Introduction
Acute ST-segment elevation myocardial infarction (STEMI) is a cardiovascular emergency that threatens patients’ lives and health. Timely PCI to restore the coronary blood supply is critical to improve the prognosis of these patients [1]. PCI reperfusion therapy is the preferred treatment strategy for patients with STEMI, because it can open acutely blocked coronary arteries and save ischemic cardiomyocytes; it also significantly decreases the risk of death in patients with acute myocardial infarction (AMI) and improves prognosis [2]. The incidence rate of NRP in patients with AMI is as high as 20% to 30% [3]. In addition, NRP is associated with adverse cardiovascular events in patients with STEMI [4, 5]. The pathophysiological mechanism of NRP remains unclear but is currently believed to be associated with factors such as distal embolism of diseased vessels, reperfusion injury, microcirculation disturbance, vasospasm, and oxidative stress [6]. SII, a new inflammatory index determined from the counts of neutrophils, lymphocytes, and platelets, can be used to simultaneously evaluate the immune thrombosis state and inflammatory state of the body. Previous studies have studied the relationship between SII and NRP. However, owing to the many complications and poor vascular condition in older patients with STEMI, identifying high-risk patients as soon as possible is essential to improve the prognosis of older patients [7]. Higher SII levels are significantly associated with short-term mortality and NRP in patients with STEMI undergoing PCI [8]. However, no clinical NRP risk prediction method is currently available, and the relationship between the SII level and NRP in older patients with STEMI is unclear. Therefore, this study focused on examining the correlation between SII and NRP in older patients with STEMI, to provide a basis for the early identification of high-risk patients and improvement of their prognosis.
Materials and Methods
Study Sample
This retrospective study included 578 older patients (≥60 years of age) who underwent primary PCI for STEMI at Hebei General Hospital between January 2017 and June 2020. STEMI was defined by chest discomfort or other ischemic symptoms, and development of new ST-segment elevations in two contiguous leads or new bundle branch blocks with an ischemic repolarization pattern. The exclusion criteria were treatment with fibrinolytic drugs, previous coronary artery bypass surgery, inflammatory disease or active infection, autoimmune disease, hematologic diseases, kidney or liver failure, and malignancy. A total of 578 patients were enrolled, and we collected relevant clinical and demographic data through the hospital’s electronic medical record system.
This study was approved by the Ethics Committee of Hebei General Hospital. Because this study was retrospective, the requirement to obtain patients’ informed consent was waived. This study strictly followed the Declaration of Helsinki.
Coronary Procedures
All enrolled patients were immediately administered a single dose of ticagrelor 180 mg or clopidogrel 300 mg and aspirin 300 mg after being diagnosed with STEMI. Before coronary intervention, patients were administered 100 μg/kg unfractionated heparin intravenously. The Judkins technique was used for coronary angiography. The radial approach was used for most patients, and the femoral approach was used for several patients. TIMI flow rating grades were evaluated by three interventional cardiologists who were blinded to the patients’ relevant clinical data. NRP was defined by TIMI blood flow grade ≤2, and no dissection, distal flushing, or spasm occurring during angiography [9]. The patients were divided into an NRP group and normal-flow group according to whether NRP occurred during operation.
Laboratory Measurements
Before coronary intervention, blood samples were collected from patients through the anterior cubital vein. Laboratory examinations included white blood cell count, monocyte count, neutrophil count, lymphocyte count, platelet count, hemoglobin, troponin T level, fasting blood glucose, creatine kinase-MB, total cholesterol, low-density lipoprotein cholesterol, triglyceride, serum creatinine, high-density lipoprotein, glomerular filtration rate, and other biochemical tests. SII was calculated as neutrophil count×platelet count/lymphocyte count [10]. NLR was calculated as neutrophil count/lymphocyte count. The medications administered during hospitalization followed the relevant clinical guidelines [11]. A cardiologist determined the regimens for angiotensin converting enzyme inhibitors, statins, beta-blockers, and other drugs. A family history of coronary heart disease, diabetes, smoking, hypertension, hyperlipidemia, and medical history of taking related drugs were determined based on patient self-reporting. Experienced echocardiographic physicians used Simpson’s method to measure the left ventricular ejection fraction by transthoracic echocardiography.
