Identification of a specific inflammatory protein biosignature in coronary and peripheral blood associated with increased risk of future cardiovascular events

Background and rationaleAs an adjunct to coronary intervention, the Liquid Biopsy System (LBS, PlaqueTec, UK) enables accurate intracoronary blood sampling at discrete sites simultaneously. We investigated variation between local coronary and remote (peripheral) blood levels of a panel of atherosclerosis-associated proteins and examined how this might relate to cardiovascular risk assessment. Methods and ResultsIn a previous proof-of-concept trial, coronary blood samples were collected using the LBS in 28 patients. For 12 of these patients, sampling was conducted across the uninstrumented lesion, prior to percutaneous coronary intervention (PCI). Peripheral blood samples were also collected, at baseline and after PCI. Protein levels in coronary and peripheral plasma samples were analysed by proximity extension assay (PEA, Olink). Before PCI, in 10 out of 12 patients, coronary levels of hepatocyte growth factor (HGF), pappalysin-1 (PAPPA) and spondin-1 (SPON1) were elevated compared with peripheral levels, in some cases >10-fold. Following PCI, involving iatrogenic plaque rupture prior to stenting, peripheral levels of these proteins were elevated to a similar degree as coronary levels. In 2 patients, peripheral elevations of HGF, PAPPA and SPON1 (all >90th centile) were observed at baseline, prior to PCI. The protein pattern that was identified, consisting of high levels of a combination of HGF, PAPPA and SPON1 was absent in healthy control peripheral blood, but when investigated in baseline peripheral blood samples from reference cardiovascular and COVID-19 patient cohorts, was associated with the occurrence of major adverse cardiovascular events (MACE) and mortality. ConclusionsFrom investigation of coronary and peripheral blood samples, we identified a novel inflammatory protein signature, which when present in peripheral blood appears to portend worse outcomes. Measurement of these proteins could therefore aid identification of individuals at high risk of cardiovascular events or death. Translational PerspectiveThrough sampling of local coronary blood, we discovered a novel protein biosignature consisting of a combination of elevated levels of HGF, PAPPA and SPON1. When this biosignature was assessed in peripheral samples from reference cardiovascular and COVID-19 cohorts, it associated with the occurrence of MACE and mortality. The biosignature protein levels correlated with markers of mast cell and neutrophil activity but not with CRP, possibly indicating a specific inflammatory status. Early detection of this protein signal has potential clinical utility to identify specific patients at increased risk of poor outcomes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=129 HEIGHT=200 SRC="FIGDIR/small/23288168v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1f282dborg.highwire.dtl.DTLVardef@6d1bbdorg.highwire.dtl.DTLVardef@138302eorg.highwire.dtl.DTLVardef@1e350f3_HPS_FORMAT_FIGEXP M_FIG C_FIG