Complement Destabilizes Cardiomyocyte Function In Vivo after Polymicrobial Sepsis and In Vitro

There is accumulating evidence during sepsis that cardiomyocyte (CM) homeostasis is compromised, resulting in cardiac dysfunc- tion. An important role for complement in these outcomes is now demonstrated. Addition of C5a to electrically paced CMs caused prolonged elevations of intracellular Ca2+ concentrations during diastole, together with the appearance of spontaneous Ca2+ transients. In polymicrobial sepsis in mice, we found that three key homeostasis-regulating proteins in CMs were reduced: Na+/K+-ATPase, which is vital for effective action potentials in CMs, and two intracellular Ca2+ concentration regulatory proteins, that is, sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and the Na+/Ca2+ exchanger. Sepsis caused reduced mRNA levels and reductions in protein concentrations in CMs for all three proteins. The absence of either C5a receptor mitigated sepsis- induced reductions in the three regulatory proteins. Absence of either C5a receptor (C5aR1 or C5aR2) diminished development of defective systolic and diastolic echocardiographic/Doppler parameters developing in the heart (cardiac output, left ventricular stroke volume, isovolumic relaxation, E9 septal annulus, E/E9 septal annulus, left ventricular diastolic volume).We also found in CMs from septic mice the presence of defective current densities for Ik1, L-type calcium channel, and Na+/Ca2+ exchanger. These defects were accentuated in the copresence of C5a. These data suggest complement-related mechanisms responsible for development of cardiac dysfunction during sepsis.