Relationship of oxidized phospholipids on apolipoprotein B-100 to cardiovascular outcomes in patients treated with intensive versus moderate atorvastatin therapy: the TNT trial.

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) is a biomarker of increased risk for major adverse cardiovascular events (MACE) in community cohorts, but its role in patients with stable coronary heart disease (CHD) is unknown. This study sought to examine the relationship between these oxidative biomarkers and cardiovascular outcomes in patients with established CHD. In a random sample from the TNT (Treating to New Targets) trial, OxPL-apoB levels were measured in 1,503 patients at randomization (after an 8-week run-in period taking atorvastatin 10 mg) and 1 year after being randomized to atorvastatin 10 or 80 mg. We examined the association between baseline levels of OxPL-apoB and MACE, defined as death from CHD, nonfatal myocardial infarction, resuscitation after cardiac arrest, and fatal/nonfatal stroke, as well as the effect of statin therapy on OxPL-apoB levels and MACE. Patients with events (n = 156) had higher randomization levels of OxPL-apoB than those without events (p = 0.025). For the overall cohort, randomization levels of OxPL-apoB predicted subsequent MACE (hazard ratio [HR]: 1.21; 95% confidence interval: 1.04 to 1.41; p = 0.018) per doubling and tertile 3 versus tertile 1 (hazard ratio: 1.69; 95% confidence interval [CI]: 1.14 to 2.49; p = 0.01) after multivariate adjustment for age, sex, body mass index, among others, and treatment assignment. In the atorvastatin 10-mg group, tertile 3 was associated with a higher risk of MACE compared to the first tertile (HR: 2.08; 95% CI: 1.20 to 3.61; p = 0.01) but this was not significant in the atorvastatin 80-mg group (HR: 1.40; 95% CI: 0.80 to 2.46; p = 0.24). Elevated OxPL-apoB levels predict secondary MACE in patients with stable CHD, a risk that is mitigated by atorvastatin 80 mg. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

Byun YS ，Lee JH ，Arsenault BJ ，Yang X ，Bao W ，DeMicco D ，Laskey R ，Witztum JL ，Tsimikas S ，TNT Trial Investigators ... -  《-》

High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial.

Tsimikas S ，Witztum JL ，Miller ER ，Sasiela WJ ，Szarek M ，Olsson AG ，Schwartz GG ，Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators ... -  《-》

Oxidized Phospholipids on Apolipoprotein B-100 and Recurrent Ischemic Events Following Stroke or Transient Ischemic Attack.

Biomarkers to predict recurrent stroke and targets of therapy to prevent stroke are lacking. This study evaluated whether patients with prior cerebrovascular events and elevated levels of oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), but without prior coronary artery disease (CAD), are at risk for recurrent stroke and CAD events following high-dose statin therapy. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, OxPL-apoB levels were measured in 4,385 patients with stroke or transient ischemic attack at baseline and in 3,106 patients at 5 years following randomization to placebo or 80 mg atorvastatin. The primary endpoint was the time from randomization to a second nonfatal or fatal stroke. Secondary endpoints included first major coronary events and any cardiovascular event. Patients with recurrent stroke had higher baseline median OxPL-apoB levels than patients without (15.5 nmol/l vs. 11.6 nmol/l; p < 0.0001). After multivariable adjustment, elevated baseline OxPL-apoB predicted recurrent stroke (hazard ratio [HR]: 4.3; p < 0.0001), first major coronary events (HR: 4.0; p < 0.0001), and any cardiovascular event (HR: 4.4; p < 0.0001). These comparisons for any endpoint did not differ by treatment, shown as a nonsignificant interaction test. The net reclassification improvement, integrated discrimination improvement, and area under the receiver-operating characteristic curve (AUC) were all significantly improved by adding OxPL-apoB to the models, with ΔAUC +0.0505 (p < 0.0001) for recurrent stroke, ΔAUC +0.0409 (p < 0.0001) for first major coronary event, and ΔAUC +0.0791 (p < 0.0001) for any cardiovascular event. Elevated OxPL-apoB levels predicted recurrent stroke and first major coronary events in patients with prior stroke or transient ischemic attack. The lack of statin-OxPL-apoB treatment interaction suggested that OxPLs might be statin-independent therapeutic targets to reduce risk of cardiovascular events. (Lipitor in the Prevention of Stroke, for Patients Who Have Had a Previous Stroke [SPARCL]; NCT00147602).

Byun YS ，Yang X ，Bao W ，DeMicco D ，Laskey R ，Witztum JL ，Tsimikas S ，SPARCL Trial Investigators ... -  《-》

Prediction of cardiovascular events in statin-treated stable coronary patients by lipid and nonlipid biomarkers.

The aim of this study was to investigate the relationship between lipid and nonlipid biomarker levels achieved during statin therapy and the incidence of major cardiovascular events (MCVEs) in patients with stable coronary heart disease (CHD). Several plasma nonlipid biomarkers have been shown to predict MCVEs in population studies. This is a nested case-control study in the TNT (Treating to New Targets) study population, a randomized trial that compared the efficacy of high- (80 mg) versus low-dose (10 mg) atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 nonlipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg and again 1 year after being randomized to 10 or 80 mg atorvastatin in 507 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1,020 control subjects. An MCVE was defined as CHD death; nonfatal, non-procedure-related myocardial infarction; resuscitated cardiac arrest; or fatal or nonfatal stroke. Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were all predictive of recurrent MCVEs (p ≤ 0.009). Concentrations of many of the 18 nonlipid biomarkers were lowered by atorvastatin therapy (independent of dose). However, almost none of the nonlipid biomarker levels, whether measured after the 8-week run-in period or after 1 year of treatment with 10 or 80 mg atorvastatin, were predictive of recurrent MCVEs. In patients with stable CHD, atorvastatin improved plasma levels of an expanded panel of nonlipid biomarkers. However, independently of atorvastatin dose, the achieved levels of the vast majority of nonlipid biomarkers did not predict MCVEs. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

Arsenault BJ ，Barter P ，DeMicco DA ，Bao W ，Preston GM ，LaRosa JC ，Grundy SM ，Deedwania P ，Greten H ，Wenger NK ，Shepherd J ，Waters DD ，Kastelein JJ ，TNT Study Investigators ... -  《-》

Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: Results from the MIRACL (Myocardia

Fraley AE ，Schwartz GG ，Olsson AG ，Kinlay S ，Szarek M ，Rifai N ，Libby P ，Ganz P ，Witztum JL ，Tsimikas S ，MIRACL Study Investigators ... -  《-》