Elevated ApoB/apoA-1 is Associated with in-Hospital Mortality in Elderly Patients with Acute Myocardial Infarction

Introduction

Acute myocardial infarction (AMI) is a common and critical cardiovascular emergency. If patients cannot receive timely treatment, could be changed to heart failure and subsequent death. The rapid development of percutaneous coronary intervention (PCI) has significantly reduced the mortality and morbidity of AMI. However, previous studies have shown that mortality within 12 months in patients with AMI is approximately 10%,^1,2 and the risk of in-hospital mortality is approximately 4% to 12%.³ Elderly patients with AMI have been one of the priorities in clinical diagnosis and treatment because the risk of death during hospitalization in such patients increases significantly with age. Therefore, it is necessary to find a convenient and accurate index to predict the risk of death during hospitalization in elderly AMI patients.

Dyslipidemia has been considered to be one of the most important causes of atherosclerotic cardiovascular disease (ASCVD), and low-density lipoprotein cholesterol (LDL-C) has been paid much attention among many lipid parameters.⁴ However, many studies have shown that apolipoprotein B/apolipoprotein A-1 (apoB/apoA-1) is superior to LDL-C in predicting the risk of cardiovascular disease.^5,6 Physiologically, each very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and lipoprotein (α) particle contains an apoB molecule, so apoB in plasma represents the sum of almost all atherogenic particles in the body,^7–9 while apoA-1 is the main apolipoprotein in high-density lipoprotein (HDL) particles and is considered to have an anti-atherosclerotic effect.¹⁰ Compared with apoB and apoA-1, apoB/apoA-1 reflects the balance between atherogenic and anti-atherogenic factors in the body in the form of a combination of two apolipoproteins.¹¹ The results of the AMORIS (Apolipoprotein-related Mortality Risk) study¹² and the INTERHEART study⁵ indicate that apoB/apoA-1 is an important predictor of future coronary events. However, few studies have investigated the association between apoB/apoA-1 and the risk of in-hospital mortality in AMI patients, especially in elderly AMI patients.

Therefore, the aim of this study was to investigate the association between apoB/apoA-1 and the risk of in-hospital mortality in elderly AMI and whether there is a dose-response relationship for this association.

Methods

Study Population

This was a single-center, retrospective and observational study of 1495 elderly patients 60 years of age and older with AMI who were hospitalized at the Second Hospital of Dalian Medical University from December 2015 to December 2021. This study is an observational study, in which patients informed consent can be exempted and ethical requirements in the Declaration of Helsinki have been met, and has been approved by the Ethics Committee of the Second Hospital of Dalian Medical University (No. 2023–118). Inclusion criteria: 1. Age ≥ 60 years; 2. Diagnosis of acute myocardial infarction (including NSTEMI and STEMI) at admission.^13,14 Exclusion criteria: 1. Patients with the following conditions: Familial hypercholesterolemia, hyperthyroidism or hypothyroidism, nephrotic syndrome, Cushing syndrome; 2. Patients with severe coronary artery disease, requiring cardiac bypass surgery or having previously undergone cardiac bypass surgery less than half a year; 3. Life expectancy less than half a year.

Data Collection, Processing and Outcome Definition

The clinical characteristics, medical history, and laboratory test results of the patients at admission and during hospitalization were collected from the electronic medical record system. The laboratory tests performed at admission mainly included liver and kidney function, blood lipid, serum ion levels, and myocardial enzyme levels. Venous blood samples were collected after fasting for at least 12 h and assayed within 24 h of admission. Lipid parameters, including apoB and apoA-1, were measured directly by a homogeneous method under fasting conditions. The drug use during hospitalization was also recorded, including lipid-lowering drugs, β-blockers, ACEI/ARBs, and aspirin. The outcome was defined as all-cause mortality during hospitalization.

