Atherosclerosis is the leading cause of cardiovascular disease, and continues to be the leading cause of death worldwide.¹ The presence of inflammation in the atherosclerotic area has a critical pathophysiological role for plaque formation and rupture.² Vulnerable atherosclerotic plaque and thrombus formation that results in the cessation of coronary blood flow is the primary pathophysiologic mechanism in patients with ST-segment elevation myocardial infarction (STEMI).³ The first choice of treatment for STEMI patients is primary percutaneous coronary intervention (pPCI). Despite advances in antithrombotic treatment and reperfusion techniques, patients with STEMI still have a poor prognosis.

Early risk stratification of patients who are at high risk for future adverse cardiovascular events is very crucial. Previous studies have shown that inflammation and thrombosis have been linked to the initiation, progression, and prognosis of STEMI.⁴ So, the discovery of novel inflammatory biomarkers has be of interest to detect high-risk patients and to provide information for prognosis.^{5 , 6} Platelets and leukocytes play crucial roles in the development of atherosclerosis and acute coronary syndromes. Higher platelet counts might reflect destructive inflammatory processes and prothrombotic status.⁷ Neutrophils are the first leukocytes to migrate from the blood to the damaged myocardial area, and increased neutrophil counts have been associated with large infarct size, mechanical complications, and mortality.^{8 , 9} In contrast, lymphocytes control the immune response, providing less myocardial damage.¹⁰ The systemic immune-inflammation index (SII) is a simple marker, which has been established based on the neutrophil, platelet, and lymphocyte counts [SII= (neutrophil x platelet) / lymphocyte] to determine the inflammatory and immune status. Recently, SII was considered an independent predictor of prognosis in several conditions, including tumors and cardiovascular diseases.^{1 , 11 , 12} We aimed to investigate the predictive ability of SII for adverse clinical outcomes in patients with STEMI after pPCI.

A total of 1,187 consecutive patients admitted to our hospital with STEMI who underwent pPCI between 2012 and 2020 were retrospectively included in this study. Of them, 344 patients with previous coronary revascularization, hematological, oncological, or inflammatory disease, active infection, hepatic or renal insufficiency, severe valvular heart disease, and cardiogenic shock at admission were excluded. Also, patients with missing data and patients whose follow-up data could not be obtained were not included in the study population. Finally, the study was completed with 843 patients. The study was carried out according to the Declaration of Helsinki of 1975, as revised in 2008 and approved by the local ethics committee.

The diagnosis of STEMI was made based on the updated guidelines for the universal definition of myocardial infarction (MI).^{13 , 14} Baseline characteristics, clinical histories, laboratory measurements, and angiographic images of patients were obtained from the hospital database. All blood samples of patients were obtained at admission to the emergency department. Blood measurements were analyzed using a Beckman Coulter LH 780 hematology analyzer (Beckman Coulter, FL, USA) for hematologic parameters and a Roche Cobas 6000 c501 (Roche, Mannheim, Germany) for biochemical parameters. The SII was calculated with the formula SII= (P x N) / L, where P = total peripheral platelet count; N = neutrophil count (N), and L = lymphocyte count. Creatinine clearance was calculated using the Cockcroft- Gault equation: Creatinine clearance = ([140 - age in years] x weight[kg]) / (72 x serum creatinine [mg/dL]) for men and was corrected by multiplying with 0.85 for women. Hypertension (HT) was diagnosed as systolic blood pressure 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg at least two times or the use of current antihypertensive drugs. Diabetes mellitus (DM) was diagnosed based on fasting glucose ≥ 126 mg/dL or postprandial glucose ≥ 200 mg/dL or the use of antidiabetic drugs. Cigarette smoking was defined as patients who had smoked for at least six months continuously during the past year. A family history of coronary artery disease (CAD) was defined as a history of CAD in first-degree relatives less than 55 years for women and 65 years for men.

