Combined Serum Albumin and Left Ventricular Ejection Fraction Predict All-Cause Death in Patients with Stable Coronary Artery Disease

Objective To explore the feasibility of serum albumin (Alb) and left ventricular ejection fraction (LVEF) in predicting all-cause death (ACD) in patients with stable coronary artery disease (SCAD). Methods Patients with SCAD were divided into 4 groups according to their Alb and LVEF levels: Group A: Alb ≤4 g/dL and LVEF > 50%; Group B: Alb ≤4 g/dL and LVEF ≤50%; Group C: Alb >4 g/dL and LVEF ≤50%; Group D: Alb >4 g/dL and LVEF >50%. The K–M curve and log-rank test were used to compare ACD among the four groups over three years. Receiver operating characteristic (ROC) curves were used to compare the efficacy of predicting ACD among the combination of Alb and LVEF and either Alb or LVEF alone. Cox regression analysis identified the influencing factors of ACD in patients with SCAD and detected the correlation between Alb and LVEF. Results ACD occurred in 18 (8.9%) of 203 patients with SCAD, with an average follow-up of 26.53 ± 14.34 months. In the Kaplan‒Meier analysis, the risk of ACD in the four groups ranged from high to low: Group B (17.6%) > Group A (26.7%) > Group D (0.9%) > Group C (0%, P < 0.001). The ROC curve showed that the combination of Alb and LVEF (AUC = 0.888) had better predictive value for ACD than either Alb (AUC = 0.879) or LVEF alone (AUC = 0.651), P < 0.001. Multivariate Cox regression analysis showed that Alb ≤4 g/dL predicted ACD events after adjusting for baseline (HR: 12.16, 95% CI: 1.57 to 94.41; P=0.017) and treatment (HR: 19.36, 95% CI: 2.53–147.78, P=0.004). Alb was positively correlated with LVEF (r = 0.22, P=0.002). Conclusions Alb combined with LVEF is more effective than a single index in predicting ACD in SCAD and could be used as a new model to judge the prognosis of SCAD.


Introduction
Stable coronary heart disease (SCAD) refers to the presence of atherosclerotic plaques in the coronary arteries or is accompanied by uncomfortable symptoms of angina pectoris, and the stable period after the onset of acute coronary syndrome (ACS) also belongs to this category [1,2].SCAD is one of the most common types of coronary heart disease, and the incidence rate over 60 years may exceed 12%, making this a major public health concern [3].SCAD can induce heart failure, arrhythmia, sudden death, stroke, and other adverse complications, which seriously threaten the health of the global population.
C-reactive protein (CRP) and high-sensitivity cardiac troponin T (hs-cTnT) are classic indicators commonly used to evaluate the prognosis of SCAD [4,5].Serum albumin (Alb) can not only maintain the plasma colloid osmotic pressure and reduce the extravasation of liquid into the intercellular matrix but also can be anti-infammatory and can be an antioxidant and plays an important role in acute and chronic heart failure (HF), acute coronary syndrome (ACS), septic shock, nephrotic syndrome, cirrhosis, stroke, and malignant tumours [6][7][8][9][10][11][12].In recent years, studies have shown that Alb is closely related to the prognosis of SACD after percutaneous coronary intervention [13,14].Left ventricular ejection fraction (LVEF) is an important index to measure left ventricular systolic function and guide medical treatment of HF [15].It is also an important indicator for evaluating the prognosis of coronary heart disease [16,17].At present, there was no report about the prognosis of SCAD by combined Alb and LVEF.Terefore, our aim is to explore the application value of Alb combined with LVEF in evaluating the all-cause mortality risk of SCAD patients through this retrospective study.

Methods
2.1.Data Download.Tis was a single-centre retrospective study.As a secondary analysis, all the data were derived from the published article shared by Suzuki et al. [13].We obtained the data from the "DATADRYAD" database (https:// datadryad.org/stash/).Dryad is a public database, and users can download data freely.Dryad data package: Suzuki, et al.Data from: prognostic signifcance of serum albumin in patients with stable coronary artery disease treated by percutaneous coronary intervention, Dryad, Dataset, https:// doi.org/10.5061/dryad.fn6730j[18].A total of 204 patients were newly diagnosed with SCAD, were admitted to Shinonoi General Hospital, Japan, from October 2014 to October 2017, and agreed to receive percutaneous coronary intervention (PCI) treatment.Patients with malignant tumours or old myocardial infarctions were excluded.Te study was approved by the Shinonoi General Hospital Ethics Committee, and all patients signed informed consent forms.Te data collected included clinical characteristics, medical history, major risk factors, medications, laboratory, echocardiography, and angiography results, and comorbidities during follow-up.

