Relationship Between C-reactive Protein And Visceral Fat Obesity And Their Impacts On Target Organ Damage

Background and objectivesObesity 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:â‘ clinical trial: relationship between hs-CRP and visceral fat obesity and their impacts on target organ damage in patients with cardiometabolic diseases;â‘¡experimental study: effects of CRP on RAS and ERK in adipocyte and vascular smooth muscle cells;â‘¢clinical intervention trial: effects of telmisartan on hs-CRP, visceral obesity and cardiometabolic risk factors in patients with cardiometabolic diseases.Objects and methodsClinical study include 887 patients with hypertension or/and type 2 diabetes1.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 weeksResults1.Clinical cross-sectional study1) 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 damageLVMI 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 study1) 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 trial1) 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.