bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 210: Kawasaki Disease in Patients Older Than 10-years Old in a Children’s Hospital In Mexico City
Authors: RIOS-OLIVARES ITZEL E , GARRIDO-GARCIA LUIS M
Published: July 2021

Background:
Kawasaki Disease (KD) is an acute febrile illness characterized by systemic vasculitis of unknown etiology. Cardiac sequelae, such as coronary artery aneurysms (CAA), are one of the most important aspects of this disease. Actually KD is most frequently presented in children younger than 5-years old.

Objective:
To describe the clinical and laboratory features, cardiac sequelae and outcome in children older than 10-years old with KD who were attended at the Instituto Nacional de Pediatría in Mexico City.

Methods:
An observational, descriptive, retrospective and transversal case study. We reviewed the medical records of patients older than 10-years diagnosed with KD from August 1995 to May 2014, and analyzed gender, age, clinical manifestations, hemoglobin, leucocyte count, platelet count, ESR, CRP, albumin, sodium, potassium, AST, ASL, time from the onset of the symptoms to diagnosis, treatment used, the development of CAA and outcome in the acute phase of the disease.

Results:
We studied 18 cases of KD in patients older than 10-years old, 72.2% (13 of 18) were male with a mean age of 154 months (range 120 to 200). The time from the onset of the fever to diagnosis was 10.6 ± 5.8 days, (range 3 to 21 days). Skin lesions were the most common manifestation of KD and cervical lymphadenopathy was the least common clinical feature. 2 patients presented with KD shock syndrome. Complete KD was diagnosed in only 50% (9 of 18) of our cases. 16 patients received IVGG, 2 patients required a second GGIV dose and 10 patients also received steroids. 6 of 18 patients (30%) developed CAA. There were no deaths in our group.

Conclusions:
KD in patients older than 10-years old represent a clinical challenge because in the majority of the cases they presented with an atypical clinical picture which contribute to a delayed diagnosis. Also there is an increased risk of developing cardiac complications and CAA in this group of patients.
Abstract 34: Genome-wide Association Study Identified New Susceptibility Loci To Coronary Artery Aneurysm-related In Kawasaki Disease
Authors: Kim Kyu Yeun , Jung Mo Kyung , Bae Yoon-Sun , Ji Woohyuk , Shin Dongjik , Yoo Byungwon , Kim Ki Hwan , Kim Dong Soo
Published: July 2021

Kawasaki disease (KD) is an acute systemic vasculitis syndrome that predominantly affects children younger than 5 years of age, and may causes serious, sometimes life-threatening, cardiac sequela associated with coronary artery aneurysm (CAA). To identify genetic variants that confers a highly increased risk of coronary artery aneurysm-related in Kawasaki disease. In this study, we carried out genome-wide association study (GWAS) in a Korean children population including 102 CAA-related KD cases and 126 controls. Fifteen genetic loci were found to be significantly correlated with KD risk (P<1.0X10(-7)). Our case-control study revealed that rs4236089 C allele in chloride intracellular channel 5 (CLIC5) gene at 6p21.1 was significantly associated with KD patients with CAA (odds ratio (OR)=4.6, P=7.53X10(-7)). These findings suggest that the CLIC5 gene may play a crucial role in CAA development pathway of KD.
Abstract 35: Common Variants in the CRP Promoter are Associated with a High C-reactive Protein Level in Kawasaki Disease
Authors: Kim Jae-Jung , Yun Sin Weon , Yu Jeong Jin , Yoon Kyung Lim , Lee Kyung-Yil , Kil Hong-Ryang , Kim Gi Beom , Hong Young Mi , Jang Gi Young , Lee Jong-Keuk ,   The Korean Kawasaki Disease Genetics Consortium
Published: July 2021

Kawasaki disease (KD) is an acute self-limiting form of vasculitis that afflicts infants and children and manifests as fever and signs of mucocutaneous inflammation. Children with KD show various laboratory inflammatory abnormalities, such as elevations in their white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). We here performed a genome-wide association study (GWAS) of 178 KD patients to identify the genetic loci that influence 10 important KD laboratory markers: WBC count, neutrophil count, platelet count, CRP, ESR, hemoglobin (Hb), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and total protein. A total of 165 loci passed our arbitrary stage 1 threshold for replication (
p
< 1 * 10
-5
). Of these, only 2 SNPs (rs12068753 and rs4786091) demonstrated a significant association with the CRP level in replication study of 473 KD patients (
p
< 0.05). The SNP located at the
CRP
locus (rs12068753) demonstrated the most significant association with CRP in KD patients (beta = 4.73 and
p
= 1.20 * 10
-6
according to the stage 1 GWAS; beta = 3.65 and
p
= 1.35 * 10
-8
according to the replication study; beta = 3.97 and
p
= 1.11 * 10
-13
according to combined analysis) and explained 8.1% of the phenotypic variation observed. However, this SNP did not demonstrate any significant association with CRP in the general population (beta = 0.37 and
p
= 0.1732) and only explained 0.1% of the phenotypic variation in this instance. Furthermore, rs12068753 did not affect the development of coronary artery lesions or intravenous immunoglobulin resistance in KD patients. These results indicate that common variants in the
CRP
promoter can play an important role in the CRP levels in KD.
Abstract 36:
FCGR2A
Promoter Methylation and Risks for IVIG Unresponsiveness in Kawasaki Disease
Authors: Kuo Ho-Chang , Hsieh Kai-Sheng , Chang Wei-Chiao ,   Kawasaki Disease Cntr, Kaohsiung Chang Gung Memorial Hosp, Taiwan
Published: July 2021

Kawasaki disease (KD) is characterized by pediatric systemic vasculitis of an unknown cause and the Fc Fragment of IgG, Low Affinity IIa, Receptor (
FCGR2A
) gene was reported to involve in increasing susceptibility of KD. Because DNA methylation is one of the epigenetic mechanisms that control gene expression, we hypothesized that methylation status of CpG islands in
FCGR2A
promoter predisposes an individual to Kawasaki disease.

