Purpose: With regards to biomarker discovery, proteomics has overpromised, but underdelivered. The cardiovascular field is no exception. The plasma proteome is the most complex proteome of the human body. An alternative strategy is the application of proteomics to diseased tissues, where the potential biomarkers are less dilute.
Methods and Results: We have applied our proteomics method for cardiac extracellular proteins to biomarker discovery in septic hearts. C57Bl6 mice were injected with LPS, their cardiac proteome was subfractionated and extracellular proteins were analysed by liquid chromatography tandem mass spectrometry. Among the most differentially expressed proteins was long pentraxin 3 (PTX3), an acute phase protein, secreted by various cells and tissues, that is known to be associated with increased mortality in septic patients. Interestingly, PTX3 accumulated in the cardiac extracellular matrix as an octamer due to disulphide-bond formation. An octameric and tetrameric moiety of PTX3 was also detectable in plasma. Over a time course of 11 days, the redox-state of PTX3 was quantified in septic patients (n=31). On admission to the intensive care unit, there was no difference in the redox state of PTX3 between survivors and non-survivors. From day 2 onwards, however, the conversion of octameric to monomeric PTX3 was consistently associated with a greater survival after 28 days of follow-up. For example, on day 2 post admission, octameric PTX3 was undetectable in survivors, but still constituted more than half of total PTX3 in non-survivors (p<0.001). Although monomeric PTX3 was inversely associated with cardiac damage markers such as NT-proBNP, high sensitive troponin I and T, octamer- and monomer-PTX3 levels predicted the 28-day survival better than a model containing NT-proBNP only.
Conclusion: Sepsis is associated with significant mortality. In comparison to the conventional measurements of total PTX3, the assessment of the redox-sensitive oligomerization of PTX3 was more dynamic and could be a superior predictor of inflammation resolution and disease outcome in septic patients.