Background and Objectives: Early identification of cardiac dysfunction in multi-system inflammatory syndrome in children (MIS-C) is crucial for effective management. Our primary objective was to predict left ventricular systolic dysfunction (LVSD) through a multicenter collaborative assessing admission laboratory data and echocardiogram findings. Methods: Laboratory and clinical data were collected by retrospective chart review from a cohort of pediatric patients admitted and treated for MIS-C in our institutions. Laboratory data including absolute lymphocyte count, albumin, sedimentation rate, C-reactive protein, procalcitonin, d-dimer, fibrinogen, ferritin, interleukin-6 level, and lymphocyte subsets (T, B and NK quantitation, TBNK) were collected. We built a LASSO logistic regression model to predict which MIS-C patients would have left ventricular systolic dysfunction LVSD using only laboratory data obtained within the first 24 h of admission. Results: Of the 1474 MIS-C patients evaluated, 297 had LVSD. The linear kinetic analysis found differences in albumin, lymphocyte count, C-reactive proteins and fibrinogen for systolic dysfunction patients, and of these C-reactive proteins, fibrinogen and procalcitonin were more predictive earlier. The best model for coronary artery abnormalities (CAAs) performed poorly, with a mean cross-validated AUC of 0.57. The model performed well with a cross-validated AUC of 0.845. Conclusions: This model identified widely available biomarkers to successfully predict systolic dysfunction in MIS-C patients. Those at high risk of systolic dysfunction had higher peak laboratory values for C-reactive protein, fibrinogen, and procalcitonin early on. A regularized logistic regression model was validated to provide excellent discrimination for LVSD.

Congenital aortic valve stenosis (AVS) is a severe form of congenital heart disease (CHD), accounting for 3–6% of all CHD cases. It is characterized by malformation of the aortic valve, resulting in obstruction of the valve orifice. As congenital AVS is progressive, it ultimately impairs cardiac output, and without timely medical intervention, it can lead to heart failure and death. Current treatment options are limited to surgical interventions, which, due to the severity of the disease and associated risk factors, often require multiple procedures throughout a patient’s lifetime. Unfortunately, pharmacological therapies are not available, as the molecular mechanisms driving the disease are not well understood. This study aims to identify clinically relevant biomarkers for assessing disease severity and to uncover novel pharmacological targets by dissecting the mechanisms underlying the development and progression of congenital AVS. We utilized a novel Notch1;Gata5 AVS mouse model developed in our lab to investigate changes in protein composition in the aortic valves. Proteomic analyses were conducted using HPLC-MS at postnatal day 10 (P10) of age to capture early stages of the disease. Our findings reveal significant changes in 364 proteins in Notch1;Gata5 compound mutants at P10. Pathway and Gene Ontology analyses revealed that many of these dysregulated proteins are associated with ECM assembly and organization pathways, consistent with the improper aortic valve remodeling observed in the AVS phenotype. Notably, the Notch1;Gata5 compound mutant valves exhibit altered protein abundance associated with Wnt and Integrin signaling pathways at P10 highlighting potential novel therapeutic targets for congenital AVS. In conclusion, our study explores the proteomic landscape of aortic valves in the Notch1;Gata5 AVS mouse model, identifying preliminary candidates that could inform future biomarker-based diagnostics and pharmacological interventions for congenital AVS.

BACKGROUND:Optimal strategies for thromboembolism prevention, including vitamin K antagonists (VKA), direct oral anticoagulants (DOAC), and left atrial appendage occlusion (LAAO), for patients with atrial fibrillation (AF) and on dialysis have not been fully investigated. We aimed to investigate the efficacy and safety of thromboembolism prevention strategies in AF patients on dialysis through a network meta-analysis. METHODS:Multiple databases were searched through January 2024. The primary efficacy endpoint was thrombotic events, defined as ischemic stroke or systemic thromboembolism, whereas the primary safety endpoint was major bleeding. These strategies were ranked using P-scores. RESULTS:Our study identified 28 eligible studies (including 3 randomized controlled trials) that enrolled 144,630 AF patients on dialysis. The risks of thrombotic events in any DOAC and VKA were comparable to no-anticoagulant, whereas LAAO was associated with a lower risk of thrombotic events (HR [95% CI]: 0.19 [0.06-0.60]). Compared to no-anticoagulant, VKA, regular-dose rivaroxaban, and dabigatran were associated with a higher risk of major bleeding, but rivaroxaban 10 mg daily, and apixaban 2.5 or 5 mg twice daily were not. LAAO, rivaroxaban 10 mg daily and apixaban 2.5 or 5 mg twice daily were highly ranked in efficacy and safety outcomes. CONCLUSIONS:LAAO may possibly be the reasonable therapeutic option for AF patients on dialysis, but rivaroxaban 10 mg daily and apixaban 2.5 or 5 mg twice daily can also be considered. Further studies are warranted to confirm these findings.

