Relevance of complement activation in cardiomyopathy during sepsis

• Applicant: Professorin Dr. Miriam Kalbitz
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 223274482

It is known that sepsis is often accompanied by cardiac failure, which may be life-threatening. This has been referred to as the „cardiomyopathy of sepsis“ and is considered to be reversible. The basis for this frequent complication of sepsis is poorly understood. Using the experimental sepsis model in rodents (caecal ligation and puncture, CLP), we have shown that, when the complement activation product (C5a) is neutralized in vivo, cardiac failure is largely averted and survival is greatly enhanced. We have also shown that, when normal cardiomyocytes (CMs) are incubated in vitro with C5a, they develop contractile defects. Therefore, in the proposed studies I will pursue preliminary data which suggest that C5a interferes with the ability of CMs to regulate intracellular Ca2+, cytosolic clearance of which is necessary for normal contractility of paced CMs. I will further define the electrophysiological defects in CMs exposed to C5a and determine if this C5a-related defect is due to loss of CM enzymes that regulate intracellular Ca2+. The relevant C5a receptors on CMs will also be evaluated. In addition, because some cytokines (TNFý, IL-1ý) also have „cardiosuppressive“ effects, effects of C5a will be compared to effects of TNFý on CMs. It will be determined if there may be a linkage between the effects of C5a and TNFý on CMs or if the effects of these two classes of mediators are independent. Such information may lead to interventions that could reverse the cardiomyopathy developing during sepsis.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Peter A. Ward