We recruited 36 KD patients and 24 healthy subjects with informed consents. And eleven potential methylation loci within the targeted promoter region (chr1:161474603-161475102) of Fc Fragment of IgG, Low Affinity IIa, Receptor were selected for investigation.

Methylation at the CpG sites G, H and J displayed a strongly associations with KD, whereas CpG sites B,C,E,F,H,J and K were found to be correlated with non-responsive to IVIG treatment. In addition, CpG sites G, J and K were predicted as the significant transcription factor binding site for NF-kB, Myc-Max and SP2 respectively.

Our study reports a significant association between the promoter methylation of
FCGR2A
, susceptibility of Kawasaki disease and therapeutic outcomes of IVIG treatment. The methylation levels of CpG sites of
FCGR2A
gene promoter may be an important marker for optimizing IVIG therapy.
Abstract 38: Variations in ORAI1 gene associated with Kawasaki disease
Authors: Onouchi Yoshihiro , Fukazawa Ryuji , Yamamura Kenichiro , Suzuki Hiroyuki , Suenaga Tomohiro , Takeuchi Takashi , Yoshikawa Norishige , Hamada Hiromichi , Honda Takafumi , Yasukawa Kumi , Terai Masaru , Ebata Ryota , Higashi Kouji , Saji Tsutomu , Kemmotsu Yasushi , Takatsuki Shinichi , Ouchi Kazunobu , Kishi Fumio , Yoshikawa Tetsushi , Nagai Toshiro , Hamamoto Kunihiro , Sato Yoshitake , Honda Akihito , Kobayashi Hironobu , Sato Junichi , Shibuta Shoichi , Miyawaki Masakazu , Oishi Ko , Yamaga Hironobu , Aoyagi Noriyuki , Iwahashi Seiji , Murata Yuji , Fujino Akihiro , Ozaki Kouichi , Kawasaki Tomisaku , Abe Jun , Seki Mitsuru , Kobayashi Tohru , Arakawa Kouichi , Ogawa Shunichi , Hara Toshiro , Hata Akira , Tanaka Toshihiro ,   Japan Kawasaki Disease Genome Consortium
Published: July 2021

Kawasaki disease (KD; MIM611775) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD have suggested up-regulation of Ca2+/NFAT pathway as one of the main pathophysiological processes in KD. In this study, we focused on ORAI1, a gene for a channel involved in store operated Ca2+ entry located on 12q24 where positive linkage signal was seen in our previous sib pair study of KD, and conducted a genetic association study. By re-sequencing 17.4kb of ORAI1 region for 94 subjects, we identified 37 variants with minor allele frequencies larger than 0.05. After selecting 9 tagging SNPs which represent 37 variants we performed an association study using 730 KD cases and 1315 controls. As a result, one tagging SNP located within exon2 showed nominal association (rs3741596; OR = 1.19, 95%CI 1.02~1.40, P = 0.028). The same trend of association was observed in an independent case control panel (1813 KD cases and 1097 controls, OR=1.22, 95% CI 1.06-1.40, P = 0.0056) and a significant P value was observed in a meta-analysis (OR = 1.21, 95%CI 1.09~1.34, P = 0.00041). Furthermore, we also found a rare 6 base-pair insertion polymorphism which cause elongation of proline repeat within N-terminal cytoplasmic domain of the ORAI1 protein was overrepresented in KD cases (rs78448924; OR = 3.91, 95%CI 1.30~11.80, P=0.010). These data indicate altered ORAI1 function confers susceptibility of KD and further highlight importance of the Ca2+/NFAT pathway in the disease pathogenesis.
Abstract 41: Evidence Against Mycoplasma pneumonia as An Etiologic Agent of Kawasaki Disease
Authors: Dominguez Samuel R , Anderson Marsha S , Heizer Heather R , Jone Pei-Ni , Robinson Christine C , Glodé Mary P
Published: July 2021

Background:
The etiology of Kawasaki Disease (KD) remains unknown. The majority of KD patients present with a history of, or concurrent respiratory symptoms. Isolated case reports of Mycoplasma pneumoniae (Mp) associated with KD have been reported. Since Mp can cause mucous membrane disease (eye and mouth lesions), rash, and fevers, it remains a possible etiological agent for KD.

Objective:
To evaluate the prevalence of Mp identified in the upper respiratory tract of patients admitted with a diagnosis of KD.

Methods:
All KD patients admitted to Children’s Hospital Colorado (CHCO) over a 14 month period (Feb 2013 - Mar 2014) who had a nasopharyngeal wash (NPW) submitted for diagnostic testing were included in the study. Mp PCR was performed using the Film Array Respiratory Panel (BioFire Diagnostics, Salt Lake, City, UT). Furthermore, a CDC investigated pediatric outbreak of Mp in our community afforded the opportunity to investigate an epidemiological association between Mp and KD by comparing the incidence of KD to the incidence of Mp positive respiratory samples from Jan 2013 - May 2014.