Here, we describe Notch1;Gata5 compound mutant mice as a novel mouse model of highly penetrant congenital aortic valve disease displaying bicuspid aortic valve and progressive aortic valve stenosis. Further, we find downregulation of smooth muscle genes in the neonatal aortic valves in Notch1;Gata5 compound mice consistent with an immature valve phenotype. Our findings demonstrate a novel genetic interaction between Notch1 and Gata5 in mice that is critical for proper aortic valve development. This novel model is an important tool to define dysregulated signaling pathways for congenital aortic valve stenosis and stenotic disease progression that can be investigated as therapeutic targets.

Congenital heart disease (CHD) is a common type of birth defect and a leading cause of infant and childhood mortality. Although recent advancements in genetic technologies have allowed for the discovery of new genomic variation associated with CHD, the prioritization and interpretation of variants for pathogenicity remain a challenge. Further, the underlying molecular genetic mechanisms for CHD remain incompletely defined. In this article, we summarize established genetic etiologies of CHD and highlight advances in knowledge of the underlying genetic architecture of CHD, along with challenges in genetic variation interpretation, the clinical implications of these genomic advances, and future directions.

BACKGROUND:Remimazolam, an ultra-short-acting benzodiazepine, has similar clinical effects to propofol for sedation in general anaesthesia. However, it remains uncertain whether remimazolam could increase postoperative delirium (POD) compared with propofol. OBJECTIVES:The purpose of our study was to compare the incidence of POD between remimazolam and propofol as sedative agents in general anaesthesia. STUDY DESIGN:Systematic review and meta-analysis of randomised controlled trials (RCTs). METHODS:PubMed, Embase, Cochrane Library, and Web of Science databases were searched for prospective RCTs published through September 16, 2024. RCTs reporting the incidence of POD and comparing remimazolam with propofol for general anaesthesia were included. Odds ratio (ORs) were calculated using a random-effects model. The primary outcome was the incidence of POD. The secondary outcomes included time to extubation, awakening time, and adverse events such as intraoperative hypotension. RESULTS:A total of six RCTs involving 1107 patients were included in this meta-analysis. For the primary outcome, the incidence of POD did not differ between the remimazolam and propofol groups (OR, 0.92; 95 % confidence interval [CI], 0.58-1.44). Regarding the secondary outcomes, remimazolam was associated with a lower incidence of intraoperative hypotension compared with propofol (OR, 0.31; 95 % CI, 0.21-0.46). There were no significant differences in other secondary outcomes. In the sensitivity analysis on three RCTs including only older patients (≥60 years old), there was no significant difference in the incidence of POD (OR, 1.00; 95 % CI, 0.52-1.93). CONCLUSION:Perioperative remimazolam administration did not increase POD and reduced the risk of intraoperative hypotension compared to propofol. Further large-scale RCTs are warranted to explore the association of remimazolam and POD. Systematic review protocol: PROSPERO CRD42024544122.

OBJECTIVES:Concerns persist regarding pulmonary regurgitation after transannular patch repair (TAP) for tetralogy of Fallot. Despite the introduction of various architectural preservation techniques, the optimal strategy remains controversial. Our goal was to compare different right ventricular outlet tract reconstruction techniques. METHODS:PubMed, EMBASE and Cochrane Central were searched through March 2024 to identify comparative studies on right ventricular outlet tract reconstruction techniques (PROSPERO ID: CRD42024519404). The primary outcome was mid-term pulmonary regurgitation, with secondary outcomes including postoperative mortality, postoperative pulmonary regurgitation, length of intensive care unit stays, postoperative right ventricular outlet tract pressure gradient and mid-term mortality. We performed a network meta-analysis to compare outcomes among TAP, valve-repairing (VR), TAP with neo-valve creation (TAPN) and valve-sparing (VS). RESULTS:Two randomized controlled studies and 32 observational studies were identified with 8890 patients. TAP carried a higher risk of mid-term pulmonary regurgitation compared to TAPN [hazard ratio, 0.53; 95% confidence interval (CI) (0.33; 0.85)] and VS [hazard ratio, 0.27; 95% CI (0.19; 0.39)], with no significant difference compared to VR. VS was also associated with reduced postoperative mortality compared to TAP [risk ratio, 0.31; 95% CI (0.18; 0.56)], in addition to reduced ventilation time. TAP also carried an increased risk of postoperative pulmonary regurgitation compared to the other groups. The groups were comparable in terms of length of intensive care unit stay, right ventricular outlet tract pressure gradient and mid-term mortality. CONCLUSIONS:VR was associated with a reduced risk of postoperative pulmonary regurgitation, whereas TAPN was associated with reduced risks of both postoperative and mid-term pulmonary regurgitation.