Statistics
SPSS 26.0 was used for statistical analysis. Kolmogorov-Smirnov test was used to determine the normality of continuous variables. Continuous variables with a normal distribution were analyzed with t tests and are expressed as mean±standard deviation. Continuous variables with non-normal distribution were analyzed with Mann-Whitney U tests. Categorical variables were statistically analyzed with X2 tests and are expressed as numbers and percentages. Variables with P<0.05 were selected for inclusion in univariate and multivariate logistic regression analyses to determine the independent factors influencing NRP. The ability of SII and NLR to predict NRP after PCI in older patients with STEMI was evaluated with receiver operating characteristic (ROC) curve analysis, and the best cut-off value was determined. Multiple linear regression was used to analyze the correlations of independent factors with NRP and SII. Both tests were two sided. When P<0.05, differences were considered statistically significant.
Results
Baseline characteristics are listed in Table 1. The study population included 578 patients (mean age 69.95±7.52 years, 183 women [31.7%]), 123 (21.3%) of whom were in the NRP group. Compared with the normal-flow group, the NRP group had a higher incidence of hypertension and smoking (P<0.05). The age, body mass index (BMI), sex, diastolic blood pressure, systolic blood pressure, heart rate, previous drug use, hospitalization drug use, door-to-balloon time, left ventricular ejection fraction, Killip grade at admission ≥2, and previous medical history showed no significant differences between groups.
Baseline Information Between Groups.
Characteristics | Normal-flow (n=455) | No reflow (n=123) | P value |
---|---|---|---|
Age (year) | 70.02±7.60 | 69.67±7.21 | 0.650 |
BMI (kg/m2) | 25.35 (23.44–27.68) | 25.53 (23.40–27.42) | 0.802 |
Male, gender (n, %) | 308 (67.7%) | 87 (70.7%) | 0.520 |
Systolic blood pressure (mmHg) | 129.62±25.80 | 127.07±25.65 | 0.332 |
Diastolic blood pressure (mmHg) | 78.66±15.24 | 76.35±15.33 | 0.137 |
Heart rate (bpm) | 74.29±19.26 | 75.85±19.25 | 0.428 |
Family history of coronary heart disease (n, %) | 41 (9.0%) | 12 (9.8%) | 0.799 |
Diabetes mellitus (n, %) | 128 (28.1%) | 35 (28.5%) | 0.944 |
Smoking (n, %) | 199 (43.7%) | 67 (54.5%) | 0.034 |
Hypertension (n, %) | 258 (56.7%) | 87 (70.7%) | 0.005 |
History of hyperlipidemia (n, %) | 43 (9.5%) | 10 (8.1%) | 0.653 |
Time from pain to intervention (≤6 h) | 359 (78.9%) | 98 (79.7%) | 0.852 |
Door-to-balloon time (min) | 60.00 (46.00–83.00) | 61.00 (46.00–86.75) | 0.606 |
Left ventricular ejection fraction (n, %) | 54 (46–60) | 56 (48–60) | 0.134 |
Killip class ≥2 at admission (n, %) | 171 (37.6%) | 47 (38.2%) | 0.898 |
Previous drug used | |||
β-blocker (n, %) | 92 (20.2%) | 23 (18.7%) | 0.708 |
Statins (n, %) | 35 (7.7%) | 9 (9.4) | 0.889 |
Clopidogrel (n, %) | 49 (10.8%) | 12 (9.8%) | 0.746 |
Aspirin (n, %) | 98 (21.5%) | 21 (17.1%) | 0.277 |
ACEI/ARB (n, %) | 51 (11.2%) | 14 (11.4%) | 0.957 |
In-hospital ACEI therapy (n, %) | 317 (69.7%) | 84 (68.3%) | 0.769 |
In-hospital statin therapy (n, %) | 449 (98.7%) | 120 (97.6%) | 0.631 |
In-hospital diuretics therapy (n, %) | 286 (62.9%) | 66 (53.7%) | 0.064 |
In-hospital β-blocker therapy (n, %) | 375 (82.4%) | 104 (84.6%) | 0.577 |
ACEI/ARB, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers; BMI, body mass index.