Statistical Analysis

Data were processed by SPSS (version 26.0, IBM Corp. in Armonk, NY. www.ibm.com/products/spss-statistics), MedCalc (version 20.022, MedCalc Software Ltd, Ostend, Belgium. www.medcalc.org), R(version 4.2.1, R Core Team 2020, Vienna, Austria. www.r-project.org). For categorical variables, data were described as frequencies or percentages. For continuous variables, data were presented as mean ± standard deviation if normal distribution was met; otherwise, data were presented as quartiles [median (quartiles 25, 75%)]. If continuous data satisfied normality, comparisons between two or more groups were analyzed by t-test or ANOVA; otherwise, nonparametric tests were used. Categorical variables were compared using Fisher ‘s exact test or Chi-square test. Receiver operating characteristic (ROC) curves were used to explore the performance of apoB/apoA-1. Multivariate logistic regression was used to analyze the association between apoB/apoA-1 and outcome events. In addition, restricted cubic splines (RCS) were used to explore the dose-response relationship between apoB/apoA-1 and in-hospital mortality. A discordance analysis was further performed to quantify the association of apoB/apoA-1 and LDL-C/HDL-C with In-hospital death when the two ratios were not in concordance. P < 0.05 was considered statistically significant.

Results

Sample Characteristics

The cohort of the study is baseline in Table 1. A total of 1495 elderly patients with AMI were included in this retrospective study, and a total of 128 deaths (8.6%) were recorded during hospitalization. The mean age and proportion of females in the death group (mean age 79.80 ± 8.69, 46.1% female) were higher than those in the non-death group (72.59 ± 8.34, 39.2% female). Among the lipid related parameters, apoB/apoA-1 levels were higher in patients who died than in patients without death[0.75 (0.60, 1.00) vs 0.72 (0.57, 0.88)]; apoA-1 and TG levels were lower in patients who died than in patients without death, and the difference was statistically significant (P < 0.05).

Table 1 Basic Characteristics of Enrolling Patients

Associations of apoB/apoA-1 with Risk of in-Hospital Mortality in Elderly Patients with AMI

Logistic regression analysis was used to analyze the factors affecting in-hospital death in elderly AMI patients. Univariate logistic regression showed that age, apoB/apoA-1, diabetes, type of AMI (including NSTEMI and STEMI, NSTEMI as reference), heart failure, cardiac troponin I(CTNI) and eGFR class were positively associated with the risk of in-hospital death in elderly AMI patients, as detailed in Table 2. We developed three logistic regression models based on the results of univariate logistic analysis. Model 1 was not adjusted for any confounders, model 2 was adjusted for sex and age. Model 3 was adjusted for body mass index(BMI), type of AMI, eGFR, CTNI, presence of heart failure, diabetes, PCI during hospitalization, history of stroke, and in-hospital medication (Aspirin use and Statins use) on the basis of model 2. Multivariate logistic regression results showed that apoB/apoA-1 was associated with the risk of in-hospital death in elderly AMI patients [Model 3 OR = 3.524 (1.622–7.659), P = 0.001], as detailed in Table 3. We also evaluated the association between common clinical lipid parameters and the risk of death during hospitalization in elderly AMI patients in a multivariate logistic regression model. Except for apoA-1, other lipid indicators or lipid ratios were not correlated with the risk of death during hospitalization, as detailed in Supplementary Table 1.

Table 2 Univariate Analysis of Factors Affecting in-Hospital Mortality in Elderly Patients with AMI

Table 3 Multivariate Logistic Regression Analysis of ApoB/apoA-1 and in-Hospital Mortality in Elderly Patients with AMI

Predictive Value of apoB/apoA-1 for the Risk of in-Hospital Mortality in Elderly Patients with AMI

ROC curves were used to evaluate the predictive value of apoB/apoA-1 for in-hospital mortality in elderly patients with AMI. The results showed that the AUC of apoB/apoA-1 were 0.572 (95% CI 0.547–0.597, P = 0.011). The optimal cut-off levels of apoB/apoA-1 were 0.938 (Sensitivity = 32.81%, Specificity = 82.44%). In addition, we assessed whether apoB/apoA-1 has differential predictive power for elderly patients with NSTEMI or STEMI. The results showed that there was no difference in the predictive ability of apoB/apoA-1 for in-hospital mortality risk between elderly patients with NSTEMI and STEMI (P for difference between areas = 0.341), as detailed in Figure 1.

