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Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with substantial cardiovascular implications. Although infection with SARS-CoV-2 is usually mild in children, some children later develop a severe inflammatory disease that can have manifestations similar to toxic shock syndrome or Kawasaki disease. This syndrome has been defined by the US Centers for Disease Control and Prevention as multisystem inflammatory syndrome in children. Although the prevalence is unknown, >600 cases have been reported in the literature. Multisystem inflammatory syndrome in children appears to be more common in Black and Hispanic children in the United States. Multisystem inflammatory syndrome in children typically occurs a few weeks after acute infection and the putative etiology is a dysregulated inflammatory response to SARS-CoV-2 infection. Persistent fever and gastrointestinal symptoms are the most common symptoms. Cardiac manifestations are common, including ventricular dysfunction, coronary artery dilation and aneurysms, arrhythmia, and conduction abnormalities. Severe cases can present as vasodilatory or cardiogenic shock requiring fluid resuscitation, inotropic support, and in the most severe cases, mechanical ventilation and extracorporeal membrane oxygenation. Empirical treatments have aimed at reversing the inflammatory response using immunomodulatory medications. Intravenous immunoglobulin, steroids, and other immunomodulatory agents have been used frequently. Most patients recover within days to a couple of weeks and mortality is rare, although the medium- and long-term sequelae, particularly cardiovascular complications, are not yet known. This review describes the published data on multisystem inflammatory syndrome in children, focusing on cardiac complications, and provides clinical considerations for cardiac evaluation and follow-up.

Background:Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries.Methods and Results:To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and long-term outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized asZscores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up.Conclusions:These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances.

Background— Up to 25% of patients with untreated Kawasaki disease (KD) and 5% of those treated with intravenous immunoglobulin will develop coronary artery aneurysms. Persistent aneurysms may remain silent until later in life when myocardial ischemia can occur. We sought to determine the prevalence of coronary artery aneurysms suggesting a history of KD among young adults undergoing coronary angiography for evaluation of possible myocardial ischemia. Methods and Results— We reviewed the medical histories and coronary angiograms of all adults Conclusions— Coronary sequelae of KD are present in 5% of young adults evaluated by angiography for myocardial ischemia. Cardiologists should be aware of this special subset of patients who may benefit from medical and invasive management strategies that differ from the strategies used to treat atherosclerotic coronary artery disease.

Introduction: Patients with coronary artery aneurysms (CAA) resulting from Kawasaki Disease (KD) are at risk for thrombosis and myocardial infarction. Current guidelines recommend using CAA diameter >8mm as the criterion for initiating systemic anticoagulation, but this is not based on outcome or simulation data. Transluminal Attenuation Gradient (TAG) has been proposed as a non-invasive method for evaluating the functional significance of coronary stenoses from CT Angiography (CTA). However TAG has not been previously used for the assessment of CAA. Hypothesis: We hypothesized that abnormal flow conditions in CAA caused by KD could be quantified using TAG. Methods: We studied 23 patients with a history of KD who had undergone clinically indicated CTA. We quantified TAG in the major coronary arteries by performing linear regression of the average lumen intensity as a function of vessel length. Aneurysm geometry was characterized using maximum aneurysm diameter, aneurysm shape index (ASI) and sphericity index. Results: A total of 41 arteries were analyzed, 22 of which had at least one aneurysmal region. TAG of aneurysmal arteries was significantly lower than in normal arteries (-22.4±10.5 vs. -9.3±10, p=0.0003). Differences were also significant in aneurysmal vs. normal LAD and RCA sub-groups (-26.7±9.7 vs. -16.5±9.0, p=0.02; -14.7±8.2 vs. -0.1±4.4, p=0.001). Aneurysm diameter, ASI, and sphericity index showed little to no correlation with TAG (r2=0.04, r2=0.18, r2=0.17). Conclusions: This study is the first application of TAG in CAA from KD, and demonstrates significantly different TAG values in aneurysmal compared to normal arteries. Lack of correlation between TAG and CAA geometry suggests that TAG may provide information on hemodynamic conditions not available from anatomy alone. The use of TAG in KD patients represents a possible extension to standard CTA that could aid in clinical decision-making and help to better evaluate the risk of thrombus formation.

