Clinical Study On The Relationship Between Fibrinogen And Lipid Metabolism And Coronary Heart Disease

Objectives Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been confirmed as a major factor regulating sterol homeostasis. Meanwhile, fibrinogen, an established inflammatory and coagulation marker in the circulation, has been studied for decades due to its close relationship with cardiovascular risk. Recently, both PCSK9 and fibrinogen have been proposed as novel markers for atherosclerotic diseases. In fact, the atherosclerotic cardiovascular disease is a very complex process involving dyslipidemia and chronic inflammation. However, no data is currently available regarding the relationship between circulating PCSK9 and fibrinogen concentration up to now. The aim of the present study was to explore the potential link of the circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease (CAD).Methods From October 2012 to November 2013, we studied 219 un-treated consecutive patients with angiographically proven stable CAD in our institution of Fu Wai hospital. Baseline clinical and laboratory data were collected. Plasma PCSK9 concentration was measured by ELISA. Fibrinogen, high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), D-dimer and albumin were also measured in all subjects as inflammatory markers. The relation of the circulating PCSK9 concentration to fibrinogen as well as other inflammatory markers was evaluated in the current study.Results The data indicated that the plasma fibrinogen levels were dramatically increased according to PCSK9 tertiles (p=0.037). However, we did not found significant difference with regard to other inflammatory markers including hs-CRP, ESR, D-dimer, and albumin (p>0.05, all). Spearman correlation analysis revealed a positive relation between plasma PCSK9 concentration and fibrinogen (r=0.211, p=0.002). Additionally, the circulating PCSK9 concentration was also correlated positively with total cholesterol, low-density lipoprotein cholesterol (LDL-C) and the inflammatory marker, hs-CRP levels (r=0.333, p<0.001; r=0.302, p<0.001; r=0.153, p=0.023, respectively), whereas not associated with the other inflammatory markers, such as ESR, D-dimer and albumin (p>0.05, all). In the stepwise multivariate linear regression analysis, after adjusting for the traditional cardiovascular risk factors including age, gender, body mass index, current smoking, family history of CAD, systolic blood pressure, and fasting blood glucose, plasma PCSK9 was proved to be positively associated with fibrinogen levels β=0.199, p=0.003). After further adjusting for the lipid profiles including triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and LDL-C, the relation between plasma PCSK9 levels and fibrinogen was slightly decreased (β=0.173, p=0.008). Moreover, when we further adjusted for other inflammatory marker, hs-CRP and D-dimer, the association between PCSK9 and fibrinogen remained significant in the current analysis (β=0.168, p=0.011).Conclusions The present study firstly demonstrated that the circulating PCSK9 concentration was positively associated with fibrinogen in patients with stable CAD independent of potential confounders including age, gender, body mass index, current smoking, systolic blood pressure, fasting blood glucose, family history of CAD, TG, HDL-C, LDL-C, hs-CRP and D-dimer. Our data suggested that the levels of plasma PCSK9 may be affected by chronic inflammation in the status of chronic CAD, and the interaction between PCSK9 and fibrinogen may be needed further investigation in the future studies.Objectives Fibrinogen is a coagulation/inflammatory biomarker strongly associated with lipid parameters and atherogenesis. However, no data is currently available regarding the association of fibrinogen level with the presence and severity of new-onset coronary atherosclerosis assessed by Gensini score (GS), particularly in Han Chinese population with a large sample size. Therefore, the aim of the present study was to investigate the association of plasma fibrinogen with the presence and severity of new-onset coronary atherosclerosis in a large cohort of Han Chinese population.Methods From April 2011 to March 2014, we studied 2288 consecutive, new-onset subjects undergoing coronary angiography with angina-like chest pain. Of them,1935 subjects have been diagnosed as having new-onset coronary atherosclerosis. Clinical and laboratory data were collected. Coronary stenotic lesions were considered to be the incidence of coronary atherosclerosis. The severity of coronary stenosis was determined by the GS system and was stratified by tertiles. The upper GS tertiles have been determined as high GS group. Spearman correlation analysis and logistic regression analyses were performed to determine the association of fibrinogen with the presence and severity of coronary atherosclerosis. Receiver operating characteristics (ROC) curves were constructed to document the predictive value of fibrinogen for high GS.Results Data indicated that patients with high GS had significantly elevated fibrinogen level (p<0.001). The prevalence and severity of coronary atherosclerosis were dramatically increased according to fibrinogen tertiles. Spearman correlation analysis revealed a positive association between fibrinogen level and GS (r=0.138, p<0.001). Multivariate logistic regression analysis demonstrated that plasma fibrinogen level was independently associated with high GS (OR=1.275, 95% CI 1.082-1.502, p=0.004) after