Figure 1 The ROC analysis of apoB/apoA-1 predicting in-hospital death in elderly AMI patients. (A) The ROC analysis of apoB/apoA-1 predicting in-hospital death in elderly AMI patients; (B) Comparison of the predictive ability of apoB/apoA-1 on the risk of in-hospital mortality between elderly STEMI patients and NSTEMI patients. Abbreviations: AMI, acute myocardial infarction; NSTEMI, non-ST segment elevation myocardial infarction; STEMI, ST segment elevation myocardial infarction. apoA-1, apolipoprotein A-1; apoB, apolipoprotein B.

Dose-Response Relationship Between Apolipoprotein-Related Markers and Risk of in-Hospital Mortality in Elderly Patients with AMI

The relationship between apolipoprotein-related parameters (apoB, apoA-1, and apoB/apoA-1) and the risk of in-hospital death in elderly patients with AMI was assessed by RCS, as detailed in Figure 2. The results showed a linear dose-response relationship between apoB/apoA-1 and outcome events (P for non-linearity = 0.119), which remained when confounders were adjusted (P for non-linearity = 0.762). This suggests that with increasing apoB/apoA-1, there is also an increased risk of in-hospital mortality in older patients with AMI. However, there was a non-linear dose-response relationship between apoA-1 and outcome events, roughly in an “L” pattern (P for adjusted non-linearity = 0.009).

Figure 2 Dose-response relationship between apolipoprotein-related markers and in-hospital mortality in elderly patients with AMI. (A) Unadjusted dose-response relationship between apoB and in-hospital mortality in elderly patients with AMI; (B) Adjusted dose-response relationship between apoB and in-hospital mortality in elderly patients with AMI; (C) Unadjusted dose-response relationship between apoA-1 and in-hospital mortality in elderly patients with AMI; (D) Adjusted dose-response relationship between apoA-1 and in-hospital mortality in elderly patients with AMI; (E) Unadjusted dose-response relationship between apoB/apoA-1 and in-hospital mortality in elderly patients with AMI; (F) Adjusted dose-response relationship between apoB/apoA-1 and in-hospital mortality in elderly patients with AMI. Adjusted factors include sex, age, BMI, type of AMI, eGFR, cardiac troponin I(CTNI), presence of heart failure, diabetes, PCI during hospitalization, history of stroke, and in-hospital medication (Aspirin use and Statins use). Abbreviations: AMI, acute myocardial infarction. apoA-1, apolipoprotein A-1; apoB, apolipoprotein B.

Discordance Analysis of apoB/apoA-1 and LDL-C/HDL-C

Spearman correlation analysis was performed for lipid parameters included in the baseline data, as shown in Figure 3. The results showed that apoB/apoA-1 had the highest correlation with LDL-C/HDL-C (R = 0.82, P < 0.001), which exceeded the correlation between apoB/apoA-1 and other lipid parameters. Concordance quantifies the variance of one variable at any level to the other. In fact, two variables can be highly correlated but be highly discordant, ie They do not correspond well, either they are too high or too low compared with the other variable. Therefore, we analyzed the discordance between apoB/apoA-1 and LDL-C/HDL-C. Discordance and concordance was defined by calculating the respective medians for apoB/apoA-1 and LDL-C/HDL-C: concordance was defined if both were < or ≥ their respective medians, and vice versa. The associations between discordance and risk of in-hospital mortality in older patients with AMI were assessed by multivariate logistic regression models. Although discordance (apoB/apoA-1 ≥ median_apoB/apoA-1 and LDL-C/HDL-C < median_LDL-C/HDL-C) may be associated with outcome events before adjustment for confounders [Model 1 OR = 1.892(1.104–3.243), P = 0.020], this association disappeared after adjustment for confounding factors [Model 3 OR = 1.139 (0.575–2.253), P = 0.709], as detailed in Table 4.

Table 4 Multivariate Logistic Regression Analysis Between Discordance Between ApoB/apoA-1 and LDL-C/HDL-C and Risk of in-Hospital Mortality in Elderly AMI Patients

Figure 3 Spearman correlation analysis between each pair of lipid measures. Abbreviations: TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; NHDL-C, non-high-density lipoprotein cholesterol; RC, remnant cholesterol; apoA-1, apolipoprotein A-1; apoB, apolipoprotein B. Notes: Asterisk (*) indicates whether the association between the two lipid parameters is statistically significant. The color of the squares indicates the strength of the correlation between the two lipid parameters, and darker colors represent the stronger correlation between the two, and vice versa. None*P > 0.05; ***P < 0.001.