Results:
Forty-seven (65%) of 72 KD patients had a NPW submitted and tested for Mp. None of these 47 patients tested positive for Mp. During 2013 - 2014 there was no correlation between the overall incidence of Mp positive respiratory samples and the incidence of KD.

Conclusions:
Our data do not support the hypothesis that Mp is an etiological agent of KD. Although unlikely, this study does not exclude the possibility that another Mycoplasma species could be involved in the pathogenesis of KD.
Abstract 44: Uveitis As An Important Ocular Sign To Help Early Diagnosis In Kawasaki Disease
Authors: Hong Young Mi , Choi Han Seul , Kim Hae Soon , Sohn Sejung
Published: July 2021

Purpose:
Atypical or incomplete Kawasaki disease (KD) frequently leads to delay in diagnosis and treatment. Delayed diagnosis is associated with increased risk of coronary artery aneurysm. Anterior uveitis peaks about a week after the onset of fever. The purpose of this study was to assess the differences in laboratorial findings including echocardiographic measurements, clinical characteristics such as duration of fever and treatment responses between KD patients with and without uveitis.

Materials and Methods:
106 KD patients were studied from January 2008 to June 2013. Study group (n=28, KD with uveitis) was compared with control group (n=78, KD without uveitis). Laboratory data were obtained from each patients including complete blood count (CBC), erythrocyte sedimentation rate (ESR), platelet count, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total protein, albumin, C-reactive protein (CRP), brain natriuretic peptide (BNP). Echocardiographic measurement and intravenous immunoglobulin responses were compared between two groups.

Result:
The incidence of uveitis was 26.4%. Neutrophil counts were higher in the uveitis group compared with the control group (64.3±15.8(х10
3
/mm
3
) vs. 54.4±19.3 (х10
3
/mm
3
)). The age of patients was higher in the uveitis group compared with the control group (40.5±21.4 months vs. 33.4±29.3 months). ESR (43.3±27.2 mm/hr vs. 30.8±24.6 mm/hr) and CRP (8.1±6.1 mg/dL vs. 7.9±10.7mg/dL) were slightly increased in the uveitis group compared with the control group, but there was no significant difference between the two groups. Coronary artery diameter was slightly increased in the uveitis group but there was no significant difference between the two groups. There were no significant differences in duration of fever, BNP, coronary arterial complication and treatment responses between the two groups.

Conclusion:
Uveitis is the one of the important ocular signs to diagnose incomplete KD. It is significantly associated with the patient’s age and neutrophil count but not with the other laboratory measurements, coronary arterial complication or treatment responses.
Abstract 52: The Gut Microbiome Alters Susceptibility to Coronary Inflammation in Kawasaki Disease
Authors: Yeung Rae S , Chan Daniel , Duong Trang T
Published: July 2021

The gut microbiome has been shown to have immunomodulatory capabilities, and changes in the composition of the microbiome have altered the pathogenesis of inflammatory diseases. In this study, we sought to investigate the effects of the microbiome on the pathogenesis of Kawasaki Disease (KD) using the Lactobacillus cell wall extract (LCWE)-induced coronary arteritis model. Using qPCR on mouse fecal samples, we quantified bacterial communities through the 16S rRNA gene. Animals originating from the same supplier where housed in two independent facilities. There were marked elevations in Bacteroides, Bifidobacteria, Lactobacillus and segmented filamentous bacteria (SFB) and decrease in Clostridia in Facility A compared to Facility B. The transition to the newer Facility B resulted in a reduction in disease induction by LCWE to 26% (25/95), compared to 50% (35/70) at Facility A.

Addition of antibiotics to the drinking water to deplete the microbiome reduced disease incidence to 40% (2/5) of mice housed at Facility A compared to 100% (5/5) of untreated mice, suggesting that components of the microbiome are necessary to exacerbate inflammation. To address whether the gut microbiome was sufficient to support disease susceptibility, the cecal contents of the susceptible mice at A were gavaged into the less susceptible mice at B. Recipients of the cecal contents from Facility A had an increased disease incidence of 91% (10/11) compared to 60% (6/10) in control mice which received cecal contents from mice housed in Facility B.

We also report elevated levels of IL-17 in the serum of SFB-colonized mice. SFB, known to exacerbate several models of autoimmunity, was completely absent in mice housed at Facility B. Interestingly Th17 and its associated cytokine IL-17 have been associated with acute KD, but its role in pathogenesis remains unclear. Th17 cells have been implicated in autoimmunity, and are also important players in gut homeostasis. Our data provide evidence for the role of the gut microbiome in modulating the immunopathogenesis of KD, pointing to the important interactions of commensal and pathogenic factors as determinants of disease.
Abstract 64: Correlation Of The Platelet Count With Immunoglobulin G, M, And A Levels In The Early Convalescent Stage Of Kawasaki Disease
Authors: Lee Kyung-Yil
Published: July 2021

Background:
The clinical course of Kawasaki disease (KD), which is self-limiting and immune-mediated, is controlled by the host’s immune system. The incidence of incomplete KD is increasing in Korea. We evaluate the changes in the platelet count and immunoglobulin (Ig) levels (IgG, IgM, IgA, and IgE) during hospitalization and the relationships among these parameters.

Methods:
We examined the platelet count and levels of the four above-mentioned Igs twice at presentation and at discharge (mean of 6.2 days apart) in 43 patients with complete KD who received intravenous Ig at 2 g/kg. The relationships across all parameters were evaluated.

