Jane C Burns

Rady Children's Hospital, San Diego, California, United States

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Publications (186)1077.57 Total impact

  • Lori B Daniels · Jane C Burns ·
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    ABSTRACT: Acute Kawasaki disease (KD) is diagnosed and treated by pediatricians, but decades later, these individuals are presenting to adult cardiologists with a variety of cardiovascular sequelae, including myocardial ischemia and infarction, congestive heart failure secondary to myocardial fibrosis, and claudication because of vascular insufficiency from thrombosed peripheral arteries. There are no clinical trials to guide management, interventions, and medical therapy in this patient population. This review summarizes the emerging information regarding evaluation of the cardiovascular status of adults decades after childhood KD.
    Circulation Journal 10/2015; 79(11). DOI:10.1253/circj.CJ-15-0996 · 3.94 Impact Factor
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    ABSTRACT: Background: Important therapeutic decisions are made based on the presence or absence of fever in patients with Kawasaki disease (KD), yet no standard method or threshold exists for temperature measurement during the diagnosis and treatment of these patients. We sought to compare surface and internal (rectal or oral) routes of temperature measurement for the detection of fever as a marker of treatment resistance. Methods: From a randomized, placebo-controlled trial of infliximab as an adjunct to primary intravenous immunoglobulin treatment for acute KD, we collected concurrent (within 5 minutes) axillary and internal temperature measurements and performed receiver-operating characteristic and Bland-Altman analyses. We also determined the ability of surface temperatures to detect treatment resistance defined by internal temperature measurements. Results: Among452 oral-axillary and 439 rectal-axillary pairs from 159 patients, mean axillary temperatures were 0.25°C and 0.43°C lower than oral and rectal temperatures and had high receiver-operating characteristic areas-under-curves. However, axillary temperatures ≥38.0°C had limited sensitivity to detect fever defined by internal temperatures. Axillary thresholds of 37.5°Cand 37.2°Cprovided maximal sensitivity and specificity to detect oral and rectal temperatures ≥38.0°C, respectively. Conclusions: Axillary temperatures are an insensitive metric for fevers defining treatment resistance. Clinical trials should adopt temperature measurement by the oral or rectal routes for adjudication of treatment resistance in KD.
    The Pediatric Infectious Disease Journal 09/2015; DOI:10.1097/INF.0000000000000923 · 2.72 Impact Factor
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    ABSTRACT: Objective: To determine if fever in the early post intravenous immunoglobulin (IVIG) time period (first 36 hours after IVIG completion) for Kawasaki disease (KD), with or without additional infliximab, can predict IVIG resistance and coronary artery abnormalities (CAA). Methods: Acute KD subjects enrolled in a clinical trial of infliximab plus IVIG (n=96) versusplacebo/IVIG (n=94) had temperatures recorded every 6 hours after completion of IVIG infusion. Fever was defined as temperature ≥38.0C; patients with persistent or recrudescent fever ≥36 hours after completion of IVIG were classified as IVIG-resistant. Multivariable logistic regression by fever pattern was performed to predict outcomes (IVIG resistance and CAA). Results: There was no difference in the time to defervescence between the infliximab/IVIG group (n=96) versusplacebo/IVIG group (n= 94). There was no fever after completion of IVIG in the majority of subjects [66% of those with no CAA (n=139) and 76.5% of those with CAA, (n=51)]. Although subjectswith at least one fever 24-36 hours post-IVIG had a higher probability of IVIG resistance (OR=30.6 [95%CI 6.7-139.8]p<0.0001), fever at 24-36 hours was not associated with higher likelihood of CAA. There were also 11% (n=19) of IVIG responders who had fever at 24-36 hours post-IVIG. The majority of subjects with CAA (43 of 51, 84.3%) were identified by the initial echocardiogram, so the effect of fever on development of CAA could not be assessed. Conclusion: Fever in the first 36 hours following IVIG completion is not predictive of CAA. Our data support refraining from re-treatment until 36 hours after completion of IVIG.