At the operator’s discretion, the standard coronary angiography (CAG) was performed through the transradial or transfemoral approach using the Seldinger technique. Acetylsalicylic acid (300 mg), a loading dose of P₂Y₁₂inhibitors (Clopidogrel), and a standard dose of unfractionated heparin (70-100 U/kg) were given to all patients before the CAG procedure. The use of glycoprotein IIb/IIIa receptor blockers (tirofiban) was left to the operator’s discretion. The angiographic images of patients were carefully reviewed by two experienced investigators who were blinded to all clinical data. Thrombolysis in myocardial infarction (TIMI) flow and TIMI myocardial perfusion grade (TMPG) were assessed as previously defined.^{15 - 17} No-reflow was defined TIMI 0, I, and II in the final angiogram. Distal embolization was determined as a new distal filling defect of one or more peripheral coronary artery branches of the infarct-related artery, with an abrupt occlusion distal to the coronary intervention site.

Baseline characteristics, laboratory data, and angiographic features of 843 patients of the high and low SII groups are described in Table 1 . The high SII group was older than the low SII group (p=0.002). The presence of familial CAD was more frequent in the high SII group than in the low SII group (p=0.005). White blood cell (WBC) count, platelet count, neutrophil count, and LDL cholesterol levels were more elevated in the high SII group, whereas lymphocyte count was lower. Regarding angiographic data, there was a higher frequency of implanted stents > II, multivessel disease, distal embolization, and no-reflow in the high SII group compared to the low SII group. TMPG and TIMI flow were worse in the high SII group than in the low SII group. The high SII group had higher rates of percutaneous transluminal coronary angioplasty (PTCA) (p=0.002) and lower rates of direct stenting (p=0.008) rates than the low SII.

Table 1

Variables	SII<554.9 (N=421)	SII≥554.9 (N=422)	p value
Age, years	59.2(7.9)	61.2(11.2)	0.002
Male gender, n (%)	277(65.8)	288(68.3)	0.449
Diabetes, n (%)	90(21.4)	111(26.3)	0.093
Hypertension, n (%)	131(31.1)	148(35.1)	0.222
Smoking, n (%)	129(30.6)	156(36.9)	0.052
Hyperlipidemia, n (%)	154(36.6)	171(40.5)	0.239
Family history of CAD, n (%)	74(17.6)	108(25.6)	0.005
BMI, kg/m2	23.8(22-25.3)	23.7(21.4-26.6)	0.589
Previous Medication
ASA, n (%)	98(23.3)	123(29.2)	0.053
ACEi/ARB, n (%)	154(36.6)	176(41.7)	0.127
Beta blocker, n (%)	147(34.9)	165(39.1)	0.209
Diuretic, n (%)	37(8.8)	52(12.3)	0.096
Statin, n (%)	75(17.8)	94(22.3)	0.106
LVEF, %	42.3(7)	41.6(10.5)	0.256
WBC, 103mL	7.6(6-8.9)	7.9(6.4-9.7)	0.007
Haemoglobin, mg/dL	14.2(1.1)	14.2(1.7)	0.651
Platelet, /mm3	204.1(173.6-228.7)	243.7(189-279)	<0.0001
Neutrophil, 103mL	6.3(5.4-7)	6.5(5.4-7.8)	0.004
Lymphocyte, 103/mL	2.7(2-3.3)	2.1(1.3-3.4)	<0.0001
Serum Creatinine, mg/dL	0.9(0.2)	0.9(0.3)	0.825
Total cholesterol, mg/dL	171.3(147.1-191.6)	163.4(129.8-204.6)	0.120
LDL cholesterol, mg/dL	111.9(102.8-121.5)	117.5(99.7-135.9)	0.006
HDL cholesterol, mg/dL	43(36.3-48.5)	40.4(31.5-51.8)	0.057
Triglyceride, mg/dL	137.2(98.6-177.7)	129.8(87.9-204.1)	0.858
Glucose, mg/dL	116(29.5)	114.5(37.6)	0.534
Angiographic Characteristics
Pain to balloon time, hours	4.3(2.8-5.5)	4.4(2.5-6.5)	0.152
Total number of stents > II	27(6.4)	82(19.4)	<0.0001
Multivessel disease, n (%)	86(20.4)	123(29.2)	0.0034
Total stent length, mm	23.7(4.1)	23.9(6)	0.598
Procedure, n (%)			0.0008
Direct stenting	135(32.1)	101(23.9)	0.008
PTCA+stenting	274(65.1)	289(68.5)	NS
Only PTCA	12(2.8)	32(7.6)	0.002
TMPG>II, n (%)	272(64.6)	228(54)	0.0018
Postprocedural TIMI flow >III, n (%)	410(97.4)	374(89.6)	<0.0001
Use of GpIIb/IIIa inhibitor, n (%)	41(9.7)	77(18.3)	0.0004
Distal embolization, n (%)	2(0.5)	15(3.6)	0.002
No reflow, n (%)	11(2.6)	48(11.4)	<0.0001
DAPT interruption <30 days	6(1.4)	11(2.6)	0.224
DAPT interruption <6 months	22(5.3)	29(6.9)	0.316
Adherence for DAPT for 12 months	399(94.8)	393(93.1)	0.317