Background Pathogenic GATA6 variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenic GATA6 variation in humans remains to be fully understood. Methods Exome sequencing was performed in a family where four members had CHD. In vitro functional analysis of the GATA6 variant was performed using immunofluorescence, western blot, and dual-luciferase reporter assay. Results A novel, heterozygous missense variant in GATA6 (c.1403 G > A; p.Cys468Tyr) segregated with affected members in a family with CHD, including three with persistent truncus arteriosus. In addition, one member had childhood onset diabetes mellitus (DM), and another had necrotizing enterocolitis (NEC) with intestinal perforation. The p.Cys468Tyr variant was located in the c-terminal zinc finger domain encoded by exon 4. The mutant protein demonstrated an abnormal nuclear localization pattern with protein aggregation and decreased transcriptional activity. Conclusions We report a novel, familial GATA6 likely pathogenic variant associated with CHD, DM, and NEC with intestinal perforation. These findings expand the phenotypic spectrum of pathologic GATA6 variation to include intestinal abnormalities. Impact Exome sequencing identified a novel heterozygous GATA6 variant (p.Cys468Tyr) that segregated in a family with CHD including persistent truncus arteriosus, atrial septal defects and bicuspid aortic valve. Additionally, affected members displayed extracardiac findings including childhood-onset diabetes mellitus, and uniquely, necrotizing enterocolitis with intestinal perforation in the first four days of life. In vitro functional assays demonstrated that GATA6 p.Cys468Tyr variant leads to cellular localization defects and decreased transactivation activity. This work supports the importance of GATA6 as a causative gene for CHD and expands the phenotypic spectrum of pathogenic GATA6 variation, highlighting neonatal intestinal perforation as a novel extracardiac phenotype.

Congenital aortic valve stenosis (AVS) is one of the most common valve anomalies and accounts for 3%–6% of cardiac malformations. As congenital AVS is often progressive, many patients, both children and adults, require transcatheter or surgical intervention throughout their lives. While the mechanisms of degenerative aortic valve disease in the adult population are partially described, the pathophysiology of adult AVS is different from congenital AVS in children as epigenetic and environmental risk factors play a significant role in manifestations of aortic valve disease in adults. Despite increased understanding of genetic basis of congenital aortic valve disease such as bicuspid aortic valve, the etiology and underlying mechanisms of congenital AVS in infants and children remain unknown. Herein, we review the pathophysiology of congenitally stenotic aortic valves and their natural history and disease course along with current management strategies. With the rapid expansion of knowledge of genetic origins of congenital heart defects, we also summarize the literature on the genetic contributors to congenital AVS. Further, this increased molecular understanding has led to the expansion of animal models with congenital aortic valve anomalies. Finally, we discuss the potential to develop novel therapeutics for congenital AVS that expand on integration of these molecular and genetic advances.