Results:
The mean patient age was 29.9 ± 16.4 months, and there were 28 male and 15 female patients. The mean platelet count and IgG, IgM, IgA, and IgE levels at presentation and at discharge were 366 ± 92 and 548 ± 135 х10
3
/μL, 718 ± 317 and 2433 ± 426 mg/dL, 125 ± 45 and 234 ± 71 mg/dL, 63 ± 57 and 98 ± 79 mg/dL, and 69 ± 70 and 57 ± 64 IU/mL, respectively. The values of these parameters were correlated with the time of examination from fever onset, in comparing three groups with fever duration of the <5 days, the 5-10 days, and the 11-16 days (Nonparametric Kruskal Wallis test and Dunn’s mehod for each post-hoc pair-wise test). A correlation was also noted in the degree of increase calculated at the two time points between the platelet count and IgG (
P
= 0.002), IgM (
P
= 0.01) or IgA level (
P
= 0.002), respectively (Spearman correlation coefficient).

Conclusions:
The platelet count and Ig levels (IgG, IgM, and IgA) increased in the early convalescent stage of KD and were correlated with each other. This finding suggests that the host’s immune/repair system is involved in recovery from KD and may help to differentiate KD, especially incomplete KD, from other KD-like diseases if these phenomena do not occur in other diseases.
Abstract 69: Possible Involvement Of Proline-rich Tyrosine Kinase 2 (pyk2) In The Pathogenesis Of Kawasaki Disease
Authors: Suzuki Chinatsu , Nakamura Akihiro , Okigaki Mitsuhiko , Miura Noriko , Ohno Naohito , Yahata Tomoyo , Okamoto Akiko , Yoshioka Ayako , Kuchitsu Yuki , Ikeda Kazuyuki , Hamaoka Kenji
Published: July 2021

Introduction:
Although etiology of Kawasaki disease (KD) remains elusive, a line of recent experimental studies implies that some kinds of infectious stimuli are implicate in the vasculitis through uncontrolled innate immune systems such as pattern recognition receptor (PPR)-mediated inflammatory signaling. It has already known that Candida albicans water-soluble fraction (CAWS) inducing KD-like vasculitis in mice function through PRP. Furthermore, it is reported that proline-rich tyrosine kinase (Pyk2), which is molecule involved in the PRPs-dependent signaling pathways, plays an important role in activation of NF-κB. Therefore, we investigated a possible relevance of Pyk2 in the pathogenesis of KD.

Methods:
Pyk2-knock out (Pyk2-KO) and wild-type C57BL/6 mice (WT) were administered CAWS to induce KD-like vasculitis. Extension of the experimental vasculitis was immunohistochemically determined with anti-MPO antibody. CAWS-stimulated NF-κB activation was evaluated by quantifying nuclear translocation of NF-κB p65 subunit in peritoneal macrophages isolated from PYK2-KO and wild-type mice in vitro. Cytokines and chemokines across each mice were compared by cytokine array.

Results:
Pyk2-KO mice didn’t show any apparent defective phenotype. While marked inflammation was observed in the aortic root of CAWS-treated WT mice, such vasculitis was barely detected in CAWS-treated Pyk2-KO mice. CAWS-induced NF-κB activation was also less observed in macrophages from Pyk2-KO mice. There were differences in some cytokines and chemokines production between mice.

Conclusion:
We speculate that Pyk2 is involved in the pathogenesis of KD. Pyk2 might be a potential therapeutic target for KD.
Abstract 95: Increased Circulating Endothelial Microparticles In The Acute Phase Of Kawasaki Disease
Authors: Nakaoka Hideyuki
Published: July 2021

Backgroud:
Kawasaki disease (KD) is a typically acute inflammatory syndrome that takes the form of systemic vasculitis. The acute inflammation and subsequent reparative process may lead to lasting changes in arterial structure even in the convalescence of KD including increased endothelial dysfunction. Endothelial microparticles (EMPs) are vesicles formed by the cell membrane after endothelial activation, and their composition can be used to characterize the status of the parent endothelial cell. EMPs were reported in cardiovascular diseases with endothelial dysfunction, such as acute coronary syndrome, pulmonary hypertension, diabetes, and vasculitis. Our aim of this study is to elucidate whether EMPs are involved in vasculitis during acute stage of Kawasaki disease.

Method:
We enrolled 9 patients (aged 3 months to 14 years, 6 male, 3 female), 7 common febrile children and 5 healthy children. KD patients in the convalescent phase were divided into two subgroups; coronary artery lesion (CAL, n=2) and no coronary lesion (NCAL, n=7). Blood samples were collected at the time of diagnosis before the initiation of IVIG treatment, then immediately after the first IVIG infusion and at 2-4 weeks after disease onset. Samples were measured using flow cytometry.

Result:
The percentage counts of EMPs were 2.90±1.26% in KD children before initial treatment, which were significantly higher (P<0.005) than those of disease controls (0.12±0.13%) and healthy controls (0.09±0.08%) before initial treatment, and reached normal levels within 4 weeks (0.05±0.05%). The highest percentage count of EMPs (5.47%) was observed in the patient with CAL before initial treatment. Further, prolonged high percentage count of EMPs (3.34%) was recognized in the patient with multiple gaint aneurysms at 2 weeks after onset.

