摘要
背景和目的
肥胖已成为全世界一个主要的社会健康问题,与正常体重者相比,肥胖者发展成多种慢性疾病的危险性极高。心血管代谢病与肥胖之间的联系涉及到多个相互关联的危险因子,不仅包括传统的冠心病危险因子如糖尿病和高血压,还可能涉及一些炎症因子等。研究证实肥胖与前炎症状态高度相关,减肥能显著降低心血管和代谢病的危险,并导致一些炎症标记物,如白介素-6(IL-6)和C反应蛋白(CRP)相应减少。因此,慢性低度炎症反应在介导心血管代谢病中起重要作用。近年高敏CRP(hs-CRP)巳在临床上作为一个反映低度炎症的指标,研究显示健康人群血清CRP基线水平可以比较准确地预测未来心脏病、中风、心脏猝死危险性和外周血管性疾病的发生情况。
近年的研究提示肥胖可以直接和间接导致CRP水平升高。肥胖与促炎症状态有关。脂肪组织可能直接参与和调节炎症因子诱导CRP的产生,但脂肪组织中产生的CRP有何病理生理意义尚不清楚。多个横断面研究证实,肥胖和CRP水平存在较强的相关性,如女性CRP与体重指数(BMI)的相关性强于男性,而男性中心性肥胖则与CRP相关性更好。此外,许多研究还证实血浆CRP水平与血压、血脂和血糖等心血管代谢危险因素相关,我们既往研究表明hs-CRP水平还与代谢综合征的心肾血管等靶器官损害有关。Rideker报道如将CRP和低密度脂蛋白胆固醇(LDL-c)水平结合起来更能反映心血管事件的预后。新近的JUPITER研究显示在LDL-c水平不高,而hs-CRP水平升高的“健康人群”中予以他汀类药物干预则能显著降低心脑血管事件达44%。另外,肾素血管紧张素系统(RAS)在心血管和代谢病的病理生理过程中也发挥重要作用,临床上应用血管紧张素受体阻断剂(ARB)和血管紧张素转换酶抑制剂均能有效地减少心血管代谢危险因素和保护靶器官,也能减少炎症反应。他人与我们既往的实验研究和初步的临床观察显示ARB能减少内脏脂肪堆积。上述研究给予我们以下启示:1.仅依据LDL-C水平尚不足以反映人群的心血管风险;2.hs-CRP在预测心血管事件方面有其独特之处,但临床应用hs-CRP时,最好结合其他危险因素综合分析;3.他汀类能降低CRP,是否ARB也有类似作用。4.CRP是否与RAS有内在联系。由于CRP与肥胖关系密切,因此,高水平hs-CRP同时合并腹型肥胖的人群与LDL-c升高合并腹型肥胖的人群,在心血管代谢危险性和靶器官损害方面有何差异尚不明确;其次肥胖状态下脂肪的CRP表达和分布,及其对脂肪细胞和血管细胞的RAS有何影响?应用ARB干预后心血管代谢危险因素的改变与内脏脂肪堆积和hs-CRP的变化是否关联?为此,本研究将分三个部分进行:①临床研究:hs-CRP在内脏脂肪型肥胖及其靶器官损害中的作用;②实验研究:探讨CRP对脂肪和血管平滑肌细胞RAS和增殖信号分子的作用;③临床药物干预试验:观察替米沙坦治疗肥胖型高血压合并糖尿病24周后的心血管代谢危险因素、内脏脂肪和hs-CRP的变化。
对象与方法
1.临床横断面研究:检测住院患者的hs-CRP水平、肥胖相关指标、腹部脂肪分布情况,通过统计分析,观察hs-CRP与内脏脂肪型肥胖及其相关靶器官损害的作用。
2.动物实验研究:观察CRP在人及大鼠脂肪组织中的表达,并探讨CRP对脂肪和血管平滑肌细胞RAS和增殖信号分子的作用。
3.临床试验:采取开放、阳性对照、干预治疗试验,入选56例肥胖型高血压合并糖尿病患者,给予替米沙坦干预24周,观察其血压、hs-CRP水平、脂肪组织测量指标及代谢相关指标的变化,观察替米沙坦能否有效地减少腹内脂肪堆积,对hs-CRP及其心血管代谢危险因素有何影响。主要研究结果
1.临床横断面研究:
1) hs-CRP与内脏脂肪型肥胖的关系
不管是男性还是女性,内脏脂肪面积(VA)升高的患者血浆hs-CRP水平均显著高于VA正常的患者(p<0.01),而男性和女性比较无显著差异;Logistic逐步回归分析结果显示,男性和女性患者中,hs-CRP水平均是发生内脏脂肪型肥胖的独立危险因素。
2)血浆hs-CRP水平与靶器官损害的关系
VA升高+hs-CRP升高和VA升高+hs-CRP正常组LVMI、IMT均显著高于VA正常+hs-CRP正常组(p<0.01);VA升高+LDL升高和VA升高+LDL正常组UAER、LVMI、IMT均显著高于VA正常+LDL正常组(p<0.01);VA升高+LDL升高组LVMI、IMT显著高于VA正常+LDL升高组(p<0.01,p<0.05),VA升高+LDL正常组的LVMI显著高于VA正常+LDL升高组(p<0.01);VA升高+hs-CRP升高组左室肥厚、颈动脉粥样硬化的罹患率显著高于VA正常+hs-CRP正常组(p<0.05,p<0.05),VA升高+hs-CRP正常组颈动脉粥样硬化罹患率明显高于VA正常+hs-CRP正常组(p<0.05);VA升高+LDL升高组颈动脉粥样硬化的罹患率显著高于VA正常+LDL正常组和VA正常+LDL升高组(p<0.05,p<0.05),VA升高+hs-CRP正常组颈动脉粥样硬化罹患率明显高于VA正常+hs-CRP正常组(p<0.05)。
2.动物实验研究
1) CRP在人和大鼠的脂肪组织均有表达,而肥胖的人和大鼠的肠系膜白色脂肪组织中CRPmRNA和蛋白表达与正常体重对照组比较无显著性差异,且CRP蛋白表达也无性别差异。
2) CRP能显著增加3T3-L1前脂肪细胞和平滑肌细胞内游离钙浓度。
3) CRP干预24小时能浓度依赖性地显著增加诱导成熟的3T3-L1脂肪细胞和大鼠平滑肌细胞ACE、Ang II、AT1R、P-ERK的蛋白表达;而显著减少ACE2的蛋白表达;但对总ERK蛋白表达没有显著性影响。
3.临床试验研究
1)替米沙坦干预24周后,女性患者的WC、WHR、VA较干预前显著下降(p<0.05,p<0.01 p<0.05),男性患者干预前后各体脂参数无显著变化。
2)男性VA减少的患者,hs-CRP显著下降(p<0.05),而女性患者不管体脂参数增加或减少,hs-CRP均无显著变化。
3)VA减少的男性患者干预后UA水平明显下降(p<0.01),其他指标干预前后无明显变化。
结论
1.hs-CRP与腹内脂肪堆积关系密切,hs-CRP是发生内脏脂肪型肥胖的独立危险因素。
2.在内脏脂肪型肥胖患者中,合并hs-CRP水平增高者,其靶器官损害也更显著。
3.CRP显著上调血管和脂肪细胞的RAS和ERK增殖信号分子,可能部分通过刺激钙内流来介导。
4.替米沙坦治疗可以显著减少部分患者的内脏脂肪面积,男性内脏内脏面积减少伴随相应hs-CRP下降,但女性则未显示这种作用。
5.替米沙坦干预后内脏脂肪和hs-CRP的减少与心血管代谢危险因素的改变并不平行。
Background and objectives