    The Pediatric Infectious Disease Journal 09/2015; DOI:10.1097/INF.0000000000000891 · 2.72 Impact Factor
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    ABSTRACT: As Kawasaki disease (KD) shares many clinical features with other more common febrile illnesses and misdiagnosis, leading to a delay in treatment, increases the risk of coronary artery damage, a diagnostic test for KD is urgently needed. We sought to develop a panel of biomarkers that could distinguish between acute KD patients and febrile controls (FC) with sufficient accuracy to be clinically useful. Plasma samples were collected from three independent cohorts of FC and acute KD patients who met the American Heart Association definition for KD and presented within the first 10 days of fever. The levels of 88 biomarkers associated with inflammation were assessed by Luminex bead technology. Unsupervised clustering followed by supervised clustering using a Random Forest model was used to find a panel of candidate biomarkers. A panel of biomarkers commonly available in the hospital laboratory (absolute neutrophil count, erythrocyte sedimentation rate, alanine aminotransferase, gamma glutamyl transferase, concentrations of alpha-1-antitrypsin, C-reactive protein, and fibrinogen, and platelet count) accurately diagnosed 81 to 96% of KD patients in a series of three independent cohorts. After prospective validation, this 8-biomarker panel may improve the recognition of KD.Pediatric Research (2015); doi:10.1038/pr.2015.137.
    Pediatric Research 08/2015; DOI:10.1038/pr.2015.137 · 2.31 Impact Factor
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    ABSTRACT: Galectin-3 (Gal-3) is a multifunctional matricellular protein associated with heart failure and cardiovascular events. Gal-3 is required for transforming growth factor-β pathway-mediated myofibroblast activation that is a key process in coronary artery aneurysm formation in Kawasaki Disease (KD). Autopsies from young adults late after KD onset (AKD) have demonstrated bridging fibrosis throughout the myocardium and arteries. In this study, we postulated that Gal-3 may participate in the pathogenesis of myocardial and vascular fibrosis and the remodeling of coronary artery aneurysms following acute KD. We measured plasma Gal-3 levels in 63 pediatric KD (PKD) and 81 AKD subjects. AKD subjects with giant aneurysms had significantly higher Gal-3 levels compared to the other adult groups (all p<0.05). All PKD groups had significantly higher Gal-3 levels than pediatric healthy controls (HC) (all p<0.05). Histological and immunohistochemical staining was performed on tissues from 10 KD autopsies and one explanted heart. Gal-3 positive staining was detected associated with acute inflammation and in spindle-shaped cells in the myocardium and arterial wall in KD subjects with giant aneurysms. AKD subjects with giant aneurysms and PKD subjects had significantly higher plasma Gal-3 levels than HC and Gal-3 expression was increased in the myocardium of KD subjects who died with either acute inflammation or marked myocardial fibrosis. Gal-3 may be a clinically useful biomarker that identifies a subset of KD patients at highest risk of myocardial and vascular fibrosis, and may be an attractive therapeutic target to prevent myocardial dysfunction in this subset. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology 07/2015; 201:429-437. DOI:10.1016/j.ijcard.2015.07.063 · 4.04 Impact Factor
  • Adriana H Tremoulet · Sonia Jain · Jane C Burns ·
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    ABSTRACT: Introduction: Since the 1980s, the primary treatment of acute Kawasaki disease (KD) has been intravenous immunoglobulin and aspirin. However, 5 – 10% of children with acute KD will develop coronary artery abnormalities despite treatment within the first 10 days after fever onset. There is no approved adjunctive therapy to prevent progression of coronary artery damage in these patients.Areas covered: The rationale and study design of a Phase I/IIa trial of atorvastatin in children with acute KD and coronary artery inflammation is presented. The studies of host genetics and KD pathogenesis leading up to this trial are reviewed.Expert opinion: The repurposing of well-studied drugs used in the adult population is a cost-effective and efficient strategy to identify new therapies for pediatric diseases. Exploiting the anti-inflammatory, non-lipid-lowering effects of statins may open up new applications for this class of drugs for the pediatric age group.
    Expert Opinion on Orphan Drugs 07/2015; DOI:10.1517/21678707.2015.1066246 · 0.53 Impact Factor
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    ABSTRACT: 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. Key Words: Genetics Kawasaki disease
    Circulation; 07/2015
  • Jane C Burns · Alessandra Franco ·
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    ABSTRACT: The introduction of intravenous immunoglobulin (IVIG) for modulation of inflammation in acute Kawasaki disease was a great therapeutic triumph. However, three decades later, the mechanisms underlying immune regulation by IVIG are only beginning to be revealed. Stimulation of an immature myeloid population of dendritic cells that secretes IL-10 and the elucidation of Fc-specific natural regulatory T cells provide insights into the mechanisms of IVIG. Other potential mechanisms include provision of agent-specific neutralizing antibody, anti-idiotype and anti-cytokine antibodies, blockade of activating Fcγ receptors and stimulation of the inhibitory FcγRIIb receptor. New initiatives must seek to understand the mechanisms of IVIG in order to replace it one day with more affordable and more targeted therapies.
