Study on the Predictive Effect of Fibrinogen on Vascular Calcication

Background: The levels of brinogen (FIB), lipoprotein and high-density lipoprotein (HDL) are related to vascular calcication (VC), but their predictive ability for VC has not been reported. Aims: The purpose of this study was to evaluate the predictive ecacy of FIB, lipoprotein and HDL by retrospective analysis of FIB, lipoprotein and HDL levels in patients with VC. Methods: We collected the relevant indicators of 462 patients admitted to the Department of Vascular Surgery of the First Hospital of Hebei Medical University from August 2018 to July 2020, including 189 patients with vascular calcication (40.9%) and 273 patients without vascular calcication (59.1%).75% of the collected data is used for modeling (modeling group) and 25% for verication (verication group). Univariate analysis and multivariate analysis were used to evaluate the effects of FIB, lipoprotein and HDL on VC, and the predictive model ROC curve was used to evaluate its predictive eciency. Results: The results of multivariate analysis showed that FIB, lipoprotein and HDL were independent predictors of VC. Then the models of the three factors are established respectively. The area under the ROC curve of the prediction model of FIB, lipoprotein and HDL was 0.8018, 0.7348 and 0.7019, respectively. Conclusions: Fibrinogen has a better predictive ability than high-density lipoprotein and lipoprotein in patients with arteriosclerosis.


Introduction
Vascular calci cation (VC) is a very common disease, and the prevalence rate of calci cation increases with age. Relevant statistics show that VC exists in ≥ 90% of men and ≥ 67% of women over the age of 70 [1] . VC is not only an important cause of increased morbidity and mortality of cardiovascular disease but also a widespread pathological phenomenon harmful to the health of the middle-aged and elderly. VC is a marker of atherosclerosis and an independent predictor of cardiovascular events. It is closely related to all-cause mortality and has always been an important eld of cardiovascular medical research [1][2][3][4] .
Fibrinogen is a glycoprotein of 340kd, which consists of three different pairs of polypeptide chains a, b and g. It is mainly synthesized by hepatocytes in the liver and can be degraded by brinolytic enzymes to form brinogen degradation products. Lipoprotein is a kind of hydrophobic core rich in sterolipid and triglyceride and spherical particles composed of protein, phospholipid, cholesterol, and so on. Lipoproteins play an important role in the packaging, storage, transport and metabolism of extracellular lipids. High-density lipoprotein (HDL) is a complex lipoprotein composed of lipids and proteins and their regulatory factors, mainly produced by the liver and small intestine. Current studies have shown that serum in ammatory markers are signi cantly correlated with VC [5] , but the predictive e ciency of FIB in VC has not been reported. Although previous studies have shown that there is a correlation between lipoprotein and HDL and VC, its ability to predict VC has not been reported. Therefore, the purpose of this study is to further evaluate the predictive ability of FIB, lipoprotein and HDL to VC.

Patients
This study was approved by the Ethics Committee of the First Hospital of Hebei Medical University (ethics code is 20200617). We collected the relevant indicators of 462 patients admitted to the Department of Vascular Surgery of the First Hospital of Hebei Medical University from August 2018 to July 2020, including 189 patients with vascular calci cation (40.9%) and 273 patients without vascular calci cation (59.1%). Abdominal aortic calci cation score described by Kauppila et al. [6] . Lateral lumbar spine radiographs were obtained in the standing position to measure the severity of calci cation in the aorta at the level of the rst four lumbar vertebrae. The following scores were assigned for the presence of calci cations in the longitudinal aortic wall opposite each vertebra: 1, small calci ed deposits occupying less than 1/3 of the aortic wall; 2, one-third or more but less than two-thirds of the wall of the aorta; and 3,calci cation of two-thirds or more of the wall of the aorta. The anterior and posterior aortic walls were evaluated separately and the total was obtained to get a score out of 24 [7] . The abdominal aortic calci cation score of 0 is the patient without vascular calci cation, and the abdominal aortic calci cation score > 0 is the patient of vascular calci cation.

Data collection
We collected indicators of age, height, weight, brinogen, brinogen degradation products, triglycerides, cholesterol, HDL, low-density lipoprotein, lipoprotein, glutamyl transferase, and C-reactive protein from the database, and collected related indicators of vascular-free calci cation for 273 patients for comparison.

Statistical analysis
All statistical analyses and random allocation were performed by Empower Stats and R project version 3.3.3 (http://www.rproject.org/). The measurement data that obey normal distribution are expressed by mean ± standard deviation, and the comparison between groups is expressed by independent sample ttest, count data use case (%), chi-square test or Fisher exact probability method. Univariate analysis and multivariate regression analysis were used to analyze the differences between groups by Kaplan-Meier method and Log-Rank method. The test level was α = 0.05 (p < 0.05). The VC prediction ROC curve based on FIB, lipoprotein and low-density lipoprotein was established by Empower Stats. Table 1. 4.2 All variables were analyzed by univariate analysis (Table 2). Result variable: vascular calci cation.

