Association between lactate/albumin ratio and all-cause mortality in critical patients with acute myocardial infarction

It has been demonstrated that lactate/albumin (L/A) ratio is substantially relevant to the prognosis of sepsis, septic shock, and heart failure. However, there is still debate regarding the connection between the L/A ratio and severe acute myocardial infarction (AMI). The aim of this study is to determine the prognostic role of L/A ratio in patients with severe AMI. Our retrospective study extracted data from the Medical Information Mart for Intensive Care III (MIMIC-III) database, included 1,134 patients diagnosed with AMI. Based on the tertiles of L/A ratio, the patients were divided into three groups: Tertile1 (T1) group (L/A ratio<0.4063, n=379), Tertile2 (T2) group (0.4063≤L/A ratio≤0.6667, n =379), and Tertile3 (T3) group (L/A ratio>0.6667, n =376). Uni- and multivariate COX regression model were used to analyze the relationship between L/A ratio and 14-day, 28-day and 90-day all-cause mortality. Meanwhile, the restricted cubic spline (RCS) model was used to evaluate the effect of L/A ratio as a continuous variable. Higher mortality was observed in AMI patients with higher L/A ratio. Multivariate Cox proportional risk model validated the independent association of L/A ratio with 14-day all-cause mortality [hazard ratio (HR) 1.813, 95% confidence interval (CI) 1.041-3.156 (T3 vs T1 group)], 28-day all-cause mortality [HR 1.725, 95% CI 1.035-2.874 (T2 vs T1 group), HR 1.991, 95% CI 1.214-3.266 (T3 vs T1 group)], as well as 90-day all-cause mortality [HR 1.934, 95% CI 1.176-3.183 (T2 vs T1 group), HR 2.307, 95% CI 1.426-3.733 (T3 vs T1 group)]. There was a consistent trend in subgroup analysis. The Kaplan-Meier (K-M) survival curves indicated that patients with L/A ratio>0.6667 had the highest mortality. Even after adjusting the confounding factors, RCS curves revealed a nearly linearity between L/A ratio and 14-day, 28-day and 90-day all-cause mortality. Meanwhile, the areas under the receiver operating characteristic (ROC) curve (AUC) of 14-day, 28-day and 90-day all-cause mortality were 0.730, 0.725 and 0.730, respectively. L/A ratio was significantly associated with 14-day, 28-day and 90-day all-cause mortality in critical patients with AMI. Higher L/A ratio will be considered an independent risk factor for higher mortality in AMI patients.

Cardiovascular disease remains the leading cause of death worldwide 1 .Acute myocardial infarction (AMI), as a common serious coronary event may develop complications, including heart failure, arrhythmia, cardiogenic shock, cardiac arrest and other serious adverse outcomes [2][3][4] .Despite the advanced treatment strategies, such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), the mortality rate of AMI varies globally, resulting in a great health burden [5][6][7] .To provide more clinical information, a growing number of indicators are explored to forecast the prognosis of AMI patients.
Lactate, a familiar indicator often used to predict the prognosis of disease and the severity of shock 8 , has been shown to be associated with mortality from a variety of diseases [9][10][11] .A previous study involving 1,176 patients with ST-segment elevation myocardial infarction found that elevated lactate levels were associated with increased 1-day acute mortality and increased 30-day mortality 12 .Albumin is an available and inexpensive clinical indicator.In addition to judging liver function and nutritional status, it has been demonstrated that cardiovascular disease incidence and hypoalbuminemia are closely connected.Hypoalbuminemia is an independent prognostic factor and modifiable risk factor that deserves attention for many cardiovascular diseases 13 .A retrospective study indicated that patients with low serum albumin on admission had a poor prognosis 14 .Therefore, both of the two indicators have important potential roles in a variety of diseases, especially for cardiovascular diseases.Recently, as a straightforward and simple-to-obtain composite indicator, the lactate/albumin (L/A) ratio has been proposed.Currently, most studies focus on its prognostic effect on sepsis patients [15][16][17][18] .Some studies have shown that L/A ratio has higher predictive value than lactate or albumin in mortality of sepsis patients 15,16 .In addition to sepsis, studies also have found that the L/A ratio is related to both short-and long-term mortality in individuals who suffered from heart failure driven on by AMI 19,20 .
However, it is still unclear whether lactate/albumin ratio and all-cause mortality in critical patients with AMI are relevant.Therefore, the aim of our study is to evaluate the predictive value of L/A ratio for mortality after AMI.