Objective: We recently defined that a critical mechanism of IVIG therapy in KD patients is the activation and expansion of natural regulatory T cells (nTreg) that recognize the heavy constant region (Fc) of IgG1. Lack of circulating Fc-specific nTreg in the sub-acute phase of KD strongly correlates with arterial complications. Notably, Fc-specific nTreg are always detectable in circulation in healthy donors, suggesting their importance in maintaining vascular homeostasis. Here we aim at the characterization of the fine specificity of these nTreg by testing the immunogenicity of synthetic peptides (> 97% purity) 15 amino acid long, overlapping 10 amino acids, spanning the whole Fc protein. Methods: To define the immunodominat Fc sequences for nTreg expansion, T cell lines have been established with pools of two consecutive overlapping peptides been generated from PBMC ex vivo from: 1) healthy donors, 2) sub-acute KD subjects (2 weeks after IVIG), and 3) KD subjects that received IVIG 1-2 years earlier. IL-10 secretion and CD4+ CD25high T cell expansion have been the read-outs in these experiments. Results: 14 peptides have been defined immunogenic in all the 3 cohorts with several peptides recognized by the large majority of the subject studied, including patients with arterial complication that did not respond to the whole Fc protein. The algorithm prediction of the HLA binding affinity of these nTreg peptide epitopes suggests that these immunodominant regions of the Fc protein are promiscous for HLA binding and very good candidate for future therapeutic use. Clinical relevance of the findings: Immunodominat Fc peptides are an optimized, low cost alternative to IVIG, potentially capable to overcome the lack of nTreg responses in KD patients that develop arterial complications.

Objective: To determine if fever patterns in the first 36 hours after completion of intravenous immunoglobulin (IVIG) for Kawasaki disease (KD), with or without additional infliximab, can predict eventual resistance to treatment and coronary artery abnormalities (CAA). Study design: Subjects with acute KD enrolled in a clinical trial of infliximab plus IVIG (n=96) versus placebo plus IVIG (n=94) had temperatures taken axillary and either oral or rectal every 6 hours after completion of IVIG infusion. Fever was defined as any temperature > 38.0 o C and resistance to treatment was defined as persistent or recrudescent fever ≥36 hours after completion of IVIG. CAA was defined as a Z-score >2.5 based on the maximum internal diameters of the proximal right coronary or left anterior descending artery. Multivariable logistic regression was performed to predict two outcomes (resistance to treatment and development of CAA) by the variables of presence of fever at 0-12, 12-24, and 24-36 hours post IVIG. All analyses were controlled for treatment, age, and sex. Results: After completion of IVIG, 131 subjects (68.9%) had no fever. There was no difference in the median time to defervescence between the infliximab + IVIG group (n=96) versus the IVIG alone group (n= 94). Subjects who had at least one fever at 24-36 hours post-IVIG had a higher probability of having a fever at least 36 hours post-IVIG (p Conclusion: Fevers in the first 12 hours after completion of IVIG are associated with CAA, which can be demonstrated on the initial echocardiogram in the majority of CAA+ subjects. Fever 24-36 hours after IVIG completion is associated with subsequent resistance to treatment, but also occurred in 11% of responders. Our data suggest that patterns of fever can be useful as prognostic indicators of disease outcome in KD patients.

Background: Coronary artery aneurysms (CAA) put patients (pts) at risk for thrombosis and myocardial infarction. Clinical guidelines recommend systemic anticoagulation for giant CAA, diameter ≥ 8mm. Pt-specific modeling and computer simulations in KD pts suggest that hemodynamic data can predict regions with increased risk of thrombus formation and may be superior to simple assessment of the geometry of the aneurysm. Specifically, regions with high Particle Residence Time gradients (PRTg) have correlated with regions of thrombus formation. Methods: Transluminal Attenuation Gradient (TAG) is determined from the change in radiological attenuation on CT angiography (CTA) images in Hounsfield units per vessel length. TAG analysis has been used for characterizing coronary artery stenoses; however this approach has not been used for CAA. We analyzed the correlation between TAG and PRTg in KD pts with CAA and evaluated TAG for prediction of thrombotic risk. Results: Pt-specific anatomic models for flow simulations were constructed from CTA image data from 6 KD pts with CAA and one normal control. TAG was calculated for all aneurysmal vessels and one control vessel. TAG values for the CAA were markedly lower than for the non-aneurysmal vessel (mean -23.76 vs. -2.21). In addition, TAG values were compared to PRTg and other hemodynamic data obtained for each pt. Conclusion: TAG analysis is a new technique that can be applied to pt data obtained non-invasively through CTA. Thrombotic risk stratification for CAA and decisions about whether to start systemic anticoagulation may be improved by incorporating TAG and should be evaluated in future prospective studies.

