Adiponectin and cardiovascular mortality: Evidence for "Reverse epidemiology"
Adiponectin and cardiovascular mortality: Evidence for "Reverse epidemiology"
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DOI：
10.1055/s-2007-958630
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发表时间：
2007-01-01
影响因子：
2.2
通讯作者：
Herder, C.
中科院分区：
文献类型：
--
作者：
Rathmann, W.;Herder, C.
Rathmann W，Herder C.adiponectin：反向流行病学…Horm Metab Res 2007；39：1-2表[14]。然而，最近的一项研究表明，肾病患者血清HMW脂联素的升高与总脂联素相似[15]。尽管有迹象表明翻译后机制确实与脂联素活性具有生理相关性，但仍有待证明它们在上述情况下发挥作用。►脂联素水平也可能因清除不足而增加。在慢性肾脏疾病[8]和肝硬变[10]中，脂联素水平的升高与组织损伤的程度相关，这一发现表明这些器官参与了脂联素的清除。然而，调整蛋白尿和肾小球滤过率作为肾功能的标志物并不能改变脂联素与慢性肾脏疾病心血管死亡率的关系，因此清除减少不能解释观察到的效果[8]。►脂联素被认为是血管保护和抗动脉粥样硬化的[2]，因此必须考虑与已确定的心血管危险因素的相关性。有趣的是，在有反向流行病学证据的队列中，脂联素的增加与基线时更有利的整体心血管危险因素相关，但尽管如此，脂联素的升高与全因和心血管死亡的风险增加相关[8]。在慢性心力衰竭中，高脂联素的死亡风险增加与N末端前B型利钠肽(NT-PRO-BNP)作为心脏损伤的标志无关[4]。因此，经典的心血管危险因素可能无法解释脂联素反向流行病学的现象。►有什么与脂联素浓度升高的情况有共同之处，可以指出反向流行病学的机制？总而言之，脂联素水平在严重心血管疾病[4-7]、终末期肾病[8]、肝硬变[10]、类风湿性关节炎[11]、IBD[12]、1型糖尿病和糖尿病视网膜病变或肾病[9]、系统性红斑狼疮[13]和老年人[2-7]中升高。所有这些情况的特征都是明显的全身性促炎状态，而且常常还表现为内皮功能障碍。我们假设，在这些情况下，脂联素水平升高是为了试图反向调节或补偿全身炎症，并且脂联素的血管保护和抗炎作用被影响全身多个组织的潜在疾病所取代，而这些疾病不能仅通过调整GFR或NT-Pro-BNP作为局部组织损伤的标志来估计。有人可能会争辩说，肥胖和2型糖尿病与全身脂联素下降相关，也是促炎状态，但肥胖症和2型糖尿病的免疫激活程度是亚临床的，显然可以预期其程度和影响与上述疾病不同。我们的假设间接得到了缺乏数据的支持，这些数据描述了脂联素如何因果地参与了直接增加心血管死亡率的机制。全身炎症和内皮功能障碍的影响可以使用由急性时相蛋白、细胞因子、趋化因子和内皮功能障碍的可溶性标记物(如C-反应蛋白、肿瘤坏死因子、IL-18、IL-8、E-选择素、CD146)组成的炎症评分来衡量。假设我们的假设是正确的，对这样的评分进行调整应该会减弱甚至逆转…患者中高脂联素与不良预后之间的关联
Rathmann W, Herder C. Adiponectin: Reverse Epidemiology… Horm Metab Res 2007; 39: 1–2 form [14]. However, a recent study demonstrated that serum HMW adiponectin was increased in nephropathy similarly to total adiponectin [15]. Although there are indications that post-translational mechanisms are indeed of physiological relevance for adiponectin activity, it remains to be shown that they play a role in the aforementioned conditions.► Adiponectin levels could also be increased by insufficient clearance. The finding that the increase in adiponectin levels was correlated with the extent of tissue damage in chronic kidney disease [8] and liver cirrhosis [10] indicates that these organs are involved in adiponectin clearance. However, adjusting for proteinuria and glomerular filtration rate (GFR) as markers of renal function did not alter the association of adiponectin with cardiovascular mortality in chronic kidney disease so that reduced clearance cannot explain the observed effects [8].► Adiponectin has been suggested to be vasoprotective and anti-atherogenic [2], so that the association with established cardiovascular risk factors has to be considered. Interestingly, increased adiponectin was associated with a more favorable overall cardiovascular risk factor profile at baseline in cohorts showing evidence of reverse epidemiology, but nevertheless high adiponectin was associated with an increased risk for all-cause and cardiovascular mortality [8]. In chronic heart failure the increased hazard ratio for mortality of high adiponectin was independent of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) as a marker of heart damage [4]. Thus, classical cardiovascular risk factors may not explain the phenomenon of reverse epidemiology of adiponectin.► Is there anything that conditions with increased adiponectin concentrations have in common which could point to the mechanism underlying the reverse epidemiology? Taken together, adiponectin levels are elevated in severe cardiovascular disease [4–7], end-stage renal disease [8], liver cirrhosis [10], rheumatoid arthritis [11], IBD [12], type 1 diabetes and diabetic retinopathy or nephropathy [9], SLE [13] and old age [2–7]. All of these conditions are characterized by a marked systemic pro-inflammatory state and very often also by endothelial dysfunction. We hypothesize that adiponectin levels are increased in these conditions as an attempt to counter-regulate or compensate for the systemic inflammation, and that adiponectin’s vasoprotective and anti-inflammatory effects are superseded by the underlying disease affecting multiple tissues throughout the body that cannot be estimated by only adjusting for GFR or NT-pro-BNP as markers of local tissue damage. One might argue that obesity and type 2 diabetes, which are associated with decreased systemic adiponectin, are also pro-inflammatory states, but the extent of immune activation in obesity and type 2 diabetes is subclinical and can clearly be expected to differ in its extent and impact from the aforementioned diseases. Our hypothesis is indirectly supported by the lack of data describing how adiponectin could be causally involved in mechanisms that directly increase cardiovascular mortality. The impact of systemic inflammation and endothelial dysfunction could be addressed using an inflammation score consisting of acute phase proteins, cytokines, chemokines and soluble markers of endothelial dysfunction (such as C-reactive protein, TNF, IL-18, IL-8, E-selectin, CD146). Assuming that our hypothesis is correct, adjusting for such a score should attenuate or even reverse the association between high adiponectin and poor outcome in cohorts with …