Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review.
Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review.
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DOI：
10.1371/journal.pmed.0050078
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发表时间：
2008-04-08
期刊：
影响因子：
15.8
通讯作者：
Gudnason, Vilmundur
中科院分区：
文献类型：
--
作者：
Danesh, John;Kaptoge, Stephen;Mann, Andrea G.;Sarwar, Nadeem;Wood, Angela;Angleman, Sara B.;Wensley, Frances;Higgins, Julian P. T.;Lennon, Lucy;Eiriksdottir, Gudny;Rumley, Ann;Whincup, Peter H.;Lowe, Gordon D. O.;Gudnason, Vilmundur
调控炎症级联反应的细胞因子（如白细胞介素 - 6（IL - 6））与冠心病（CHD）的相关性可能被低估了，因为这类介质作用时间短且容易波动。我们在两个人群队列中评估了长期循环IL - 6水平与冠心病风险（定义为非致命性心肌梗死[MI]或致命性冠心病）的关联，通过连续测量来校正个体内的变异性。我们更新了一项系统综述，以便将新发现置于相应背景中。
测量是在基线时从24230名参与者中的2138名在随访期间首次发生非致命性心肌梗死或死于冠心病的患者以及4267名对照者的样本中进行的。利用数百名参与者相隔数年的重复测量数据对个体内变异性进行了校正。个体内IL - 6值的年际变异性相对较高（4年期间回归稀释比为0.41，95%置信区间[CI]为0.28 - 0.53；12年期间为0.35，95%CI为0.23 - 0.48）。忽略这种变异性，我们发现，在校正了几个已确定的风险因素后，基线IL - 6值每增加2个标准差（SD），冠心病的比值比为1.46（95%CI为1.29 - 1.65），与基线C - 反应蛋白相似。在校正个体内变异性后，长期平均（“通常”）IL - 6水平下冠心病的比值比为2.14（95%CI为1.45 - 3.15），与一些已确定的风险因素相似。IL - 6水平升高与冠心病风险逐渐增加相关。对电子数据库和其他来源的更新系统综述确定了15项先前相关的基于人群的IL - 6与临床冠心病结局（即心肌梗死或冠心病死亡）的前瞻性研究。包括当前两项研究在内，17项可用的前瞻性研究得出，基线IL - 6每增加2个标准差，合并比值比为1.61（95%CI为1.42 - 1.83）（对应于通常[长期平均]IL - 6水平每增加2个标准差，比值比为3.34[95%CI为2.45 - 4.56]）。
长期IL - 6水平与冠心病风险的关联强度与一些主要的已确定风险因素大致相同，但因果关系仍不确定。这些发现凸显了IL - 6介导的通路与冠心病的潜在相关性。
约翰·达内什及其同事表明，长期IL - 6水平与冠心病风险相关，从而凸显了IL - 6介导的通路与冠心病的潜在相关性。
冠心病（CHD）是发达国家成年人的主要死因，在美国每分钟就有一人死于该病。随着年龄增长，“动脉粥样硬化斑块”——脂肪、钙和各种细胞废弃物的沉积物——会覆盖动脉壁，导致动脉狭窄和硬化，阻断身体的血流。当这种情况发生在为心肌提供营养的冠状动脉时，最终结果就是冠心病。如果斑块从动脉壁脱落，它可能会卡在动脉中，完全阻断血流，导致心肌死亡。其专业术语是“心肌梗死”（MI），不过更通俗的说法是心脏病发作。吸烟、高血压、血液中胆固醇（一种脂肪）水平高、超重以及缺乏身体活动都会增加患冠心病的风险，一些遗传因素也是如此。冠心病的治疗包括生活方式改变（例如，减肥和定期锻炼）以及降低血压和血液胆固醇的药物。在最严重的情况下，可以使用一种叫做支架的装置来扩张狭窄的动脉，或者通过手术进行搭桥。
动脉粥样硬化可能至少在一定程度上是一种炎症性疾病。炎症——一种对损伤的免疫反应，其特征是肿胀和发红——涉及一种叫做“细胞因子”的蛋白质的产生，这些蛋白质会将免疫系统的细胞吸引到损伤部位。在动脉粥样硬化中，动脉壁的损伤似乎会引发炎症，这有助于动脉粥样硬化斑块的生长。由于炎症可能参与动脉粥样硬化，循环细胞因子水平升高可能与冠心病风险增加有关。如果是这样，细胞因子可能为冠心病的治疗提供一个新的治疗靶点。在这项研究中，研究人员探究了血液中细胞因子白细胞介素 - 6（IL - 6）长期适度升高是否与冠心病风险相关。IL - 6在炎症早期产生，在人体内仅短暂存在，其水平在个体内波动。因此，在先前的研究中，它与冠心病的相关性并不明确。
在1967年至1991年期间，将近25000名健康的、主要是中年的人被纳入两项研究——雷克雅未克研究和英国地区心脏研究——并随访了约20年，在此期间，2138人首次发生非致命性心脏病发作或死于冠心病。研究人员测量了这些参与者以及4267名未发生冠心病事件的类似参与者的基线IL - 6血液水平。他们还在研究进行几年后测量了558名健康参与者的IL - 6水平，以确定IL - 6的“回归稀释比”。这个比率可以反映IL - 6水平逐年的一致性。当研究人员使用这个比率来估计IL - 6水平长期升高对冠心病的影响时，他们发现，在他们的研究人群中，长期IL - 6水平升高使冠心病风险增加了一倍多。研究人员随后将这些新结果与15项先前相关研究的结果相结合。这种综合分析得出的结果与新数据非常相似。
这些发现表明，IL - 6水平长期适度升高与冠心病风险的关联强度与几个主要的已确定风险因素（包括血压和血液胆固醇水平）相当，但是否存在因果关系仍不清楚。需要更多的研究来确定这个结果是否适用于其他人群，但冰岛和英国的研究之间的广泛一致性表明应该是适用的。这项研究重新激发了人们对IL - 6介导的炎症通路和冠心病的兴趣。
请通过本摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0050078
阅读相关的《公共科学图书馆·医学》观点文章
MedlinePlus百科全书有关于冠心病和动脉粥样硬化的页面（有英语和西班牙语版本）
美国国家心肺血液研究所提供关于冠心病和动脉粥样硬化的信息
美国心脏协会为患者和护理人员提供关于心脏病各个方面的信息，包括炎症和心脏病
英国心脏基金会提供关于心脏病和保持心脏健康的信息
有关雷克雅未克研究和英国地区心脏研究的更多细节可供查询
维基百科有关于炎症和白细胞介素 - 6的页面（请注意，维基百科是一个任何人都可以编辑的免费在线百科全书；有多种语言版本）
The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context. Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28–0.53, over 4 y, and 0.35, 95% CI 0.23–0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29–1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45–3.15) with long-term average (“usual”) IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42–1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45–4.56] per 2 SD increase in usual [long-term average] IL-6 levels). Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6–mediated pathways to CHD. John Danesh and colleagues show that long-term IL-6 levels are associated with coronary heart disease risk, thus highlighting the potential relevance of IL-6−mediated pathways to coronary heart disease. Coronary heart disease (CHD), the leading cause of death among adults in developed countries, kills one person in the US every minute. With age, “atherosclerotic plaques”—deposits of fats, calcium, and various cellular waste products—coat the walls of arteries, causing them to narrow and harden, interrupting blood flow through the body. When this occurs in the coronary arteries, which nourish the heart muscle, the end result is CHD. If a plaque breaks off the artery wall, it can get trapped in the arteries and completely stop the blood flow, causing death of the heart muscle. The technical term for this is “myocardial infarction” (MI), although it is more commonly known as a heart attack. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), being overweight, and being physically inactive all increase the risk of developing CHD, as do some inherited factors. Treatments for CHD include lifestyle changes (for example, losing weight and exercising regularly) and medications that lower blood pressure and blood cholesterol. In the worst cases, the narrowed artery can be widened using a device called a stent or surgically bypassed. Atherosclerosis might, at least partly, be an inflammatory condition. Inflammation—an immune response to injury characterized by swelling and redness—involves the production of proteins called “cytokines,” which attract cells of the immune system to the site of injury. In atherosclerosis, damage to the artery walls seems to trigger inflammation, which helps the atherosclerotic plaques grow. Because of the potential involvement of inflammation in atherosclerosis, increased levels of circulating cytokines might be associated with an increased risk of CHD. If they are, cytokines might provide a new therapeutic target for the treatment of CHD. In this study, the researchers have asked whether prolonged moderate increases in the cytokine interleukin-6 (IL-6) in the bloodstream are associated with CHD risk. IL-6, which is produced very early in inflammation, survives only briefly in the human body and its levels fluctuate within individuals. Consequently, its relevance to CHD has been unclear in previous studies. Between 1967 and 1991, nearly 25,000 healthy, mainly middle-aged people were enrolled into two studies—the Reykjavik Study and the British Regional Heart Study—and followed for about 20 years, during which time 2,138 people had a first-ever nonfatal heart attack or died of CHD. The researchers measured baseline IL-6 blood levels in these participants and in 4,267 similar participants who had not had a CHD event. They also measured IL-6 levels in 558 healthy participants several years into the study to determine a “regression dilution ratio” for IL-6. This ratio gives an idea of the year-to-year consistency of IL-6 levels. When the researchers used this ratio to estimate the impact of prolonged increases in IL-6 levels on CHD, they found that increased long-term IL-6 levels more than doubled the risk for CHD in their study populations. The researchers then combined these new results with those of 15 previous relevant studies. This combined analysis indicated very similar findings to those in the new data. These findings indicate prolonged moderate increases in IL-6 levels are associated with risk of CHD as strongly as several major established risk factors, including blood pressure and blood cholesterol levels, but whether there is a cause-and-effect relationship remains unknown. More studies are needed to find out whether this result is generalisable to other populations, but the broad agreement between the Icelandic and British studies suggests that they should be. This study renews interest in IL-6–mediated inflammatory pathways and CHD. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050078. Read a related PLoS Medicine Perspective article The MedlinePlus encyclopedia has pages on coronary heart disease and atherosclerosis (in English and Spanish) Information is available from the US National Heart Lung and Blood Institute on coronary heart disease and atherosclerosis Information for patients and caregivers is provided by the American Heart Association on all aspects of heart disease, including inflammation and heart disease Information is available from the British Heart Foundation on heart disease and on keeping the heart healthy Further details are available about the Reykjavik Study and the British Regional Heart Study Wikipedia has pages on inflammation and on interleukin-6 (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
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影响因子：
5.9
作者：
Harris, TB;Ferrucci, L;Wallace, R
通讯作者：
Wallace, R
影响因子：
5
作者：
Kuller, LH;Tracy, RP;Meilahn, EN
通讯作者：
Meilahn, EN
DOI：
10.1161/01.atv.0000040224.49362.60
发表时间：
2002-12-01
影响因子：
8.7
作者：
Jenny, NS;Tracy, RP;Humphries, SE
通讯作者：
Humphries, SE
影响因子：
16.2
作者：
Langenberg, Claudia;Bergstrom, Jaclyn;Barrett-Connor, Elizabeth
通讯作者：
Barrett-Connor, Elizabeth
影响因子：
37.8
作者：
Pearson, TA;Mensah, GA;Vinicor, F
通讯作者：
Vinicor, F