Obesity has become an important public health problem. Compared to normal weighted subjects, the obese patients at high risk are prone to many chronic disease. Several related risk factors are implicated in the linkage with the cardiometabolic diseases, not only including some traditional cardiovascular risk factors such as diabetes and hypertension, but also involving some potential inflammatory factors. Obesity is closely associated with pro-inflammatory status. In addition, body weight reduction can significantly decrease cardiometabolic risk factors and reduce some inflammatory markers, such as IL-6 and hs-CRP. Therefore, chronic low-degree inflammatory status plays a critical role in the prevalence of cardiometabolic diseases. Recent years, hs-CRP has been regarded as a biomarker of low-degree inflammation in clinical practice. Baseline serum hs-CRP level in health subjects is a good predictor for future incidence of cardiovascular disease, stroke, cardiac sudden death and peripheral vascular diseases.
Recent studies demonstrated that obesity can directly or indirectly increase the CRP level. Obesity was related to the pro-inflammatory status. Adipose tissue was implicated in the regulation of CRP production mediated by inflammatory factors. However the pathophyiologic role of adipose tissue derived CRP was unknown. Several cross-sectional clinical trials suggested that obesity was intimately related to the level of CRP. Moreover, some studies indicated that serum CRP level was related to the blood pressure, plasma lipid, and plasma glucose and so on. Our previous study demonstrated that the CRP level was also related to the target organ damage in subjects with metabolic syndrome. Rideker et al. reported that LDL-c combinated with CRP was more effective in prediction of cardiovascular outcome. Recent JUPITER trial reported that intervention with statins can significantly reduce the cardio-cerebro-vascular events by 44% in“heath subjects”with normal LDL-c and higher hs-CRP levels. Renin angiotensin system (RAS) plays a crucial role in the pathophysiology of cardiometabolic diseases. Angiotensin II receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEI) can effectively reduce the cardiometabolic risk factors and protect the target organs, as well as relieve the inflammation. Others and our previous study have found that ARB can reduce the intra-abdominal fat depots. Take together, these studies suggested that: 1. LDL-c level is not sufficient in the evaluation of cardiovascular risk; 2. CRP level is a potential predictor of cardiovascular events; 3. the effect of ARB on CRP level is to be determined. 4. Whether CRP is work on the RAS. Following questions remain to be elucidated: the differences between cardiometabolic risk and target organ damage in abdominal obese subjects with different CRP levels and different LDL-c levels; the expression and distribution of CRP in adipose tissue; whether CRP has effect on RAS in adipocyte and vascular smooth muscle cells. To answer these questions, current project aims to investigate the following issues:①clinical trial: relationship between hs-CRP and visceral fat obesity and their impacts on target organ damage in patients with cardiometabolic diseases;②experimental study: effects of CRP on RAS and ERK in adipocyte and vascular smooth muscle cells;③clinical intervention trial: effects of telmisartan on hs-CRP, visceral obesity and cardiometabolic risk factors in patients with cardiometabolic diseases.