Discussion

In this retrospective study of 1495 elderly patients with AMI, we investigated the association between apoB/apoA-1 and the risk of in-hospital death in elderly patients with AMI. Univariate logistic regression showed that apoB/apoA-1 was associated with the risk of in-hospital death in elderly patients with AMI (OR = 4.002 (2.058–7.784), P < 0.001). Subsequently, we adjusted for some confounding factors that may influence outcome by multivariate logistic regression and showed that apoB/apoA-1 remained strongly associated with the risk of in-hospital mortality in elderly patients with AMI [Model 3 OR = 3.524 (1.622–7.659), P = 0.001]. The results of ROC curve analysis showed that apoB/apoA-1 could also be used to predict the occurrence of in-hospital death events in elderly AMI patients. We also further investigated the dose-response relationship of apoB/apoA-1 with the risk of in-hospital mortality in elderly AMI patients based on the RCS model for the first time, and the results showed that the risk of in-hospital mortality in elderly AMI patients also showed a linear trend to increase when apoB/apoA-1 increased. Finally, we found that apoB/apoA-1 showed the strongest association with LDL-C/HDL-C (R = 0.82, P < 0.001). Because highly correlated two variables can also be highly inconsistent (poor correspondence between the two variables),¹¹ discordance between apoB/apoA-1 and LDL-C/HDL-C was further analyzed, but discordance between high apoB/apoA-1 and low LDL-C/HDL-C was not associated with outcome events after multivariate adjustment [Model 3 OR = 1.139 (0.575–2.253), P = 0.709], which may be due to the small sample size in this group.

