Monocyte-to-serum albumin Ratio as a Novel Predictor of Long-Term Adverse Outcomes in Patients after Undergoing Percutaneous Coronary Intervention: A Retrospective Cohort Study

Background: Inammation plays a signicant role in the initiation and progression of atherosclerosis. Monocyte and serum albumin have been proved to be involved in the process of systemic inammation. Therefore, we investigated the prognostic value of monocyte-to-serum albumin ratio (MAR) in patients who underwent percutaneous coronary intervention (PCI). Methods (cid:0) A total of 3,561 patients enrolled in this study from January 2013 to December 2017, who were divided into two groups according to the cut-off value of MAR (MAR<0.014, n=2220 and MAR ≥ 0.014, n=1119). The average follow-up time was 37.59±22.24 months. Results: There were signicant differences between the two groups in the incidences of all-cause mortality (ACM) (P<0.001), cardiac mortality (CM) (P<0.001), major adverse cardiovascular events (MACEs, P=0.038) and major adverse cardiovascular and cerebrovascular events (MACCEs, P=0.037). Kaplan–Meier survival analysis suggested that patients with higher MAR value tended to have an increased accumulated risk of ACM and CM (Log rank P<0.001 and Log rank P<0.001, respectively). And multivariate Cox regression analyses showed MAR was an independent predictor for ACM (hazard ratio [HR]=1.461, 95% condence interval [CI]:1.009–2.115, P=0.045) and CM (HR=1.695, 95% CI:1.056-2.721, P=0.029). Conclusion: The present study suggests that MAR is a novel independent predictor of long-term mortality in patients who underwent PCI.


Background
Over the past few decades, percutaneous coronary intervention (PCI) has revolutionized the management of coronary heart disease (CHD), with a signi cant mortality reduction [1]. However, the long-term mortality bene t of PCI has not been shown in these patients and the prognostic bene ts still remain uncertain [2]. Consequently, a long-term risk strati cation in patients treated with primary PCI is very important to help guide management decisions in these patients.
The role of in ammation in the pathogenesis and prognosis of CHD has gained wide attention [3].
Recently, in ammation based indexes, such as monocyte to high-density lipoprotein cholesterol ratio, platelet-to-lymphocyte ratio (PLR) and C-reactive protein-to-albumin ratio, have been reported as useful prognostic indicators in patients with CHD [4][5][6].
A large number of evidences implicate that monocyte plays an important role in the progression of atherosclerosis, by interacting with platelets and leading to chronic activation of pro-in ammatory leukocyte subpopulations [7,8]. Berg et.al showed that the percentage and number of classical monocytes could predict cardiovascular events [9]. As a negative acute phase protein, serum albumin is considered as the intensity of the infection-triggered in ammatory response [10]. Population-base studies have shown that the lower serum albumin is associated with the development of atherosclerosis, and the initiation of myocardial infarction [11,12].
Considerably, the monocyte and serum albumin are associated with the progression of CHD. However, the value of monocyte to albumin ratio (MAR) in CHD patients after PCI has not been investigated. Therefore, we investigated the prognostic value of MAR in patients who underwent PCI.

Participants
A total of 3,561 patients with CHD who underwent PCI at the First A liated Hospital of Zhengzhou University between January 2013 to December 2017 were enrolled. The inclusion criteria were CHD patients who were con rmed by coronary angiography, including non-ST-segment elevation acute coronary syndrome (ACS), ST-segment elevation ACS and stable angina and implanted at least one stent.
Exclusion criteria included severe valvular heart disease, decompensated heart failure, pulmonary heart disease, rheumatic heart disease, serious renal or hepatic disease, pernicious anemia, infective diseases and malignancy. This study complies with the Declaration of Helsinki and was approved by the ethics committee of the First A liated Hospital of Zhengzhou University.

Follow Up
Two hundred and twenty-two patients were excluded for the monocyte or albumin data not being available or the presence of renal failure, infective disease and malignancies. Finally, 3,339 patients were evaluated and categorized into two groups by MAR value (MAR < 0.014, n = 2220 and MAR ≥ 0.014, n = 1119). The cut-off value of MAR (0.014) was according to the analysis of the ROC curve for the baseline monocyte-to-serum albumin ratio of the study population. The owchart of the participants' enrollment is shown in Fig. 1. In our center, all patients undergoing PCI received a regular follow up conducted by telephone interview. During the duration of follow up, all events were carefully checked and veri ed by an independent group of clinical physicians.

Outcome
The primary endpoints included all-cause mortality (ACM) and cardiac mortality (CM). The secondary endpoints were stroke, bleeding, rehospitalization, major adverse cardiovascular events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs). MACEs were de ned as the composite of cardiac death, recurrent myocardial infarction (MI), or target-vessel revascularization. And MACCEs were de ned as MACES plus stroke [13,14].

Statistical Analysis
All data was analyzed by the SPSS 22.0 for Windows statistical software (SPSS Inc, Chicago, Illinois, United States). The enrolled patients were grouped into 2 categories based on the value of MAR (MAR < 0.014 and MAR ≥ 0.014). Continuous data were given as the mean ± standard deviation, and categorical variables were presented as numbers and percentages. To compare the difference of parametric continuous variables, Student's t tests were used; and Mann-Whitney U tests were used when compared the difference of nonparametric continuous variables. Chi-squared (χ 2 ) tests were used for the comparison of categorical variables. Kaplan-Meier analysis was used for cumulative incidence rates of long-term outcomes and the log-rank test was employed to compare between groups. Multivariate Cox regression analysis was performed to examine the predictive value of the MAR for outcomes during and up to the 6-year follow-up. Hazard ratios (HRs) and 95% con dence intervals (CIs) were calculated. The P values were 2-sided, considered being signi cant difference when P < 0.05.

