Association between the neutrophil-to-lymphocyte ratio and risk of in-hospital heart failure and arrhythmia in patients with acute myocardial infarction

Background This study was to probe into the relationship between the neutrophil-to-lymphocyte ratio (NLR) and both in-hospital and long-term heart failure risk in patients with acute myocardial infarction (AMI). Methods 990 patients with AMI, including 386 with non-ST-segment elevation myocardial infarction (NSTEMI) and 604 with segment elevation myocardial infarction (STEMI) were recruited between January 2019 and March 2022. The in-hospital acute heart failure (AHF) and arrhythmia events were recorded. Results The NLR was significantly greater in the AHF group in STEMI and NSTEMI patients, with a higher frequency of arrhythmia in comparison to the non-AHF group. A high NLR was related to a high level of myocardial injury markers, accompanied with more AHF and arrhythmia events. Multivariate logistic regression analyses revealed that high NLR is independently linked with increased in-hospital AHF and arrhythmia risk. Receiver operating characteristic curve analyses revealed that the prognostic value of NLR for in-hospital AHF was 0.704 in STEMI patients and 0.766 in NSTEMI patients. However, during a median follow-up of 28 months with 32 heart failure patients, there was no significant difference between the low NLR group (n = 18) and the high NLR group (n = 14). Further analysis showed that the two groups did not significantly differ in the occurrence of heart failure within 12 months of discharge. Conclusion Our results indicate that NLR is an independent risk factor of in-hospital AHF in AMI patients. However, NLR has no value in predicting long-term heart failure.


Introduction
According to the 2021 China Cardiovascular Health and Disease Report, about 330 million patients have been suffered from cardiovascular and cerebrovascular diseases in China, including about 24 million patients with coronary heart disease and stroke.Acute myocardial infarction (AMI) has a high mortality rate, and although interventional treatment can markedly reduce the mortality rate, AMI prognosis remains relatively poor, and the incidence of acute heart failure (AHF) is high (1).
The neutrophil-to-lymphocyte ratio (NLR) is a well-established indicator in the study of cardiovascular disease prognostic models.A recent study found that the NLR is an important predictor of inhospital death in AMI patients (2).In addition, NLR had predictive value in heart failure readmissions and prognosis in patients undergoing transcatheter aortic valve replacement (3).However, there is currently a lack of research on the potential use of NLR to predict the occurrence of in-hospital and long-term heart failure in patients with AMI.Although NLR does not directly reflect changes in cardiac inflammation and metabolic environment, it can be used to evaluate the prognosis of patients early on upon initial presentation to the emergency department.Furthermore, when combining NLR with classical markers of myocardial injury, the predictive value can be further improved.Moreover, due to the easy acquisition of NLR and the low cost to patients, a relatively complete cohort data can be obtained during follow-up.
During the course of clinical management of patients, a reciprocal causal relationship between heart failure and malignant arrhythmias was observed, in which both can be induced by the inflammatory environment.Additionally, major adverse cardiovascular events (MACE) in AMI patients following discharge represent a crucial research area that requires additional attention.It is found that NLR available at the time of admission could be applied for the evaluation of short-term outcomes in patients with cardiogenic shock as a complication of AMI, and higher NLR is an independent risk factor for elevated 30-day all-cause mortality and MACE (4).Besides, a study found that postoperative NLR (within 24 h) may be more effective in predicting the incidence of MACE in NSTEMI patients within one year after elective percutaneous coronary intervention (5).However, we found that most prognostic studies on NLR are confined to a duration of less than one year, and there is a lack of evidence for longer-term prognostic evaluations beyond this timeframe.
In the present study, the correlation between NLR and inhospital AHF in patients with AMI was investigated.Moreover, we assessed the predictive utility of NLR for arrhythmia during hospitalization and MACE during the follow-up period.

Participants
This study was carried out in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Clinical Investigation of The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University (KY314-01).Additionally, the study was registered in the China Clinical Trial Registration Center (ChiCTR2300067892).The clinical informed consent was collected from all subjects and/or their legal guardian(s), in ethics and consent section under declaration.We included a total of 1,058 AMI patients, and after exclusion criteria, 990 patients were ultimately included.A total of 990 patients with AMI were admitted in the study, including 386 with NSTEMI and 604 with STEMI, all of whom were admitted to the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University between January 2019 and March 2022.The primary outcome measure was in-hospital AHF, and the secondary outcome measures were in-hospital arrhythmia and MACE.
The following inclusion criteria were used: (1) age between 18 and 80 years, (2) admitting diagnosis of AMI (STEMI and NSTEMI).Diagnostic criteria of STEMI and NSTEMI have been described in the previous study (6).Diagnostic criteria of STEMI: (1) chest pain history; (2) continuous elevation of ST segments (≥ 0.1 mV for more than 30 min, or V2 or V3 ≥ mV in two or more adjacent ECG leads), or new onset of left bundle branch block; (3) myocardial injury markers increased beyond the 99th percentile of the laboratory reference limit.Diagnostic criteria of NSTEMI: (1) a history of chest pain; (2) in leads with R wave dominant or R/S >1, a new horizontal or downwardly inclined ST segment depression (≥0.05 mV or T wave inversion ≥0.1 mV in two adjacent leads); (3) myocardial injury markers increased beyond the 99th percentile of the laboratory reference limit.The following exclusion criteria were used: (1) known history of heart failure or arrhythmia, (2) malignant tumor, (3) pregnancy, (4) severe liver dysfunction (decompensated liver cirrhosis, liver failure, etc), (5) severe hematological disorders (acute and chronic leukemia, lymphoma, etc), (6) history of coronary artery bypass grafting, (7) cardiogenic shock, (8) mechanical ventilation, and (9) mechanical circulatory support.The inclusion and follow-up process of this study population is consistent with previous studies (6,7).

