Apolipoprotein C‐III predicts cardiovascular mortality in severe coronary artery disease and is associated with an enhanced plasma thrombin generation

Abstract

predicts cardiovascular mortality in severe coronary artery disease and is associated with an enhanced plasma thrombin generation. J Thromb Haemost 2010; 8: 463-71.Summary. Background: Apolipopoprotein C-III (apo C-III) plays a pivotal role in controlling plasma triglyceride (TG) and contributes to the atherogenic properties of TG-rich lipoproteins. Objectives: (i) To examine the predictive value of serum apo C-III for cardiovascular mortality in the setting of secondary prevention of coronary artery disease (CAD); and (ii) to evaluate possible associations between apolipoprotein levels and the thrombin generation assay, a global test to estimate plasma thrombogenic potential. Methods and results: A cohort of 633 patients with angiographically proven CAD was prospectively followed for a median follow-up of 57 months. The large majority of them (92%) underwent coronary (endovascular or surgical) revascularization. During the follow-up, 91 (14.3%) out of 633 patients died, with 64 events (10.1%) attributed to cardiovascular causes. After adjustment for all the other predictors of mortality during univariate analysis (i.e. age, statin therapy, myocardial infarction history, diabetes, hs-CRP and creatinine), elevated apo C-III levels ( ‡ 10.5 mg dL )1 -the median value) significantly predicted both total and cardiovascular mortality (HR for total mortality 2.22 with 95% CI 1.16-4.24; HR for cardiovascular mortality 2.35 with 95% CI 1.19-4.62). In a subgroup of 225 subjects, apo C-III levels were significantly associated with endogenous thrombin potential in regression models (standardized b coefficient = 0.207, P = 0.002). Conclusions: Basal concentrations of apo C-III levels ‡ 10.5 mg dL )1 in CAD patients independently predicted cardiovascular mortality during the subsequent 5-year period. Such concentrations were associated with an enhanced plasma endogenous thrombin generation, suggesting a complex interplay between TG-rich particles and the coagulation cascade as well as a new ÔthrombogeneticÕ role for apo C-III.

Association of ApoE genetic polymorphisms with proximal deep venous thrombosis

“…However, the pathophysiological mechanism of these associations requires further investigation. One study reported that apo C-III is related to increased endogenous generation of thrombin and hence interferes in the coagulation cascade [3]. In this study the association with thrombotic events involved the e2 allele thus suggesting that an increase in the endogenous generation of thrombin should be investigated.…”

“…Such concentrations were associated to an enhanced endogenous thrombin generation in plasma suggesting a complex interplay between triglycerides-rich particles and the coagulation cascade as well as a new 'thrombogenic' role for apo C-III [3].…”

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

“…Антисенс-технологии открыли широкую перспективу для попытки воздействия на концентрацию ТГ с исполь-зованием в качестве мишеней генов многочисленных белков, вовлеченных в их метаболизм [7]. Одной из наиболее очевидных мишеней является апоСIII, из-за связи данного апобелка с развитием триглице-ридемии, атеросклероза, ССЗ и других метаболиче-ских нарушений [28,29]. Генетические исследования свидетельствуют о положительном влиянии пони-женного уровня апоСIII на уровень ТГ и атерогенных апоВ100-содержащих липопротеидов, а также на про-должительность жизни [30].…”

Thrombin Generation and Atherothrombosis: What Does the Evidence Indicate?

“…Differences between the populations, for instance, in the degree of hyperlipidemia, were suggested to be involved in some of these risk associations. Indeed, Olivieri et al found that Apo C‐III was an independent risk factor for CAD and that it was associated with endogenous thrombin potential (ETP) and peak thrombin activity 45. This was not the case for total cholesterol, low‐density lipoprotein, triglycerides, and apoE, suggesting that Apo C‐III may play a functional role in thrombin generation.…”

“…From the present analysis, Apo‐CIII and Lp(a) emerge as determinants of TG. Olivieri et al provide an explanation for the effect of Apo‐CIII showing that elevated concentrations of Apo CIII are associated with an increase in thrombin activity to an extent comparable to the carriership of G20210A gene variant and modulating TG in subjects with or without CAD 45. Direct effects of Lp(a) on TG have not been reported.…”