Hs-CRP to albumin ratio predicts mortality of acute myocardial infarction patients with chronic kidney disease undergoing coronary angiography

Background The diagnosis and treatment of acute myocardial infarction (AMI) patients with chronic kidney disease (CKD) is still a challenging problem. The high sensitivity C-reactive protein (hs-CRP) to albumin ratio (HCAR) was proved to be a sensitive biomarker in predicting the prognosis of many diseases. The purpose of this study was to investigate the prognostic value of HCAR in postoperative 2-year mortality of AMI patients with CKD undergoing coronary angiography(CAG). HDL, Hemoglobin low-density eGFR, Estimated Glomerular Filtration Rate; CKD, chronic kidney disease; CAG, Corconary angiography; BUN, blood urea nitrogen; HbA1C, Hemoglobin A1C; WBC, WBC: alanine aminotransferase; AST, Aspertate Aminotransferase; CK-MB, Aspertate Aminotransferase; TnI, troponin I; LVEF, ventricular ejection HCAR, hs-CRP


Introduction
Acute myocardial infarction (AMI), a localized necrosis of the myocardium caused by myocardial ischemia, is still a major contributor to morality worldwide. Early-onset, more severe diseases and complications such as cardiac failure, arrhythmia, cardiogenic and shock are features of AMI.
Percutaneous coronary intervention (PCI) is the main treatment for AMI patients. It can de nitely promote the recovery of cardiac function, effectively increase the coronary blood ow and cardiac function reserve by 10%-30%, and signi cantly improve the prognosis and postoperative survival rate of AMI patients [1].
However, the treatment of AMI patients with chronic kidney disease (CKD) still poses a challenge. Low glomerular ltration rate, poor renal tubular function and lipid metabolism disorder may lead to complications such as contrast nephropathy and negative outcomes such as sudden cardiac death, arrhythmias, arterial calci cation, valve calci cation and hemorrhagic stroke, thus the postoperative survival rate and prognosis are less satisfactory [2,3]. Literature has shown that as a common in ammatory biomarker in clinics, high sensitivity C-reactive protein (hs-CRP), mainly produced in hepatocytes, is of great value in rehabilitation assessment and associated with atherosclerosis progression and cardiovascular events. Besides, several studies have shown that it is also an independent risk factor for renal function injury [4][5][6]. In contrast, serum albumin (Alb), a negative phase agent, is preferable to reduce in in ammation. The decrease of Alb usually indicates the aggravation of in ammation, malnutrition and cachexia [7]. Moreover, studies have shown a signi cant association of low Alb with adverse cardiovascular outcomes in AMI patients, and the level of Alb is also one of the best predictors of mortality in patients with terminal renal failure [8,9]. Studies have shown the CRP to Alb ratio could be used as a sensitive marker of in ammatory process and predicting the prognosis of patients with AMI, critical illness, malignant tumor and severe septicemia [10][11][12][13]. Thus, the hs-CRP to Alb ratio (HCAR), calculated by dividing hs-CRP by Alb obtained from clinical blood biochemical examination, may be more valuable in indicating higher residual in ammation with malnutrition status than either alone [14][15][16].
However, to the knowledge of the authors, no data have been reported on the comparable relationship between the HCAR and the risk of subsequent death in AMI patients with CKD. Therefore, this retrospective study was performed to investigate the relationship between HCAR and postoperative 2-year mortality of AMI patients with CKD undergoing CAG.

Study population and data collection
The present study was a single-center, observational, and retrospective study carried out between January 2013 and August 2019. All the data and follow-up records were derived from Cardiovascular Center of Beijing Friendship Hospital Bank(CCB Bank). A total of 11933 patients underging CAG were collected.
This study included 558 patients with CKD, which was de ned as an estimated glomerular ltration rate (eGFR) of less than 60 mL/minute/1.73 m2, as calculated by the MDRD equation, and modi ed with a Japanese coe cient using baseline serum creatinine. Patients with severe infection or malignancies, lacking complete medical records or lost follow-up were excluded (Fig. 1). A total of 466 patients met the eligibility criteria and were enrolled in the study. Subsequently, the patients were divided into two groups according to the HCAR cutoff value in predicting 2-year mortality by the Receiver operating characteristic (ROC) curve analysis. This study was approved by the ethics committee of Beijing Friendship Hospital, Capital Medical University and written informed consent was obtained from all patients