Importance Early behavior problems in children with developmental delay (DD) are prevalent and impairing, but service barriers persist. Controlled studies examining telehealth approaches are limited, particularly for children with DD. Objective To evaluate the efficacy of a telehealth parenting intervention for behavior problems in young children with DD. Design, Setting, and Participants A randomized clinical trial was conducted from March 17, 2016, to December 15, 2020, in which children with DD and externalizing behavior problems were recruited from early intervention and randomly assigned to a telehealth parenting intervention or control group and evaluated through a 12-month follow-up. Most children were from ethnic or racial minoritized backgrounds. Over one-half of children were in extreme poverty or low income-need ratio categories. Interventions Internet-delivered parent-child interaction therapy (iPCIT), which leverages videoconferencing to provide live coaching of home-based caregiver-child interactions. Families received 20 weeks of iPCIT (provided in English or in Spanish) or referrals as usual (RAU). Main Outcomes and Measures Observational and caregiver-report measures of child and caregiver behaviors and caregiving stress were examined at preintervention, midtreatment, and postintervention and at 6- and 12-month follow-ups. Results The sample included a total of 150 children (mean [SD] age, 36.2 [1.0] months; 111 male children [74%]) and their caregivers with 75 each randomly assigned to iPCIT or RAU groups. Children receiving iPCIT relative to RAU displayed significantly lower levels of externalizing problems (postintervention Cohen d = 0.48; 6-month Cohen d = 0.49; 12-month Cohen d = 0.50) and significantly higher levels of compliance to caregiver direction after treatment. Of those children with data at postintervention, greater clinically significant change was observed at postintervention for children in the iPCIT group (50 [74%]) than for those in the RAU group (30 [42%]), which was maintained at the 6-month but not the 12-month follow-up. iPCIT did not outperform RAU in reducing caregiving stress, but caregivers receiving iPCIT, relative to RAU, showed steeper increases in proportion of observed positive parenting skills (postintervention odds ratio [OR], 1.10; 95% CI, 0.53-2.21; 6-month OR, 1.31; 95% CI, 0.61-2.55; 12-month OR, 1.64; 95% CI, 0.70-3.07) and sharper decreases in proportion of observed controlling/critical behaviors (postintervention OR, 1.40; 95% CI, 0.61-1.52; 6-month OR, 1.72; 95% CI, 0.58-1.46; 12-month OR, 2.23; 95% CI, 0.53-1.37). After treatment, iPCIT caregivers also self-reported steeper decreases in harsh and inconsistent discipline than did than RAU caregivers (postintervention Cohen d = 0.24; 6-month Cohen d = 0.26; 12-month Cohen d = 0.27). Conclusions and Relevance Results of this randomized clinical trial provide evidence that a telehealth-delivered parenting intervention with real-time therapist coaching led to significant and maintained improvements for young children with DD and their caregivers. Findings underscore the promise of telehealth formats for expanding scope and reach of care for underserved families. Trial Registration ClinicalTrials.gov Identifier: NCT03260816

BACKGROUND:The relationship between coronavirus disease 2019 (COVID-19) vaccination and long COVID has not been firmly established. We conducted a systematic review and meta-analysis to evaluate the association between COVID-19 vaccination and long COVID. METHODS:PubMed and EMBASE databases were searched on September 2022 without language restrictions (CRD42022360399) to identify prospective trials and observational studies comparing patients with and without vaccination before severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We also included studies reporting symptomatic changes of ongoing long COVID following vaccination among those with a history of SARS-CoV-2 infection. Odds ratios (ORs) for each outcome were synthesized using a random-effects model. Symptomatic changes after vaccination were synthesized by a one-group meta-analysis. RESULTS:Six observational studies involving 536,291 unvaccinated and 84,603 vaccinated (before SARS-CoV-2 infection) patients (mean age, 41.2-66.6; female, 9.0-67.3%) and six observational studies involving 8,199 long COVID patients (mean age, 40.0 to 53.5; female, 22.2-85.9%) who received vaccination after SARS-CoV-2 infection were included. Two-dose vaccination was associated with a lower risk of long COVID compared to no vaccination (OR, 0.64; 95% confidence interval [CI], 0.45-0.92) and one-dose vaccination (OR, 0.60; 95% CI, 0.43-0.83). Two-dose vaccination compared to no vaccination was associated with a lower risk of persistent fatigue (OR, 0.62; 95% CI, 0.41-0.93) and pulmonary disorder (OR, 0.50; 95% CI, 0.47-0.52). Among those with ongoing long COVID symptoms, 54.4% (95% CI, 34.3-73.1%) did not report symptomatic changes following vaccination, while 20.3% (95% CI, 8.1-42.4%) experienced symptomatic improvement after two weeks to six months of COVID-19 vaccination. CONCLUSIONS:COVID-19 vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID, while most of those with ongoing long COVID did not experience symptomatic changes following vaccination.

