Background

Acute coronary syndrome (ACS) remains the leading cause of morbidity and mortality worldwide despite prolonged and rigorous cardiovascular risk factor management [1]. Left ventricular systolic dysfunction (LVSD) is a common and serious complication of acute myocardial infarction (AMI), which can lead to greatly increased risks of sudden death and heart failure (HF) [2]. LVSD remains a major prognostic indicator for adverse cardiovascular events in patients with coronary artery disease (CAD) [3]. The presentation of left ventricular dysfunction shows a significant impact on the prognosis of ACS patients. Left ventricular ejection fraction (LVEF) is a conventional parameter to evaluate left ventricular systolic function in clinical practice and has been recognized as a significantly independent predictor of mortality in patients with ACS [4, 5]. In this context, the evaluation of clinical biomarkers associated with the occurrence of left ventricular dysfunction for further optimal management is considered to improve risk stratification in ACS patients.

Fibrinogen-to-albumin ratio (FAR) is measured by dividing serum fibrinogen by serum albumin. Both fibrinogen and albumin are reliable indicators of chronic systemic inflammation. Inflammation plays a crucial part in the initiation and progression of the atherosclerotic plaque rupture, thrombus formation and endothelial dysfunction [6]. Several studies have demonstrated that inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR) [7], platelet-to-lymphocyte ratio (PLR) [8], monocyte-to-lymphocyte ratio (MLR) [9], fibrinogen [10] and albumin [11], correlate with the prognosis of ACS. However, the predictive role of FAR in occurrence of left ventricular dysfunction in ACS patients is still indistinct. This study aims to explore the significance of FAR on the occurrence of LVSD, so as to provide insights for the role of inflammation in the deterioration of left ventricular function in patients with ACS. Moreover, We aim to compare the predictive value of FAR, NLR, PLR, and MLR for LVSD to provide instructions for clinical treatment of ACS patients.

Methods

Participants

Patients who were diagnosed with ACS and underwent percutaneous coronary intervention (PCI) were consecutively enrolled from January 2017 and December 2018 at the First Affiliated Hospital of Medical College of Xi’an Jiaotong University in this single-center, retrospective, observational cohort study. The inclusion criteria were as follows: (1) age ≥ 18 years; (2) diagnosis of ACS, including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI); (3) treated with elective PCI. The exclusion criteria included patients with prior cardiovascular events; type 2 diabetes; severe hepatic injury; hematologic disorders; acute infection; immune system diseases; thyroid dysfunction; renal insufficiency or chronic dialysis; malignant tumors; pregnancy; PCI failure; incomplete clinical and angiographic data. Ultimately, a cohort of 650 patients based on strict inclusion and exclusion criteria were enrolled (Fig. 1). This retrospective study obtained the ethical approval from the Ethical Committee of the First Affiliated Hospital of Xi’an Jiaotong University and was performed in accordance with the principles of the Declaration of Helsinki.

Fig. 1
figure 1

Flowchart of the study population enrollment. ACS acute coronary syndromes, LVEF left ventricular ejection fraction, LVSD left ventricular systolic dysfunction, PCI percutaneous coronary intervention

Full size image

Clinical data collection

Baseline data of demographic characteristics, including age, gender, weight, height, smoking, drinking, family history, and medication use were extracted from the standard medical records. BMI was calculated as weight in kilograms divided by squared height in meters (kg/m2). Heart rate and blood pressure measurements on admission was recorded. Patients with repeated systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, or receiving anti-hypertensive agents were considered criteria for hypertension [12]. Smoking was defined as an individual smoked a cigarette in the past 30 days or > 100 cigarettes in lifetime. Family history of CAD was defined as the occurrence of CAD in a first-degree relative. The routine hematology and biochemical parameters for baseline laboratory tests were drawn from the antecubital vein on admission and on the second day of hospitalization after an 8-h fast overnight. The Gensini score was calculated according to the results of coronary angiography. PCI was conducted in accordance with existing practice guidelines in China [13].

Definition of inflammatory markers

FAR is the ratio between serum fibrinogen and serum albumin. NLR is calculated by dividing neutrophil count by lymphocyte count. PLR is defined as the ratio of the platelet value and lymphocyte value. The ratio of the monocyte value and lymphocyte value means MLR.