Conclusion:
The relation between the increased levels of EMPs and the involvement of CAL may suggest that EMPs could serve as a sensitive marker of the severity of endothelial dysfunction and vasculitis in patients with KD. Although the function of EMPs has not been fully elucidated, there is evidence that it plays an important role for distinct inflammatory reactions in endothelium.
Abstract O.22: Analysis of The Mechanisms of Intravenous Immunoglobulin-resistant Kawasaki Disease Using iPS Cell Technology
Authors: Ikeda Kazuyuki , Ameku Tomonaga , Nomiya Yui , Nakamura Masahiro , Mae Shinichi , Matsui Satoshi , Yahata Tomoyo , Okamoto-Hamaoka Akiko , Suzuki Chinatsu , Yoshioka Ayako , Kuchitsu Yuki , Watanabe Akira , Osafune Kenji , Hamaoka Kenji
Published: July 2021

Introduction:
Although the treatment of intravenous immunoglobulin (IVIG) significantly resolves inflammation, 10-20% of Kawasaki disease (KD) patients have persistent or recurrent fever after the administration of IVIG, and IVIG-resistant patients have a particularly high risk of developing coronary artery abnormalities. The mechanisms of IVIG-resistant KD have been analyzed using the patients’ leukocyte samples. However, vascular endothelial cells (ECs), closely related to the vasculitis of KD, have not been examined in the previous reports. We propose a hypothesis that ECs are mainly involved in the etiology of IVIG-resistance.

Methods:
The purpose of this study is to establish new in vitro disease models of vasculitis using induced pluripotent stem cell (iPSC) technology, and clarify the mechanisms of IVIG-resistance in KD. Dermal fibroblasts or T cells from 2 IVIG-resistant and 2 IVIG-responsive KD patients were reprogrammed by episomal vectors encoding Oct3/4, Sox2, Klf4, L-Myc, LIN28, and p53 shRNA. The iPSC lines were then differentiated into ECs by using a previously-reported differentiation method, and the EC samples were subjected to the microarray analyses.

Results:
The KD patient-derived iPSCs could be differentiated into ECs. The gene expression profiles were compared between iPS-derived ECs (iPS-ECs) generated from IVIG-resistant and IVIG-responsive KD patients. We found the expression of chemokine X, which stimulates migration of monocytes and T-lymphocytes through its receptors, was significantly up-regulated in iPS-ECs from IVIG-resistant KD patients compared with those from IVIG-responsive patients. The Principle Component Analysis (PCA) was performed, but the gene expression levels showed no significant differences between the groups. The Gene Set Enrichment Analysis (GSEA) revealed that the gene sets related to IL-6, NRAS (a member of the RAS oncogene family) and breast cancer were up-regulated in iPS-ECs from IVIG-resistant KD patients.

Conclusions:
Taking into account that the concentration of IL-6 has been reported to be elevated in acute phase of IVIG-resistant KD, our results suggest that the up-regulation of IL-6 related genes in ECs might be involved in the pathogenesis of IVIG-resistant KD.
Abstract O.36: Kawasaki Disease and Systemic Juvenile Idiopathic Arthritis - Two Ends of the Same Spectrum
Authors: Yeung Rae S , van Veenendaal Mira , Manlhiot Cedric , Schneider Rayfel , McCrindle Brian W
Published: July 2021

Background:
Clinical similarities between Kawasaki disease (KD) and systemic Juvenile Idiopathic Arthritis (sJIA) are well known. We critically reviewed children with KD and sJIA to identify those with both diagnoses in order to characterize discriminating findings at baseline.

Methods:
Data from prospectively acquired KD (n=1765) and sJIA (n=112) cohorts were reviewed for common patients (1990-2011). Those with both diagnoses (KD/sJIA n=8) were reviewed for clinical presentation, laboratory investigations, treatment regimens, coronary artery outcome and complications including macrophage activation syndrome, and results were compared to the overall KD cohort.

Results:
All children with KD/sJIA fulfilled diagnostic criteria for KD and sJIA (ILAR classification). Co-diagnosis was present in 0.45% (8 of 1765) and 7.1% (8 of 112) of those with KD and sJIA, respectively. Time between diagnosis of KD and presumptive diagnosis of sJIA was a median of 24 days (IQR 21-45 days). KD/sJIA patients had bilateral conjunctival injection less frequently, lower hepatic transaminases together with signs of more intense inflammation as expressed a by higher white blood cell count and lower albumin than the KD cohort alone. All KD/sJIA patients had recalcitrant disease consisting of prolonged fever requiring multiple doses of intravenous immunoglobulin and steroids. Coronary artery abnormalities (CAAs) were observed in 5 KD/sJIA patients. Macrophage activation syndrome occurred in one KD/sJIA patient and in 0.9% and 8% of KD patients and sJIA patients respectively.

Conclusions:
A small portion of our patients with KD developed subsequent sJIA. KD/sJIA patients were characterized by more intense inflammation at initial presentation, a recalcitrant disease course and a high prevalence of CAAs. These patients may provide clues to potentially shared immunopathology. The clinical presentations of MAS, KD and sJIA are quite similar with fever, rash, hepatomegaly, and lymphadenopathy. All 3 entities are syndrome complexes defined by massive immune activation. We propose that the intensity and duration of the immune response may be the key distinguishing features, which dictate which one of these clinical syndromes the affected child presents with.
Abstract O.38: Fever Patterns in KD Patients after Treatment with IVIG
Authors: Jaggi Preeti , Wang Wei , Printz Beth , Burns Jane , Kovalchin John , Tremoulet Adriana
Published: July 2021

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<0.0001, odds ratio=30.6 [95%CI 6.7-139.8]), although 11% of those who eventually responded to treatment also had fever between 24-36 hours post-completion of IVIG. Subjects who had at least one fever within the first 12 hours post-IVIG had a higher likelihood of having CAA (odds ratio=3.782, p=0.037)). Of those with CAA (n=51), 43 (84%) had abnormalities on the initial baseline echocardiogram.