    Expert Review of Clinical Immunology 07/2015; 11(7):819-25. DOI:10.1586/1744666X.2015.1044980 · 2.48 Impact Factor
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    ABSTRACT: Coronary artery aneurysms (CAA) remain an important complication of Kawasaki disease (KD), the most common form of pediatric acquired heart disease in developed countries. Potentially life-threatening CAA develop in 25% of untreated children and 5% of children treated with high-dose intravenous immunoglobulin during the acute phase of the self-limited vasculitis. Non-coronary artery aneurysms (NCAA) in extra-parenchymal, muscular arteries occur in a minority of patients with KD who also develop CAA, yet little is understood about their formation and remodeling. We postulated that activation of the transforming growth factor-β (TGF-β) pathway in KD may influence formation and remodeling of aneurysms in iliac, femoral, and axillary arteries, the most common sites for NCAA. We studied a resected axillary artery from one adult and endarterectomy tissue from the femoral artery from a second adult, both with a history of CAA and NCAA following KD in infancy. Histology of the axillary artery aneurysm revealed destruction of the internal elastic lamina and recanalization of organized thrombus, while the endarterectomy specimen showed dense calcification and luminal myofibroblastic proliferation. Immunohistochemistry for molecules in the TGF-β signaling pathway revealed increased expression of TGF-β2, TGF-β receptor 2, and phosphorylated SMAD3. These findings suggest ongoing tissue remodeling of the aneurysms decades after the acute injury and demonstrate the importance of the TGF-β signaling pathway in this process.
    Pediatric and Developmental Pathology 04/2015; 18(4). DOI:10.2350/14-12-1588-OA.1 · 0.87 Impact Factor
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    ABSTRACT: The activation of natural regulatory T cells (nTreg) recognizing the heavy constant region (Fc) of IgG is an important mechanism of action of intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD). Lack of circulating Fc-specific nTreg in the sub-acute phase of KD is correlated with the development of coronary artery abnormalities (CAA). Here, we characterize the fine specificity of nTreg in sub-acute (2- to 8-week post-IVIG) and convalescent (1- to 10-year post-IVIG) KD subjects by testing the immunogenicity of 64 peptides, 15 amino acids in length with a 10 amino acid-overlap spanning the entire Fc protein. About 12 Fc peptides (6 pools of 2 consecutive peptides) were recognized by nTreg in the cohorts studied, including two patients with CAA. To test whether IVIG expands the same nTreg populations that maintain vascular homeostasis in healthy subjects, we compared these results with results obtained in healthy adult controls. Similar nTreg fine specificities were observed in KD patients after IVIG and in healthy donors. These results suggest that T cell fitness rather than T cell clonal deletion or anergy is responsible for the lack of Fc-specific nTreg in KD patients who develop CAA. Furthermore, we found that adolescents and adults who had KD during childhood without developing CAA did not respond to the Fc protein in vitro, suggesting that the nTreg response induced by IVIG in KD patients is short-lived. Our results support the concept that peptide epitopes may be a viable therapeutic approach to expand Fc-specific nTreg and more effectively prevent CAA in KD patients.
    Autoimmunity 03/2015; 48(3):1-8. DOI:10.3109/08916934.2015.1027817 · 2.71 Impact Factor
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    ABSTRACT: Coronary artery aneurysms (CAA) may remain silent after Kawasaki disease (KD) until adulthood when myocardial ischemia can lead to sudden death. We postulated that there would be young adults with sudden, unexpected death due to CAA from KD who would have a state-mandated autopsy performed by the San Diego County Medical Examiner's Office (SDCMEO). We reviewed all autopsy cases <35years of age from 1997 to 2012 at the SDCMEO with a cardiovascular cause of death (n=154). We found 2 cases meeting inclusion criteria. Case 1 was a 22-year-old Korean male with chronic ischemic changes due to a partially occluded and diffusely calcified 15mm aneurysm at the bifurcation of the left main coronary artery. Interview of the mother revealed that this patient had been diagnosed with KD complicated by giant aneurysms at age two years. Case 2 was a 30-year-old Hispanic male with myocardial infarction due to thrombosis of a calcified left anterior descending artery aneurysm. Histologic findings included diffuse myocardial fibrosis and a recanalized aneurysm in the right coronary artery. Interview of the family revealed a KD-compatible illness in childhood. Immunohistochemical staining showed expression of transforming growth factor β pathway molecules in the aneurysmal arterial wall. In a medical examiner's office serving a population of approximately 3 million people, 2 of 154 (1.3%) cardiovascular deaths in persons <35years were attributed to cardiovascular complications of KD in childhood. Antecedent KD should be considered in the evaluation of all cases of sudden, unexpected death in young adults. Copyright © 2015. Published by Elsevier Inc.
    Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 02/2015; 24(5). DOI:10.1016/j.carpath.2015.02.006 · 2.00 Impact Factor
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    ABSTRACT: Coronary artery aneurysms that occur in 25% of untreated Kawasaki disease (KD) patients may remain clinically silent for decades and then thrombose resulting in myocardial infarction. Although KD is now the most common cause of acquired heart disease in children in Asia, the United States, and Western Europe, the incidence of KD in Egypt is unknown. We tested the hypothesis that young adults in Egypt presenting with acute myocardial ischemia may have coronary artery lesions because of KD in childhood. We reviewed a total of 580 angiograms of patients ≤40 years presenting with symptoms of myocardial ischemia. Coronary artery aneurysms were noted in 46 patients (7.9%), of whom 9 presented with myocardial infarction. The likelihood of antecedent KD as the cause of the aneurysms was classified as definite (n = 10), probable (n = 29), or equivocal (n = 7). Compared with the definite and probable groups, the equivocal group had more traditional cardiovascular risk factors, smaller sized aneurysms, and fewer coronary arteries affected. In conclusion, in a major metropolitan center in Egypt, 6.7% of adults aged ≤40 years who underwent angiography for evaluation of possible myocardial ischemia had lesions consistent with antecedent KD. Because of the unique therapeutic challenges associated with these lesions, adult cardiologists should be aware that coronary artery aneurysms in young adults may be because of missed KD in childhood. Copyright © 2014 Elsevier Inc. All rights reserved.
    The American Journal of Cardiology 11/2014; 115(4). DOI:10.1016/j.amjcard.2014.11.024 · 3.28 Impact Factor
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    ABSTRACT: Global gene expression profiling can provide insight into the underlying pathophysiology of disease processes. Kawasaki disease (KD) is an acute, self-limited vasculitis whose etiology remains unknown. Although the clinical illness shares certain features with other pediatric infectious diseases, the occurrence of coronary artery aneurysms in 25% of untreated patients is unique to KD. To gain further insight into the molecular mechanisms underlying KD, we investigated the acute and convalescent whole blood transcriptional profiles of 146 KD subjects and compared them with the transcriptional profiles of pediatric patients with confirmed bacterial or viral infection, and with healthy control children. We also investigated the transcript abundance in patients with different intravenous immunoglobulin treatment responses and different coronary artery outcomes. The overwhelming signature for acute KD involved signaling pathways of the innate immune system. Comparison with other acute pediatric infections highlighted the importance of pathways involved in cell motility including paxillin, relaxin, actin, integrins, and matrix metalloproteinases. Most importantly, the IL1β pathway was identified as a potential therapeutic target. Our study revealed the importance of the IL-1 signaling pathway and a prominent signature of innate immunity and cell migration in the acute phase of the illness.
    Genome Medicine 11/2014; 6(11):541. DOI:10.1186/s13073-014-0102-6 · 5.34 Impact Factor
  • Andrew C. Krakowski · Silvia S. Kim · Jane C. Burns ·
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    ABSTRACT: We present a case of transient lingual papillitis associated with confirmed herpes simplex virus 1 that developed after a child received intravenous immunoglobulin and infliximab for acute Kawasaki disease.
