Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers.

Benoit J Arsenault,Gregory M Preston,Nanette K Wenger,John J P Kastelein,Heiner Greten,Weihang Bao,John C Larosa,David A Demicco,David D Waters,Prakash Deedwania,Philip Barter,James Shepherd,Scott M Grundy,Jeffrey S Berger

doi:10.1371/journal.pone.0114519

Abstract

Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive of recurrent MCVEs (P≤0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.Trial RegistrationClinicalTrials.gov NCT00327691.

Highlights

There has been much recent interest in the ability of non-lipid biomarkers associated with systemic inflammation, oxidative stress, tissue remodelling and/or insulin resistance to predict adverse cardiovascular outcomes and to identify individuals at high risk of future coronary heart disease (CHD) events and stroke [1, 2]
Plasma levels of adiponectin, cystatin C, Lp-PLA2, monocyte chemoattractant protein-1 (MCP-1), Matrix metalloproteinase-9 (MMP-9), MPO, osteopontin, soluble CD40 ligand (sCD40L), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were not associated with the risk of recurrent major cardiovascular events (MCVEs)
Our results suggest that plasma levels of Lp(a), neopterin, NT-proBNP, and soluble receptor for advanced glycation end products (sRAGE) are significantly associated with the risk of recurrent MCVEs

Summary

Introduction

There has been much recent interest in the ability of non-lipid biomarkers associated with systemic inflammation, oxidative stress, tissue remodelling and/or insulin resistance to predict adverse cardiovascular outcomes and to identify individuals at high risk of future coronary heart disease (CHD) events and stroke [1, 2]. The concentration of one of these, high-sensitivity C-reactive protein (hsCRP), predicts future cardiovascular events in apparently healthy individuals and in subjects treated with statins [3,4,5] The results of these studies have been used to support the argument that the concentration of non-lipid biomarkers such as hsCRP should be included in algorithms designed to predict cardiovascular outcomes and to measure the efficacy of statin treatment [6]. There are inconsistencies, with some studies finding that levels of nonlipid biomarkers have minimal predictive power beyond of established CHD risk factors [7,8,9] We further address this issue by investigating how the concentrations of plasma lipids and non-lipid biomarkers relate to cardiovascular events in the Treating to New Targets (TNT) study

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