Defne Grouping and Prognosis
. SCAD was defned as coronary angiography showing ≥90% epicardial coronary artery stenosis or ≥75% coronary artery stenosis with angina symptoms induced by drugs or exercise stress tests.Alb was detected by the bromocresol purple assay and the LABO-SPECT 008 analyser (Hitachi Ltd., Tokyo, Japan) at admission.Te normal value range of Alb for adults is 4-6 g/dL.According to the cut-of point of 4 g/dL, all patients were divided into a hypoalbuminemia group (Alb ≤4 g/dL) and a normal albuminemia group (Alb >4 g/dL).Te left ventricular systolic function was obtained by measuring LVEF in the Teich method with echocardiography.Te LVEF equals the LV stroke volume (LVSV) divided by the LV enddiastolic volume (LVEDV) and is usually expressed as a percentage.According to the HF guidelines [15], we regarded patients with LVEF ≤50% as the group with reduced cardiac function and patients with LVEF >50% as the group with normal cardiac function.Ten, all patients were divided into four groups: Group A: Alb ≤4 g/dL and LVEF >50%; Group B: Alb ≤4 g/dL and LVEF ≤50%; Group C: Alb >4 g/dL and LVEF ≤ 50%; and Group D: Alb >4 g/dL and LVEF >50% (Figure 1).
All patients were followed up until the occurrence of ACD.Survival time was calculated from the date of PCI until an adverse event occurred.

Statistical Analysis.
Continuous data are presented as the mean ± standard deviation (SD), whereas categorical data are presented as percentages (%).One-way analysis of variance (ANOVA) was used to compare continuous variables among groups, and the chi-square or Fisher's exact test was used for categorical variables.To compare the survival diferences among the four groups composed of diferent Alb and LVEF, Kaplan-Meier (K-M) curves were plotted, and the log-rank test was used for statistical analysis.Receiver operating characteristic (ROC) curves were used to compare the discriminative power among the combination of Alb and LVEF and either Alb or LVEF alone.Ten, the Youden index was calculated using the formula sensitivity + specifcity −1.In the univariate analysis of ACD in patients with SCAD, all variables were analysed by the logrank test, and variables with P < 0.10 were screened.Continuous variables were classifed according to the mean value.Multivariate Cox regression was stratifed according to the baseline, treatment, and laboratory data.Finally, correlation analysis and scatter plots were used to detect the relationship between Alb and LVEF.All statistical tests were two tailed, and P < 0.05 was considered statistically significant, with the tests being performed using SPSS version 27.0.1 and MedCalc version 20.116.

Clinical Characteristics of the Four Groups.
After excluding one patient whose LVEF data were missing, 203 patients with SCAD were included in the study.All patients were divided into four groups depending on their Alb and LVEF.In Table 1, those in the four groups were on average 72.6 ± 10.4 years old.Males accounted for 69.5% (141/203).Te mean body mass index (BMI) was 23.6 ± 0.5.
Group C had the highest proportion of smoking (83.3%), whereas Group D had the highest percentage of dyslipidaemia (63%).Te lowest mean LVEF was 34.5 ± 7.5% in Group C, followed by 40.4 ± 6.5% in Group B. Tere were no diferences in blood pressure (BP) or additional previous medical history.
Te average statin use rate of the four groups exceeded 50%.Groups B and C belonged to the heart failure group and antiheart failure drugs were used more commonly than in the other two groups.
Coronary angiography showed that 50.2% of the patients had bifurcation lesions, only 5% had chronic obstruction and left main artery lesions, and the highest degree of coronary artery calcifcation in Group A was 25.7%.A total of 94.6% of the patients were implanted with drug-eluting stents (DES).Nearly 1/4 of the patients underwent multivessel percutaneous coronary intervention (PCI).
Te average Alb, hemoglobin (Hb), and low-density lipoprotein cholesterol (LDL-C) of Groups A and B were lower than those of the other two groups, and the lowest average Alb of Group B was only 3.3 ± 0.4 g/dL.All four groups had an estimated glomerular fltration rate (eGFR) less than 90 mL/min/1.73m 2 , and the lowest level in Group B was 45.7 ± 23.5 mL/min/1.73m 2 .Te levels of total cholesterol (CHOL) and triglycerides (TG) in Groups C and D were the highest, and the level of C-reactive protein (CRP) in Group B was higher than those in the other three groups (P < 0.001).According to the ROC curve, combined Alb and LVEF (AUC � 0.888) had a better predictive value for ACD than Alb (AUC � 0.879) or LVEF (AUC � 0.651) alone, with a Youden index � 0.680, P < 0.001 (Figure 2(d)).

Correlation between Alb and LVEF.
As shown in Figure 3, scatter plots were generated, and Pearson's correlation coefcients were calculated to explore correlations between Alb and LVEF.Tere was a signifcant positive correlation between Alb levels and LVEF (r = 0.22, P � 0.002).