Results
Baseline characteristics of the study population.A total of 1,134 patients were included in our analysis.The average age of which was 68.87 and the percentage of men was 67.9%.Among all individuals, there were 145(12.8%)all-cause death within 14 days, 174 (15.3%) all-cause death within 28 days and 186 (16.4%) all-cause death within 90 days after intensive care unit (ICU) admission.A group analysis based on the tertiles of lactate/ albumin ratio were shown in Table 1.The patients in Tertile3 (T3) group were older and more female, higher proportion of patients suffering from atrial fibrillation (AF), acute kidney injury (AKI), acute respiratory distress syndrome (ARDS) and sepsis, lower proportion of patients with hypertension and hyperlipidemia, and fewer patients using aspirin, beta blockers, diuretics, statin, insulin, and oral hypoglycemic agents.With increasing L/A ratio, heart rate, respiratory rate, base excess (BE), anion gap (AG), lactate, white blood cell (WBC), blood urea nitrogen (BUN), prothrombin time (PT) increased, systolic blood pressure (SBP) and albumin decreased.As L/A ratio increased, scores from the Simplified Acute Physiology Score II (SAPS II) and sequential organ failure assessment (SOFA) became greater.Higher L/A ratio were substantially correlated with higher 14-day, 28-day and 90-day all-cause mortality, cardiac arrest and cardiac shock and less invasive ventilation.However, there was no significant difference among the three groups regarding the type of coronary artery revascularization after admission.

The association between the L/A ratio and AMI.
The outcomes of the Cox proportional-risk model for 28-day all-cause mortality were displayed in Table 2.In the unadjusted Cox model, Tertile2 (T2) and T3 groups had greater 28-day all-cause mortality compared to Tertile1 (T1) group [hazard ratio (HR) 2.266, 95% confidence interval (CI) 1.385-3.708for T2; HR 4.970, 95% CI 3.158-7.821for T3].After adjusting for confounding factors, 28-day risk of death was 1.725-fold (HR 1.725, 95% CI 1.035-2.874)higher in T2 and 1.991-fold (HR 1.991, 95% CI 1.214-3.266)higher in T3 than T1.More results were observed for 14-day all-cause mortality (Supplementary Table 1).After adjusting for confounding factors, 14-day mortality was still statistically higher in T3 than in T1(HR 1.813, 95% CI 1.041-3.156).It is concluded that higher L/A ratio (>0.6667) is an independent risk factor for short-term 14-day and 28-day all-cause mortality to AMI patients.At the same time, we further studied the relationship between L/A ratio and 90-day all-cause mortality (Supplementary Table 2), and the similar results have been achieved.
The Kaplan-Meier (K-M) survival curve analysis revealed statistical differences in 28-day mortality among the three groups by L/A ratio tertiles.Compared to the T2 and T1 groups (Fig. 1), the T3 group had substantially greater 28-day all-cause mortality (p<0.001).Similar results were found in K-M analysis of 14-day and 90-day allcause mortality (Supplementary Figure 1).According to restricted cubic spline (RCS) analysis, 28-day all-cause mortality risk rose non-linearly of increasing L/A ratio in unadjusted models (P for non-linear <0.001), whereas a nearly linear association existed between L/A ratio and the risk of 28-day mortality in models adjusted for age, gender, SBP, diastolic blood pressure (DBP), hypertension, diabetes, hyperlipemia, AF, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), aspirin, clopidogrel, beta blockers, diuretics, digitalis, statin, insulin, oral hypoglycemic agents, BUN, serum creatinine (Scr), glucose, WBC, hemoglobin (Hb), BE, saturation of hemoglobin with oxygen (SpO 2 ) (P for non-linearity =0.086) (Fig. 2).In addition, we found that the L/A ratio also had a nearly linear relationship with all-cause mortality at 14 and 90 days (Supplementary Figure 2 and Supplementary Figure 3).
The area under the receiver operating characteristic (ROC) curve of the L/A ratio for 28-day all-cause mortality was shown in Fig. 3.Meanwhile, Supplementary Figure 4 and 5also showed similar ROC curves for 14-day and 90-day all-cause mortality.The area under the ROC curve (AUC) manifested that the L/A ratio was able to predict mortality in AMI patients (The AUCs for 14-day, 28-day and 90-day all-cause mortality were 0.730, 0.725, and 0.730, respectively).

Subgroup analysis.
To further explore whether the association might vary under multiple conditions, we performed a subgroup analysis of age, gender, hypertension, diabetes, AF, CHF, potential of hydrogen (pH), and SpO 2 (Fig. 4).Interestingly, within all subgroups, high level of L/A ratio had higher 28-day all-cause mortality.These results suggested that the L/A ratio has good predictive value for AMI patients.