Objects and methods
Clinical study include 887 patients with hypertension or/and type 2 diabetes
1.Clinical cross-sectional study: measurement of hs-CRP levels by commercial kit, body fat parameters and abdominal fat distributions determined by CT; target organ damage are measured by UCG and kit for MAU.
2.Animal experimental study: Identify the expression of CRP in adipose tissue from human and rats, and evaluate the effects of CRP on the rennin-angiotensin-aldosterone system and ERK pathways in adipocyte and vasculal smooth muscle cells.
3.Clinical trial: Conducted an open-label, positive controlled interventional trial, and enrolled 56 patients with obesity-related hypertension and diabetes, to evaluate the blood pressure, hs-CRP levels, abdominal visceral fat area and metabolic parameters before and after administration with telmisartan for 24 weeks
Results
1.Clinical cross-sectional study
1) The relationship between hs-CRP levels and visceral fat obesity
The level of hs-CRP was significant higher in patients with increased level of VA than that with normal VA level in both male and female subjects (both P<0.01). Logistic gradual regressive analysis indicated that hs-CRP level was an independent risk factor for visceral fat obesity in both male and female subjects.
2) The relationship between serum hs-CRP level and target organ damage
LVMI and IMT in subjects with increased VA and hs-CRP level and in subjects with increased VA and normal hs-CRP level were significant higher than the one with normal VA and hs-CRP level (P<0.01). UAER, LVMI and IMT in group with increased VA and LDL level and in that with increased VA and normal LDL level were significant higher than the one with normal VA and LDL level (P<0.01). LVMI and IMT in group with increased VA and LDL level were significant higher than the one with normal VA and increased LDL level (P<0.01 and P<0.05, respectively). LVMI in group with increased VA and normal LDL level were significant higher than the one with normal VA and increased LDL level (P<0.01). The prevalence of left ventricular hypertrophy and carotid artery artherosclerosis in group with increased VA and hs-CRP level were significant higher than that with normal VA and hs-CRP level (P<0.05 and P<0.05, respectively). The prevalence of carotid artery artherosclerosis in group with increased VA and normal hs-CRP level were significant higher than that with normal VA and hs-CRP level (P<0.05). The prevalence of carotid artery artherosclerosis in group with increased VA and LDL level was significant higher than that with normal VA and LDL level and the one with normal VA and increased LDL level (P<0.05 and P<0.05, respectively). The prevalence of carotid artery artherosclerosis in group with increased VA and normal hs-CRP level was significant higher than that with normal VA and hs-CRP level (P<0.05).
2.Animal experimental study
1) CRP is present in adipose tissue from both human and rats; there was no difference in CRP mRNA and protein expression between obese and lean human and rats, as well as between male and female human.
2) CRP markedly increased the intracellular free calcium levels in both 3T3-L1-preadipocytes and vascular smooth muscle cells.
3) Administration of CRP for 24 hours significantly increased the protein expression of ACE, Ang II, AT1R and P-ERK in 3T3-L1-adipocytes and vascular smooth muscle cells in a dose-dependent manner; but markedly decreased the protein expression of ACE2.
3.Clinical trial
1) After administration with telmisartan for 24-week, WC, WHR and VA subjects were significantly decreased compared to baseline data in some subjects.
2) hs-CRP level were significantly decreased in male patients with reduced VA (P<0.05). However, there was no change in hs-CRP level in female patients.
3) The level of UA after administration was significantly decreased in male patients with decreased VA level (P<0.01), but there was no changes in other parameters before and after administration.
Conclusion:
1.hs-CRP level is closely linked to the intra-abdominal fat depots and is an independent risk factor for the visceral fat obesity.
2.Among the patients with visceral fat obesity, subjects with higher hs-CRP level have more severe target organ damage.
3.CRP can markedly upregulate the components RAS and p-ERK in vascular smooth muscle cells and adipocytes,which at least partly meadiated by activation of calcium influx.
4.Administration of telmisartan can significantly reduce the area of visceral adiposity in a part of patients. Moreover, reduced area of visceral adiposity is accompanied with hs-CRP level reduction in male subjects, but not in female.
5.The reductions of visceral adiposity and hs-CRP level after administration of telmisartan are not paralleled with the changes in cardiometabolic risk factors in patients.
引文
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