    Pediatric Dermatology 11/2014; 31(6). DOI:10.1111/pde.12477 · 1.02 Impact Factor
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    ABSTRACT: Background: The diagnosis of Kawasaki disease (KD) is solely based on clinical findings and auxiliary laboratory tests, and is difficult to distinguish from HAdV. Objective: 1) To characterize the specific transcriptional profiles of KD patients versus acute HAdV infection 2) To determine whether the molecular distance to health (MDTH) score (a molecular score that reflects the perturbation derived from whole genome transcriptional analysis) correlates with response to therapy. Methods: RNA samples from peripheral whole blood were analyzed using Illumina chips and GeneSpring software from 76 pediatric patients with complete KD, 13 with incomplete KD, and 19 patients with HAdV and age- and sex-matched healthy controls (HC). We used class comparison algorithms (Mann-Whitney p< 0.01, Benjamini-Hochberg, and 1.25 fold change filter) and modular analysis to define the KD profiles. Results: Statistical group comparisons identified 7,899 genes differentially expressed in 39 complete KD patients versus HC, and was subsequently validated in another 37 patients with complete KD and in 13 patients with incomplete KD. Using the KD biosignature, modular analysis demonstrated overexpression of inflammation, neutrophils, myeloid cell, coagulation cascade, and cell cycle genes in KD. To differentiate KD from HAdV, we used 25-classifier genes; cross-validation of the training set correctly classified 21 of 22 samples. In the validation analysis (test set) classifier genes correctly categorized 20 of 22 independent patient samples. Thus, the KNN algorithm demonstrated a sensitivity of 92% (95% CI [73%-99%]) and a specificity of 90% [67%-98%] to differentiate KD from HAdV. KD patients that remained febrile 36 hours after treatment with IVIG had higher baseline, pre-treatment MDTH values compared with responders [5572 in responders versus 12,290 for non-responders, p=0.009]. MDTH score significantly correlated with the baseline c-reactive protein (R=0.29, p=0.008), and was inversely related to the days of fever at the time of sample acquisition of the(R=-0.2, p=0.03). MDTH in KD patients was significantly higher than in HAdV patients 5097 [IQR 2772-8152] vs. 1331 [IQR 638-2058]. Conclusion: Transcriptional signatures can be used as a tool to discriminate between KD and HAdV infection, and may also provide prognostic information.
    IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
  • Michael Levin · Jane C Burns · John B Gordon ·

    Cardiology 10/2014; 129(3):174-177. DOI:10.1159/000366052 · 2.18 Impact Factor
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    ABSTRACT: Objective: To test the hypothesis that children and adults with a history of Kawasaki disease (KD) are more likely to have abnormal lipoprotein particle profiles that could place them at increased risk for developing atherosclerosis later in life. Study design: Fasting serum samples were obtained from 192 children and 63 adults with history of KD and 90 age-similar healthy controls. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy (LipoScience Inc, Raleigh, North Carolina), and serum was assayed for total cholesterol (TC), triglycerides, and high-density lipoprotein (HDL) cholesterol (HDL-C). Low-density lipoprotein (LDL) cholesterol was estimated using the Friedewald formula. Data were analyzed in a least-square means model, with adjustment for age and sex and with the use of Holm correction for multiple comparisons. Results: Compared with respective control groups, both adult and pediatric subjects with KD had significantly lower mean very low-density lipoprotein-chylomicron particles, intermediate-density lipoproteins, triglycerides, and TC concentrations. Pediatric subjects with KD had significantly lower LDL particle and LDL cholesterol concentrations and lower mean TC/HDL-C ratio (P < .001). In contrast, the adult subjects with KD had significantly lower HDL particle, small HDL particle, and HDL-C concentrations (P < .001), but HDL-C was within normal range. Conclusions: Nuclear magnetic resonance lipoprotein particle analysis suggests that pediatric and adult subjects with KD, regardless of their aneurysm status, are no more likely than age-similar, healthy controls to have lipid patterns associated with increased risk of atherosclerosis.
    Journal of Pediatrics 07/2014; 165(4). DOI:10.1016/j.jpeds.2014.06.017 · 3.79 Impact Factor
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    Ethan Kung · Andrew M Kahn · Jane C Burns · Alison Marsden ·
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    ABSTRACT: To perform experimental validation of computa- tional fluid dynamics (CFD) applied to patient specific coronary aneurysm anatomy of Kawasaki disease. We quantified hemodynamics in a patient-specific coronary artery aneurysm physical phantom under physiologic rest and exercise flow conditions. Using phase contrast MRI (PCMRI), we acquired 3-component flow velocity at two slice locations in the aneurysms. We then performed numer- ical simulations with the same geometry and inflow condi- tions, and performed qualitative and quantitative comparisons of velocities between experimental measure- ments and simulation results. We observed excellent quali- tative agreement in flow pattern features. The quantitative spatially and temporally varying differences in velocity between PCMRI and CFD were proportional to the flow velocity. As a result, the percent discrepancy between simulation and experiment was relatively constant regardless of flow velocity variations. Through 1D and 2D quantitative comparisons, we found a 5–17% difference between mea- sured and simulated velocities. Additional analysis assessed wall shear stress differences between deformable and rigid wall simulations. This study demonstrated that CFD pro- duced good qualitative and quantitative predictions of velocities in a realistic coronary aneurysm anatomy under physiological flow conditions. The results provide insights on factors that may influence the level of agreement, and a set of in vitro experimental data that can be used by others to compare against CFD simulation results. The findings of this study increase confidence in the use of CFD for investigating hemodynamics in the specialized anatomy of coronary aneurysms. This provides a basis for future hemodynamics studies in patient-specific models of Kawasaki disease.