Discussion
In our study, we discovered that in critical AMI patients, L/A ratio was substantially relevant to 14-day, 28-day and 90-day all-cause mortality.The correlation of L/A ratio with all-cause mortality remained stable after adjusting for confounders and also significant in subgroup analysis.Moreover, RCS analysis indicated that L/A ratio and all-cause mortality were found to be nearly linearly correlated and the cut-off value is 1.00.In addition, the AUCs of the L/A ratio for predicting 14-day, 28-day and 90-day all-cause mortality in AMI patients were 0.730, tissue hypoxia, and hypoperfusion 24,25 .Lactate has shown prognostic value and risk stratification in critical patients 26 .Previous studies showed that lactate is significantly correlated with the prognosis of various shock states, including septic shock 27 , cardiogenic shock 28 and traumatic shock 29 .AMI is the most common cause of cardiogenic shock 30 .Previous studies have shown that increased serum lactate in acute coronary syndrome (ACS) could predict the survival outcome 12,31 .This is consistent with our findings.In this study, our study population consisted of critically ill patients with acute myocardial infarction, we found that with the increase of L/A ratio, lactate level increased, and the mortality of patients increased significantly.However, lactate has complex metabolic and clearance mechanisms 32,33 , it is not easy to accurately identify a disease by using this indicator alone.
As the most abundant protein in plasma, serum albumin is widely used in clinical disease monitoring 34 .Studies have shown that hypoalbuminemia is not only associated with short-term mortality and new heart failure during hospitalization in patients with acute myocardial infarction 14 , but also independently predicts long-term cardiovascular outcomes.Meanwhile, there has a dose-response relationship between hypoalbuminemia and increased long-term all-cause mortality 35,36 .This is also consistent with our findings that the L/A group with higher mortality rates had lower serum albumin levels.However, serum albumin levels can also be affected by a patient's blood glucose, nutritional status, and liver function 13 , so it also has certain limitations.The adjusted cubic spline model on the association between L/A ratio on a continuous scale and adjusted risk of 28-day all-cause mortality in patients with AMI.Crude hazard ratio (HR) and 95% CI for L/A ratio in 28-day mortality(A).Adjusted HR and 95% CI for L/A ratio in 28-day mortality (B).Adjusted variables included age, gender, SBP, DBP, hypertension, diabetes, hyperlipemia, AF, COPD, CHF, aspirin, clopidogrel, beta blockers, diuretics, digitalis, statin, insulin, oral hypoglycemic agents, BUN, Scr, glucose, WBC, Hb, BE, SpO 2 .
Vol:.( 1234567890 www.nature.com/scientificreports/Although both plasma lactate and albumin have a connection to cardiovascular disease, previous studies demonstrated limited evidence about those systemic inflammatory biomarkers alone examining this reciprocal relationship to prognosis of AMI.Thus, a combined indicator L/A ratio has been proposed by more studies, which could reflect the state of oxygen supply and inflammation levels, and the combination of these two indicators can reflect the current pathophysiological state of patients more comprehensively than a single indicator from different mechanisms.Shin, Jikyoung's study 15 demonstrated that the L/A ratio had a higher predictive value than lactate for 28-day mortality in patients with critical sepsis and Esra Cakir 16 further demonstrated that the  www.nature.com/scientificreports/L/A ratio had a higher predictive value than either lactate or albumin alone for mortality in patients with sepsis in the ICU.According to this study, we discovered that L/A ratio was connected to 14-day, 28-day and 90-day all-cause mortality of AMI patients.Higher L/A ratios reflected increased lactate levels and decreased albumin levels.In addition, we used Cox proportional risk model and RCS model to analyze the connection between L/A ratio and the risk of AMI.The correlation between them is explained as follows.In the event of a severe AMI, the myocardium begins to work ineffectively due to insufficient oxygen uptake, leading to a decrease in myocardial extraction of lactic acid from the circulation 37 , as well as inducing the cell to preferentially undergo anaerobic glucose metabolism, which results in the production of lactic acid from pyruvate 38 .What's more, the increase of lactate can participate in the process of inflammatory injury in the body, triggering the activation of a series of cell signaling pathways, so as to regulate the progression of inflammation 39 .Serum albumin has anti-inflammatory, antioxidant, anticoagulant and antithrombotic physiological properties, which is may be its potential role in cardiovascular disease 13 .It has been reported that inflammation has a negative effect on serum albumin levels 14 .Atherosclerosis is an inflammatory disease 40 , which can gradually progress to acute myocardial infarction 41 , which also lead to hypoalbuminemia.Our study demonstrates that L/A ratio is significantly associated with the prognosis in AMI patients, suggesting that this combined biomarker may capable to be better indicative of risk of AMI patients.Therefore, regarding the prognosis of individuals suffering from severe acute myocardial infarction, a significant emphasis on the L/A ratio has important clinical implications.
Our study also has some limitations.First of all, the MIMIC-III database is a large, single-center database with a large number of critically ill patients, which has the common limitations of a single-center database.Our results may not be fully applicable to intensive care units in other countries, but the patients included were from different ethnic groups and therefore are somewhat representative.Secondly, our study only included lactic acid and albumin data at the time of admission, without dynamic changes after admission.Meanwhile, due to the limitations of the database, it's possible that our model doesn't include more risk variables.Thirdly, the database lacks the position and number of stents in PCI, so we could not explore the link between the position as well as number of stents and prognosis of AMI.Fourthly, the database did not record the time of occurrence of AMI, so we didn't analyzed the impact of time-laps on the L/A ratio in patients with AMI.Thus, greater evidence is needed to support our findings.