Background: Echocardiography (echo) is recommended in patients (pts) with KD at baseline, 2 wks, and 6 wks after fever onset to detect coronary artery (CA) abnormalities. However, echo imaging is expensive and in infants and toddlers often requires sedation, which is burdensome and carries some risk. Objective: To assess the benefit of additional echo imaging in uncomplicated KD pts with normal CAs at baseline and 2 wks. Methods: In this retrospective two-center study, eligibility criteria were: 1) admission and treatment at center for acute KD; 2) no significant congenital heart disease; 3) available echo measurements of both the right (R) CA and left anterior descending (LAD) at ≤ Day 10 (baseline), 2 (±1) wks and 6 (±3) wks; and 4) normal CAs = RCA and LAD z scores [zMax] ≤2.0 and no aneurysms. Results: Of 2,600 pts treated for KD from 1976 - 2014, 457 had normal CAs at baseline and 2 wks and met other inclusion criteria. Of these, 57% were male; median age was 3.3 yrs [IQR 1.8 to 5.4 yrs]; 77% had complete KD; and 14% received IVIG retreatment. At 6 wks, 450 (98.5%) had normal CAs. Of the remaining 7 pts, zMax was 2.0-2.4 in 5 (1.1%); their z scores subsequently normalized at 1 yr. The zMax was 2.5-2.9 in 1 (0.2%) pt who remained on low dose aspirin until 6 mos, when ECHO normalized. The zMax was ≥3.0 in 1 pt (0.2%, 95% CI [0.0%, 1.2%]) with a dilated LAD, which was normal 3 wks later. Sensitivity analysis using zMax of Conclusion: New CA abnormalities are rarely detected at 6 wks in KD pts with normal CAs at baseline and 2 wks. The 6 wk echo may be unnecessary for uncomplicated KD pts with normal CAs at baseline and 2 wks. Figure - CA zMax shown as mean (+), median, 25th to 75th %tile.

The human FCGR2/3 locus contains highly homologous genes encoding the five major receptors for IgG (Fc-gamma receptors, FcγRs). In two prior GWAS on Kawasaki disease (KD), a SNP in FCGR2A (131H>R; rs1801274) was identified to be associated with disease susceptibility. However, the FCGR2/3 locus contains multiple single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), which were not covered by the detection platforms used in the GWAS. In this study we therefore focused on further fine-mapping of this locus to investigate the association of the different genetic variations with KD susceptibility. A highly accurate and validated multiplex ligation-dependent probe amplification (MLPA) assay was used to analyze all functionally relevant SNPs and CNVs within this locus. In a genetic association study involving case-control and family-based testing with 1028 patients with KD, the previous finding of FCGR2A-131H as a susceptibility marker for KD was confirmed (OR 1.16; 95%CI 1.08-1.32, meta-P = 0.01). In addition, we found a novel significant association of the FCGR2C-ORF haplotype with susceptibility to KD (OR 1.34; 95% confidence interval 1.11-1.62, meta-P = 0.003). FCGR2C-ORF leads to the expression of an extra, functionally activating FcγR (i.e. FcγRIIc) on myeloid cell types and NK cells. Being absent in Asian individuals, the FCGR2C-ORF haplotype only contributed to KD susceptibility in European subjects, independent of the established association with FCGR2A-H131R. We did not find any significant association of CNV of the locus with susceptibility to KD. Our data point to an important role of the activating FcγRs in KD pathology. We hypothesize that the identified functional SNPs might alter the balance between the activating and inhibitory FcγRs leading to unbalanced inflammation and KD.

Background: Coronary artery aneurysms resulting from vascular inflammation associated with Kawasaki disease (KD) in childhood may remain clinically silent until adulthood. Young adults presenting with large aneurysms, unstable angina, or myocardial infarction (MI) following KD in childhood present unique challenges to the interventional cardiologist and cardiothoracic surgeon. We present a range of management issues raised by this patient population. Methods: Participants who underwent cardiovascular interventions were identified from an observational cohort of 154 individuals with a history of KD enrolled in the San Diego Adult KD Collaborative. Of these 154 participants, 63 (40.9%) were originally diagnosed with KD and followed by one of the co-authors (JCB) and were designated as Cohort 1. The remaining 91 participants (Cohort 2) were referred by their physician or self-referred for participation in the study. Results: Of the 154 participants, 20 (12.9%; 2 from Cohort 1 and 18 from Cohort 2) underwent cardiovascular interventions: 9 had percutaneous interventions and 11 had surgery. Twelve participants had been diagnosed with KD in childhood, 7 had a history of a KD-compatible illness in childhood, and 1 had proximal coronary artery aneurysms compatible with KD. Fourteen participants were asymptomatic until experiencing a major cardiovascular event: 8 presented with an acute MI, 3 presented with angina, 1 presented with end-stage congestive heart failure requiring cardiac transplantation, and 2 presented with extremity claudication. Conclusions: Cardiovascular complications in individuals with a history of KD illustrate the following points: 1) Even small to moderate-sized aneurysms that “normalize” by echocardiography in childhood can lead to stenosis and thrombosis decades after the acute illness; 2) Coronary interventions without intravascular ultrasound may result in underestimation of vessel lumen diameter; 3) Failure to assess the extent of calcification may lead to suboptimal procedural outcomes, and 4) Patients with symptomatic peripheral aneurysms may benefit from endarterectomy or resection. Interventional cardiologists should be aware of the complications encountered in this growing population of young adults.