Laboratory analysis
The blood samples were collected on the morning of the second day after hospitalization. Blood parameters including serum hs-CRP and albumin levels were detected. The HCAR was determined by dividing serum hs-CRP by serum albumin. Left ventricular ejection fraction (LVEF) was calculated using Simpson's method.
Statistical analysis SPSS 21.0 was used for statistical analysis. Normally distributed continuous variables were presented as mean ± standard deviation, and those with non-normal distribution were presented as median (25th-75th), while continuous variables were analyzed using Student's t-test or non-parametric test. Categorical variables were described as absolute values and percentages, and analyzed by the chi-square test. The ROC curve analysis was performed, and Youden index was used to determine the best cut-off value for the HCAR. The Kaplan-Meier method was conducted using the log-rank test. The Cox proportional hazards regression model was used to analyze the independent predictor of mortality. The results with a P-value < 0.05 were considered statistically signi cant.

Results
The baseline demographic and biochemical characteristics of all 466 patients are listed in Table 1. Among the 466 patients enrolled in the study, the mean age was 72.98 ± 10.12 years old. 257 were male, 76 were of CKD 5 Stage and 390 were of CKD 3-4 Stage. The median HCAR was 0.25(0.08-0.65). The scatter diagrams and correlation analysis showed the correlation between HCAR and the indices re ecting the cardiac function, the severity of myocardial damage and renal function: NT-proBNP, LVEF, CK-MB, TnI and eGFR (Fig. 2). Besides, the HCAR was signi cantly correlated with WBC (r = 0.331, P < 0.001), hs-CRP(r = 0.996, P < 0.001) and ALT(r = 0.139, P = 0.003), which indicated that MLR could also re ect both the degree of in ammation and hepatic function. The patients were divided into 2 groups according to the HCAR cutoff value of 0.24 in predicting 2-year mortality. The group with a higher HCAR (HCAR ≤ 0.24) included 236 patients (136 males, aged 72.37 ± 10.95 years old) and the group with a lower HCAR (HCAR < 0.24) included 230 patients (121 males, aged 73.60 ± 9.17 years old). Overall, the group with a higher HCAR had lower eGFR and higher FBG, WBC, PLT, ALT, AST, CK-MB, TnI and NT-proBNP (P < 0.05) ( Table 1). Besides, the group with a higher HCAR was signi cantly associated with a higher 2-year mortality (45/236 (19%) vs. 23/230 (10%), P = 0.006) (Fig. 4). The Kaplan-Meier curve showed that the group with a higher HCAR had a worse prognosis (logrank P < 0.001, Fig. 5).
As shown in Table 2, compared to survivors, nonsurvivors had lower BMI, eGFR, HBG, and LVEF and older age, AST, NT-proBNP and HCAR (P < 0.05). CK-MB tended to be higher in nonsurvivors with a critical Pvalue of 0.095. The use of antiplatelet agents, ACEI/ARB, β-blocker and statins could reduce mortality signi cantly(P < 0.01). Finally, a Cox regression analysis was used to assess the risk factors for 2-year mortality. Based on the results shown in Table 2, traditional risk factors, including age, gender, CKD stage, BMI, HT, DM, family history of CAD, TG ,TC, LDL-C, HDL-C, smoke and FBG, LVEF, NT-proBNP, HCAR, the use of antiplatelet agents, ACEI/ARB, β-blocker and statins were included into the multivariable Cox regression analysis. The regression analysis shown in Table 3 demonstrated that HCAR was an