Baseline characteristics
In the study, 3,339 patients who underwent PCI were enrolled. The median follow-up time is 37.59 ± 22.24months. The participants were categorized into two groups according to the cut-off value of MAR: the lower MAR group (MAR < 0.014, n = 2220) and the higher MAR group (MAR ≥ 0.014, n = 1119). All the baseline data were shown in Table 1. The variables in regards to age, gender, smoking, heart rate, creatinine (Cr), uric acid (UA) and high-density lipoprotein (HDL-C) showed signi cant differences between the two groups (all P < 0.05).

Comparison Of Clinical Outcomes
We showed the clinical outcomes in Table 2. For the primary endpoints, the incidence of ACM was 2.9% in the lower MAR group and 5.5% in the higher MAR group (P < 0.001). And the incidence of CM was a signi cant difference between the two groups (1.7% vs. 3.8%, P < 0.001). For the secondary endpoints, the incidence of MACEs and MACCEs between the two groups showed signi cant differences (10.5% vs. 13.0%, P = 0.038 and 13.8% vs. 16.5%, P = 0.037, respectively). However, there were no signi cant differences between the two groups in regards to the incidence of stroke, bleeding events and readmission. As Kaplan-Meier survival analysis suggested that CHD patients with higher MAR tended to have an increased accumulated risk of ACM and CM (Log rank P < 0.001 and Log rank P < 0.001, respectively) ( Fig. 2 and Fig. 3).

Discussion
In the present study, we found the prognostic value of MAR in patients who underwent PCI and demonstrated higher MAR value was independently associated with adverse outcomes of patients who underwent PCI.
Considering the high prevalence and poor prognosis of CHD, the early diagnostic biomarkers for patients with CHD are in need. Vascular in ammation plays a crucial role in the progression of CHD, and in ammation-based biomarkers have been shown previously [15][16][17], such as monocyte [18], highsensitivity C-reactive protein and serum albumin [19]. However, it is still elusive which cell plays a role in initiation of the cascade processes.
Atherosclerosis has long been associated with chronic in ammation, and monocytes and monocytederived macrophages account for the coronary plaque progression [20]. Circulating monocytes populate plaques and adhere to the dysfunctional endothelial surface via binding to leukocyte adhesion molecules only expressed by abnormal endothelial cells [21,22]. Cao et al have reported that all stages of atherogenesis, from the earliest lesions (fatty strips) to the formation of complex plaque, are associated with macrophages which are considered as a driving force [23]. In another recent study, e cient degradation of CCR2 mRNA in monocytes attenuated the number of monocytes in atherosclerotic plaques, reduced the infarct size following coronary artery occlusion [24], which may be a novel therapeutic strategy for CHD patients undergoing PCI. Serum albumin is considered as a negative acutephase protein in the progression of in ammation [25]. As previous studies demonstrated, low serum albumin concentration can predict the clinical outcome of acute myocardial infarction [12]. As shown in Table 1, age, gender, smoking, Cr and UA have signi cant differences between the 2 groups. Aging, gender and smoking are often characterized by a number of dysfunctional conditions including: myocardial sarcopenia, hypertrophy, vascular hyperpermeability, hypertension, in ammation, and functional impairment [26][27][28][29][30]. Increasing evidence demonstrates that age is a major risk factor in cardiac-related morbidity and mortality resulting from the decrease of the self-renewal of yolk sac-derived resident macrophages that play a key role in the post-MI repair and maintaining the cardiac homeostasis with age [31]. Ovaries removed or natural menopausal women exhibit systematic in ammation [32]. CHD has been considered to be male disease [28] because men are at a greater risk of CVD than women [29], who may decrease signi cantly the secretion of pro-in ammatory markers interleukin-6 (IL-6), IL-1, TNF-α via the estrogen [33]. Smoking has been known as an independent risk factor of atherosclerosis via promoting in ammation, thrombosis, and oxidative stress [30]. There are no doubts that age, gender, smoking, etc are confounding factors in our study, while after including these confounding factors in the multivariate Cox regression analysis, we still obtained positive results which demonstrated that the high MAR is an independent risk factor for ACM and CM in patients who underwent PCI.
To the best of our knowledge, it is the rst time to demonstrate the MAR, which is a novel, powerful, inexpensive and effective predictor for outcomes of CHD after PCI. There are some limitations in our study. Firstly, we did not monitor the dynamic change of their variables. Secondly, our study is a single retrospective cohort design. Thirdly, we failed to collect in ammatory markers such as high sensitive C reaction protein (hsCRP) and erythrocyte sedimentation rate (ESR). Besides, to demonstrate the association between MAR and the outcomes of CHD after PCI, our study needs to be further veri ed by a multi-center, prospective study. And we expect more researches about the mechanism of MAR will be explored.

Conclusion
In conclusion, our ndings suggest that the MAR is a sensitive, reliable and effective predictor of adverse outcomes in CHD patients undergoing PCI.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
This study complies with the Declaration of Helsinki and was approved by the ethics committee of the First A liated Hospital of Zhengzhou University.

Consent for publication
Not applicable.