Article Text

PDF
OP0197 High-Resolution, Integrated Molecular Profiling Reveals Persistent Inflammation in Kawasaki Disease Patients with Coronary Artery Aneurysms
  1. L.E. Ling1,
  2. D. Bulik1,
  3. J. Duffner1,
  4. C. Shimizu2,
  5. H. Sarvaiya1,
  6. B. Kapoor1,
  7. J. Brown1,
  8. L. Markowitz1,
  9. E. Arevalo1,
  10. B. Schultes1,
  11. I. Capila1,
  12. R. Saldova3,
  13. H. Stockmann3,
  14. S. Albrecht3,
  15. C. McManus3,
  16. P.M. Rudd3,
  17. G.V. Kaudinya1,
  18. A.M. Manning1,
  19. A.H. Tremoulet4,
  20. C. Bosques1,
  21. J.C. Burns5
  1. 1Research, Momenta Pharmaceuticals, Cambridge
  2. 2Pediatrics, University of CA, San Diego School of Medicine, San Diego, United States
  3. 3NIBRT Glycoscience Group, National Institute for Biopreocessing Research and Training, Dublin, Ireland
  4. 4Pediatrics, University of CA, San Diego; Rady Children's Hopital
  5. 5Pediatrics, University of CA, San Diego; Rady Children's Hospital, San Diego, United States

Abstract

Background The course and sequelae of Kawasaki disease (KD), an acute, self-limited pediatric vasculitis, vary widely among patients. Autopsy evidence of chronic cardiovascular inflammation years after KD resolution suggests a need to monitor and address this potential underlying cause of late cardiovascular morbidity and mortality.

Objectives A unique high resolution, multi-analytics systems biology approach was employed to yield insights into individual patient disease biology driving their clinical course of disease. In particular, comprehensive and longitudinal molecular profiling aims to more fully characterize biological processes contributing to the development of post-acute coronary aneurysms, to identify biomarkers to monitor them and to suggest therapies to mitigate these serious sequelae in KD.

Methods We applied an individual patient-oriented, high-resolution integrated analytics approach to eight KD subjects with and without coronary aneurysm. A longitudinal analysis across acute, subacute and convalescent stages was performed with a combination of whole blood gene transcript profiling and plasma analysis via shotgun proteomics, ELISA, and plasma protein glycomics to analyze longitudinal samples from eight KD subjects with different clinical outcomes.

Results Subject samples clustered into two molecular profiles corresponding to the acute or the subacute and convalescent stage of KD. The individual subjects' molecular profile trajectories across these stages of KD showed significant differences between patients which corresponded to their clinical course. Notably, subjects who developed post-acute stage giant aneurysms showed molecular profiles indicative of unresolved inflammation. This persistent inflammation was characterized by markers of acute phase response, cardiovascular injury, a pro-coagulant state, increased cell adhesion/migration, and increased activation of granulocytes.

Conclusions Personalized high-resolution, integrated analytics provided a comprehensive view of the clinical state of individual patients and the trajectory of their disease. Novel biomarkers of tissue-level inflammation and potential new molecular targets for therapeutic intervention were identified.

Acknowledgements We thank Dr. K. Frank Austen and Dr. Jan Hillson for helpful discussions of this work. This work supported in part by grants from the National Institutes of Health, Heart, Lung, and Blood Institute to JCB (U54 HL108460 and HL69413). R.S. acknowledges funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 260600 (“GlycoHIT”). H.Stockmann acknowledges the support of the EU FP7 program HighGlycan, Grant No. 278535 and S.A. acknowledges Science Foundation Ireland ((08/SRC/B1393, Alimentary Glycoscience Research Cluster (AGRC).

Disclosure of Interest L. Ling Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, D. Bulik Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, J. Duffner Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, C. Shimizu: None declared, H. Sarvaiya Shareholder of: Momenta Pharmaceuticals, B. Kapoor: None declared, J. Brown Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, L. Markowitz Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, E. Arevalo Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, B. Schultes Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, I. Capila Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, R. Saldova: None declared, H. Stockmann: None declared, S. Albrecht: None declared, C. McManus: None declared, P. Rudd: None declared, G. Kaudinya Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, A. Manning Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, A. Tremoulet: None declared, C. Bosques Shareholder of: Momenta Pharmaceuticals, Employee of: Momenta Pharmaceuticals, J. Burns: None declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.