Conclusions
The L/A ratio was substantially related to 14-day, 28-day and 90-day all-cause mortality in critical patients with AMI.Therefore, L/A ratio was capable of being used as a reliable predictor of prognosis in patients with AMI.Inclusion and exclusion criteria.In this study, we comprised a total of 3,177 first time ICU admissions for AMI patients [using the International Classification of Diseases Version 9 (ICD-9) code].There excluded 1,984 patients who were under 18 years of age, over 80 years of age or with an inexact age, 59 patients who didn't have lactate or albumin at admission.Data extraction.Data were collected from the MIMIC III database using Structured Query Language (SQL) with PostgreSQL (version 9.6).Demographic information (age, sex, ethnicity), Vital Signs (systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate, respiratory rate, body temperature), type of hospital admission (Elective, Emergency, Urgent), past medical history [AF, hypertension, diabetes, hyperlipidemia, COPD, AKI, ARDS, sepsis, CHF], laboratory indicators were measured multiple times within 24 h of admission, the first measurement was used [pH, SpO 2 , BE, AG, lactate, hemoglobin, platelet (PLT), WBC, albumin, BUN, Scr, glucose, sodium, potassium, PT, prothrombin time activity (PTA), oral medication on admission (aspirin, clopidogrel, beta blockers, diuretics, digitalis, statin), anti-diabetic therapy (the use of insulin and oral hypoglycaemic agents), cronary artery revascularization [(PCI, percutaneous transluminal coronary angioplasty (PTCA), CABG], SAPS II and SOFA were recorded.To minimize bias due to missing data, variables with more than 10% missing values were excluded from the final cohort.In fact, the missing values of indicators included in our study were less than 10%, such as body temperature, BE.We predicted the missing data using the multiple imputation method.

Methods
Clinical outcomes.We obtained patient's clinical outcome and the specific time of death through the records of the Social Security Death Index, and the endpoints were 14-day, 28-day and 90-day all-cause mortality after ICU admission.

Data analysis.
Based on the tertiles of L/A ratio, the patients were divided into three groups : T1 group (L/A ratio<0.4063,n=379), T2 group (0.4063≤L/A ratio≤0.6667,n =379), and T3 group (L/A ratio>0.6667,n =376).Continuous variables that conform to the normal distribution are expressed as mean ± standard deviation.

Figure 1 .
Figure 1.Kaplan-Meier survival curve of 28-day all-cause mortality stratified by L/A ratio.

Figure 4 .
Figure 4. Association between L/A ratio and risk of all-cause mortality in subgroups.Forest plot and adjusted HR with 95% CI for 28-day all-cause mortality.
Source of data.The data sources is a large database called Medical Information Mart for Intensive Care III (MIMIC III) database.This free database contains information on various hospitalization categories from more than 40,000 patients who were older than 16 and admitted to Beth Israel Deaconess Medical Center's intensive care units (ICU) between 2001 and 201221 .To obtain data access, we successfully completed the Cooperative Institution Training Initiative exam and Cyber Training Program of the National Institutes of Health (NIH) which was to protect participants of human research.Due to patient's anonymity and the absence of protected information in the database, the ethics committee decided to waive informed consent.

Table 1 .
Baseline 22,23nued Vol:.(1234567890)ScientificReports | (2023) 13:15561 | https://doi.org/10.1038/s41598-023-42330-8www.nature.com/scientificreports/0.725 and 0.730.These results indicated that L/A ratio was capable of serving as a better predictive marker of prognosis in AMI clinical practice.The clinical significance of lactate has been raised since its discovery in 1780 and its introduction into medicine in 184322,23.Studies have shown that elevated serum lactate levels can reflect reduced systemic blood flow, characteristics across L/A ratio.Continuous variables that conform to the normal distribution are expressed as mean ± standard deviation.Continuous variables that are not normally distributed are expressed as median (interquartile range).Categorical variables are expressed as numbers (percentages).AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; CHF, congestive heart failure; SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; HR, heart rate; RR, respiratory rate;T, temperature; pH, potential of hydrogen; SpO2, saturation of hemoglobin with oxygen; BE, base excess; AG, anion gap; PLT, platelet; WBC, white blood cell; ALB, albumin; BUN, blood urea nitrogen; SCr, serum creatinine; PT, prothrombin time; PTA, prothrombin time activity; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft; SOFA, sequential organ failure assessment; SAPS II, the Simplified Acute Physiology Score II.