Compared with LDL-C, apoB provides more information about the risk of cardiovascular disease in patients, which is determined by its physiological properties. Simply put, LDL can be divided into two subtypes: small-dense LDL (sd-LDL) and large floating LDL. But sd-LDL particles tend to be more dangerous than large, floating LDL particles. Because sd-LDL particles are more easily oxidized and promote inflammatory responses and plaque growth, exacerbating cardiovascular disease risk.^15–18 When the body ‘s LDL is dominated by sd-LDL, the body needs the liver to make enough LDL to carry cholesterol, and there is an apoB molecule on each LDL surface, so apoB reflects the content of sd-LDL in the body to a certain extent.¹¹ When LDL-C levels are the same in both patients, if sd-LDL particles predominate in one patient and large buoyant LDL particles in the other, the risk of potential cardiovascular disease is significantly different despite the same LDL-C levels in both patients,¹⁹ which is one of the important reasons why apoB is more predictive of the risk of cardiovascular disease in patients than LDL-C. ApoA-1 transports HDL particles, which have anti-inflammatory, antioxidant, antithrombotic, and vasodilator effects and are critical in the anti-atherosclerotic process,^20–22 and therefore tends to provide more information about the risk of cardiovascular disease than HDL-C. ApoB/apoA-1 actually reflects the balance between atherogenic and anti-atherosclerotic factors in the human body and is more significant than apoB, apoA-1, and other common lipid parameters alone to predict cardiovascular disease risk.¹¹ The AMORIS study¹² is the first cohort study to systematically evaluate the long-term risk of apoB, apoA-1, and apoB/apoA-1 with cardiovascular disease, and its results suggest that apoB/apoA-1 is very closely related to the risk of myocardial infarction, stroke, and other cardiovascular diseases. Similar results were also described in the INTERHEART study,⁵ which found the strongest association between apoB/apoA-1 and AMI (OR = 3.25, 99% CI 2.81–3.76). Walldius et al found that apoB/apoA-1 was associated with major adverse cardiovascular events(MACEs).²³ Steyn et al⁶ found that apoB/apoA-1 was more strongly associated with AMI than LDL-C and other lipid ratios (South African population), which is similar to that found in the overall INTERHEART population. Similar conclusions were reached by the findings of Goswami et al,²⁴ who found that apoB/apoA-1 identified CAD risk more than other lipid ratios (TC/HDL-C, NHDL-C/HDL-C, LDL-C/HDL-C). In addition, several studies have demonstrated that apoB/apoA-1 is a strong predictor of future coronary events in people initially free of coronary artery disease.^25–28 Li et al observed that apoB/apoA-1 was also associated with total occlusion in CAD patients (OR = 2.590, 95% CI 2.049–3.274).²⁹ In recent years, some studies have also shown that apoB/apoA-1 is associated with the severity of coronary artery disease,^30,31 aortic valve stenosis,³² aortic stenosis,³³ and poor prognosis of acute ischemic stroke.³⁴ But few studies have investigated the relationship between apoB/apoA-1 and short-term prognosis in AMI patients, especially in this critical population of elderly AMI patients. Our findings suggest that apoB/apoA-1 is strongly associated with in-hospital mortality in elderly AMI patients. Other lipid parameters did not appear to be associated with outcome events in our study, and we considered that this may be related to the fact that most patients were taking lipid-lowering drugs chronically, thereby weakening the association of some common lipid parameters with outcome events, such as LDL-C and NHDL-C. In addition, it may also be related to the higher age of our enrolled patients, and previous studies have shown that the association between LDL-C, TC, TG and cardiovascular events is weakened by increasing patient age,^11,35,36 perhaps because elderly AMI patients usually have other diseases, such as heart failure, renal insufficiency, diabetes, hypertension, etc., which are closely related to the risk of in-hospital death in elderly AMI patients. Of course, it may also be related to the relatively small number of patients who died during hospitalization in our study. Some previous studies have shown that apoB/apoA-1 is associated with atherosclerosis progression when it is > 0.74,³⁷ and the results of the AMORIS study¹² and INTERHEART study⁵ defined apoB/apoA-1 > 0.70 as a moderate risk of cardiovascular disease. Similarly, our RCS models suggest that the risk of in-hospital mortality in elderly AMI patients increases with increasing apoB/apoA-1 when apoB/apoA-1 is > 0.73. In conclusion, we believe that the association between apoB/apoA-1 and the risk of in-hospital death in elderly AMI patients may be due to the fact that apoB/apoA-1 represents a trend of atherosclerosis and anti-atherosclerosis in human body,¹¹ and the process of atherosclerosis is always accompanied by the progression of inflammation.^38–40 Therefore, high apoB/apoA-1 not only indicates the predominance of atherogenic factors in vivo, but may also indicate the enhancement of inflammatory response in vivo. Previous studies have also shown that certain inflammatory markers are significantly associated with in-hospital mortality in elderly patients with acute myocardial infarction.^41–43 Of course, this hypothesis needs to be tested with larger samples. When we identify these high-risk patients through apoB/apoA-1, we can use some feasible measures to reduce their risk of death in clinical treatment, such as earlier revascularization, more refined care strategies, and the use of mechanical adjuvant therapy if necessary.^13,44 In addition, apoB/apoA-1 can be measured and used in non-fasting conditions.⁴⁵ We can measure apoB/apoA-1 as soon as possible after admission in patients with AMI to assess the risk of death during hospitalization. It is worth mentioning that some factors associated with PCI are closely related to the risk of in-hospital mortality in AMI patients, such as the incidence of perioperative complications,⁴⁶ whether radial artery puncture is performed,⁴⁷ the experience of the operator, and whether the puncture was performed through the radial artery.⁴⁸ Whether adding the above factors can affect the association between apoB/apoA-1 and in-hospital death in elderly patients with AMI needs to be further explored in subsequent studies.

This study has the following limitations: First, it is a single-center study and its results may be influenced by patient selection bias. Second, we failed to obtain results on the long-term prognosis of patients discharged normally. Finally, case-control studies could not identify a causal relationship between apoB/apoA-1 and the risk of in-hospital mortality in elderly AMI patients.

Conclusion

Our findings suggest that apoB/apoA-1 is strongly associated with the risk of in-hospital mortality in older patients with AMI, but this association has not been found in other traditional lipid parameters. In addition, we found a linear dose-response relationship between apoB/apoA-1 and in-hospital mortality in elderly patients with AMI. As the apoB/apoA-1 ratio increases, the risk of in-hospital mortality also increases. Clinicians may consider using apoB/apoA-1 as risk stratification marker for elderly inpatients with AMI to better improve their short-term prognosis.