The laboratory data and angiography results for the two groups of patients are shown in Table 2. The median SII was significantly higher in the NRP group than the normal flow group [1909.29 (1010.61–2854.94) vs 1088.76 (679.45–1546.71), P<0.001, Figure 1]. The white blood cell count, neutrophil count, platelet count, hemoglobin level, platelet to lymphocyte ratio, neutrophil-to-lymphocyte ratio, incidence of multivessel disease, and IABP use were significantly higher in the NRP group than the normal flow group, whereas the NRP group had lower lymphocyte counts. No significant differences were observed in lesion vessel, stent length, and stent diameter between groups.
Laboratory Examinations and Angiography Results for the Two Groups.
Variable | Normal-flow (n=455) | No reflow (n=123) | P value |
---|---|---|---|
White blood cell count (×109/L) | 9.12 (7.31–11.03) | 10.37 (8.63–12.46) | <0.001 |
Monocyte count (×109/L) | 0.41 (0.31–0.54) | 0.44 (0.33–0.59) | 0.173 |
Neutrophil count (×109/L) | 7.15 (5.21–9.04) | 8.62 (6.55–10.49) | <0.001 |
Lymphocyte count (×109/L) | 1.41 (1.09–1.83) | 1.07 (0.92–1.51) | <0.001 |
Platelet count (×109/L) | 213 (181–249) | 252 (225–278) | <0.001 |
Hemoglobin (g/dL) | 132 (121–144) | 137 (125.25–149) | 0.011 |
Serum glucose (mg/dL) | 113.22 (94.32–150.12) | 122.58 (94.14–187.20) | 0.190 |
Peak cardiac troponin T (ng/mL) | 978 (870–1247.75) | 958.50 (869.75–1229.50) | 0.820 |
Peak creatine kinase-MB (U/L) | 130.55 (60.74–240.89) | 139.67 (79.17–270.51) | 0.063 |
NT-pro BNP peak (pg/mL) | 1771.18±2703.04 | 1612.97±2171.23 | 0.550 |
Total cholesterol (mg/dL) | 76.5 (65.7–88.92) | 80.64 (67.14–94.86) | 0.117 |
Triglyceride (mg/dL) | 20.7 (15.84–28.8) | 22.68 (17.28–32.94) | 0.139 |
High-density lipoprotein cholesterol (mg/dL) | 18.54 (16.02–21.24) | 18.54 (16.38–21.78) | 0.687 |
Low-density lipoprotein cholesterol (mg/dL) | 50.58 (41.4–59.76) | 54 (42.48–63.18) | 0.054 |
Serum creatinine (mg/dL) | 77.25 (66.93–88.90) | 78.48 (65.76–92.88) | 0.568 |
Glomerular filtration rate (mL/min/1.73 m2) | 81.60 (67.04–90.53) | 82.28 (69.75–90.99) | 0.326 |
Uric acid (mg/dL) | 310.24 (257.96–381.80) | 329.20 (263.28–407.49) | 0.211 |
Systemic immune-inflammation index | 1088.76 (679.45–1546.71) | 1909.29 (1010.61–2854.94) | <0.001 |
Monocyte to high-density lipoprotein cholesterol ratio | 0.41 (0.30–0.56) | 0.44 (0.32–0.56) | 0.459 |
Platelet to lymphocyte ratio | 147.69 (117.89–196.25) | 235.09 (154.61–286.27) | <0.001 |
Neutrophil-lymphocyte ratio | 5.04 (3.28–7.13) | 7.71 (4.80–10.83) | <0.001 |
Culprit vessel (n, %) | 0.057 | ||
LAD | 193 (42.4%) | 67 (54.5%) | |
LCX | 84 (18.5%) | 17 (13.8%) | |
RCA | 178 (39.1%) | 39 (31.7%) | |
Multivessel disease | 173 (38.0%) | 71 (57.7%) | 0.001 |
Thrombus aspiration (n, %) | 124 (27.3%) | 33 (26.8%) | 0.925 |
Initial TIMI flow grade (n, %) | 0.266 | ||
0–1 | 267 (58.7%) | 79 (64.2%) | |
≥2 | 188 (41.3%) | 44 (35.8%) | |
Number of stent | 1.13±0.421 | 1.17±0.474 | 0.326 |
Stent diameter (mm) | 3.00 (2.75–3.50) | 3.00 (2.75–3.50) | 0.168 |
Stent length (mm) | 24 (18–32) | 24 (18–31.50) | 0.654 |
IABP used in procedure | 28 (6.2%) | 15 (12.2%) | 0.023 |
SII, systemic immune-inflammation index; NT-proBNP, N-terminal pro brain natriuretic peptide; PLR, platelet to lymphocyte ratio; NLR, neutrophil-lymphocyte ratio; LCX, left circumflex; LAD, left anterior descending; RCA, right coronary artery; IABP, intra-aortic balloon pump; TIMI, thrombolysis in myocardial infarction.