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.
Abstract O.46: A Phase I/IIa Dose Escalating, Open-label Study of Atorvastatin in Children with Acute Kawasaki Disease and Coronary Artery Abnormalities
Authors: Tremoulet Adriana H , Jone Pei-Ni , Dominguez Samuel , Anderson Marsha , Heizer Heather , Glode Mary , Burns Jane C
Published: July 2021

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.
Abstract 10079: Socioeconomic Status and the Development of Atrial Fibrillation in Hispanics, African Americans and non-Hispanic Whites
Authors: Shulman Eric , Aagaard Philip , Kargoli Faraj , Hoch Ethan , Schafler Scott , Di Biase Luigi , Fisher John D , Gross Jay N , Kim Soo G , Ferrick Kevin J , Krumerman Andrew
Published: July 2021

Introduction:
Atrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. Despite having a higher burden of traditional AF risk factors, African American and Hispanic minorities have a lower incidence of AF when compared to non-Hispanic Whites, referred to as the “racial paradox.”

Hypothesis:
We investigated if socioeconomic status (SES) could be an explanatory factor for the “racial paradox.”

Methods:
An ECG/EMR database from a tertiary-care center in New York State was interrogated for individuals free of AF for development of subsequent AF from 2000-2013. SES was assessed per zip code via a log composite of six measures Z-scored to the New York State average (income; value of housing unit; percentage of receiving interest/dividend/rental income; education; percentage completed college; individuals in professional positions). SES was reclassified into decile groups (1 lowest and 10 highest). The Log-Rank test was used to determine difference in survival times to develop AF by race/ethnicity stratified by SES decile. Cox regression analysis controlling for all baseline differences was used to estimate the independent predictive ability of SES for AF. P-trend was calculated by race/ethnicity to determine if there was a trend by SES decile to develop AF.

Results:
We identified 48,631 persons (43% Hispanic, 37% African Americans and 20% non-Hispanic White, mean age 59 years, mean follow-up of 3.2 years) of which 4,556 AF cases occurred. Hispanics and African Americans had lower AF risk than Whites in all SES deciles (p-value < 0.001 by Log Rank Test). Higher SES was borderline associated with lower AF risk (HR=0.990, 95% CI 0.980-1.001, p=0.061). P-trend analysis was not significant by any race/ethnic group by SES deciles for AF (Figure 1).

Conclusions:
Our study suggests that non-Hispanic Whites are at higher risk for AF compared to non-Whites, and this is independent of socioeconomic status.
Abstract 10188: Circulating Levels of MIF, GROα And RANTES Chemokines and Interleukin 17E Correlate With Severity of Pulmonary Hypertension in Young Pediatric Patients With Congenital Heart Disease
Authors: Zorzanelli Leína , Maeda Nair Y , Clavé Mariana M , Thomaz Ana M , Rabinovitch Marlene , Lopes Antonio A
Published: July 2021

Introduction:
Inflammation and immunity are central in the pathogenesis of pulmonary arterial hypertension (PAH), but have not been fully explored in young patients with congenital heart disease and elevated pulmonary artery pressure (PAH-CHD) undergoing surgical repair.

Hypothesis:
Cytokines and related proteins may be differentially expressed in PAH-CHD patients with distinct hemodynamic patterns.

Methods:
Sixteen patients with PAH-CHD were enrolled (Group 1, age 1.13 (0.76-2.48) years, median and interquartile range). Pulmonary artery pressure was 52 (43-66) mmHg, and pulmonary vascular resistance was 5.2 (4.2-8.9) Wood units•m
2
. Patients with pulmonary overcirculation, with no need for cardiac catheterization were included for comparison (Group 2, N=31, age 0.71 (0.43-1.02) years). Pulmonary-to-systemic blood flow ratio (echocardiography) in Group 1 and Group 2 was 1.9 (1.3-2.6) and 2.8 (2.3-3.3) respectively (p=0.008). Thirty-six cytokines were analyzed in serum using a chemiluminescence array.

Results:
In the whole patient group (N=47), MIF chemokine (macrophage migration inhibitory factor) was significantly increased compared to pediatric controls (respective densities 7510±2755 pixels and 5697±2051 pixels, mean±SD, p=0.027). In patients, GROα chemokine (growth-regulated oncogene alpha) was elevated early in life, but decreased exponentially with the age (R
2
=0.21, p=0.001), while interleukin 17E (also called IL-25) increased progressively (R
2
=0.24, p<0.001). MIF was specifically increased in Group 1 compared to Group 2 and controls (respectively, 8494±619 pixels, 6618±477 pixels and 6548±726 pixels, age-adjusted mean±SEM, p=0.037). In contrast, RANTES chemokine (regulated on activation, normal T cell expressed and secreted) was specifically elevated in Group 2 compared to Group 1 and controls (respectively, 74183±3865 pixels, 60130±6455 pixels and 59332±3970 pixels, mean±SEM, p=0.039).