Data retrieval and definitions
The Information related to demographics and clinical data during the patient's hospital stay was obtained from an electronic medical record system of hospital.The diagnosis of AHF was based on typical symptoms, signs, and laboratory examination, such as orthopnea, acute pulmonary edema, and B-type natriuretic peptide (BNP) levels, which was consistent with previous study (6).The definition of Arrhythmia is single or multiple episodes of atrial fibrillation, atrial flutter, ventricular fibrillation, or ventricular flutter, which was also consistent with previous study (6).The Gensini score was calculated to assess the severity of coronary artery disease, according to a previously described protocol (8).

Follow-up
786 AMI patients recruited from January 2019 to August 2021 were followed up.Patients were interviewed one month after discharge and every three months afterward.General information, inpatient data, and medication situation were collected at each interview.Based on the information gathered  ), and this information has been previously described in another study (7).The definition of heart failure during follow-up is consistent with that during hospitalization.Nonfatal MI was defined as new pathological Q waves in ≥2 contiguous electrocardiogram leads.Patients with acute ischemic cerebral vascular events were marked as stroke.
Finally, URR was defined as any non-staged revascularization after Percutaneous Coronary Intervention (PCI).

Statistical analyses
All continuous data have been normality tested.Normally distributed data were represented by the mean ± standard deviation, while skewed continuous data were represented by the median (interquartile range).Student's t-test or the Mann-Whitney U-test was performed to compare continuous variables between two groups, and the chi-squared test was used to compare categorical variables between two groups.Univariate and multivariate logistic regression analyses were conducted to assess the predictive value of the NLR for in-hospital AHF or arrhythmia risk.Receiver operating characteristic (ROC) curve analysis was performed to measure the cutoff value of the NLR for AHF during hospitalization.All tests were two-tailed, and p values <0.05 were considered significant.All statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, N.Y., USA).

Results
The clinical characteristics of the 990 patients who participated in the study were presented in Table 1.The AHF events was recorded in 38 out of 604 STEMI patients, and in 51 out of 386 NSTEMI patients.Among the STEMI group, patients who had AHF were significantly older than those without AHF (64.9 ± 12.3 vs. 60.4 ± 14.2, P = 0.038).In both STEMI and NSTEMI patients, the proportion of concurrent arrhythmia events in the AHF patients was significantly higher than that in the non-AHF patients.Furthermore, The NLR was notably higher in the AHF group compared with the non-AHF group (10.5 ± 6.9 vs. 6.6 ± 5.6, P = 0.001).
As BNP and myocardial injury indicators tests are used to assess the prognosis for in-hospital AMI patients, we grouped patients based on their NLR quartiles.The results indicated a significant increase in the levels of BNP, CPK, CK-MB and HBDH, with an increase in the NLR.Moreover, the proportion of patients with AHF and arrhythmia also increased significantly, particularly in the highest quartile (fourth quartile) group (Table 2 and Figure 1).
Both univariate and multivariate logistic regression analyses suggested that a high NLR was associated with an increased risk of in-hospital AHF in both STEMI (HR = 2.928, 95% CI: 1.393-6.158,P = 0.005) and NSTEMI patients (HR = 2.336, 95% CI: 1.236-4.416,P = 0.009) (Tables 3, 4).We also evaluated the potential of NLR in predicting arrhythmia occurrence during hospitalization.It was indicated that a high NLR was related with an increased risk of in-hospital arrhythmia in STEMI patients in both univariate and multivariate logistic regression analyses (HR = 2.133, 95% CI: 1.107-4.133,P = 0.024), but not in NSTEMI patients (Tables 5, 6).
Finally, we investigated the association of the NLR and longterm AHF occurrence.As presented in Table 7, the prevalence of overall death, heart failure, non-fatal MI, non-fatal stroke and URR had no significant difference between the low and high NLR groups.Since NLR is a short-term inflammation indicator, we then analyzed the correlation between the NLR and AHF occurrence within 12 months of discharge.Similarly, there was no significant difference observed in overall mortality, heart failure, non-fatal MI, non-fatal stroke and URR between the low and high NLR groups during the 12-month period following discharge (Supplementary Table S1).