Endpoint

LVEF was assessed using an ultrasonic cardiogram by two-dimensional Simpson’s method to determine the left ventricular systolic function. Patients were categorized into two groups based on their LVEF at 24 h after admission. Preserved systolic function was defined as LVEF ≥ 50% (n = 389) and LVSD was defined as LVEF < 50% (n = 261).

Statistical analysis

Continuous variables were, respectively, expressed as the mean ± standard deviation or median (interquartile ranges) according to whether normal distribution or not, while categorical variables were presented as percentages. The Kolmogorov–Smirnov test was used to analyze the normality of distribution. Student’s t test was used for comparison of continuous variables with normal distribution, and asymmetrically distributed variables were compared by Mann–Whitney U test, while percentages were analyzed by the Chi-squared test. The correlations between FAR and traditional cardiovascular risk factors were evaluated by adopting the Spearman’s rank correlation test or Pearson correlation test when variables appropriate. The receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic efficiency of inflammatory indicators for LVSD by determining the value of the area under the ROC curve (AUC) and the optimal cut-off values was counted according to the maximum Youden index. The predictive value of the FAR for LVEF was assessed by univariate and multivariate logistic regression model. Predictors of the endpoint determined by univariate analysis, potential confounders, and clinical importance were all included in multivariate analysis. Further subgroup analyses according to gender, age (< 65 and ≥ 65 years), hypertension, BMI (< 25 and ≥ 25 kg/m2), and diagnosis (NSTE-ACS and STEMI) were employed to examine the consistence of the prediction of FAR for LVSD. The performance of the nomogram was assessed by calibration and decision curve analyses (DCA). Statistical analyses were conducted using SPSS software version 23.0 and R 3.1.2. All the statistics are two-tailed and P < 0.05 was considered to be statistically significant.

Results

Patient characteristics

The baseline characteristics of enrolled patients stratified by the occurrence of LVSD (left ventricular systolic dysfunction) at admission are illustrated in Table 1. A total of 650 patients (age: 61.63 ± 10.57 years; 77.2% men) were finally enrolled in present study. Compared with those without LVSD, patients with systolic dysfunction had lower systolic blood pressure, higher heart rate and higher prevalence of smoking. Patients with LVSD presented higher level of NT-proBNP, white blood cells, NLR, MLR, PLR, hs-CRP, ALT, AST, creatinine, HCY, FAR, INR, APTT, FIB, d-dimer, FDP as well as higher prevalence of STEMI diagnosis but lower levels of albumin and apolipoprotein A. As for the angiographic findings, patients with LVSD were more likely to have three-vessel disease and significantly higher Gensini score. While there was no significant difference considering body mass index, age, drinking habits, hypercholesterolemia and FBG.

Table 1 Baseline clinical and procedure characteristics of patients according to ejection fraction
Full size table

Baseline clinical and procedure characteristics of patients categorized by the FAR tertiles are presented in Table 2. Patients with high FAR seemed to be older and higher heart rate. Laboratory indexes including NT-proBNP, cardiac troponin T, white blood cells, NLR, MLR, PLR, hs-CRP, cystatin C, FIB, FDP and FAR increased, whereas SBP, DBP, hemoglobin, triglycerides and LVEF decreased in proportion to the FAR tertiles. The rate of smoking, drinking, hypertension, family history of CAD and BMI level were not different among the different FAR groups. In the top FAR tertile, most patients were diagnosed as STEMI and showed significantly higher Gensini score.

Table 2 Baseline clinical and procedure characteristics of patients stratified by the FAR tertiles
Full size table

Correlation between FAR with LVEF and other cardiovascular risk factors

Spearman correlation analysis revealed significantly negative associations between LVEF and FAR (r = − 0.360, P < 0.001) (Fig. 2). FAR was positively correlated with age, HR, NT-proBNP, cardiac troponin T, platelet, white blood cells, neutrophils, monocytes, NLR, MLR, PLR, hs-CRP, AST, cystatin C, PT, INR, APTT, D-dimer, FDP and Lp (a), while negatively correlated with SBP, DBP, eGFR, serum Na+, serum Ca2+, PTA, TT, triglycerides, HDL, apoA (Table 3).

