C3 convertase as a novel biomarker of cardiovascular pathology, insulin resistance and endothelial dysfunction

Resum

Introduction: Atherothrombotic disease is the leading aetiology of mortality in the Western countries. Its main cause is not hypercholesterolemia but the Metabolic Syndrome (MetS). In the last three decades MetS evolved from a quintet (hyperglycaemia, hypertension, hypertriglyceridemia, low HDL and waist) to become an octet named Cardiometabolic Syndrome (CMS), where the triad, consisting of inflammation/metaflammation, oxidative stress (OS) and endothelial dysfunction (ED) is essential to understand its impact at the vascular level. Insulin resistance (IR) is located at the heart of both syndromes. From the inflammatory point of view, the most used marker has been the CRP with the inconvenience of being highly unspecific. Finding new markers has become the researchers¿ goal for the last years. The present work confirms that the C3 convertase in plasma can be useful as a marker and possibly as a pathogenic factor, which if confirmed, would postulate C3 as a target of future preventive strategies. Objectives: Assess the behaviour of C3 convertase, key enzyme that controls the complement cascade in relation to MetS, CMS including ED, IR and cardiovascular (CV) risk in a population referred to cardiometabolic secondary care. Methodology: An observational retrospective cross-sectional study was performed on a random cohort of adult individuals from Madrid. Specific cardiometabolic factors were measured as part of the clinical routine of the Cardiometabolic Unit. CV risk was calculated by REGICOR formula. IR was estimated by HOMA-IR formula in a non-exogenous insulin replacement group. Subjects were stratified by C3 complement quartiles to assess the distribution of the cardiometabolic markers. Multivariable regression analysis was applied to identify predictors of C3 variability. Results: A total of n=374 subjects were selected (53.60±14.80 yr. old, 44.9% females), where 65% were hypertensive, 42% hyperglycaemic and 35% MetS. C3 complement levels were associated with: 1. MetS: MetS diagnosis, each single MetS criterion, proportional number of MetS criteria and new MetS criteria (p<0.001). 2. CMS: inflammation (CPR, fibrinogen, p<0.001) and metaflammation (Adiponectin, IL-6, p¿0.05), ED (TPA, PAI-1, VCAM, p¿0.050) and OS showed tendency (TBARS, p=0.084). 3. IR: HOMA (p<0.001). 4. CV risk: factors and CV risk (p<0.001). All of these correlations were independent of age and gender. Most of the previous variables were also correlated with C3 quartiles. Hypertriglyceridemia had the highest impact on C3 differing from clinical guidelines according to multivariate analysis (p<0.001). Conclusions: In relation with the MetS quintet, C3 resulted a strong predictor of each criteria, C3 was proportional to number of MetS criteria and described a possible arbitrary threshold between two and three criteria suggesting earlier CV prevention through equal risk. In relation to the CMS octet, C3 also predicted strongly inflammation/metaflamation, ED and showed tendency with OS. In this order, hypertriglyceridemia, CRP, HTA, waist, HOMA and hyperglycaemia resulted predictors of the 34% of C3 complement variability by multivariate analysis. The association with HOMA may influence the results of this study but can not explain all the correlations. This study suggested that simultaneous evaluation of CRP and C3 would increase the intrinsic reliability of CRP as required in precise Cardiometabolic Medicine