Background: The association between inflammation and the risk of cardiovascular disease (CVD) has been previously investigated. However, the recent emergence of the concept of persistent elevation of c-reactive protein (CRP) in the context of Spondyloarthritis (SpA) has garnered increased attention. Despite this, the molecular mechanisms underpinning this relationship remain unknown.

Objectives: 1 ) to explore the relationship between persistent inflammation and CVD complications, specifically focusing on endothelial dysfunction and the occurrence of atherosclerotic (AT) plaques in axial SpA (axSpA); 2 ) to investigate the molecular intricacies associated with endothelial dysfunction or the formation AT plaques in the context of persistent inflammation, with the goal of identifying in vivo potential biomarkers indicative of these cardiovascular manifestations in axSpA and 3 ) to determine the in vitro molecular mechanisms underlying the development of CVD complications in the context of axSpA.

Methods: a cohort of 160 axSpA patients was enrolled at the Reina Sofia Hospital. CRP levels were documented for the preceding five years, including the day of the visit. AxSpA patients were categorized into two groups based on the extent of prolonged CRP elevation (>50% and <50% determinations of CRP over the normal value during the last 5 years, classified as persistent or non-persistent inflammation, respectively). AT plaque presence was assessed through ultrasound scanning employing carotid duplex equipment (LOGIC E9), while endothelial function analysis was conducted using laser Doppler linear Periflux 5010. Levels of 184 proteins were measured using Olink technology. Comprehensive analysis of clinical and analytical variables was performed. Additionally, in vitro experiments involving human endothelial cells were conducted.

Results: axSpA patients with persistent inflammation did not exhibit significant differences in age, sex, or disease duration when compared to those with non-persistent inflammation. The prevalence of obesity, hypertension, insulin resistance, type 2 diabetes mellitus, and endothelial dysfunction was notably higher in the axSpA group with persistent inflammation. From a molecular perspective, 37 out of 184 analysed proteins exhibited significant alterations in axSpA patients with persistent elevated CRP levels compared to those without persistent elevated CRP. Similarly, 37 out of 184 proteins were significantly altered in axSpA patients with AT plaques compared to those without AT plaques. The biological enrichment analysis of the altered proteome in patients with persistent elevated CRP levels revealed enrichment in processes such as monocyte and neutrophil chemotaxis, leukocyte migration, humoral immune response, inflammatory response, and response to bacteria and cytokines. A common pattern emerged among proteins altered in the presence of prolonged elevated CRP and AT plaques, involving 13 key proteins including GDF-15, CDCP1, PON3, TNFRSF9, CTSZ, CXCL9, CCL20, CCL25, PLAUR, IL2RA, IL10, and TNF-R1. These proteins appear to play a pivotal role in the development of CVD alterations associated with elevated CRP levels in the previous five years in axSpA patients. To gain a deeper understanding of the role of these proteins in the development of cardiovascular complications, we conducted an analysis of their potential impact on human endothelial cells.

Conclusion: 1) AxSpA patients with over 50% of positive determinations for CRP in the preceding five years exhibited elevated rates of CVD comorbidities, underscoring the presence of endothelial dysfunction and an increased incidence of atherosclerotic plaques. 2) The discerned molecular pattern associated with these conditions unveiled potential biomarkers indicative of the development of CVD comorbidities. 3) These biomarkers may exert an impact on the endothelium, thereby fostering abnormalities in cardiovascular function.

Supported the “Instituto de Salud Carlos III” (PMP21/00119 and RICOR-RD21/0002/0033) co-financed by the European Union.

REFERENCES: NIL.

Acknowledgements: Supported the “Instituto de Salud Carlos III” (PMP21/00119 and RICOR-RD21/0002/0033) co-financed by the European Union.

Disclosure of Interests: None declared.