troponin I (TnI), and echocardiography. Regression analyses were used to determine associations between cardiac biomarker levels, diagnosis, and cardiac involvement. Higher NTproBNP (≥ 1500 ng/L) and TnI (≥ 20 ng/L) at presentation were associated with MIS-C versus KD with specificity of 77 and 89

•Isolated RSCA from the PA is a rare finding in d-TGA.•Atypical differential cyanosis in d-TGA may indicate abnormal aortic branching.•Fetal imaging can provide evidence of an isolated RSCA.

Introduction: Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 share clinical features and are both associated with coronary artery (CA) involvement. Methods: From January 2020 through January 2022, n=2566 contemporaneous KD, MIS-C and acute COVID-19 pediatric patients from 39 sites in 8 countries were enrolled into the International KD Registry. The study population was confined to 875 MIS-C patients meeting CDC criteria with confirmed or probable COVID-19 infection, and 492 KD patients meeting AHA guideline criteria without COVID-19 infection who had sufficient echo data. CA involvement was defined by maximum Z score in any branch at any timepoint (maxCAZ). Associated factors for each diagnosis were determined with multivariable logistic regression for maxCAZ>2. Results: Median maxCAZ was higher for KD (+1.43) vs MIS-C patients (+1.33; p=0.004). The groups did not differ regarding the incidence of maxCAZ>2 (KD 26% vs MIS-C 24%; p=0.42), although MIS-C patients had less severe Z score categories of involvement (FIGURE). In univariate analyses, higher peak troponin I (p<0.05) and NTproBNP (p=0.06) were associated with maxCAZ>2 for MIS-C but not KD patients. Lower LV ejection fraction was likewise associated with maxCAZ>2 for MIS-C (p=0.009) but not KD patients. For KD patients, independent factors associated with maxCAZ>2 were male sex, age <6 months, greater total days of fever, shock presentation, and higher peak platelet count and CRP (c-statistic 0.69). In contrast, for MIS-C patients the only independent factor associated with maxCAZ>2 was male sex (c-statistic 0.56). Conclusions: Compared to KD patients, MIS-C patients have a similar incidence but lesser severity of CA involvement with few associated factors, male sex being the only one in common. CA involvement was significantly associated with higher cardiac biomarkers and lower LV ejection fraction for MIS-C patients only.

Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (–0.2%) in the placebo group ( P =0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus –9±193 [–0.9%] mL/min, P =0.012), ventilatory equivalents of carbon dioxide (–0.8 versus –0.06, P =0.014), and work rate (+3.8 versus +0.34 W, P =0.021). There was no an improvement in myocardial performance index (–0.02 vs 0.01, P =0.030), but no change in reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02741115.