Development and Utility of Quality Metrics for Ambulatory Pediatric Cardiology in Kawasaki Disease.

The Adult Congenital and Pediatric Cardiology (ACPC) Section of the American College of Cardiology sought to develop quality indicators/metrics for ambulatory pediatric cardiology practice. The objective of this study was to report the creation of metrics for patients with Kawasaki disease. Over a period of 5 months, 12 pediatric cardiologists developed 24 quality metrics based on the most relevant statements, guidelines, and research studies pertaining to Kawasaki disease. Of the 24 metrics, the 8 metrics deemed the most important, feasible, and valid were sent on to the ACPC for consideration. Seven of the 8 metrics were approved using the RAND method by an expert panel. All 7 metrics approved by the ACPC council were accepted by ACPC membership after an "open comments" process. They have been disseminated to the pediatric cardiology community for implementation by the ACPC Quality Network

Gene-expression patterns reveal underlying biological processes in Kawasaki disease

Background: Kawasaki disease (KD) is an acute self-limited vasculitis and the leading cause of acquired heart disease in children in developed countries. No etiologic agent(s) has been identified, and the processes that mediate formation of coronary artery aneurysms and abatement of fever following treatment with intravenous immunoglobulin (IVIG) remain poorly understood. Results: In an initial survey, we used DNA microarrays to examine patterns of gene expression in peripheral whole blood from 20 children with KD; each was sampled during the acute, subacute, and convalescent phases of the illness. Acute KD was characterized by increased relative abundance of gene transcripts associated with innate immune and proinflammatory responses and decreased abundance of transcripts associated with natural killer cells and CD8+ lymphocytes. There was significant temporal variation in transcript levels during the acute disease phase and stabilization thereafter. We confirmed these temporal patterns in a second cohort of 64 patients, and identified additional inter-individual differences in transcript abundance. Notably, higher levels of transcripts of the gene for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) were associated with an increased percentage of unsegmented neutrophils, fewer days of illness, higher levels of C-reactive protein, and subsequent non-response to IVIG; this last association was confirmed by quantitative reverse transcription PCR in a third cohort of 33 patients, and was independent of day of illness. Conclusion: Acute KD is characterized by dynamic and variable gene-expression programs that highlight the importance of neutrophil activation state and apoptosis in KD pathogenesis. Our findings also support the feasibility of extracting biomarkers associated with clinical prognosis from gene-expression profiles of individuals with systemic inflammatory illnesses

Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

Temporal clustering of Kawasaki disease cases around the world

In a single-site study (San Diego, CA, USA), we previously showed that Kawasaki Disease (KD) cases cluster temporally in bursts of approximately 7 days. These clusters occurred more often than would be expected at random even after accounting for long-term trends and seasonality. This finding raised the question of whether other locations around the world experience similar temporal clusters of KD that might offer clues to disease etiology. Here we combine data from San Diego and nine additional sites around the world with hospitals that care for large numbers of KD patients, as well as two multi-hospital catchment regions. We found that across these sites, KD cases clustered at short time scales and there were anomalously long quiet periods with no cases. Both of these phenomena occurred more often than would be expected given local trends and seasonality. Additionally, we found unusually frequent temporal overlaps of KD clusters and quiet periods between pairs of sites. These findings suggest that regional and planetary range environmental influences create periods of higher or lower exposure to KD triggers that may offer clues to the etiology of KD

Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy.

BackgroundHistone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac diseases. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle (SV) heart disease of right ventricular morphology, as well as in a rodent model of right ventricular hypertrophy (RVH).MethodsHomogenates of right ventricle (RV) explants from non-failing controls and children born with a SV were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day-old rat pups were placed in hypoxic conditions, and echocardiographic analysis, gene expression, HDAC catalytic activity, and isoform expression studies of the RV were performed.ResultsClass I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in the hearts of children born with a SV. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression, elevated class I and class IIb HDAC catalytic activity, and protein expression in the RV compared with those in the control.ConclusionsThese data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. Although further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for preclinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies

Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease

BACKGROUND: Kawasaki disease (KD) is a self limited vasculitis in which host genetics plays a prominent role. To further the understanding of the role of host genetics in KD, a three-stage genetic study was conducted that began with a family linkage study and ultimately involved more than 3000 individuals to identify new genetic contributions to KD susceptibility. METHODS AND RESULTS: A 26-family linkage study followed by fine mapping was performed in a cohort of 1284 KD subjects and their family members (total 3248 individuals). Suggestive evidence of disease linkage (logarithm of odds (LOD) ≥3.0, p<1.00×10(-4)) was found for five genomic locations (Chr 3q, 4q, 10p, 13q, 21q). Two of these loci (Chr 4q and Chr 13q) overlapped with validated findings from a recent KD genome-wide association study. Fine mapping analysis revealed three single nucleotide polymorphisms (SNPs) in ATP-binding cassette, subfamily C, member 4 (ABCC4) underlying the Chr 13q linkage peak showing evidence of association to KD (lowest p=8.82×10(-5); combined OR 2.00, 95% CI 1.41 to 2.83). ABCC4 is a multifunctional cyclic nucleotide transporter that stimulates the migratory capacity of dendritic cells. It is also a mediator of prostaglandin efflux from human cells and is inhibited by non-steroidal anti-inflammatory medications such as aspirin. CONCLUSION: These genetic data suggest that ABCC4 could play a fundamental role in KD pathogenesis with effects on immune activation and vascular response to injury

Kawasaki syndrome: an intriguing disease with numerous unsolved dilemmas

More than 40 years have passed since Kawasaki syndrome (KS) was first described. Yet KS still remains an enigmatic illness which damages the coronary arteries in a quarter of untreated patients and is the most common cause of childhood-acquired heart disease in developed countries. Many gaps exist in our knowledge of the etiology and pathogenesis of KS, making improvements in therapy difficult. In addition, many KS features and issues still demand further efforts to achieve a much better understanding of the disease. Some of these problem areas include coronary artery injuries in children not fulfilling the classic diagnostic criteria, genetic predisposition to KS, unpredictable ineffectiveness of current therapy in some cases, vascular dysfunction in patients not showing echocardiographic evidence of coronary artery abnormalities in the acute phase of KS, and risk of potential premature atherosclerosis. Also, the lack of specific laboratory tests for early identification of the atypical and incomplete cases, especially in infants, is one of the main obstacles to beginning treatment early and thereby decreasing the incidence of cardiovascular involvement. Transthoracic echocardiography remains the gold-standard for evaluation of coronary arteries in the acute phase and follow-up. In KS patients with severe vascular complications, more costly and potentially invasive investigations such as coronary CT angiography and MRI may be necessary. As children with KS with or without heart involvement become adolescents and adults, the recognition and treatment of the potential long term sequelae become crucial, requiring that rheumatologists, infectious disease specialists, and cardiologists cooperate to develop specific guidelines for a proper evaluation and management of these patients. More education is needed for physicians and other professionals about how to recognize the long-term impact of systemic problems related to KS

Genotype- phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non- missense, including 20 stop- gain, 11 affecting splicing, five large deletions, four in- frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non- missense, and 17 for two non- missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty- five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non- missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non- missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/1/ajh25753.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/2/ajh25753_am.pd