Fig. 2
figure 2

Scatter dot presentation comparison of FAR and LVEF. LVEF left ventricular ejection fraction, FAR fibrinogen-to-albumin ratio

Full size image
Table 3 Correlations between FAR and traditional cardiovascular risk factors
Full size table
Table 4 Predictive value of FAR for LVEF in different logistic regression analysis
Full size table

The predictive implication of FAR

Univariate and multivariate logistic regression analyses and predictors of LVSD in ACS patients are presented in Additional file 1: Table S1. Univariate analyses showed that FAR, gender, HR, SBP, smoking history, hypertension, NT-proBNP, white blood cells, NLR, MLR, PLR, hs-CRP, ALT, AST, albumin, creatinine, cystatin C, eGFR, serum Na+, serum Ca2+, HCY, PT, PTA, INR, APTT, FIB, d-dimer, FDP, triglycerides, Lp(a), Gensini score, initial diagnosis (STEMI), Killip class(≥ III) and plaque property were risk factors for LVSD in ACS patients after PCI (all P < 0.05). FIB and albumin were not included in the multivariate analysis because FAR was calculated from them. Multivariate logistic regression showed that FAR, NT-proBNP, NLR, HCY and initial diagnosis (STEMI) were independent predictors of LVSD in ACS patients after adjustment for sex and other potential confounding factors (all P < 0.05) .

In univariate analysis, FAR as a continuous variable was associated with an OR of 1.037 (95% CI 1.029–1.046; P < 0.001). Four models, including variables of statistical significance (P < 0.05) and/or clinical importance, were constructed to assess the predictive potential of FAR for LVSD in multivariate logistic regression analysis. Adjustment for multiple confounding variables did not attenuate the correlation and FAR remained to be an independent risk predictor for endpoint (OR 1.030, 95% CI 1.011–1.049; P = 0.002) (Table 4). The incidence of the LVSD increased monotonically across the tertiles of FAR in crude model (P for trend ≤ 0.001) (Fig. 3A). Taking T1 as the reference, multivariate analysis revealed that T3 increased the ORs for the incidence of LVSD, while T2 did not reach the statistical significance (T2: OR 2.105, 95% CI 0.869–5.094; T3: OR 3.395, 95% CI 1.303–8.848) (Table 4).

Table 5 AUCs of the inflammatory marker values for predicting the occurrence of LVSD
Full size table
Fig. 3
figure 3

OR of impaired left ventricular ejection fraction according to FAR groups. A Crude model. B Model4 adjusted. Taking T1 as reference. OR Odds ratio, FAR fibrinogen-to-albumin ratio

Full size image

The predictive effect of FAR for LVSD was greater than that of MLR, NLR, and PLR

The ROC curves predicting LVSD in ACS patients after PCI are illustrated in Fig. 4. FAR had the highest area under receiver operating characteristic curve (AUC) for prediction of LVSD compared with white blood cells, NLR, MLR and PLR (0.735, 0.680, 0.706, 0.688 and 0.594, respectively) (Table 5). The optimal value of FAR as an indicator for predicting the occurrence of LVSD was 79.16, which yielded a sensitivity of 59.6% and a specificity of 75.9%. The AUCs of FAR, FIB and albumin for the occurrence of LVSD are shown in Additional file 2: Table S2. The AUCs of FAR for predicting the occurrence of LVSD after adjusting for sex and hypertension are shown in Additional file 3: Table S3.

Fig. 4
figure 4

The receiver operating characteristic (ROC) curves based on FAR, white blood cells, NLR, MLR and PLR to predict LVSD in ACS patients after PCI. FAR fibrinogen-to-albumin ratio, WBC white blood cells, MLR monocyte-to-lymphocyte ratio, NLR neutrophil-to-lymphocyte ratio, PLR platelet-to-lymphocyte ratio

Full size image

Subgroup analysis

Relevant clinical variables like sex, age, BMI and clinical diagnosis were subject to post hoc subgroup analyses. The model adjusted in the subgroup analyses comprised all covariates used in Model 4 except for the variables used for stratification. Further evaluation of the predictive value of FAR for LVSD was performed in different subclasses. Increased FAR (per 1 unit) was consistently related to LVSD in various subgroups, including female or male, age ≥ 65 years, BMI < 25 kg/m2, with hypertension, NSTE-ACS or STEMI (Fig. 5). However, the results were not similar in patients aged below 65 years and patients without hypertension.