Discussion
The study was to assess the association between NLR and in-hospital heart failure in AMI patients.The findings revealed that AHF patients had a significantly higher NLR with a higher incidence of arrhythmia compared to the non-AHF group.In addition, elevated NLR was independently associated with increased risk of in-hospital AHF and arrhythmia.NLR was predictive of in-hospital AHF in AMI patients, however,   Following myocardial infarction, necrosis of the myocardium can lead to an inflammatory storm that can further disrupt the homeostasis of the myocardial environment, potentially resulting in adverse cardiovascular events (9).In this context, the neutrophil-to-lymphocyte ratio is a readily available, inexpensive, and credible indicator of systemic inflammation, and thus has been evaluated in our study as a potential biomarker for predicting in-hospital and long-term cardiovascular outcomes.
Due to the standardization of clinical diagnosis and treatment, patients with suspected AMI are now subjected to laboratory investigations, including blood routine tests, myocardial enzyme profiling, and coagulation tests upon their initial admission to the emergency department.Furthermore, NLR has been confirmed to possess a good predictive value in evaluating the degree of sepsis and local inflammation (10,11).Inflammatory The proportion of patients with in-hospital AHF and arrhythmia in each of the 4 groups.markers, including NLR, are also influenced by the patient's hyperglycaemic state and that it also has an impact on long-term prognosis (12,13).In this setting, NLR can be obtained at an early stage as an inflammatory indicator.Inflammatory storms are triggered by various factors such as trauma, shock, infection, and injury (14).Firstly, mononuclear macrophages activate inflammatory cells by presenting antigens through natural immunity.These inflammatory cells then release cytokines, which enter the blood circulation and act on different cells including, white blood cells, red blood cells, platelets, and vascular endothelial cells (15,16).This action leads to the production of platelet aggregation factor, prostaglandin, peroxidase synthase, leukotriene, nitric oxide, and other cytokines, which can increase the concentration of C-reactive protein, α2-macroglobulin, and fibrinogen while decreasing the concentration of albumin and transferrin (17,18).Ultimately, these effects lead to high discharge and low resistance of the entire heart circulation, eventually resulting in heart failure (19,20).Our study revealed a significant increase in NLR in the AHF group among STEMI and NSTEMI patients.Conversely,   In this study, we analyzed the predictive value of NLR in arrhythmia.Logistic regression analysis showed that a high NLR is an independent predictor of arrhythmia in STEMI patients during hospitalization.We also observed that the AHF group had a high proportion of patients who have arrhythmia in STEMI and NSTEMI patients.Arrhythmia can lead to hemodynamic disorders and exacerbate cardiac workload.In addition, the occurrence of AHF activates the sympathetic nervous system in vivo, which triggers abnormal pacemakers in the heart cavity (21).Therefore, a reciprocal cause-and-effect relationship between NLR and arrhythmia has been reported in several studies.Elevated NLR significantly increases the risk of left atrial thrombosis in non-valvular atrial fibrillation patients, where NLR is an independent risk factor.Moreover, NLR is an independent predictor of long-term outcomes in patients with atrial fibrillation (AF) (22)., while a high NLR is associated with an increased risk of new-onset AF (23).Noteworthy, the small sample size in this study may have contributed to the lack of statistical significance in the predictive value of NLR in patients with NSTEMI.
The primary purpose of this study was to investigate the effect of SGLT2i on the risk of cardiovascular and cerebrovascular adverse events in patients with AMI.Therefore, we extracted the health and medical information of patients after discharge.The protective role of SGLT2i on in-hospital outcome in AMI patients was consistent with the previous studies (24)(25)(26).In this study, there was no statistically association between the NLR ratio and the incidence of long-term heart failure.This is likely due to the fact that the NLR data were obtained from patients admitted to the emergency department and is indicative of shortterm inflammation levels.Clinical cohort studies examining the association between NLR and long-term outcomes in AMI patients may provide valuable insights into the management of these patients.

Limitations
This single-center, retrospective study, was limited by a potential bias caused by confounding factors.However, univariate and multivariate logistic regression analyses were employed to mitigate the interference of such confounding factors.Besides, the results may not be generalizable to populations of different ethnic backgrounds and over 80 years of age.The small sample size is also a limitation.

Conclusion
Our study found that a high NLR was independently related with an increased risk of in-hospital AHF and arrhythmia in patients with acute myocardial infarction.Furthermore, NLR was found to be a predictive marker for in-hospital AHF in AMI patients.However, a high NLR could not predict long-term heart failure in AMI patients.These findings provide further evidence for the relationship between NLR and the prognosis of AMI patients, which is expected to play a role in the clinical management of AMI patients.

TABLE 1
Baseline characteristics of the study population.

TABLE 2
The levels of myocardial injury markers and the occurrence of AHF and arrhythmia were correlated with NLR.

Table 3
Univariate and multivariate logistic analyses for the in-hospital AHF risk in STEMI patients.

TABLE 4
Univariate and multivariate logistic analyses for the in-hospital AHF risk in NSTEMI patients.

TABLE 5
Univariate and multivariate logistic analyses for the in-hospital arrhythmia risk in STEMI patients.