Discussion
Tis study mainly retrospectively analysed 203 newly diagnosed SCAD patients, compared the diference in ACD under diferent combinations of Alb and LVEF, and discussed whether the predictive efcacy of Alb and LVEF in evaluating ACD was diferent from that of Alb or LVEF alone.
Alb is a single-chain protein composed of 580-585 amino acids, accounting for 60% of the total plasma protein [19].It is only generated by the liver and participates in various pathological and physiological functions [20].Te normal human serum Alb concentration range is 4-6 g/dL.Usually, less than 4 g/dL can be considered a decrease in albumin concentration [21], and some studies have considered that less than 3.5 g/dL as hypoalbuminemia [10,22,23].Tere is a prevalence of 21-70% of hypoalbuminemia in hospitalized individuals among acutely ill patients [24].Hypoalbuminemia has been linked to morbidity and mortality in hospitalized patients [25], including those with coronavirus disease 2019 (COVID-19), which is associated with a higher incidence of cardiac injury and other organ damage [26].A study of 8,750 patients with acute myocardial infarction found that admission Alb levels were an 4 Cardiology Research and Practice independent predictor of long-term ACD [27].Tere is evidence that hypoalbuminemia has been associated with reduced survival in patients with acute and chronic HF and ACS [10,12,28].Moreover, the predictive value of hypoproteinaemia is related not only to the absolute value of albumin but also to the degree of albumin decline.A greater decrease in Alb in 5449 patients undergoing PCI is associated with a higher risk of long-term major adverse cardiac events [29].
Our study showed that the survival time of SCAD patients with Alb ≤4 g/dL was signifcantly lower than that of SCAD patients with Alb >4 g/dL.According to the multivariate Cox regression, the predicted risk of ACD in SCAD patients with Alb ≤4 g/dL at baseline and after PCI treatment was 12.16 and 19.36 times higher than that in SCAD patients with Alb >4 g/dL, respectively.Alb ≤4 g/dL was an independent predictor of ACD in SCAD patients.We speculated that the mechanism of hypoalbuminemia in SCAD may be related to various factors.Hypoalbuminemia could lead to fuid extravasation into the interstitial space, which causes pulmonary oedema and fuid retention and aggravates myocardial dysfunction by promoting myocardial oedema [30,31].Hypoalbuminemia can increase blood viscosity, increase the risk of vascular thrombosis [32,33], and may also accelerate the damage of infammation and oxidative stress on endothelial function [34].HF is a common adverse complication of SCAD and may be associated with DNA-dependent protein kinase catalytic subunits (DNA-PKcs) [35].LVEF is commonly used to measure left ventricular systolic function as an important tool to evaluate the prognosis of cardiovascular diseases such as CAD, cardiomyopathy, and valvular heart disease and has been used to guide the treatment of HF [15].Both LVEF and scarring were independent risk factors for all-cause and cardiac death [36].Our study showed that the survival rate of the K-M curve consistent with SCAD decreased with decreasing LVEF, suggesting that LVEF was associated with the prognosis of patients with SCAD.
When establishing the ROC curve of ACD (Figure 2(d)), the results show that the optimal cut-of values of Alb and LVEF are 3.8 g/dL and 68%, respectively.However, we did not use this result as the basis for grouping, considering that it is related to the basic conditions of the patients during the study enrolment period and the relevant parameters of the Cardiology Research and Practice ROC curve model.Terefore, the clinically recognized cutof value Alb of 4.0 g/dL and LVEF of 50% was fnally selected as the cut-of with the patients divided into four groups for statistical analysis.Te serum Alb level was determined by laboratory examination, while LVEF was determined by imaging index.We wanted to explore whether the combination of Alb and LVEF could bring new fndings to the ACD assessment of SCAD patients.At present, there is no report on the ACD risk assessment of SCAD patients by combining Alb and LVEF, so it was an innovation of this study.We used the ROC curve to evaluate the ACD of SCAD in three cases of either Alb or LVEF alone and combined Alb and LVEF.Te results showed that the test efciency of the combined index was signifcantly higher than that of the single index, suggesting that the combined indicator may be a new important reference indicator for evaluating the prognosis of SCAD.

Limitations.
Tere were still some defciencies in this study.First, due to the limited research time, the number of patients in Group B and Group C was relatively small, which easily caused deviations in the statistical results.Second, only Alb was included after the adjustment of the baseline and treatment variables by the Cox regression equation, but not LVEF.Tird, the correlation analysis between Alb and LVEF only suggested a weak correlation (r � 0.22), which did not rule out the correlation with the screening of LVEF cut-of values or the small number of enrolled patients.Further research was conducted to expand the sample size and try to conduct statistical analysis on diferent cut-of values of LVEF to observe whether there were diferent outcomes.

Conclusion
Serum Alb concentration is associated with many diseases and is often used as an important evaluation indicator for chronic liver disease, kidney disease, malignant tumours, and other diseases.In recent years, it has been found that Alb is also of great signifcance for the cardiovascular system, especially in patients with SCAD.Our study combined Alb and LVEF to evaluate the risk of ACD in SCAD patients, indicating that the dual-index evaluation has advantages over the single-index evaluation, and Alb was an independent risk factor afecting the prognosis of ACD.With the continuous deepening of research and the accumulation of sample size, there will be stronger evidence to support and provide a new idea for accurately judging the prognosis of SCAD patients.
design, data analysis, thesis writing and revision.All authors have read and agreed to the fnal text.

Figure 2 :
Figure 2: K-M curves for ACD based on Alb (a), or LVEF (b), or the combination of Alb and LVEF (c).ROC curve for the combination of Alb and LVEF, and either Alb or LVEF alone (d).K-M: Kaplan-Meier; ACD: all cause death; ROC: receiver operating characteristic.

Table 1 :
Clinical characteristics of four groups of patients with SCAD.