adjusting for potential confounders. Moreover, fibrinogen level was also independently related to the presence of coronary atherosclerosis (fibrinogen tertile 2:OR=1.192,95% CI 0.889-1.598, p=0.241; tertile 3:OR=2.003,95% CI 1.383-2.903, p <0.001) and high GS (fibrinogen tertile 2:OR=1.079,95% CI 0.833-1.397, p=0.565; tertile 3:OR=1.524,95% CI 1.155-2.011, p=0.003) in a dose-dependent manner. The area under the ROC curves (AUC) indicated a well discriminatory power of plasma fibrinogen (AUC=0.63,95% CI 0.59-0.67, p<0.001) in predicting the severity of coronary atherosclerosis, and the optimal cut-off value was 3.21 g/L (sensitivity of 52% and specificity of 69%).Conclusions Higher fibrinogen level is independently linked with the presence and severity of new-onset coronary atherosclerosis in Han Chinese population, suggesting that fibrinogen may be a useful biomarker in predicting new-onset coronary atherosclerosis.Objectives It has been proposed that plasma fibrinogen is a pivotal coagulation/inflammation biomarker, which is associated increased cardiovascular risk, although the causal relationship and mechanisms have not been clarified. It has been proven that dyslipidemia is the causal risk factor for atherosclerosis. Actually, fibrinogen is associated with multiple lipid parameters, such as proprotein convertase subtilisin/kexin type 9, total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C) levels. However, the interrelationship between fibrinogen and lipid parameters has not been well-elucidated. We hypothesize that lipids may be potential mediators.Methods We enrolled 4748 consecutive subjects scheduled for selective coronary angiography from April 2011 to October 2014 in this study. Baseline clinical and laboratory data were collected. The severity of coronary atherosclerosis was assessed by Gensini score (GS) system. The upper titles of GS were defined as high GS. By principle component analysis, a multi-marker lipid index was extracted weighting the coefficients of six atherogenic lipid parameters:TC, LDL-C, non-high-density lipoprotein-cholesterol (non-HDL-C), apolipoprotein (apo) B, apoB/apoA-I, and TC/HDL-C ratio. All the subjects have been classified as low or high multi-marker lipid index group based on the 50% cutoff value. Moreover, using mediation analysis, the relationship between fibrinogen and lipids with high GS was evaluated.Results Fibrinogen was positively associated with GS after adjustment (β=0.100, P<0.001). We stratified our analyses by statin use status and found that subjects in the upper fibrinogen tertiles had higher levels of atherogenic lipid parameters irrespective of statin status (p<0.001, all). Significantly, we observed a synergistic effect of fibrinogen and concurrent elevated lipid index for high GS. The adjusted odds ratios were greater in participants had high fibrinogen levels and also high lipid index compared to those with low lipid index [on statin: 1.725(1.258-2.364) vs.1.261(0.962-1.652); not on statin: 2.197(1.450-3.328) vs.1.166(0.417-3.258)] tested by multivariate Logistic regression analysis adjusting for gender, age, smoking, systolic blood pressure, fasting blood glucose, HDL-C, LDL-C, and high sensitivity C reactive protein. Specially, mediation analysis indicated that around 24% of the effect of fibrinogen on high GS was mediated by lipid index, which was attenuated to 13% by statin status.Conclusions The increased risk of fibrinogen on coronary atherosclerosis appeared to be enhanced by the high atherogenic lipid levels, which mediated around 13%-24% of this effect in patients with or without statin treatment.Objectives The recent studies reveal that low-density lipoprotein (LDL) subfractions are more accurately capture the cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). Among various LDL subfractions, small dense LDL (sdLDL) subfraction has been suggested to be a very atherogenic subspecies of LDL particles. Nowadays, proprotein convertase subtilisin-kexin type 9 (PCSK9) has been emerged as a novel regulator of LDL metabolism. Moreover, it has been proved to be strongly associated with increased cardiovascular risk. To date, the association of sdLDL with PCSK9 is still unclear. The aim of the present study is to determine the association of sdLDL, as assayed by sdLDL-cholesterol (sdLDL-C), with PCSK9 in a cohort of subjects undergoing coronary angiography.Methods Four hundred and ninety consecutive non-treated subjects scheduled for selective coronary angiography were enrolled from October 2012 to April 2014. All the subjects were classified into stable coronary artery disease (CAD) and non-CAD group based on the angiography results. LDL separation was performed by Lipoprint System: 7 LDL subfractions were obtained (LDL1-7) and the LDL score (%sdLDL) was calculated. The plasma PCSK9 levels were measured by ELISA.Results The data indicated that PCSK9 levels were significantly increased by sdLDL-C quartiles (p=0.028). In the age-and sex-adjusted analysis plasma sdLDL-C was positively correlated with PCSK9 levels (r=0.157, p<0.01). To rule out the confounding effect of dyslipidemia, we performed the analysis in subjects with and without dyslipidemia separately. Interestingly, the positive correlation of sdLDL-C with PCSK9 was only significant in patients with dyslipidemia and stable CAD (r=0.177, p<0.01). In a model adjusting for traditional risk factors including dyslipidemia, PCSK9 was an independent predictor of high sdLDL-C in CAD group (OR= 12.919,95% CI 