Allan Sirsjö

Background: Bone morphogenetic protein 10 (BMP10) has atrial-specific and vascular properties and may reflect both atrial and vascular pathophysiology. We investigated whether BMP10 levels were associated with new-onset atrial fibrillation (AF), major adverse cardiovascular events (MACE), and all-cause mortality after open revascularisation for symptomatic peripheral arterial disease (PAD) or carotid stenosis (CS). Methods: Patients scheduled for endarterectomy for symptomatic PAD or CS were enrolled. BMP10 concentrations were measured using a multiplex immunoassay. Clinical outcomes were obtained from medical records during one-year follow-up. Associations between BMP10 and outcomes were assessed using Cox proportional hazards regression. Results: A total of 210 patients were included (63% men; 61% underwent surgery for PAD). Women were older than men and had higher BMP10 levels. Forty patients had known preoperative AF. During one-year follow-up, 26 patients experienced MACE and 13 died. Among 170 patients without AF at baseline, 10 developed new-onset AF. In unadjusted Cox regression, higher BMP10 levels were associated with MACE (HR 1.01, 95% CI 1.00-1.03; p = 0.047) and all-cause mortality (HR 1.03, 95% CI 1.01–1.04; p < 0.001), but not with new-onset AF (HR 1.00, 95% CI 0.97–1.03; p = 0.80). Effect estimates were similar after adjustment for age and sex. Model-based point estimates of one-year cumulative incidence were numerically higher at higher BMP10 concentrations for MACE and all-cause mortality, although confidence intervals were wide; no corresponding pattern was observed for new-onset AF. Conclusions: In this exploratory cohort, higher BMP10 levels were associated with MACE and all-cause mortality after endarterectomy for symptomatic PAD or CS. Women had higher BMP10 levels than men. These findings should be interpreted cautiously and considered hypothesis-generating; larger studies are required to validate the observed associations.

Background: Blockade of IL1RAP (interleukin 1 receptor associated protein) was recently shown to reduce atherosclerosis in mice, but the effect on human vascular cells is largely unknown. Targeting the IL1RAP coreceptor represents a novel strategy to block the IL1RAP‐dependent cytokines IL (interleukin)‐1, IL‐33, and IL‐36. In the present study, we aimed to evaluate the role of novel antibodies targeting IL1RAP to reduce the effects of IL‐1β, IL‐33, or IL‐36γ in human vascular cells. Methods: Expression of IL1RAP was observed in human atherosclerotic plaques by immunohistochemistry and microarray and in endothelial cells by flow cytometry. Endothelial cells were cultured with IL‐1β, IL‐33, or IL‐36γ cytokines with or without IL1RAP antibodies and analyzed with Olink proteomics, ELISA, Western blot, and real‐time quantitative polymerase chain reaction. The functional effect of IL1RAP antibodies on endothelial cells were analyzed with adhesion and permeability assays. Results: Olink proteomics showed inhibition of the inflammatory proteins LIF (leukemia inhibitory factor), OPG (osteoprotegerin), CCL4 (C‐C motif chemokine ligand 4), and MCP‐3 (monocyte chemoattractant protein 3) by IL1RAP‐blockade in endothelial cells after IL‐1β stimulation. In addition, the IL1RAP antibodies inhibited IL‐1β, and IL‐33 induced IL‐6 and IL‐8 secretion. Secretion of MCP‐1 (monocyte chemoattractant protein 1) was induced by IL‐1β, IL‐33, and IL‐36γ, and subsequently was inhibited by IL1RAP antibodies. Similar effects were found on mRNA expression level. Endothelial expression of the adhesion markers ICAM1 , VCAM1, and SELE were significantly reduced by IL1RAP antibodies, and neutrophil adhesion to endothelial cells induced by IL‐1β and IL‐33 was reduced by IL1RAP blockade. In human atherosclerotic lesions, IL1RAP expression correlated with markers of inflammation like IL6 , IL8, and MCP1 . Conclusions: IL1RAP‐targeting antibodies can reduce the expression of inflammatory cytokines and markers of adhesion in endothelial cells, which may be of importance for future putative targeted treatments against cardiovascular disease.