Background: Tropospheric winds from northeastern China have been linked to fluctuations in Kawasaki disease (KD) cases in Japan. These winds may carry aerosols that trigger KD in genetically susceptible children. We investigated whether reduced numbers of KD cases were linked to large scale circulation patterns affecting the U.S. West Coast. Methods: KD cases with either date of onset of fever or date of hospitalization (PHIS, Pediatric Health Information System) were obtained from 5 sites from Seattle to San Diego from 1995-2014. Six days were subtracted from date of hospitalization to approximate date of onset. For each site, periods from December-March were identified for which there were no KD cases for an interval of ≥10 days, called “KD dry spells”. Daily NCEP-NCAR atmospheric Reanalysis 700hPa height anomalies were used to represent the atmospheric circulation. Results: From 27-48 dry spells were defined for each site. Composites of atmospheric circulation from Day -20 to Day +10 relative to first day of a dry spell were created for each study site. The atmospheric circulation preceding the KD dry spell featured a higher than normal pressure center (results in weakened onshore flow) either offshore over the North Pacific or directly over the site. The circulation anomalies were statistically significant, and unlikely to have occurred by chance. The dry spell pattern intensified and persisted over several days. The strongest anomalous atmospheric circulation (and associated blocked wind flow) occurred between Day -6 to -1 relative to the start of the dry spell. A similar pattern was shared by 4 of the 5 sites. One site featured strong high pressure anomalies > 6 days before the KD dry spells, but only a weak anomaly in the Day -6 to-1 interval preceding the dry spell. Conclusion: This analysis reinforces results from previous studies of KD case fluctuations in Japan wherein anomalous KD activity was associated with particular wind flow patterns. The circulation patterns associated with the West Coast KD “dry spells” suggest that reduced wind flow from the North Pacific results in reduced KD occurrences. These results support the hypothesis that a KD agent is transported by winds, possibly from a shared source region with transport of the agent across the Pacific.

Background: The endothelium is a single layer of epithelial cells that lines the blood vessels and is a major component in maintaining vascular homeostasis. Impaired endothelial cell (EC) function can contribute to cardiovascular disease states, but whether there is an association between endothelial dysfunction and the presence of coronary artery aneurysms after Kawasaki disease (KD) is unknown. Methods: We enrolled 110 teens and young adults, ages 16 to 30 years, with a history of KD (61% male), as well as 30 healthy controls (HC, 53% male). EC function (reactive hyperemic response after a 5 minutes brachial artery occlusion) was measured using the EndoPAT 2000. Reactive hyperemia index (RHI) and PAT ratios were determined. KD subjects were categorized based on their worst coronary artery status (normal, transiently dilated/resolved aneurysm, aneurysm). Results: The mean age of KD subjects and HC at the time of EndoPAT was 25 ± 9 and 26 ± 7 years, respectively (p=0.42). Mean time since onset of KD was 23 ± 19 years. Subjects with a history of transiently dilated/resolved aneurysms had a higher mean lnRHI compared to other KD subjects (0.91 vs 0.74, p=0.01) and HC (0.72, p=0.02). When PAT ratio was evaluated as a function of time after occlusion release, those with transiently dilated/resolved aneurysms had a trend toward a more favorable profile while other groups appeared similar (Figure). Conclusion: Most young adults with a history of KD have normal EC function. Individuals with a history of transiently dilated coronary arteries had a paradoxical trend toward better EC function, which may indicate healthier vasculature. The significance of this finding merits further study.

Background: ITPKC controls calcium homeostasis and was identified in genome-wide studies to be associated with susceptibility and severity of KD. NLRP3 is activated by danger signals, leading to inflammasome activation and release of IL-1beta and IL-18. Ca 2+ mobilization mediates NLRP3 activation. We studied the contribution of ITPKC and NLRP3 inflammasome activation in KD. Methods: Cytokine levels were measured using ELISA. Gene expression was assayed using Illumina HumanHT-12v4. EBV-transformed B-cell lines from KD patients with different ITPKC genotypes were used to study the gene and protein expression and Ca 2+ flux using qRT-PCR, Western blot analysis, and FACS respectively. In vivo and in vitro analyses from ITPKC-deficient and wildtype mice were performed using ELISA, spinning disc confocal and Westerns, to determine cytokine release, Ca 2+ flux and protein expression responses respectively. Results: Children with KD show increased circulating IL-1beta, IL-18, IL-1RA and IL18BP protein during acute phase of KD (KD n=48, febrile controls n=41 p2+ ] i mobilization resulting in NLRP3 activation and increased production of IL-1beta and IL-18, as demonstrated by gene expression, circulating protein levels and functional assays of PBMCs and immortalized cell lines from affected children. These biologic data are partnered with evidence showing resistance to IVIG therapy in those with the ITPKC polymorphism associated with the highest basal and stimulated [Ca 2+ ] i levels. Studies using ITPKC-deficient mice in an animal model of KD support the molecular, cellular and clinical findings in affected children. Significance: ITPKC regulates NLRP3 activation via control of [Ca 2+ ] i mobilization, directing production of IL-1beta and IL-18, pointing to the key role of calcium mobilization in the immunopathogenesis of KD.

