Original Article
Fibrinogen and the Severity of Coronary Atherosclerosis among Adults with and without Statin Treatment: Lipid as a mediator

https://doi.org/10.1016/j.hlc.2016.01.001Get rights and content

Background

It has been proposed that plasma fibrinogen is associated with lipid levels and increased cardiovascular risk. However, the interrelationship has not been well-elucidated. We hypothesise that lipids may be potential mediators.

Methods

We enrolled 4748 consecutive subjects scheduled for coronary angiography in this study. The severity of coronary atherosclerosis was assessed by Gensini score (GS). By principle component analysis, a multi-marker lipid index was extracted weighting the coefficients of six atherogenic lipid parameters: total cholesterol (TC), low-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol (non-HDL-C), apolipoprotein (apo) B, apoB/apoA1, and TC/HDL-C ratio. 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 who 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)]. Specifically, 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 24% of this effect.

Introduction

Coronary artery disease (CAD) due to atherosclerosis is the major cause of associated morbidity and mortality in the world. Current perspectives regard low grade chronic inflammation as well as imbalanced lipid metabolism as critical contributors for atherosclerosis progression and plaque instability [1], [2]. This recognition has stimulated the evaluation of different inflammatory markers as potential predictors of cardiovascular risk.

Fibrinogen is a coagulation/inflammatory biomarker closely related to cardiovascular risk. In addition to its essential properties as a cofactor of platelet aggregation and as the main substrate for thrombin in the plasmatic coagulation, fibrinogen has been suggested to play a pivotal role in the initial and advanced stages of atherosclerosis [3], [4]. Early evidence from previous decades pointed to a strong association between fibrinogen and early signs of atherosclerosis in asymptomatic individuals [5], [6]. Also, several investigations have proposed fibrinogen as an important risk factor for future cardiovascular events in patients with CAD [7], [8], [9] and in apparently healthy individuals [10], [11]. Although fibrinogen has been suggested to be a predictor of cardiovascular risk, the underlying mechanism has not yet been well-elucidated.

One possible mechanism is that fibrinogen, an acute phase protein, reflects the inflammatory state of the vascular wall [12], however, this notion may not fully account for the risk of fibrinogen in the development of CAD. Previous studies implied that increased basal fibrinogen expression could enhance cholesterol synthesis in HepG2 cells [13] and elevated plasma fibrinogen was associated with increased lipid peroxidation [14]. Meanwhile, our recent data suggested a positive association between fibrinogen and the major cholesterol regulator, proprotein convertase subtilisin/kexin type 9 in the status of atherosclerosis [15]. Furthermore, the genetic study revealed that the expression of gene clusters which control inflammatory processes and lipid metabolism was an interrelated response to metabolic overload [16]. Nonetheless, clinical data regarding the interplay between fibrinogen and lipids in coronary atherosclerosis is largely unavailable. In light of the preceding discussion, it is plausible to hypothesise that there may be an interaction between fibrinogen and lipids and the latter may be potential mediators in coronary atherosclerosis.

Therefore, in this large cohort of Chinese individuals (n=4748) undergoing diagnostic or interventional coronary angiography, we sought to investigate the interaction between fibrinogen and lipids with the severity of coronary atherosclerosis assessed by Gensini score (GS), and further evaluate whether the plasma lipids partly mediate the association between fibrinogen and high GS.

Section snippets

Study Design and Population

The study protocol complied with the Declaration of Helsinki, and was approved by the hospital ethics review board (FuWai Hospital & National Center for Cardiovascular Diseases, Beijing, China). All patients gave their informed, written consent.

This was a hospital-based cross-sectional study. We enrolled 4748 consecutive subjects with suspected coronary atherosclerosis for elective coronary angiography in our institution from April 2011 to October 2014. Complete medical history was taken from

Baseline Clinical Characteristics

Diagrammatic presentations of our sample size are shown in Figure 1. Our total sample size was 4748 and consisted of 3557 and 1191 participants with and without statin treatment, respectively. The baseline demographic, clinical characteristics and laboratory data are summarised in Table 1. This study population consisted of patients with an average age of 58±10 years, and 70.8% of this population was male. The prevalent CAD was 82.9%. The median GS level was 21(7-44) and the mean fibrinogen

Discussion

To the best of our knowledge, this is the first large-scale study evaluating the interplay between fibrinogen and lipids in relation to the severity of coronary atherosclerosis. The novel finding of the present study is that the relationship between fibrinogen and severity of coronary atherosclerosis appears to be enhanced by the increased atherogenic lipid levels, which mediated around 24% of this effect.

Fibrinogen is a soluble glycoprotein with a molecular weight of 340 kDa which consists of

Declaration of Interest

The authors have no conflict of interests.

Acknowledgments

This work was partly supported by National Natural Scientific Foundation (81070171, 81241121), Specialized Research Fund for the Doctoral Program of Higher Education of China (20111106110013), Capital Special Foundation of Clinical Application Research (Z121107001012015), Capital Health Development Fund (2011400302), and Beijing Natural Science Foundation (7131014) awarded to Dr. Jian-Jun Li, MD, PhD.

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