Conclusion:
The data indicate a relationship between cytokine levels and severity of the disease (age, groups), with potential pathophysiological implications. Furthermore, involvement of interleukin 17E and MIF emphasize the role of Th2 immune response already described in PAH.
Abstract 10290: αB-crystallin Knockout Alleviate Tsc1 Deletion Induced Cardiomyopathy
Authors: Liu Kemei , Wang Lianmei , Chen Yi , Zhang Hongbing , Yan Hongbing
Published: July 2021

Introduction:
Mechanistic target of rapamycin (mTOR) signaling is important in many diseases, such as cancer, metabolic diseases and cardiac diseases. Inactive mutation of either TSC1 or TSC2 leads to activation of mTOR. We recently reported that cardiomyocyte-specific TSC1 deficiency induced cardiomyopathy and impaired cardiac function in mice. A ubiquitous small heat-shock protein (sHSP), αB-crystallin as a downstream target protein of mTOR signaling pathway is one of the central controllers of cell growth, proliferation and cancer development.

Hypothesis:
Hyper-activation of mTOR induces cardiac hypertrophy through upregulation of αB-crystallin and inhibition of αB-crystallin may abolish mTOR activation-induced cardiomyopathy.

Methods:
Cardiomyocyte-specific
Tsc1
knockout (
Tsc1
-cKO) mice were mated with
αB-crystallin
knockout (
αB
-KO) mice to create
Tsc1
and
αB-crystallin
double knockout (dKO) mice. Tamoxifen(TMX) was used to induce cardiomyocyte-specific
Tsc1
knockout. Analysis of morphology, cardiac function and fetal gene expression were performed in different genotypes of mice.

Results:
Tsc1
-cKO mice showed higher heart weight/body weight (HW/BW) ratio, thinner ventricular walls and larger cardiac chambers, nevertheless all of these changes significantly alleviated in the dKO mice(Figure A and B). Cardiac function detected by echocardiography impaired in the
Tsc1
-cKO mice, while dKO mice showed no different with the control littermates (Figure C). The mRNA expression of fetal genes including α-skeletal actin (α-SKA), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) elevated significantly in the
Tsc1
-cKO mice, however, the expression of these genes in the dKO mice was the same as the control mice(Figure D).

Conclusions:
The present study indicates that αB-crystallin plays a critical role in TSC1 deficiency induced cardiomyopathy.
Abstract 10342: Frailty Status and Outcomes Following Trans-catheter Aortic Valve Replacement
Authors: Huded Chetan P , Huded Jill M , Lindquist Lee A , Holly Thomas A , Sweis Ranya N , Ricciardi Mark J , Malaisrie Sukit C , Davidson Charles J , Flaherty James D
Published: July 2021

Introduction:
Frailty is associated with increased disability, morbidity, and mortality. We assessed the impact of frailty status on outcomes following trans-catheter aortic valve replacement (TAVR).

Methods:
We included all 142 patients who underwent prospective modified Fried frailty assessments prior to TAVR at a single tertiary care academic medical center between February, 2012 and February, 2015 in a retrospective cohort study. We stratified patients into 3 groups (non-frail, pre-frail, and frail). The primary outcome was a composite of 30 day mortality, stroke, acute kidney injury > stage 2, major vascular injury, major or life-threatening bleeding, valve malpositioning, conversion to sternotomy, and respiratory failure. Secondary outcomes included length of hospital stay, discharge destination, hospital re-admission within 30 days, and overall survival.

Results:
Non-frailty was present in 39 patients (27%), pre-frailty in 64 patients (45%), and frailty in 39 patients (27%). Mean age increased with increasing frailty status (non-frail 80.1 +/- 9.3 years, pre-frail 84.0 +/- 8.2 years, frail 84.7 +/- 7.1 years, P=0.03). There was no difference in the mean Society of Thoracic Surgeons risk score between groups. There was no difference in the rate of the primary composite endpoint, length of hospital stay, rate of hospital re-admission within 30 days, or overall survival between the groups. Frail patients had a higher rate of discharge to a rehabilitation facility (non-frail 23%, pre-frail 23%, frail 51%, P<0.01). In a multivariable logistic regression, frailty was a significant independent predictor of discharge to a rehabilitation facility (table).

Conclusions:
Outcomes following TAVR are not impacted by pre-frailty, while frail patients are less likely to be discharged directly home.
Abstract 10355: Physiologic Effect of Repeated Epinephrine Doses During Cardiopulmonary Resuscitation: A Randomized Porcine Study
Authors: Madsen Härdig Bjarne , Götberg Michael , Rundgren Malin , Götberg Matthias , Zughaft David , Kopotic Robert , Wagner Henrik
Published: July 2021

Objectives and Method:
This porcine study was designed to explore the effect of repetitive epinephrine (EPI) doses on physiologic parameters during CPR. Thirty-six adult pigs were randomized to four injections of: EPI 0.02 mg/kg/dose, EPI 0.03 mg/kg/dose or saline control, given during 15 minutes of CPR. The effect on systolic, diastolic and mean arterial blood pressures (ABP), cerebral perfusion pressure (CePP), end tidal carbon dioxide (ETCO2), SpO2, cerebral tissue oximetry (SctO2), were analyzed immediately prior to each injection and at peak arterial systolic pressure. Arterial blood gases was analyzed after the baseline and after 15 min.

