Plasma levels of sCASP3 predicts carotid intima media thickness progression

Abstract Background Studies on human atherosclerotic plaques have shown that apoptosis is associated with rupture prone plaques and that apoptosis is a key process for fast plaque progression. In line with this, we showed that circulating levels of soluble Caspase-3 (sCaspase-3) predict atherosclerotic events. However, the relationship between circulating levels of apoptosis markers and plaque progression remains to be explored. Purpose Here we aimed to investigate if circulating levels of apoptosis markers could predict mean intima-media thickness in the common carotid artery (IMT-CCA) progression among individuals with atherosclerotic carotid plaques. Methods The Malmö Diet and Cancer (MDC) cardiovascular cohort was used. MDC is a prospective population-based cohort study. Baseline variables (blood, clinical information and carotid ultrasound measurements) were collected between 1991-1994 and the right carotid ultrasound re-examinations were performed between 1994-2001. IMT was measured at by ultrasound at baseline as well as at the re-examinations. The Olink Proximity Extension Assay (SciLifeLab, Uppsala, Sweden) was used to analyze plasma levels of sCaspase-3, sFADD, sCaspase-8, sTRAIL-R2 and sTNFR1 at baseline. Correlation and multiple linear regression analyses, adjusted for age, sex, and cardiovascular risk factors, were employed to evaluate the relationships between apoptosis biomarkers and IMT-CCA as well as average annual change in IMT-CCA. Results In total, 1929 participants (median age 60 years) with an ultrasound confirmed carotid plaque (focal IMT >1.2mm) at baseline were included. Subjects who underwent ultrasound IMT re-examination over a period of >4.5 years were divided into a discovery (n=406) and a validation (n=355) cohort. sCaspase-3 was identified as the marker with the strongest correlation to IMT-CCA at baseline (p=0.02) and upon re-examination (p=0.04), among the five apoptosis markers examined, in both the discovery and validation cohorts. sCaspase-3 also showed a correlation with the average annual change of IMT-CCA (r=0.12, p=8×10-4) in both cohorts. Furthermore, when diving the cohort into tertiles based on plasma levels of sCapase-3, subjects with high levels of sCaspase-3 (3rd tertile) had greater annual changes in IMT-CCA compared to the 1st tertile (p=0.03). Multiple linear regression analyses confirmed that sCapase-3 was associated with the average annual IMT-CCA change in both the discovery (beta=0.14, 95% confidence interval (CI) 0.04–0.24) cohort and the validation cohort (beta=0.11, 95%CI 0.01–0.21). Conclusion Using a large, population-based study with repeated IMT measurements, we demonstrated that circulating levels of sCapase-3 were associated with increasing IMT in the CCA. While further studies are warranted, these results suggest that sCapase-3 levels could serve as potential screening marker to identify individuals at higher risk for plaque progression.