Regenerative Medicine Utrecht


22 February 2018
Academie Gebouw

Judith de Haan

Thesis: Inflammation in adverse cardiac remodeling. Is there impact to gain?


Supervisors: Prof. Gerard Pasterkamp, Prof. Joost Sluijter, Dr. Saskia de Jager, Dr. Fatih Arslan
Defense date: 22 februari 2018


Despite improved health care, cardiovascular disease remains the number one cause of death worldwide. Most studies have been aimed at preventing adverse cardiac remodeling and improving hemodynamic parameters, not taking the inflammatory reaction into account. The aim of this thesis was to get more insights in the inflammatory responses in adverse cardiac remodeling after MI and during pressure-overload.

The inflammatory response after MI is important for proper scar formation, because cellular debris and necrotic cells need to be cleared. However, the inflammatory response after MI is often not well controlled, leading to an aggravated immune response and therefore extra damage to the myocardium. Inhibitory receptors are important in controlling immune responses. We studied the role of Leukocyte-Associated-Immunoglobin-like Receptor 1 (LAIR-1) after an MI. We found that LAIR-1 expression on circulating monocytes and neutrophils is increased in patients with an MI. Though, the absence of LAIR-1 did not influence infarct size or cardiac remodeling in mice.

The TAC model is used to study different cardiovascular diseases, namely hypertension, aortic stenosis and aortic valve stenosis. We used the TAC model to investigate the role of complement 5a Receptor (C5aR) and the protein growth differentiation factor 15 (GDF15). C5a has been described in both inflammatory and fibrotic diseases, which are both also involved in HF progression. This specific characteristic of C5a prompted us to study it in the development of pressure-overloaded heart failure (HF). Our hypothesis was that there would be less adverse cardiac remodeling in the absence of C5aR , however we were not able to confirm this. GDF knock-out mice (GDF15-/-) showed worse adverse cardiac remodeling compared to WT mice after TAC. We also studied the inflammatory response in GDF15-/- mice after TAC, but it appears that there is barely an influence of GDF15 on inflammation after TAC as we did not observe any difference in leukocyte influx in the heart or in the amount in the blood, spleen or lymph nodes.

High GDF15 levels has been associated with worse outcome in many diseases, both cardiovascular and non-cardiovascular. Though, the levels of GDF15 have never been studied in patients with peripheral artery disease (PAD). We looked at the association of GDF15 with amputation and mortality. We found that also in PAD patients, high levels of GDF15 are related to worse outcome.

Taken together, we showed the absence of LAIR-1 or C5aR did not influence cardiac remodeling. GDF15 is an interesting candidate for future research, because the absence worsens cardiac remodeling. And GDF15 plasma levels are associated with worse outcome in various cardiovascular diseases, also in PAD patients as we have shown in this thesis.