Result:
Prior to and following 4 minutes of baseline chest compressions without drug administration, there were no significant differences between the three groups. In the group given a 0.02 mg/kg/dose, there were increases in all ABP’s and CePP at the first 3 pressure peaks; at the 4th only mean ABP was increased. Decreased ETCO2 following peak 1 and beyond was seen. SctO2 and SpO2 were lowered following injection 2 and beyond. In the group given a 0.03 mg/kg/dose, all ABP’s and CePP increased at the first 3 pressure peaks. Lower ETCO2 was seen at peak 1 and beyond. SctO2 and SpO2 were lower following injection 2 and beyond. In the saline control group the systolic ABP was significantly lower at pressure peak 1 and beyond, no other parameter changed significantly compared to baseline. In the two EPI groups, pH and Base Excess were lower and lactate levels higher compared to baseline as well as compared to control.

Conclusion:
Repetitive EPI doses increased ABP’s and CePP, but this did not translate into better organ or brain perfusion.
Abstract 10378: Characterization of Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial Cardiac Magnetic Resonance Imaging
Authors: Staziaki Pedro V , Farhad Hoshang , Coelho-Filho Otávio , Shah Ravi V , Mitchell Richard N , Kwong Raymond Y , Scherrer-Crosbie Marielle , Hoffmann Udo , Jerosch-Herold Michael , Neilan Tomas G
Published: July 2021

Introduction:
Anthracyclines are a standard chemotherapeutic agent. However, the anthracyclines are associated with a late reduction in left ventricular ejection fraction (LVEF) and heart failure. Pathologically, anthracycline-induced cardiotoxicity (AIC) is characterized by the development of cardiac edema and fibrosis and cardiac magnetic resonance (CMR) is the gold-standard imaging technique for edema and fibrosis.

Hypothesis:
We hypothesized that a) cardiac edema and fibrosis would be detected by CMR after anthracyclines and b) edema and fibrosis would provide prognostic information.

Methods:
We performed a longitudinal CMR and histological study of 45 wild-type mice randomized to doxorubicin (DOX, n=30, 5 mg/kg/week for 5 weeks) or placebo (n=15). Measurements were performed at baseline, 5, 10, and 20 weeks after DOX or placebo. Measures of interest were LVEF, myocardial edema and fibrosis. Edema was assessed by T2 mapping, fibrosis by calculating the extracellular volume (ECV) from pre- and post-contrast T1 measurements.

Results:
In DOX-treated mice vs. placebo, myocardial edema at 5 weeks was increased (T2 values of 32±4 vs. 21±3 ms, P<0.05, Fig. A), while LVEF was unchanged. At 10 weeks, there was a reduction in LVEF (54±6 vs. 63±5% μL, P<0.05) and an increase in myocardial fibrosis (ECV of 0.34±0.03 vs. 0.27±0.03, P<0.05, Fig. B). There was a correlation between T2 measures and cardiac water weight (r=0.79, P=0.007, Fig. C) and between the ECV and histological myocardial fibrosis (r=0.90, P<0.001; Fig. D). Both the early increase in edema and the sub-acute increase in fibrosis predicted the late DOX-induced mortality (P<0.001, Fig. E and F).

Conclusions:
Our data suggest that, in mice, CMR can detect the early increase in edema and sub-acute increase in fibrosis after anthracyclines, that an increase in edema precedes a reduction in LVEF, that the increase in edema and fibrosis are linked and both are predictive of late animal mortality.
Abstract 10386: Clinical and Genetic Risk Factors for Post-Operative Atrial Tachycardia After Congenital Heart Surgery in Infants
Authors: O'Connor Amy M , Crum Kim , Smith Andrew H , Kannankeril Prince J
Published: July 2021

Introduction:
Atrial tachycardia (AT) after infant congenital heart disease (CHD) surgery has been associated with increased mortality. Common genetic variants in PITX2 (rs2200733) and IL6 (rs1800795) have been associated with post-operative AT in adults, but have not been studied in infants after CHD surgery.

Hypothesis:
Genetic variants in PITX2 and IL6 are associated with post-operative AT in infants with CHD.

Methods:
Children less than 1 year of age undergoing their first CHD surgery at our center between 9/2007 and 3/2014 who consented to the study were included. Subjects provided a DNA sample and had repeated daily assessment of telemetry with documentation of all arrhythmias and clinical variables. Genotyping was performed in the Vanderbilt genomics core lab using the TaqMan PCR Core Reagent Kit. Children with and without AT were compared using chi-square or unpaired t-test as appropriate.

Results:
Of 923 enrolled infants, 141 had post-operative AT (15.3%), 79 of who required treatment (8.6%). AT was associated with increased mortality (12.1% mortality with AT; vs. 5.5% no AT, P = 0.004), longer hospital stay (mean of 49 days with AT; vs. 23 days no AT, P < 0.0001), intensive care unit (ICU) stay (mean of 34 days with AT; vs.13 days no AT, P < 0.0001), and mechanical ventilation duration (mean of 22 days with AT; vs. 8 days no AT, P < 0.0001). Age, epinephrine use, milrinone use, bypass time, cross-clamp time, lactate, and number of pump runs were associated with AT and AT requiring treatment. PITX2 and IL6 genotypes were not significantly associated with AT or AT requiring treatment.

Conclusions:
AT is associated with increased mortality and longer hospital stay, ICU stay, and mechanical ventilation duration. Numerous operative factors contribute to AT after infant CHD surgery. PITX2 and IL6 genetic variants were not found to be significantly associated with post-operative AT in infants undergoing CHD surgery in our study.