Dysregulated alternative complement pathway in heart failure

In patients with heart failure and aortic stenosis, the complement system is overactive. Complement activity is also linked to prognosis, shows Negar Shahini’s PhD thesis.


MAIN RESULTS:

  1. Several promoters of the alternative complement pathway are increased in patients with heart failure.
  2. Complement activity is linked to prognosis in heart failure and aortic stenosis.
  3. Lack of complement component 3 and CD14 does not affect cardiac remodelling in mice with pressure overload.

THESIS DEFENCE:

Thesis: Dysregulation of the complement system in cardiac disease – clinical and experimental studies
Candidate: Negar Shahini
Time: December 10, 2018 at 12:15
Place: Oslo University Hospital, Rikshospitalet B: Seminar room 2
Link to university website


SUMMARY:

The complement system is an important part of our innate immune system. Uncontrolled complement activation leads to extensive inflammation and tissue damage. The complement system can be activated through three different signalling pathways, and the alternative pathway is the focus of Shahini’s PhD thesis.

(1) Factor D, factor B and the terminal complement complex (TCC) are increased in heart failure patients. Factor D is a specific activator of the alternative pathway, whereas TCC and factor B are full system activators. On the other hand, the alternative complement promoter properdin was decreased, especially in the most severely affected patients. Low levels of properdin were also significantly associated with worse prognosis, but not significantly so after adjustments for covariates. Low levels of the alternative complement inhibitor factor H, however, were independently linked to increased risk of death or heart transplantation.

The levels of the complement components were evaluated in 188 patients with chronic heart failure and compared to 67 age- og sex-matched healthy persons. The patients were followed for a median of 4.6 years.

(2) Patients with symptomatic aortic stenosis have increased complement activation. The levels of TCC were higher than in healthy control persons. Moreover, elevated levels of factor B were linked to increased risk of major cardiovascular events and all-cause mortality.

(3) Complement component 3 and CD14 does not seem to be directly involved in cardiac remodelling. In a murine model of cardiac pressure overload induced by angiotensin II, deficiency in these two bottleneck molecules in pattern recognition did not affect progression of cardiac remodelling.


REFERENCES:

(1) Shahini, N., Michelsen, A. E., Nilsson, P. H., Ekholt, K., Gullestad, L., Broch, K., Dahl, C. P., Aukrust, P., Ueland, T., Mollnes, T. E., Yndestad, A., & Louwe, M. C. (2017). The alternative complement pathway is dysregulated in patients with chronic heart failureScientific Reports7, 42532.