Cooling down the inflamed heart

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

Abstract

Inflammation at the right time and adequate intensity is essential for cardiac repair after an acute myocardial infarction (MI). However, resolution of the inflammatory response is essential for healing after injury and failure to resolve the active inflammation can lead to chronic inflammation. This chronic inflammation is central to the development and complications of cardiovascular disease. This thesis underscores the importance of inflammation in MI and heart failure and highlight the potential of anti-inflammatory treatment strategies. One promising target is the NLRP3 inflammasome, an intracellular protein complex responsible for the activation of IL-1β and IL-18. In a porcine model of acute MI, we show that inflammasome inhibition dose dependently reduces infarct size compared to placebo, leading to an improved cardiac function after MI. This effect was mediated by a reduction in systemic and myocardial inflammation. In addition, NLRP3 inflammasomes are involved in non-ischemic HF. NLRP3 deficient mice showed reduced adverse cardiac remodeling after pressure overload by transverse aortic constriction (TAC), with improvement of cardiac function compared to wild type mice. Research focussing on adverse remodeling in non-ischemic heart failure often makes use of the TAC animal model. In a systematic review we show that the TAC model is a very valuable but also variable animal model. We conclude that due to this large amount of variability, data obtained from TAC models should be interpreted with caution. In conclusion, this thesis underscored the importance of inflammation in MI and heart failure and highlighted the potential of anti-inflammatory treatment strategies. We emphasised the need for well-designed pre-clinical studies necessary to successfully translate to clinical setting. The next step will be future clinical trials with specific inflammasome inhibitors in the acute setting of MI, potentially leading to therapeutic improvements for patients.
Original languageEnglish
Awarding Institution
  • University Medical Center (UMC) Utrecht
Supervisors/Advisors
  • Pasterkamp, Gerard, Primary supervisor
  • de Jager, Saskia, Co-supervisor
  • el Azzouzi, H., Co-supervisor
Award date27 Sept 2018
Publisher
Print ISBNs978-94-9301-401-5
Publication statusPublished - 27 Sept 2018

Keywords

  • cardiovascular disease
  • heart failure
  • inflammation
  • inflammasome
  • animal models
  • transverse aortic constriction

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