ROC curve analysis indicated that SII had good predictive value for NRP in older patients with STEMI (AUC, 0.738; 95% CI: 0.686–0.790), with an optimal cut-off of 1814, a sensitivity of 52.85%, and a specificity of 85.71%. As shown in Figure 2 and Table 3, the predictive power of SII was greater than those of NLR (AUC: 0.688; 95% CI: 0.634–0.742) and PLR (AUC: 0.722; 95% CI: 0.667–0.776).
ROC Analysis of the Indicated Variables in Predicting the No-Reflow Phenomenon.
Variable | AUC | 95% CI | Cut-off | Sen. | Spe. | Youden index | P value |
---|---|---|---|---|---|---|---|
SII | 0.738 | 0.686–0.790 | 1814 | 52.85 | 85.71 | 0.386 | <0.001 |
PLR | 0.722 | 0.667–0.776 | 222.5 | 56.91 | 83.74 | 0.407 | <0.001 |
NLR | 0.688 | 0.634–0.742 | 8.264 | 47.15 | 84.40 | 0.316 | <0.001 |
PLR, platelet to lymphocyte ratio; SII, systemic immune-inflammation index; CI, confidence interval; NLR, neutrophil-lymphocyte ratio.
The univariate and multivariate logistic regression results are shown in Table 4. Collinearity was observed for NLR, PLR, white blood cell count, and neutrophil count; therefore, these variables were not included in the regression analysis. Multivariate analysis showed that SII≥1814 (OR=3.799, 95% CI: 2.190–6.593, P<0.001), hypertension (OR=2.048, 95% CI: 1.252–3.352, P=0.004), lymphocyte count (OR=0.571, 95% CI:0.368–0.885, P=0.012), platelet count (OR=1.009, 95% CI:1.005–1.013, P<0.001), hemoglobin (OR=1.015, 95% CI:1.003–1.028, P=0.018), and multivessel disease (OR=2.237, 95% CI: 1.407–3.558, P=0.001) were independent predictors of NRP after primary PCI in older patients with STEMI.
Effects of the Indicated Variables on No Reflow in Univariate and Multivariate Regression Analyses.
Variable | Univariate analysis | Multivariate analysis | ||||
---|---|---|---|---|---|---|
OR | 95% CI | P value | OR | 95% CI | P value | |
Smoking | 1.539 | 1.031–2.297 | 0.035 | 1.560 | 0.979–2.487 | 0.061 |
Hypertension | 1.845 | 1.200–2.838 | 0.005 | 2.048 | 1.252–3.352 | 0.004 |
Lymphocyte count | 0.464 | 0.314–0.686 | <0.001 | 0.571 | 0.368–0.885 | 0.012 |
Hemoglobin | 1.015 | 1.004–1.027 | 0.008 | 1.015 | 1.003–1.028 | 0.018 |
Platelet count | 1.010 | 1.006–1.013 | <0.001 | 1.009 | 1.005–1.013 | <0.001 |
SII≥1814 | 6.605 | 4.255–10.254 | <0.001 | 3.799 | 2.190–6.593 | <0.001 |
Multivessel disease | 2.226 | 1.485–3.336 | <0.001 | 2.237 | 1.407–3.558 | 0.001 |
IABP used in procedure | 2.118 | 1.093–4.105 | 0.026 | 1.907 | 0.854–4.258 | 0.115 |
IABP, intra-aortic balloon pump; OR, odds ratio; CI, confidence interval; SII, systemic immune-inflammation index.
Multiple linear regression analysis indicated no correlations of SII with hypertension, smoking, and multivessel disease (P>0.05), as shown in Table 5.