Analysis of the ROC curve of VC prediction model by FIB, lipoprotein and HDL
Univariate analysis and multivariate analysis showed that FIB, lipoprotein and HDL had effects on VC. To further detect and compare the predictive e cacy of these indexes on VC, the ROC curves of FIB, lipoprotein and HDL on VC prediction models were established (Fig. 1). The ROC curve analysis and optimal threshold analysis of FIB, lipoprotein and HDL to VC prediction model are shown in Table 4

Discussion
Vascular calci cation ((VC)) is a very common disease. VC is characterized by increased vascular wall stiffness and decreased compliance, which can lead to serious clinical adverse reactions, including systolic hypertension, left ventricular hypertrophy, coronary artery ischemia, congestive heart failure, and possible plaque rupture, thrombosis and myocardial infarction [8,9] . Once considered to be a passive process, it is now recognized that VC is a complex and highly regulated process involving a series of mediating factors, including activation of cellular signaling pathways, circulatory calci cation inhibitors, genetic factors and hormones. Different phenotypes may have different effects on plaque vulnerability and clinical outcomes [1,4] . For example, histological studies have shown that coronary artery calci cation is mainly limited to the intima, however, intima and media calci cation can occur in large arteries, including aorta; media calci cation is more closely related to aging, diabetes and severe nephropathy [10] . The structural characteristics of different vascular beds may also play a role. Because of its complex and multifaceted characteristics, there is no targeted treatment for VC at present.
The pathogenesis of intravascular calci cation is not fully understood, but recent studies have shown that it is similar to neointimal calci cation, which is considered to be a repeat of bone formation and ultimately depends on the nucleation and crystal growth of hydroxyapatite [1,11] . Related studies have shown that in ammation, vesicle secretion, oxidative stress in apoptotic bodies and plaques, as well as increased levels of VSMC and cholesterol, radiotoxicity and adipogenesis contribute to the progression of calci cation [4] .
VC is usually the result of errors in adaptive mechanisms. In ammatory reaction and oxidative stress are important pathological processes of VC [12] . In general, chronic in ammation seems to be the central factor for abnormal soft tissue calci cation, and the site of chronic in ammation in the vascular system has been proved to be the site of atherosclerotic calci cation in mice [9] . There is strong evidence that in ammation plays an important, at least partially reversible, role in the development of VC, and in ammatory markers may be useful additional tools for assessing cardiovascular risk in clinical practice. The combined evaluation of VC and in ammatory markers can improve the non-invasive assessment of cardiovascular risk, so those high-risk patients can be selected for preventive treatment or more regular physical examination, and the possibility of de-targeting therapy for pro-in ammatory mechanism can be developed in the future [13] . As an important biomarker of systemic in ammation, FIB is a glycoprotein synthesized and secreted by hepatocytes. FIB is the main coagulation protein in plasma, the determinant of blood viscosity and the cofactor of platelet aggregation. The increase of plasma FIB concentration is an independent risk factor for cardiovascular disease [14,15] . Our results also show that FIB has an effect on vascular calci cation, which is consistent with previous studies.
According to related studies, lipoprotein can regulate the initiation of VC, which is an important determinant in the progression of VC [2,16−19] . Low-density lipoprotein is more likely to cause VC, especially, the elevated level of oxidized low-density lipoprotein is a risk factor for cardiovascular disease [20][21][22] . Our results are consistent with previous studies. But HDL (HDL) has the inhibitory ability to VC [4,23] . As a controversial lipoprotein, the inhibitory effect of HDL on VC is mainly mediated by its role in cholesterol reverse transport [24] , a biological process that promotes the transfer of free cholesterol from the arterial wall back to the liver for reuse or excretion into bile. HDL can inhibit the oxidation of lowdensity lipoprotein and its anti-in ammatory effect on cellular signals caused by oxidized low-density lipoprotein. HDL also inhibits macrophage Toll-like receptor 4-mediated in ammation, which is dependent on cholesterol e ux through ATP binding cassette A1 and transporter G1. Besides, HDL has an antidiabetic effect [25] . Our results also show that high-density lipoprotein negatively regulates vascular calci cation, which is consistent with previous studies.
In this study, using univariate and multivariate analysis, we determined that FIB, lipoprotein and HDL were independent predictors of VC. The models with ROC curves ranging from 0.70 to 0.80 are considered to be good, while the models with areas under the curves ranging from 0.80 to 0.90 have excellent resolution. The ROC curve analysis of the prediction model established in our study shows that lipoprotein and HDL have good prediction e ciency for VC, and brinogen has better predictive ability than high-density lipoprotein and lipoprotein in patients with arteriosclerosis.
To sum up, this study found that FIB has a strong ability to predict VC. The results of this study have good clinical practical value, which is a necessary item for hospitalized patients, and the collection of samples is simple. FIB can also be measured repeatedly, cheap, easily accepted by patients, and can be regulated by the use of drugs such as Beza brate. FIB is expected to become a new molecular marker for VC.