Background: Kawasaki disease (KD) shares many clinical features with other pediatric febrile illnesses (FC). Clinical confusion can lead to a missed or delayed diagnosis that increases the risk of coronary artery damage. In the present study, we improved our previous KD diagnostic algorithm for point-of-care diagnosis. Methods and Results: We reviewed clinical records of 534 acute KD and 318 FC patients (development dataset) and subsequent 268 acute KD and 161 FC patients (validation dataset). KD subjects met the American Heart Association definition. Using clinical data and lab test results, we integrated our previously developed linear discriminant analysis (LDA)-based clinical model with a newly developed decision tree-based algorithm to improve KD diagnosis. To train the decision trees, sub cohorts were constructed based upon the 5 KD classic criteria. Our 1 st clinical model (LDA) stratified the subjects into FC (FC diagnosis, negative predictive value NPV >=95%), undecided (88/802 KD, 167/479 FC), and KD (KD diagnosis, positive predictive value PPV >=95%) subgroups. The subsequent 2 nd clinical model (decision trees) further classified the undecided group into FC, undecided, and KD subgroups, resulting in a much-improved algorithm with only 59/479 FC (Specificity>76%) and 26/802 KD (Sensitivity>95%) undetermined. Conclusions: Our computer-based algorithm that incorporates only clinical findings and readily available clinical laboratory data now has sufficient sensitivity and specificity in distinguishing acute KD from FC patients that a multicenter, prospective clinical trial is warranted to test the performance of the diagnostic algorithm against the gold standard of expert clinical opinion.

Background: Incomplete KD, as well as a higher incidence of CAA, has been reported to occur more commonly in infants ≤ 6 months (mos), but only small case series have been published. We characterized the KD course in infants ≤6 mos and compared to outcomes in KD pts >6 mos. Methods: We retrospectively reviewed the course of 88 subjects ≤ 6 mos diagnosed with KD between January 2004 and December 2013 at Children’s Orange County (CHOC) and Rady Children’s Hospital San Diego (RCHSD) and compared to 632 subjects >6 mos at RCHSD. Complete and incomplete KD cases were defined based on the 2004 AHA guidelines. Subjects were classified by coronary artery (CA) status (normal, dilated, or aneurysmal CA based on RCA and LAD measurements) and by Z-score (RCHSD only). IVIG resistance was defined as fever ≥38C at least 36 hours after completion of IVIG. Fisher’s Exact test was used for comparisons. Results: Of the 88 infants, 62 (70.4%) were male and 76 (86.3%) were treated at ≤ 10 days of illness. Treatments in the 88 pts were as follows: IVIG responder: 55(62.5%); IVIG resistant: 13(14.7%); infliximab for cardiac indications: 16 (18.2%); late treatment >10days: 2 (2.3%); not treated: 2 (2.3%). Infliximab was administered to a total of 27 pts (30.7%) and was well-tolerated with rash as the only adverse event in 1 pt. Worst CA status was “normal” in 37 (42.1%), dilated in 29 (32.9%), aneurysm in 15 (17.1%) and giant aneurysm in 7 (7.9%) pts. Of the 48 pts at RCHSD who presented within the first 10 days of illness, only 26 (54.2%) had a Z-score 6 mos RCHSD cohorts, there were no significant differences in number of pts treated within the first 10 days of illness (48/53, 90.5% vs. 545/632, 86.2%) or pts having incomplete presentations (12/53, 22.6% vs. 106/632, 16.8%). Conclusions: There were no significant differences in the rate of incomplete KD or rate of diagnosis within the first 10 days of illness in children ≤6 mos vs. >6 mos. Infliximab use in 30.7% of the ≤6 mos old pts was safe. Infants ≤6 mos had a high rate of aneurysms (22/88, 25%) despite timely diagnosis and treatment. Better treatments are needed for this high risk group of KD pts.

Background: Histologic study of inflamed coronary arteries from the Kawasaki disease (KD) patients shows infiltration by immune effector cells, IL-17-producing myofibroblasts, and breaks in the internal elastic lamina. Transcripts from genes associated with cell trafficking (e.g. paxillin) are elevated in whole blood from acute KD patients. Lysyl oxidase (LOX) is a multifunctional protein affecting affecting “monocyte and smooth muscle cell migration, elastogenesis, and endothelial-to-mesenchymal transition. LOX promotes cell motility through paxillin phosphorylation, which influences T-cell trafficking via the calcium signaling pathway. We investigated the role of LOX in the pathogenesis of KD. Methods: Agilent microarray data using whole blood were analyzed for differential expression of enzymes in the LOX family (LOX, LOX-like (L)1-4) in acute and convalescent KD samples (n=19). LOXL1 results were validated using RT-PCR in an independent cohort (n=20). LOXL1 transcripts levels were measured in KD whole blood, peripheral blood mononuclear cells (PBMC), T-cell clones, B-cell lines, and myeloid dendritic cells from acute KD patients. Immunohistochemical staining for LOXL1 was performed on coronary arteries from a KD patient who died on illness day 7. Result: LOXL1 expression by microarray was 3.2-fold higher in acute than convalescent samples (p Conclusion: LOXL1 may increase inflammation in acute KD by promoting the motility of infiltrating T cells and smooth muscle cells through focal adhesion formation. However, LOXL1 may also participate in arterial wall repair by crosslinking collagen and elastin. Statins inhibit focal adhesion formation and thus cell trafficking but not the crosslinking mediated by LOXL1. Studies of LOXL1 protein levels and paxillin phosphorylation in PBMC may further our understanding of their role in KD pathogenesis.