Fig. 5
figure 5

Logistic regression analysis evaluating predictive implication of FAR in various stratifications. OR was evaluated by 1-unit increase of FAR. OR Odds ratio, CI confidence interval, BMI body mass index, NSTE-ACS non-ST-segment elevation acute coronary syndromes, STEMI ST-segment elevation myocardial infarction

Full size image

The nomogram model

A nomogram was constructed to predict LVSD based on the final regression analysis (Fig. 6A). Furthermore, the AUC of the nomogram for LVSD were 0.906 (95%CI 0.881–0.932) in patients with ACS, indicting strong discrimination (Fig. 6B). A calibration curve of the nomogram is presented in Fig. 6C. The DCA indicated that the model showed better clinical benefit (Fig. 6D).

Fig. 6
figure 6

Construction and evaluation of nomogram. A Nomogram for prediction of LVSD. B C-index curves of the model. C Calibration curves of the model. D DCA curves of the model

Full size image

Discussion

In the present study, the relationship between FAR and left ventricular systolic function was investigated in patients with ACS who underwent PCI with stent implantation. Patients with left ventricular systolic dysfunction had significantly higher FAR values than patients with preserved LVEF in the study population. FAR was a strong indicator of left ventricular dysfunction even after adjustment for confounders. In addition, the ROC curve demonstrated the predictive power of FAR was greater than that of NLR, followed by MLR, white blood cells and PLR for LVSD in ACS patients. To our knowledge, this is the first study exploring the predictive role of FAR to the LV function between ACS patients after PCI. These findings supported that inflammation indicators were effective markers for predicting LVSD in ACS patients. In addition, the results of this study may contribute to better risk stratification and management of patients with ACS.

Fibrinogen (FIB), an acute-phase protein, is synthesized primarily in hepatocytes and plays a crucial role in the physiology and pathophysiology of coagulation and inflammation [14]. Fibrinogen biosynthesis increases rapidly during the acute phase of inflammation, such as bacterial infection, severe trauma and surgery [15]. Elevated plasma fibrinogen levels are also involved in chronic, low-grade inflammatory processes, activation of platelets, adhesion molecule expression upregulation, stimulation of angiogenesis and macrophages infiltration enhancement, which consequently aggravate atherosclerotic plaque progression [16]. Increased plasma fibrinogen concentration been confirmed the cause of the development of atherosclerotic lesions. Numerous observational studies identified that increased plasma fibrinogen concentrations were closely associated with CVD. Yuan et al. reported that plasma FIB was independently associated with long-term risk of all-cause and cardiac mortality in CAD patients after PCI [17]. Jiang et al. indicated fibrinogen concentration was associated with 2-year all-cause mortality in patients undergoing PCI [18]. Many cardiovascular risk factors can reversely lead to increased plasma concentration of fibrinogen, like age, diabetes, hypertension, obesity, lipid disorders, metabolic syndrome, smoking and alcohol consumption [19]. Albumin is synthesized in the liver, and the synthesis ability is affected by both nutrition and inflammation condition [20]. Malnutrition and inflammation are considered to play a major role in occurrence of hypoalbuminemia. Serum albumin has many physiological properties, such as anti-inflammatory activity, antioxidant, anticoagulant, antiplatelet aggregation and maintenance of capillary membrane stability [21]. Evidence has emerged that hypoalbuminemia is a powerful prognostic marker in the general population and in patients with cardiovascular diseases. After adjustment for traditional cardiovascular risk factors, serum albumin levels remained inversely associated with ischemic heart disease, heart failure and stroke [22,23,24]. Also, hypoalbuminemia is a powerful predictor of the cardiovascular prognosis in patients with CVD. A previous study had shown that lower serum albumin levels were associated with adverse cardiac events in patients with CAD after PCI [25]. Given that both plasma FIB and albumin showed strong correlation with adverse cardiovascular events, subsequent studies are warranted to evaluate whether FAR could be helpful in identifying high-risk populations in ACS patients undergoing PCI.