The optimal treatment strategy using pulmonary vasodilators in pulmonary arterial hypertension associated with CHD (PAH-CHD) remains controversial. We aimed to compare the efficacy and safety of pulmonary vasodilators in PAH-CHD. PubMed and EMBASE databases were searched through May 2022 and a network meta-analysis was conducted. The primary outcomes were mean difference of changes in 6-minute walk distance, NYHA functional class, and N-terminal pro-brain natriuretic peptide. The secondary outcomes included pulmonary vascular resistance, mean pulmonary arterial pressure, and resting oxygen saturation. We identified 14 studies, yielding 807 patients with PAH-CHD. Bosentan and sildenafil were associated with a significant increase in 6-minute walk distance from baseline compared with placebo (MD 48.92 m, 95% CI 0.32 to 97.55 and MD 59.70 m, 95% CI 0.88 to 118.53, respectively). Bosentan, sildenafil, and combination of bosentan and sildenafil were associated with significant improvement in NYHA functional class compared with placebo (MD -0.33, 95% CI -0.51 to -0.14, MD -0.58, 95% CI -0.75 to -0.22 and MD -0.62, 95% CI -0.92 to -0.31, respectively). Bosentan and sildenafil were also associated with significant improvements in secondary outcomes. These findings were largely confirmed in the subgroup analysis. Various adverse events were reported; however, serious adverse event rates were relatively low (4.8-8.7%), including right heart failure, acute kidney injury, respiratory failure, hypotension, and discontinuation of pulmonary vasodilators. In conclusion, bosentan and sildenafil were the most effective in improving prognostic risk factor such as 6-minute walk distance and NYHA class. Overall, pulmonary vasodilators were well tolerated in PAH-CHD.

be very challenging to conduct large-scale randomized trials, given the ample evidence supporting the benefit of COVID-19 vaccination.Finally, our article could not extensively assess the most effective timing and dose of vaccination since only a few studies reported the difference in the maternal or neonatal protective effects among the first, second, and third trimesters.In our original article, 1 vaccination during the second or third trimester was associated with lower incidences of preterm birth and small for gestational age.However, it was compared with unvaccinated individuals instead of those vaccinated during the first trimester.Therefore, it is difficult to determine the best time to receive vaccinations to protect children.Nevertheless, even if it were proven that getting vaccinated later in pregnancy compared with earlier was more effective in reducing neonatal outcomes, that would not necessarily dictate the best timing to be vaccinated because unvaccinated individuals would have to remain having higher risks of SARS-CoV-2 infection while waiting for the second or third trimester.Under current consensus, it can be recommended that pregnant individuals or those of reproductive age be vaccinated against COVID-19.Overall, we agree that our meta-analysis has several limitations to be acknowledged.However, our findings would promote vaccinating pregnant individuals who have not received one yet due to concerns for the safety and efficacy of COVID-19 vaccines.Future investigations on the optimal dose and timing of COVID-19 vaccination, including the ones for the Omicron subvariant, for pregnant individuals, are warranted.

Long-term outcomes after invasive versus non-invasive treatment for patients with IC.CLTI=chronic limb threatening ischemia; NS=not significant; RR=rate ratio* per 1000 person-year