Background: Although high-dose intravenous immunoglobulin plus aspirin reduces the risk of coronary artery damage, 5-10% of children with Kawasaki disease (KD) will go on to develop coronary artery aneurysms that may result in myocardial ischemia, infarction, or death. Arterial damage in KD results from immune activation and vessel wall infiltration by myofibroblasts, neutrophils, and T-cells with secretion of pro-inflammatory cytokines, elastases, and matrix metalloproteinases. Resolution of inflammation and recovery from the acute illness occurs through T-cell regulation. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, have extensive anti-inflammatory effects that target all of these pathways. These effects are independent of their cholesterol-lowering effect. Given these anti-inflammatory effects, statins would be a reasonable therapy to block coronary artery abnormality (CAA) progression in KD Methods: We designed a Phase I/IIa, two-center, dose-escalating, 6-week open-label study of atorvastatin. Acute KD patients within the first 20 days after fever onset are eligible if they are between the ages of 2 and 17 years old, have had fever for ≥ 3 days, and have ≥ 2 clinical criteria with LAD/RCA z-score ≥ 2.5 or a coronary artery aneurysm (≥ 1.5 x the adjacent segment). Dose escalation (0.125-0.75 mg/kg/day) follows a 3+3 design with evaluations for dose limiting toxicities at 2 and 6 weeks after enrollment. The primary outcome measure is safety with secondary outcome measures including the pharmacokinetics (PK) of atorvastatin, changes in measures of oxidative stress and inflammation, enumeration and characterization of regulatory T-cells, and echocardiographic changes in the internal diameter of the coronary arteries. Results: To date we have enrolled 9 subjects, 7 at Rady Children’s Hospital San Diego and 2 at Children’s Hospital Colorado. The median age at enrollment was 4 years with 5/9 (55%) males and a median illness day at enrollment of 6 days. The median baseline Z worst score was 3.5. The study is currently enrolling at the second dose level. Conclusions: The safety, tolerability, and PK of atorvastatin for acute KD patients will be established by this clinical trial.

Background: Measuring carotid strain is a noninvasive way to assess the mechanical properties of the arterial wall. Whether there is an association between carotid strain and coronary artery status after Kawasaki disease (KD) is unknown. Methods: We enrolled 82 young adults, ages 15 to 30 yrs, with a history of KD (58% male), as well as 16 healthy controls (HC) of similar age (56% male). Carotid wall strain was measured from cine loops of common carotid artery B-mode ultrasound data using an offline optical flow analysis algorithm. Strain was normalized for age (Z-score) using a regression equation derived from a separate series of healthy young adults. Subjects were categorized based on their worst coronary artery status (normal, transiently dilated, aneurysm). Results: The mean age of KD subjects and HC at the time of carotid measurements was 25 ± 8 and 28 ± 8 years, respectively (p=0.30). Mean time since onset of KD was 20 ± 8 yrs. KD subjects with transiently dilated coronary arteries had significantly higher carotid strain compared to those with normal coronaries (p=0.002) and to HC (p=0.01) (Figure); those with CAA had a nonsignificant trend toward lower carotid strain compared to other groups. KD subjects with normal coronaries had carotid strain similar to HC. Conclusion: Young adults with a history of KD with normal coronary arteries also have normal carotid artery strain. Individuals with a history of transiently dilated coronary arteries had a paradoxical trend toward higher carotid strain. Thus, KD patients whose dilated coronary arteries return to normal may have healthier vasculature compared to other KD patients. The significance of this finding merits further study.