Since fibrinogen and albumin are positively and negatively correlated with systemic inflammation, respectively, researchers have proposed the hypothesis that FAR may be more closely related to inflammation than fibrinogen or albumin alone. Previous studies have confirmed the combination of fibrinogen and albumin parameters represent a more reliable and efficient indicator for the prognosis of multiple tumors and cardiovascular events than individual parameter separately (A–E). FAR was shown to be an independent predictor of the presence and severity of CAD among angina patients [26]. Oğuz et al. demonstrated that FAR was significantly associated with SYNTAX score in STEMI patients after PCI [27]. Furthermore, Xiao et al. analyzed 475 patients with STEMI and determined that the FAR was an independent prognostic factor for all-cause mortality in the population [28]. Recent research also reported that the FAR was an independent predictor of long-term outcomes in patients with NSTE-ACS who underwent PCI [29]. Consistent with the results of the above studies, FAR has been shown to be more powerful than fibrinogen or albumin alone in predicting the prognosis of patients with malignant tumors. Qiang et al. indicated that FAR was a novel prognostic indicator for patients with stage IB-IIA cervical cancer [30]. High FAR had been shown to be inversely associated with overall survival for locally advanced or metastatic pancreatic cancer [31]. In addition, FAR was reported to be a valuable marker for predicting long-term adverse prognosis in patients with gastric cancer treated with first-line chemotherapy, and its prognostic value was superior to that of fibrinogen or albumin alone [32].

Recent studies revealed that elevated NLR was an independent predictor for LVSD in ACS patients [33, 34]. NLR was demonstrated negatively associated with LVEF in patients with NSTE-ACS [33]. Orhan et.al found that NLR was a sensitive and specific predictor of impaired LV systolic dysfunction [34]. Adem et al. reported high PLR was a strong and independent predictor for LVSD in NSTE-ACS patients [35]. It is previously shown that elevated WBC levels are an independent predictor for the occurrence of LVSD after ACS regardless of several confounding factors [36]. Consistent with these results, we also found that NLR was an independent predictor of LVSD after adjusting for multiple covariates in ACS patients undergoing PCI.

Left ventricular dysfunction has been proved as the arguably powerful predictor of morbidity and mortality in ACS patients [4]. There are multiple mechanisms contributing to adverse left ventricular remodeling after acute myocardial infarction, such as large infarct size, excessive inflammatory response, irreversible microvascular disturbance, extracellular matrix changes, collagen deposition, fibroblast aggregation, eccentric hypertrophy, oxidative stress and neurohormonal activation [37, 38]. Our findings implied that elevated FAR may be partly involved in potential mechanism of left ventricular remodeling after ACS, resulting in decreased LVEF. Previous studies showed that higher FAR levels were significantly and independently related to the presence of angiographic coronary slow flow and no-reflow [39, 40]. The occurrence of coronary no-reflow may be associated with diffuse atherosclerosis, increased systemic inflammatory load, platelet dysfunction and impaired endothelial function, leading to coronary microvascular dysfunction. Therefore, we proposed that higher FAR may have caused worse microvascular perfusion, thereby affecting left ventricular functions. Considering these findings, it is reasonable to further investigate the underlying mechanisms for FAR in left ventricular remodeling.

The present study has some limitations. Firstly, the retrospective study was based on a single-center trial with a limited sample size and may not be generalized to other cohorts. Secondly, residual confounding by other unmeasured covariates cannot be excluded despite the attempt to perform potential risk factors adjustment. Finally, the measurement of echocardiogram was performed only once within 24 h after admission and may have failed to measure changes in LVEF after revascularization. Further multi-centric studies with larger populations are needed to clarify potential association between FAR in patients with left ventricular systolic dysfunctions.

Conclusions

FAR is an affordable and reliable predictor of LV systolic dysfunction in ACS patients undergoing PCI and the predictive power of FAR is greater than that of MLR, NLR, and PLR. Thus, the practice of using FAR on admission may help identify high-risk patients and relevant treatments.