AIMS In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary therapy for atherosclerosis has altered these relationships is unknown yet has major implications for future drug development. METHODS AND RESULTS Interleukin-6, hsCRP, and LDLC were measured at baseline in up to 4168 North American patients enrolled in the contemporary Cardiovascular Inflammation Reduction Trial with prior myocardial infarction or multivessel coronary disease who additionally had diabetes or metabolic syndrome and were followed for a period of up to 5 years for incident major recurrent cardiovascular events and all-cause mortality. Three-quarters of the cohort were previously revascularized and the great majority was taking statins, angiotensin blocking agents, beta-blockers, and antithrombotic agents. Participants were randomly allocated to low-dose methotrexate 15 mg weekly or to placebo. Randomized use of methotrexate had no effect on event rates nor plasma levels of IL-6, hsCRP, or LDL over time. Yet, baseline levels of IL-6, hsCRP, and LDLC were all predictors of major recurrent cardiovascular events; adjusted hazard ratios [HR; 95% confidence interval (CI)] for the lowest to highest baseline quartiles of IL-6 were 1.0 (referent), 1.66 (1.18-2.35), 1.92 (1.36-2.70), and 2.11 (1.49-2.99; P < 0.0001), while adjusted HRs for increasing quartiles of hsCRP were 1.0 (referent), 1.28 (0.92-1.79), 1.73 (1.25-2.38), and 1.79 (1.28-2.50; P < 0.0001) and adjusted HRs for increasing quartiles of LDLC were 1.0 (referent), 1.12 (0.78-1.62), 1.25 (0.87-1.79), and 2.38 (1.72-3.30; P < 0.0001). Effect estimates were not statistically different in these analyses for comparisons between IL-6, hsCRP, or LDLC, although IL-6 was the strongest predictor of all-cause mortality. The highest absolute risks were observed among those with elevated levels of both cholesterol and inflammation [HR 6.4 (95% CI 2.9-14.1) for those in the top quartiles of baseline IL-6 and LDLC, HR 4.9 (95% CI 2.6-9.4) for those in the top quartiles of baseline hsCRP and LDLC, both P < 0.0001]. CONCLUSION Despite aggressive contemporary secondary prevention efforts, the relationships between inflammation, cholesterol, and cardiovascular risk are largely unchanged from those described two decades ago. These data are consistent with the hypothesis that future treatments for atherosclerosis may require a combination of inflammation inhibition and additional cholesterol reduction. CLINICAL TRIAL ClinicalTrials.gov NCT01594333.

中文翻译：

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白细胞介素 6、C 反应蛋白和低密度脂蛋白胆固醇作为当代实践中残留风险的生物标志物的比较：来自心血管炎症减少试验的二次分析

目的 在超过 30 年前开始的流行病学队列中，炎症生物标志物，如白细胞介素 6 (IL-6) 和高敏 C 反应蛋白 (hsCRP) 被证明可以独立预测未来的心血管事件，其影响程度与低密度脂蛋白胆固醇 (LDLC)。当代积极的动脉粥样硬化疗法是否改变了这些关系尚不清楚，但对未来的药物开发有重大影响。方法和结果 白细胞介素 6、hsCRP、和 LDLC 在基线时对多达 4168 名参加当代心血管炎症减少试验的北美患者进行了测量，这些患者既往有心肌梗塞或多支血管冠状动脉疾病，此外还患有糖尿病或代谢综合征，并被跟踪长达 5 年的主要事件复发性心血管事件和全因死亡率。四分之三的队列之前进行了血运重建，绝大多数服用他汀类药物、血管紧张素阻断剂、β 受体阻滞剂和抗血栓药物。参与者被随机分配到每周 15 毫克的低剂量甲氨蝶呤组或安慰剂组。随着时间的推移，随机使用甲氨蝶呤对事件发生率和 IL-6、hsCRP 或 LDL 的血浆水平没有影响。然而，IL-6、hsCRP、和 LDLC 都是主要复发性心血管事件的预测因子；调整后的风险比 [HR; IL-6 最低至最高基线四分位数的 95% 置信区间 (CI)] 为 1.0（参考值）、1.66 (1.18-2.35)、1.92 (1.36-2.70) 和 2.11 (1.49-2.99；P < 0.0001) ，而 hsCRP 增加四分位数的调整 HR 为 1.0（参考值）、1.28（0.92-1.79）、1.73（1.25-2.38）和 1.79（1.28-2.50；P < 0.0001），而 L10 DLC 的调整 HR 为增加的 HRs。 （参考）、1.12 (0.78-1.62)、1.25 (0.87-1.79) 和 2.38 (1.72-3.30；P < 0.0001)。在这些比较 IL-6、hsCRP 或 LDLC 的分析中，效果估计没有统计学差异，尽管 IL-6 是全因死亡率的最强预测因子。在胆固醇和炎症水平升高的人群中观察到的绝对风险最高 [HR 6.4 (95% CI 2.9-14.1) 对于那些处于基线 IL-6 和 LDLC 前四分位数的人群，HR 4.9 (95% CI 2.6-9.4) ) 对于基线 hsCRP 和 LDLC 的前四分位数，两者 P < 0.0001]。结论 尽管当代进行了积极的二级预防努力，炎症、胆固醇和心血管风险之间的关系与二十年前描述的关系基本没有变化。这些数据与未来的动脉粥样硬化治疗可能需要结合炎症抑制和额外降低胆固醇的假设是一致的。临床试验 ClinicalTrials.gov NCT01594333。4) 对于基线 hsCRP 和 LDLC 的前四分位数，两者 P < 0.0001]。结论 尽管当代进行了积极的二级预防努力，炎症、胆固醇和心血管风险之间的关系与二十年前描述的关系基本没有变化。这些数据与未来的动脉粥样硬化治疗可能需要结合炎症抑制和额外降低胆固醇的假设是一致的。临床试验 ClinicalTrials.gov NCT01594333。4) 对于基线 hsCRP 和 LDLC 的前四分位数，两者 P < 0.0001]。结论 尽管当代进行了积极的二级预防努力，炎症、胆固醇和心血管风险之间的关系与二十年前描述的关系基本没有变化。这些数据与未来的动脉粥样硬化治疗可能需要结合炎症抑制和额外降低胆固醇的假设是一致的。临床试验 ClinicalTrials.gov NCT01594333。这些数据与未来的动脉粥样硬化治疗可能需要结合炎症抑制和额外降低胆固醇的假设是一致的。临床试验 ClinicalTrials.gov NCT01594333。这些数据与未来的动脉粥样硬化治疗可能需要结合炎症抑制和额外降低胆固醇的假设是一致的。临床试验 ClinicalTrials.gov NCT01594333。