Discussion
The key role of in ammation in diseases development has attracted more attention, and the studies on in ammatory indices have been highlighted in recent years. At present, hs-CRP and CRP are widely used as indicators of in ammation. Although both the two indices are actually measured with C-reactive protein, the clinical signi cance of CRP and hs-CRP is not exactly the same [17,18]. CRP has good performance in the diagnosis of infectious and connective tissue diseases, whereas, hs-CRP, due to its higher sensitivity, precision and reproducibility, seems better for diagnosis of cardio-and cerebrovascular disease [14,[18][19][20]. Contrary to other speci c in ammatory factors or markers, the hs-CRP and serum albumin are easily measured in clinics, and are widely used in many primary hospitals, with a high penetration rate, stable results and easy to observation. Through the combination of the two indicators above, HCAR has the advantages of simplicity, low-cost and high reliability. On the basis of making full use of the existing biochemical examination, HCAR can help to excavate more detailed diagnosis and treatment information, provide reference for clinical diagnosis and treatment, and effectively save costs, which is potentially valuable in clinical application.
Previous studies have suggested that coronary atherosclerosis is a multistep and chronic in ammatory process. In ammation plays a key role in the formation, development and rupture of atherosclerotic plaques. In 2019, Zhuang conducted a randomized clinical trial, enrolling 3802 subjects followed up for 5.01 years, and it was found that hs-CRP was positively associated with the incidence of coronary heart disease in the general population [16]. In 2014, Daniel's study identi ed hs-CRP as an independent predictive factor of 30-day mortality in STEMI patients [21]. Serum albumin level can re ect the nutritional status of patients and predict prognosis of cancer, infection and critical patients. A low albumin level indicates poor prognosis of patients. Therefore, by combining hs-CRP and albumin, the predictive value of HCAR has gained increasing attention of researchers. Wang et al. have shown that HCAR is closely related to the incidence of short-term adverse cardiovascular events in patients with acute coronary syndrome, and could provide help to risk strati cation [22]. However, the clinical value of HCAR in AMI patients has not been reported, especially in patients with chronic kidney disease.
Using scatter diagrams and correlation analysis, this study showed that HCAR was signi cantly and positively correlated with in ammatory indices, leukocyte count and hs-CRP, in AMI patients with CKD undergoing CAG. Thus, HCAR is a useful indicator closely related to hs-CRP, which could also re ect in ammation. Besides, HCAR was positively correlated with NT proBNP, CK MB, TnI, AST and ALT, and negatively correlated with LVEF and eGFR (P < 0.05). These ndings indicate that HCAR is signi cantly associated with cardiac, renal and hepatic functions. Thus, in patients with AMI combined with CKD, HCAR may re ect the severity of myocardial infarction, as well as cardiac and renal function.
The current study also showed that in AMI patients with CKD undergoing CAG, HCAR has a good value in predicting mortality. The diagnostic e ciency is the highest when HCAR is 0.24, with a sensitivity of 66.2% and speci city of 52.0%. Therefore, in this study, the patients were divided into two groups with the HCAR value of 0.24 as the cut-off value. Consistent with the above correlation analysis, the group with a higher HCAR was negatively correlated with eGFR, and positively correlated with NT-proBNP, CK MB, TnI, ALT and AST, which further con rmed that HCAR has certain advantages in re ecting the severity of myocardial infarction, as well as cardiac and renal function. Especially, a negative correlation between HCAR level and mortality was observed, suggesting that HCAR may predict prognosis of the patients. Further analysis of survival rates of patients showed that the survival time of patients in the group with a lower HCAR was signi cantly longer than that in the group with a higher HCAR. Hence, a comprehensive analysis of mortality risk factors was conducted. The Cox survival analysis indicated that higher HCAR level, older age and higher NT-proBNP were independent predictors of 2-year mortality of AMI patients with CKD undergoing CAG.
Also, there was a negative correlation between HCAR and eGFR (P < 0.05). The predictive value of HCAR in CKD patients was also investigated. The results showed that HCAR had a good diagnostic value in predicting the severity of CKD. HCAR was most e cient in the diagnosis of CKD staging when HCAR was 0.17, with a sensitivity of 77.6% and speci city of 39.7%. These results indicate that HCAR is clinically valuable in evaluating the renal function of AMI patients with CKD undergoing CAG.
However, this study also has some limitations. Firstly, this was a retrospective and single-center study with a limited sample size. Thus, a prospective, multicenter and randomized controlled trial is required to corroborate our ndings. Secondly, this study only focused on value of HCAR in predicting the 2-year mortality of AMI patients with CKD undergoing CAG. Further studies need to be conducted on MACE, CKD progression and mortality in 5years or even longer time. Thirdly, this study only evaluated the association of HCAR level with prognosis of the patients upon admission, lacking the data re ecting changes over time.
In the future, more information should be collected to gain more insight into the diagnostic value of HCAR.
In conclusion, this study indicates that HCAR may comprehensively re ect the condition of AMI patients with CKD undergoing CAG. HCAR could not only re ect the degree of in ammation, but also predict the severity of myocardial infarction, renal function, liver function and prognosis. With its advantages of simplicity, cost-effectiveness, and reliability, HCAR is potentially applied clinically in the future. Flow chart of patient selection. AMI, acute myocardial infarction; CKD, chronic kidney disease; CAG, corconary angiography.