1.427-116.952) but not in non-CAD group. In addition, large LDL-C was not associated with PCSK9 levels in either CAD (r=0.102, p=0.065) or non-CAD group (r=0.114, p=0.155). However, intermediate LDL-C was related to PCSK9 in patients with stable CAD (r=0.169, p=0.002) but not in non-CAD group (r=0.070, p=0.380).Conclusion This study firstly demonstrated that plasma sdLDL-C was positively related to PCSK9 in patients with stable CAD, suggesting an interaction between sdLDL-C and PCSK9 in atherosclerotic coronary disease.Objectives Both elevated inflammatory activity and cholesterol levels reflect unfavourable cardiovascular risk, and there are evident associations between inflammatory markers and lipoprotein metabolism. Given the atherogenity of lipoprotein subspecies is highly heterogeneous, we hypothesize that the relationship between inflammation and lipoprotein subfractions may be diverse. Therefore, the aim of the present study was to investigate the association of plasma inflammatory markers with lipoprotein subfractions in a cohort of untreated patients underwent coronary angiography.Methods In the current study, we enrolled 520 consecutive subjects scheduled for coronary angiography who were not receiving any lipid-lowering therapy. All the subjects were classified into stable coronary artery disease (CAD) and non-CAD group based on the angiography results. We measured the inflammatory markers including white blood cell (WBC) count and its subsets, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, erythrocyte sedimentation rate (ESR), and D-dimer. By principle component analysis, a multi-marker inflammatory index was extracted weighting the coefficients of these parameters. The low-density lipoprotein (LDL) and high-density lipoprotein (HDL) separations were separated using Lipoprint System. The non-HDL cholesterol was calculated by total cholesterol-HDL cholesterol. The remnant cholesterol was calculated by total cholesterol-HDL cholesterol-LDL cholesterol.Results In age-and sex-adjusted analysis, multiple inflammatory markers (WBC count, hs-CRP, fibrinogen, and ESR) were positively related to circulating non-HDL cholesterol and remnant cholesterol levels (p<0.05, all). Among lipoprotein subfractions, we observed a significantly positive association of inflammatory markers with very low-density lipoprotein cholesterol, small LDL cholesterol, and LDL score (p<0.05, all). Meanwhile, a negative association was detected between inflammatory markers and mean LDL particle size (p<0.05) or large HDL cholesterol (p<0.05). Moreover, we developed a multi-marker inflammatory index and performed a subgroup analysis. Consequently, we found that the relationship between multi-marker index quartiles and small LDL cholesterol, LDL score, and mean LDL particle size were slightly stronger in CAD than non-CAD group.Conclusions Systemic inflammatory markers are positively correlated with small LDL cholesterol and LDL score while negatively linked with mean LDL particle size and large HDL cholesterol, highlighting the potential contribution of small LDL particle to increased cardiovascular risk.Objectives It has been well established that hypertension is a known cardiovascular risk factor while the exact mechanisms of hypertension contributing to atherosclerosis have not been fully elucidated. Actually, the occurrence of hypertension often accompanies by multiple cardiovascular risk factors such as dyslipidemia. Although multiple studies have clarified the association with low-density lipoprotein (LDL) subfractions, uncertainty remains about its relationship with high-density lipoprotein (HDL) subfractions. Therefore, we aimed to comprehensively determine the relationship between distribution of HDL subfractions and hypertensive status.Methods From April 2011 to January 2015, a total of 953 consecutive subjects without previous lipid-lowering drug treatment were enrolled and were categorized based on hypertension history [with hypertension (n=550) or without hypertension (n=403)]. Baseline clinical and laboratory data were collected. The HDL separation was performed using Lipoprint System and 10 HDL subfractions have been acquired (1-3: small HDL; 4-7:medium HDL; 8-10:large HDL). The relationship between HDL subfractions with hypertensive status was evaluated.Results Plasma large HDL-cholesterol (HDL-C) and large HDL percentage were dramatically lower whereas the small HDL-C and small HDL percentage were higher in patients with hypertension (all p<0.05). The anti-hypertensive drug therapy was not associated with large or small HDL subfractions (on treatment vs. not on treatment, p> 0.05; combination vs. single drug therapy, p>0.05). However, the blood pressure well controlled patients have significantly lower small HDL subfraction (p<0.05). Moreover, large HDL-C and percentage were inversely while small HDL percentage was positively associated with incident hypertension after adjusting potential confounders (all p<0.05). In the multivariate model conducted in patients with and without hypertension separately, the cardio-protective value of large HDL-C was disappeared in patients with hypertension [OR 95%CI:1.011 (0.974-1.049)].Conclusions The distribution of HDL subfractions is closely associated with the control of blood pressure but not with the drug treatment. The large HDL subfraction was inversely related to incident hypertension. The presence of hypertension may potentially impact the cardio-protective value of large HDL subfraction.