Background: As a result of the acute vasculitis associated with Kawasaki disease (KD), subsets of patients with a remote history of KD have coronary artery aneurysms and may develop coronary artery stenoses with associated risks of late morbidity. Hence, there is a need for effective non-invasive testing to detect coronary artery pathology and risk stratify patients with a remote history of KD. In a pilot study we previously showed that computed tomography (CT) coronary artery calcium (CAC) scoring with relatively low radiation doses detects late CAC in patients with aneurysms and a remote history of KD. Methods: We performed CT calcium volume scoring in 166 subjects (median age 19.5 years) with a remote history of KD (median interval from onset of KD to CT 15.1 years). Coronary arteries were classified as normal (n = 100), transiently dilated (n = 23), persistently dilated (n = 10), resolved aneurysm (n = 9), or aneurysm (n = 24) based on the initial echocardiograms. We defined coronary artery pathology as the presence of a coronary artery aneurysm or stenosis. Results: All subjects with coronary arteries classified as normal, persistently dilated, or resolved aneurysm had zero CAC. All but one of the subjects with transiently dilated coronary arteries had zero CAC (the one subject with a CAC score of 666 mm 3 had a history of severe left main coronary artery stenosis requiring bypass surgery). Of the 24 subjects with coronary aneurysms, all but 5 had CAC (median volume score 542 mm 3 ; range 17 mm 3 to 8,218 mm 3 ). Four of the 5 subjects with aneurysms and no CAC were imaged within 6 years of their episode of acute KD. For subjects imaged 9 or more years after their acute KD (n=144), the presence of CAC on CT had a sensitivity of 95% and a specificity of 100% for detecting coronary artery pathology. Conclusions: For patients with a remote history of KD, CT calcium scoring is a sensitive and specific test for detecting coronary artery pathology. Patients with coronary artery aneurysms secondary to KD develop late CAC, which may be severe. The pathophysiology and clinical significance of this calcification are currently unknown.

Background— Despite advances in medical, surgical, and critical care interventions, infective endocarditis remains a disease that is associated with considerable morbidity and mortality. The continuing evolution of antimicrobial resistance among common pathogens that cause infective endocarditis creates additional therapeutic issues for physicians to manage in this potentially life-threatening illness. Methods and Results— This work represents the third iteration of an infective endocarditis “treatment” document developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It updates recommendations for diagnosis, treatment, and management of complications of infective endocarditis. A multidisciplinary committee of experts drafted this document to assist physicians in the evolving care of patients with infective endocarditis in the new millennium. This extensive document is accompanied by an executive summary that covers the key points of the diagnosis, antimicrobial therapy, and management of infective endocarditis. For the first time, an evidence-based scoring system that is used by the American College of Cardiology and the American Heart Association was applied to treatment recommendations. Tables also have been included that provide input on the use of echocardiography during diagnosis and treatment of infective endocarditis, evaluation and treatment of culture-negative endocarditis, and short-term and long-term management of patients during and after completion of antimicrobial treatment. To assist physicians who care for children, pediatric dosing was added to each treatment regimen. Conclusions— The recommendations outlined in this update should assist physicians in all aspects of patient care in the diagnosis, medical and surgical treatment, and follow-up of infective endocarditis, as well as management of associated complications. Clinical variability and complexity in infective endocarditis, however, dictate that these guidelines be used to support and not supplant physician-directed decisions in individual patient management.

We read with interest the article by Meyer et al1 describing the incidence, causes, and survival trends from cardiovascular-related sudden cardiac arrest among children and young adults younger than 35 years of age. We were surprised to note that over this 30-year period, no cardiac arrests attributed to missed Kawasaki disease were identified. Kawasaki disease, the most common cause of acquired heart disease in US children, is an acute febrile …

Background—The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for the prevention of infective endocarditis that were last published in 1997.Methods and Results—A writing group was appointed by the AHA for their expertise in prevention and treatment of infective endocarditis, with liaison members representing the American Dental Association, the Infectious Diseases Society of America, and the American Academy of Pediatrics. The writing group reviewed input from national and international experts on infective endocarditis. The recommendations in this document reflect analyses of relevant literature regarding procedure-related bacteremia and infective endocarditis, in vitro susceptibility data of the most common microorganisms that cause infective endocarditis, results of prophylactic studies in animal models of experimental endocarditis, and retrospective and prospective studies of prevention of infective endocarditis. MEDLINE database searches from 1950 to 2006 were done for English-language papers using the following search terms: endocarditis, infective endocarditis, prophylaxis, prevention, antibiotic, antimicrobial, pathogens, organisms, dental, gastrointestinal, genitourinary, streptococcus, enterococcus, staphylococcus, respiratory, dental surgery, pathogenesis, vaccine, immunization, and bacteremia. The reference lists of the identified papers were also searched. We also searched the AHA online library. The American College of Cardiology/AHA classification of recommendations and levels of evidence for practice guidelines were used. The paper was subsequently reviewed by outside experts not affiliated with the writing group and by the AHA Science Advisory and Coordinating Committee.Conclusions—The major changes in the updated recommendations include the following: (1) The Committee concluded that only an extremely small number of cases of infective endocarditis might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100% effective. (2) Infective endocarditis prophylaxis for dental procedures is reasonable only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis. (3) For patients with these underlying cardiac conditions, prophylaxis is reasonable for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. (4) Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of infective endocarditis. (5) Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. These changes are intended to define more clearly when infective endocarditis prophylaxis is or is not recommended and to provide more uniform and consistent global recommendations.

