1Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; 2Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie 40225 Düsseldorf, Deutschland; 3Krankenhaus Düren Innere Medizin / Kardiologie Düren, Deutschland
Background:
Acute myocardial infarction (AMI) is one of the leading causes of death in high income countries. Post-infarct inflammation and remodeling of the myocardium frequently results in heart failure (HF). Despite effective treatment options for the acute complications of AMI the prevention of post-infarct HF remains challenging. Modulation of an overshooting inflammatory response could reduce the damage to the viable border zone and reduce fibrosis of the tissue in the reparational phase.
mTOR-inhibitors affect cell metabolism and strongly regulate immune cell activity, thus representing a potential therapeutic option by preventing overshooting inflammation following AMI.
Methods:
Wildtype C57Bl/6 mice underwent cardiac ischemia-reperfusion (I/R) by ligation of the left coronary artery and restoration of the blood flow after 45min. Following surgery, the mice were treated with the mTOR inhibitor Everolimus or control daily until day 5. Echocardiography was performed at baseline, one day after surgery and every week after the I/R-operation. Mice were sacrificed after 1 or 3 weeks and immune response was analyzed by flow cytometry and histological analyses.
Results:
Treatment with Everolimus from day 0 to day 5 led to significant reduction of the left ventricular end-diastolic volume (LVEDV) one week after I/R compared to the control group (52.0 µl vs. 62.7ml; p= 0.039). Three weeks after I/R the reduction of LVEDV of Everolimus-treated animals did not reach statistical significance (p=0.08). Flow cytometric analysis reveals significant reduction of T lymphocytes (p=0.005), NK-cells (p=0.001) and a nearly significant reduction of B cells (p=0.053) in the murine hearts 1 week after I/R, whereas the systemic lymphocyte-fractions in the blood did not change.
Conclusion:
This study shows that the mTOR inhibitor Everolimus prevents early LV-dilation in mice after AMI. Simultaneously the composition of the immune cells in the myocardium is altered and may be responsible for a mitigated inflammatory response in the infarcted myocardium.
As a key regulator of cell growth and activity mTOR-inhibition bears a great potential to influence the inflammatory and reparative phase after AMI by several pathways including immune cell invasion, immune cell activity, cytokine production, autophagy, and scar formation. Further research is needed to elucidate the relevant mechanisms behind the observed effect.