Importance:Evidence of the efficacy and safety of messenger RNA (mRNA) COVID-19 vaccines in children aged 5 to 11 years has been emerging. Collecting these data will inform clinicians, families, and policy makers.Objective:To evaluate the efficacy and safety of mRNA COVID-19 vaccines in children aged 5 to 11 years in a systematic review and meta-analysis.Data Sources:PubMed and Embase databases were searched on September 29, 2022, without language restrictions.Study Selection:Randomized clinical trials and observational studies comparing vaccinated vs unvaccinated children aged 5 to 11 years and reporting efficacy or safety outcomes were included. Studies reporting safety outcomes in vaccinated children only (ie, no control group) were also included.Data Extraction and Synthesis:Two investigators independently extracted relevant data from each study. Odds ratios (ORs) for efficacy and safety outcomes and incidences of adverse events (AEs) following vaccination were synthesized using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines.Main Outcomes and Measures:The primary outcome was SARS-CoV-2 infections with or without symptoms. The secondary outcomes included symptomatic SARS-CoV-2 infections, hospitalizations, and multisystem inflammatory syndrome in children. The incidences of each AE following vaccination were also evaluated.Results:Two randomized clinical trials and 15 observational studies involving 10 935 541 vaccinated children (median or mean age range, 8.0-9.5 years) and 2 635 251 unvaccinated children (median or mean age range, 7.0-9.5 years) were included. Two-dose mRNA COVID-19 vaccination compared with no vaccination was associated with lower risks of SARS-CoV-2 infections with or without symptoms (OR, 0.47; 95% CI, 0.35-0.64), symptomatic SARS-CoV-2 infections (OR, 0.53; 95% CI, 0.41-0.70), hospitalizations (OR, 0.32; 95% CI, 0.15-0.68), and multisystem inflammatory syndrome in children (OR, 0.05; 95% CI, 0.02-0.10). Two randomized clinical trials and 5 observational studies investigated AEs among vaccinated children. Most vaccinated children experienced at least 1 local AE following the first injection (32 494 of 55 959 [86.3%]) and second injection (28 135 of 46 447 [86.3%]). Vaccination was associated with a higher risk of any AEs compared with placebo (OR, 1.92; 95% CI, 1.26-2.91). The incidence of AEs that prevented normal daily activities was 8.8% (95% CI, 5.4%-14.2%) and that of myocarditis was estimated to be 1.8 per million (95% CI, 0.000%-0.001%) following the second injection.Conclusions and Relevance:In this systematic review and meta-analysis, COVID-19 mRNA vaccines among children aged 5 to 11 years were associated with measures of efficacy in preventing SARS-CoV-2 infection and severe COVID-19-related illnesses. While most children developed local AEs, severe AEs were rare, and most of AEs resolved within several days. These data provide evidence for future recommendations.

Background: Previous literature suggests that both SARS-CoV-2 infection and COVID-19 mRNA vaccine are associated with myocarditis, in which the incidence is higher in the infection group. COVID-19 mRNA vaccine-related myocarditis is noted to have a more benign course. Despite these findings, there is a need for a larger population systematic review that compares the outcomes to pre-pandemic acute myocarditis to better under-stand the extent of the current post-COVID state. Methods: We performed a literature search with PubMed and EMBASE and identified studies investigating COVID-19 and its vaccinated population, and the population prior to the pandemic (control group) who had myocarditis. We performed a one-group meta-analysis of the incidence, baseline demographics, and outcomes of myocarditis for each group. Results: The incidence in the SARS-CoV-2 infection group was 2.76 per thousand (95% CI, 0.85-8.92), 19.7 per million (95% CI, 12.3-31.6) in the vaccine group, and 0.861 per million (95% CI, 0.04-16.7) in the control group. The majority of patients were male, with the highest proportion in the vaccine group. The mean age was the youngest in the vaccine group (24.8, 95% CI, 19.1-30.6). The vaccine group had the lowest mortality (2.0%, 95% CI, 1.3-2.7) followed by the control and the SARS-CoV-2 infection group. The vaccine group had the lowest proportion of immunoglobulin and glucocorticoid use, mechanical circulatory support, and cardiogenic shock. Conclusion: Our study showed favorable outcomes of myocarditis in patients with COVID-19 mRNA vaccination, despite a higher incidence than pre-COVID controls. Further studies with standardized myocarditis diagnostic criteria outcomes are

Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome (PIMS), is a new postinfectious illness associated with COVID-19, affecting children after SARS-CoV-2 exposure. The hallmarks of this disorder are hyperinflammation and multisystem involvement, with gastrointestinal, cardiac, mucocutaneous, and hematologic disturbances seen most commonly. Cardiovascular involvement includes cardiogenic shock, ventricular dysfunction, coronary artery abnormalities, and myocarditis. Now entering the fourth year of the pandemic, clinicians have gained some familiarity with the clinical presentation, initial diagnosis, cardiac evaluation, and treatment of MIS-C. This has led to an updated definition from the Centers for Disease Control and Prevention in the USA driven by increased experience and clinical expertise. Furthermore, the available evidence established expert consensus treatment recommendations supporting a combination of immunoglobulin and steroids. However, the pathophysiology of the disorder and answers to what causes this remain under investigation. Fortunately, long-term outcomes continue to look promising, although continued follow-up is still needed. Recently, COVID-19 mRNA vaccination is reported to be associated with reduced risk of MIS-C, while further studies are warranted to understand the impact of COVID-19 vaccines on MIS-C. We review the findings and current literature on MIS-C, including pathophysiology, clinical features, evaluation, management, and medium- to long-term follow-up outcomes.