Despite 50 years of research, the cause of Kawasaki disease (KD), the most common cause of acquired heart disease in children, remains a mystery. Fueled by epidemiological and clinical clues that the disease is triggered by an infectious agent that elicited a dramatic immune response in genetically susceptible children, investigators vigorously searched for the responsible agent.1 Thus far, a long list of discarded pathogens is all that remains of these attempts to find the inflammation-causing agent. Application of reverse genetics to engineer synthetic antibodies to track down a putative new virus has shown some promise, but the agent remains elusive.2 Article see p 1542 In the absence of knowledge of the etiologic agent, animal models were created that recapitulate the pathological changes observed in human tissues. KD was a prime candidate for modeling: The disease was rarely fatal, so well-preserved autopsy tissues were difficult to find; the primary target of the vasculitis, the coronary arteries, could not be biopsied in living children; and a better understanding of disease pathogenesis was needed to devise new therapeutic approaches. It was in the spirit of meeting these challenges that 2 major mouse models of KD were created. The first, created by …

BACKGROUND Delineation of lipid values in children after Kawasaki syndrome is important because of the predilection of this disease for the coronary arteries. METHODS AND RESULTS We measured plasma concentrations of total cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides using enzymatic methods in 105 patients with a history of Kawasaki syndrome. Measurements were obtained during six time periods: 10 days or less, 11-31 days, 1-3 months, 3-12 months, 1-3 years, and more than 3 years. Total cholesterol was depressed in the first interval (122.0 +/- 19.8 mg/dl, mean +/- SD), but the mean values were normal in all periods after clinical recovery (overall mean, 149.0 +/- 24.0 mg/dl). High density lipoprotein cholesterol was also depressed in the first interval (15.2 +/- 9.9 mg/dl); although high density lipoprotein cholesterol increased significantly with duration since disease onset (p less than 0.001), it remained significantly lower than expected (p less than 0.001), even in the latest interval (47.2 +/- 10.9 mg/dl). Nonfasting triglyceride levels were high (162.5 +/- 63.4 mg/dl) in the first interval and then diminished steadily with time, but this relation did not achieve statistical significance. We compared adjusted lipid levels (z scores) of 46 Kawasaki patients after clinical recovery with those of their parents; patients had similar total cholesterol levels but significantly lower high density lipoprotein cholesterol levels (p = 0.021 for mothers, p = 0.001 for fathers). Mean high density lipoprotein cholesterol after clinical recovery tended to be lower in patients with persistent coronary abnormalities than in those without such lesions (p = 0.085). CONCLUSIONS Kawasaki syndrome is associated with important abnormalities in lipid metabolism. Continued long-term surveillance of this population is necessary to monitor lipid levels and their relation to future development of coronary atherosclerosis.

To investigate the effect of Kawasaki syndrome on myocardial function, as well as the influence of high-dose intravenous gamma-globulin therapy on resolution of functional abnormalities, we studied 98 patients with Kawasaki syndrome during five time intervals from onset of illness: 1) 10 days or less, 2) 11-31 days, 3) 1-3 months, 4) 3-12 months, and 5) 1-3 years. Normal controls included 48 children under age 8 years, without known cardiovascular disease. Using two-dimensional directed M-mode echocardiograms, we obtained chamber dimensions, fractional shortening, rate-corrected velocity of shortening (Vcfc) adjusted for end-systolic wall stress, and early diastolic function parameters that included adjusted peak rates of left ventricular dimension change, wall thinning, and their respective timing. Left ventricular systolic and diastolic dimensions were larger (both p less than 0.01) in patients than in normal subjects in period 1. Stress-adjusted Vcfc was much lower in patients in the 3 months after disease onset; by period 5, contractility was comparable in patients and normal subjects. Adjusted indexes of early diastolic function did not differ significantly between patients and normal subjects. To investigate the effect of gamma-globulin, we analyzed data on 47 patients prospectively randomized to therapy with aspirin alone (n = 19, 40%) or to aspirin plus gamma-globulin, 400 mg/kg/day for 4 consecutive days (n = 28, 60%). In period 1, before treatment, the two groups had mean fractional shortening and stress-adjusted Vcfc comparable to each other but much lower than those of normal subjects (p less than or equal to 0.001). Patients treated with aspirin alone continued to have diminished fractional shortening and Vcfc compared with normal subjects in periods 2, 3, and 4 (all p less than or equal to 0.05). In contrast, fractional shortening and Vcfc in gamma-globulin-treated patients in these periods were comparable to those of normal subjects. By period 5, no difference was detected in systolic function or contractility between either treatment group and normal subjects. We conclude that early abnormalities of left ventricular contractility and myocardial function, as assessed by echocardiography, generally resolve by 1-3 years after disease onset and that recovery is accelerated by administration of IVGG in the acute phase.