Links complement activation to heart failure and infarct size

Complement activation plays an important role in tissue injury in acute coronary syndromes, shows the research of Hilde Elisabeth Lang Orrem.


MAIN RESULTS:

  1. Complement activation relates to disease severity in heart failure.
  2. Inhibition of interleukin-6 does not affect complement activation in patients with NSTEMI.
  3. Soluble interleukin-1 receptor 2 is linked to infarct size and cardiac function following STEMI.

THESIS DEFENCE:

Thesis: Innate immunity in acute coronary syndromes. Focus on complement.
Candidate: Hilde Elisabeth Lang Orrem
Time: June 7, 2019 at 12:15
Place: Oslo University Hospital, Rikshospitalet B: Green Auditorium
Link to university website


SUMMARY:

(1) Complement activation is increased in patients with myocardial infarction complicated by heart failure. 61 patients who developed heart failure after myocardial infarction had significantly higher levels of C4bc, C23bc, C3bBbP and sC5b-9 compared to age- and sex-matched healthy controls. The levels of most markers were even higher in the nine patients with cardiogenic shock, and the levels were elevated both during the hospital stay and 42 days later. In patients with cardiogenic shock, higher complement activation correlated with decreased cardiac function.

(2) Expression of the pro-inflammatory complement receptors C5aR1 and C5aR2 are reduced following interleukin-6-inhibition with tocilizumab in patients with NSTEMI. The 60 patients in the study were randomized to receive either one dose of tocilizumab or placebo, and mRNA expression of complement receptors were analysed three times up to six months after the event. The receptor C3aR was not affected by the treatment, and neither was complement activation.

The study also includes analyses of peripheral mononuclear cells from 22 patients with stable angina, 21 patients with acute coronary syndromes without ST-elevation, and 20 patients with STEMI. C5aR1 was over-expressed in all subgroups of coronary artery disease. The expression of C5aR2 was increased in STEMI, whereas C3aR expression was increased in patients with acute coronary syndrome without ST-elevation.

(3) Interleukin-1 receptor antagonist and soluble interleukin-1 receptors are elevated following STEMI. Conversely, soluble interleukin-1 receptor accessory protein is lower compared to healthy controls. The inflammatory markers were measured in blood from 255 STEMI patients and 65 healthy individuals.

Moreover, the levels of soluble interleukin-1 receptor 2 correlates with MR-assessed myocardial infarction size both acutely and after four months. Higher levels are also associated with reduced cardiac function and adverse left ventricular remodelling.


REFERENCES:

(1) Orrem, H. L., Nilsson, P. H., Pischke, S. E., Grindheim, G., Garred, P., Seljeflot, I., Husebye, T., Aukrust, P., Yndestad, A., Andersen, G. Ø., Barratt‐Due, A., & Mollnes, T. E. (2018). Acute heart failure following myocardial infarction: complement activation correlates with the severity of heart failure in patients developing cardiogenic shock. ESC heart failure5(3), 292-301.

(2) Orrem, H. L., Nilsson, P., Pieschke, S., Kleveland, O., Yndestad, A., Ekholt, K., Damås, J. K., Espevik, T., Bendz, B., Halvorsen, B., Gregersen, I., Wiseth, R., ANdersen, G. Ø., Ueland, T., Gullestad, L., Aukrust, P., Barrett-Due, A., & Mollnes, T. E. (2018). IL-6 receptor inhibition by tocilizumab attenuated expression of C5a receptor 1 and 2 in non-ST-elevation myocardial infarction. Frontiers in immunology9, 2035.

(3) Orrem, H. L., Shetelig, C., Ueland, T., Limalanathan, S., Nilsson, P. H., Husebye, T., Aukrust, P., Seljeflot, I., Hoffmann, P., Eritsland, J., Mollnes, T. E., Andersen, G. Ø., & Yndestad, A. (2018). Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction. International journal of cardiology268, 187-192.