Background and method: Increased plasma clot density and prolonged lysis times are associated with cardiovascular disease. In this study, we employed a functional proteomics approach to identify novel clot components which may influence clot phenotypes. Results: Analysis of perfused, solubilised plasma clots identified inflammatory proteins, including complement C3, as novel clot components. Analysis of paired plasma and serum samples confirmed concentration-dependent incorporation of C3 into clots. Surface plasmon resonance indicated high-affinity binding interactions between C3 and fibrinogen and fibrin. Turbidimetric clotting and lysis assays indicated C3 impaired fibrinolysis in a concentration-dependent manner, both in vitro and ex vivo. Conclusion: These data indicate functional interactions between complement C3 and fibrin leading to prolonged fibrinolysis. These interactions are physiologically relevant in the context of protection following injury and suggest a mechanistic link between increased plasma C3 concentration and acute cardiovascular thrombotic events.

To cite this article: Ajjan R, Carter AM, Somani R, Kain K, Grant PJ. Ethnic differences in cardiovascular risk factors in healthy Caucasian and South Asian individuals with the metabolic syndrome. J Thromb Haemost 2007; 5: 754-60. Summary. Background:The metabolic syndrome is a cluster of atherothrombotic risk factors that are commonly associated with insulin resistance. Objectives: The aim of this study was to investigate ethnic differences in insulin resistance and nontraditional cardiovascular risk factors in relation to the International Diabetes Federation (IDF) definition of the metabolic syndrome. Patients and methods: A total of 245 healthy South Asians and 245 age-and sex-matched Caucasians were studied. C-reactive protein (CRP), complement C3, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) were measured and homeostasis model assessment-insulin resistance (HOMA-IR) was calculated from fasting plasma glucose and insulin levels. Results: Fifty Caucasian (20%) and 95 (39%) South Asian subjects had the metabolic syndrome as defined by the IDF. In South Asian subjects, HOMA-IR, CRP, C3, PAI-1 and t-PA were significantly higher in subjects with the metabolic syndrome. In contrast, in Caucasian individuals there was no difference in HOMA-IR or C3 levels and only CRP, PAI-1 and t-PA were higher in subjects with the metabolic syndrome. In a logistic regression model, plasma levels of CRP and PAI-1 were independent predictors of the metabolic syndrome in Caucasians, whereas plasma levels of C3 and t-PA as well as HOMA-IR were independent predictors of the metabolic syndrome in South Asian subjects. Conclusions: In the cohort of individuals studied, the IDF definition of the metabolic syndrome was associated with insulin resistance in the South Asian but not the Caucasian population. This work also showed ethnic differences in non-traditional cardiovascular risk factors in the presence of the metabolic syndrome.

Background-The magnitude of QT prolongation in response to bradycardia, rather than the bradycardia per se, determines the risk for torsade de pointes during atrioventricular block (AVB). However, we do not know why some patients develop more QT prolongation than others, despite similar bradycardia. We hypothesized that in patients who develop significant QRS vector changes during AVB, the effects of cardiac memory lead to excessive QT prolongation. Methods and Results-We studied 91 patients who presented with AVB and who also had an ECG predating the bradyarrhythmia for comparison. We correlated changes in QRS morphology and axis taking place during AVB with the bradycardia-induced QT prolongation. Patients with and without QRS morphology changes at the time of AVB were of similar age and sex. Moreover, despite similar R-R interval during AVB, cases with a QRS morphology change had significantly longer QT (648±84 versus 561±84; P<0.001) than those without. Patients who developed a change in QRS morphology at the time of AVB had a 7-fold higher risk of developing long QT. This risk nearly doubled when the change in QRS morphology was accompanied by a change in QRS axis. Conclusions-Cardiac memory resulting from a change in QRS morphology during AVB is independently associated with QT prolongation and may be arrhythmogenic during AVB. (Circ Arrhythm Electrophysiol. 2014;7:1129-1135.)

OBJECTIVEEmerging data implicate activation of the complement cascade in the pathogenesis of type 2 diabetes. The objective of the current study was to evaluate the relationships between components of the complement system, metabolic risk factors, and family history of type 2 diabetes in healthy South Asians.RESEARCH DESIGN AND METHODSWe recruited 119 healthy, first-degree relatives of South Asian subjects with type 2 diabetes (SARs) and 119 age- and sex-matched, healthy South Asian control subjects (SACs). Fasting blood samples were taken for measurement of complement factors and standard metabolic risk factors.RESULTSSARs were characterized by significantly higher properdin (mean concentration 12.6 [95% CI 12.2–13.1] mg/L vs. SACs 10.1 [9.7–10.5] mg/L, P < 0.0001), factor B (187.4 [180.1–195.0] mg/L vs. SACs 165.0 [158.0–172.2] mg/L, P < 0.0001), and SC5b-9 (92.0 [86.1–98.3] ng/mL vs. SACs 75.3 [71.9–78.9] ng/mL, P < 0.0001) and increased homeostasis model assessment of insulin resistance (2.86 [2.61–3.13] vs. SACs 2.31 [2.05–2.61], P = 0.007). C-reactive protein did not differ between SARs and SACs (P = 0.17). In subgroup analysis of 25 SARs and 25 SACs with normal oral glucose tolerance tests, properdin, factor B, and SC5b-9 remained significantly elevated in SARs.CONCLUSIONSIncreased properdin and complement activation are associated with a family history of type 2 diabetes in South Asians independent of insulin resistance, and predate the development of impaired fasting glucose and impaired glucose tolerance. Properdin and SC5b-9 may be novel biomarkers for future risk of type 2 diabetes in this high-risk population and warrant further investigation.