At some point in the years ahead, the research community will develop effective means of reversing atherosclerotic lesions, the fatty, inflammatory deposits that build up in blood vessel walls to ultimately cause stroke or heart attack. Those therapies will be best applied in a preventative manner, not used in the late stage of the condition when lesions are large, complex, and greatly distort and weaken blood vessels. That in turn means that a reliable, low cost test to assess progression of preclinical atherosclerosis is required. Researchers here propose complement C5 protein levels in a blood sample as such a test, based on recent human data.

The purpose of this study was to analyze the temporal and topologically resolved protein changes taking place in human aortas with early atherosclerosis to find new potential diagnostic and/or therapeutic targets. The protein composition of healthy aortas (media layer) or with early atheroma (fatty streak and fibrolipidic, media, and intima layers) was analyzed by deep quantitative multiplexed proteomics. Plasma levels of complement C5 were analyzed in relation to the presence of generalized (more than 2 plaques) or incipient (0 to 2 plaques) subclinical atherosclerosis in 2 independent clinical cohorts, PESA (Progression of Early Subclinical Atherosclerosis) and NEFRONA (National Observatory of Atherosclerosis in Nephrology).

Proteins involved in lipid transport, complement system, immunoglobulin superfamily, and hemostasis are increased in early plaques. Components from the complement activation pathway were predominantly increased in the intima of fibrolipidic plaques. Among them, increased C5 protein levels were further confirmed by Western blot, enzyme-linked immunosorbent assay, and immunohistochemistry, and associated with in situ complement activation. Plasma C5 was significantly increased in individuals with generalized subclinical atherosclerosis in both PESA and NEFRONA cohorts, independently of risk factors. Moreover, in the PESA study, C5 plasma levels positively correlated with global plaque volume and coronary calcification.

In conclusion, activation of the complement system is a major alteration in early atherosclerotic plaques and is reflected by increased C5 plasma levels, which have promising value as a novel circulating biomarker of subclinical atherosclerosis.