On the value of therapeutic interventions targeting the complement system in acute myocardial infarction.
The complement system plays an important role in the inflammatory response subsequent to acute myocardial infarction (AMI). The aim of this study is to create a systematic overview of studies that have investigated therapeutic administration of complement inhibitors in both AMI animal models and human clinical trials. To enable extrapolation of observations from included animal studies toward post-AMI clinical trials, ex vivo studies on isolated hearts and proof-of-principle studies on inhibitor administration before experimental AMI induction were excluded. Positive therapeutic effects in AMI animal models have been described for cobra venom factor, soluble complement receptor 1, C1-esterase inhibitor (C1-inh), FUT-175, C1s-inhibitor, anti-C5, ADC-1004, clusterin, and glycosaminoglycans. Two types of complement inhibitors have been tested in clinical trials, being C1-inh and anti-C5. Pexelizumab (anti-C5) did not result in reproducible beneficial effects for AMI patients. Beneficial effects were reported in AMI patients for C1-inhibitor, albeit in small patient groups. In general, despite the absence of consistent positive effects in clinical trials thus far, the complement system remains a potentially interesting target for therapy in AMI patients. Based on the study designs of previous animal studies and clinical trials, we discuss several issues which require attention in the design of future studies: adjustment of clinical trial design to precise mechanism of action of administered inhibitor, optimizing the duration of therapy, and optimization of time point(s) on which therapeutic effects will be evaluated.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; ICaR-VU, Institute of Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: r.emmens@vumc.nl.
Reindert W
RW
Emmens
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Diana
D
Wouters
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands.
Sacha
S
Zeerleder
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
S Marieke
SM
van Ham
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; ICaR-VU, Institute of Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Department of Cardiac Surgery, VU University Medical Center, Amsterdam, The Netherlands.
Hans W M
HWM
Niessen
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; ICaR-VU, Institute of Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
Paul A J
PAJ
Krijnen
D000818:Animals; D003167:Complement Activation; D051056:Complement Inactivating Agents / Q000627:therapeutic use; D003165:Complement System Proteins / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D058990:Molecular Targeted Therapy; D009203:Myocardial Infarction / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*
D051056:Complement Inactivating Agents; D003165:Complement System Proteins