Discussion
Inflammation plays a central role in the occurrence and development of AMI through the complex interactions between inflammatory cells and inflammatory mediators [12]. Some studies have shown that the inflammatory state after STEMI is associated with left ventricular thrombus [13].
This study investigated the relationship between SII level and NRP in older patients with STEMI undergoing percutaneous coronary intervention. The baseline SII of older patients with STEMI with NRP after coronary intervention was significantly higher than that of patients with normal flow. Furthermore, in older patients with STEMI, SII levels were independently associated with NRP.
NRP is a serious complication of acute STEMI that can lead to adverse cardiovascular events. The pathophysiological mechanism of NRP has not yet been elucidated but is currently believed to be associated with factors such as ischemia-reperfusion injury, distal embolism of diseased vessels, microcirculation disturbance, oxidative stress, and vasospasm [14]. Because no effective treatment for NRP is currently available, predicting the occurrence of no-reflow, early assessment of high-risk patients, and the use of appropriate interventions to decrease the occurrence of no-reflow would benefit patients [15, 16]. In recent years, many studies have evaluated various indicators for predicting RNP after primary PCI in patients with STEMI, but no general consensus has been reached regarding widely accepted reliable predictors. Elevated NLR levels before interventional therapy appear to predict the risk of NRP after primary PCI in patients with AMI [17]. Another study has found that PLR is a reliable predictor of no-reflow after thrombus aspiration in patients with STEMI [18]. Zhang et al. [19] have compared the relationships of NLR, mean platelet volume, and platelet distribution width with NRP in patients with STEMI. Their findings indicated that NLR, mean platelet volume, and platelet distribution width were independent predictors of NRP in patients with STEMI; although NLR had the highest predictive value, the predictive value of these metrics did not differ significantly. Admission vitamin D levels have been associated with NRP and may predict NRP after PCI in patients with STEMI [20]. The model for end-stage liver disease-XI (MELD-XI) score can be used to predict NRP and short-term prognosis in patients with STEMI [21]. In addition, Rashed et al. [22] have shown that the preoperative CHA2DS2-VASc score can be used to predict NRP in patients with STEMI.
Cells of the innate immune system, such as lymphocytes and neutrophils, promote inflammatory responses in the vascular endothelium, and directly influence oxidative stress and cytokine production [23]. Platelet activation has been reported to play a key role in the coagulation system, which has a complex association with the innate immune system [24]. The SII is calculated from neutrophils, lymphocytes, and platelets, and it reflects the body’s immune thrombotic status and inflammatory status simultaneously [7]. SII has been reported to predict new-onset atrial fibrillation after STEMI [25]. As a new inflammatory index, SII can predict the in-hospital and long-term outcomes of patients with STEMI after PCI [26].
This study showed that the baseline SII level of NRP was significantly higher in the group of older patients with STEMI after coronary intervention than in the normal-flow group; in addition, previous hypertension, neutrophils, platelets, hemoglobin, and multivessel disease were independent predictors of NRP in elderly STEMI patients. Baseline SII levels of NRP were significantly higher in older patients with STEMI after PCI than in the normal-flow group. In addition, platelets, hemoglobin, multivessel disease, previous hypertension, and lower lymphocyte levels were independent predictors of NRP in these patients. These findings are similar to the results of previous studies [27, 28]. However, the average SII in this study was higher, possibly because of the chronic low-grade sterile inflammation caused by mitochondrial dysfunction, cellular senescence, autophagy deficiency, and dysbiosis of gut flora in older patients [27]. Our findings, including the results of ROC curve analysis, indicated that the predictive ability of SII for NRP in older patients with STEMI was higher than that of NLR and PLR. Therefore, SII may serve as a risk stratification index for older patients with STEMI and NRP.
Limitations
This study has several limitations. 1. This study was a single center retrospective study with a relatively inadequate sample size. 2. Only angiography was used to determine the presence or absence of reflow, and intracavitary imaging techniques, such as optical coherence tomography and intravascular ultrasound, were not used to further evaluate vascular lesions. 3. The patients included in this study were typical older patients with STEMI. 4. Data on clinical indicators such as pre-expansion, post-expansion, and thrombus load were not available. 5. Because of the lack of follow-up data, we were unable to further determine the relationship between SII and the poor long-term prognosis of older patients with acute myocardial infarction; continue to follow up the occurrence of poor prognosis in patients.