    Cardiovascular Engineering and Technology 06/2014; 5(2). DOI:10.1007/s13239-014-0184-8 · 1.41 Impact Factor
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    ABSTRACT: Evidence indicates that the densely cultivated region of northeastern China acts as a source for the wind-borne agent of Kawasaki disease (KD). KD is an acute, coronary artery vasculitis of young children, and still a medical mystery after more than 40 y. We used residence times from simulations with the flexible particle dispersion model to pinpoint the source region for KD. Simulations were generated from locations spanning Japan from days with either high or low KD incidence. The postepidemic interval (1987-2010) and the extreme epidemics (1979, 1982, and 1986) pointed to the same source region. Results suggest a very short incubation period (<24 h) from exposure, thus making an infectious agent unlikely. Sampling campaigns over Japan during the KD season detected major differences in the microbiota of the tropospheric aerosols compared with ground aerosols, with the unexpected finding of the Candida species as the dominant fungus from aloft samples (54% of all fungal strains). These results, consistent with the Candida animal model for KD, provide support for the concept and feasibility of a windborne pathogen. A fungal toxin could be pursued as a possible etiologic agent of KD, consistent with an agricultural source, a short incubation time and synchronized outbreaks. Our study suggests that the causative agent of KD is a preformed toxin or environmental agent rather than an organism requiring replication. We propose a new paradigm whereby an idiosyncratic immune response, influenced by host genetics triggered by an environmental exposure carried on winds, results in the clinical syndrome known as acute KD.
    Proceedings of the National Academy of Sciences 05/2014; 111(22). DOI:10.1073/pnas.1400380111 · 9.67 Impact Factor
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    ABSTRACT: Kawasaki disease (KD) is the leading cause of acquired heart disease in children and can result in life-threatening coronary artery aneurysms in up to 25 % of patients. These aneurysms put patients at risk of thrombus formation, myocardial infarction, and sudden death. Clinicians must therefore decide which patients should be treated with anticoagulant medication, and/or surgical or percutaneous intervention. Current recommendations regarding initiation of anticoagulant therapy are based on anatomy alone with historical data suggesting that patients with aneurysms [Formula: see text]8 mm are at greatest risk of thrombosis. Given the multitude of variables that influence thrombus formation, we postulated that hemodynamic data derived from patient-specific simulations would more accurately predict risk of thrombosis than maximum diameter alone. Patient-specific blood flow simulations were performed on five KD patients with aneurysms and one KD patient with normal coronary arteries. Key hemodynamic and geometric parameters, including wall shear stress, particle residence time, and shape indices, were extracted from the models and simulations and compared with clinical outcomes. Preliminary fluid structure interaction simulations with radial expansion were performed, revealing modest differences in wall shear stress compared to the rigid wall case. Simulations provide compelling evidence that hemodynamic parameters may be a more accurate predictor of thrombotic risk than aneurysm diameter alone and motivate the need for follow-up studies with a larger cohort. These results suggest that a clinical index incorporating hemodynamic information be used in the future to select patients for anticoagulant therapy.
    Biomechanics and Modeling in Mechanobiology 04/2014; 13(6). DOI:10.1007/s10237-014-0570-z · 3.15 Impact Factor

Publication Stats

9k Citations
1,077.57 Total Impact Points


  • 2007-2015
    • Rady Children's Hospital
      San Diego, California, United States
  • 1994-2015
    • University of California, San Diego
      • • Department of Pediatrics
      • • Division of Rheumatology, Allergy and Immunology
      • • Department of Medicine
      San Diego, California, United States
  • 2012
    • National University (California)
      San Diego, California, United States
  • 2011
    • Genome Institute of Singapore
      Tumasik, Singapore
  • 2003
    • The Scripps Research Institute
      La Jolla, California, United States
  • 2001
    • University of Tennessee
      • Department of Pediatrics
      Knoxville, TN, United States
  • 1987-1999
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1986-1999
    • Boston Children's Hospital
      • Department of Pediatrics
      Boston, Massachusetts, United States
  • 1991-1995
    • Harvard Medical School
      • Department of Pediatrics
      Boston, Massachusetts, United States
    • University of Toronto
      Toronto, Ontario, Canada
  • 1992
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1982-1984
    • University of Colorado
      • Department of Pediatrics
      Denver, Colorado, United States