SII: systemic immune-inflammation index, CAD: coronary artery disease, BMI: body mass index, ASA: acetylsalicylic acid, ACEi: angiotensin converting enzyme inhibitors, ARB: angiotensin receptor blocker, LVEF: left ventricular ejection fraction, WBC: White blood cell, LDL: low density cholesterol, HDL: high density cholesterol, PTCA: percutaneous transluminal coronary angioplasty, TIMI: thrombolysis in myocardial infarction, TMPG: TIMI myocardial perfusion grade, DAPT: dual antiplatelet therapy; values shown as mean (standard deviation), median (interquartile range), n (%).

This study has shown that patients with high SII values had higher frequencies of cardiac death, nonfatal MI, nonfatal stroke, hospitalization for CHF, revascularization, and MACE than patients with low SII values. Furthermore, SII was an independent predictor of these adverse outcomes. Adding SII to traditional risk factors such as age, HT, DM, and male gender improved the prediction ability for adverse cardiovascular events in STEMI patients after pPCI. Finally, SII was superior to other conventional biomarkers such as NLR and PLR in predicting MACE.

MI is caused by thrombus formation in the coronary arteries as a result of coronary plaque rupture or erosion of the atheromatous plaque.³ The inflammatory process and thrombosis were found to play significant roles in the initiation and progression of this condition.²³ Neutrophils release neutrophil extracellular traps (NETs), which have been detected in atheromatous plaque and might play a causative role in atherosclerotic plaque formation and increased thrombus stability.²⁴ Zhang et al.²⁵ found that neutrophil counts were independently associated with MACE in STEMI patients.²⁵ In contrast, lymphocytes reflect a calm and regulated inflammatory process that causes suppressed immune response and less myocardial damage.²⁶ Lower lymphocyte counts have been linked to a higher risk of cardiovascular disease and mortality.²⁷ Upon activation, platelets release considerable quantities of proinflammatory chemokines and cytokines from alfa granules, which lead to destructive immune and prothrombotic status. Previous studies have shown that platelet count was associated with MACE.^{7 , 28} Biomarkers derived from these three cell types mentioned above were widely researched and reported as prognostic markers in the literature due to their relatively low cost and easiness for acquisition and calculation. Also, studies with STEMI patients have reported that both NLR and PLR are useful and powerful independent predictors of MACE.^{6 , 29}

Recently, SII has been emerged as a potential marker based on inflammatory cells, including neutrophils, lymphocytes, and platelets, and has been reported to be associated with worse outcomes in several conditions.^{1 , 11 , 12} Gok et al.³⁰ reported that SII was associated with massive acute pulmonary embolism and was superior to other inflammation-based indexes, similarly to what we observed in the present study. A previous study by Erdogan et al.³¹ showed a significant association between SII and CAD severity. SII was found to be associated with poor postoperative outcomes after elective off-pump coronary artery bypass surgery.¹² Agus et al.³² reported that SII was independently related to in-hospital mortality in patients with infective endocarditis. In addition, SII has been associated with adverse clinical outcomes in acute coronary syndrome in patients aged between 65 and 85.³³ Although this study³³ had similar results to ours, in our study, we included adult patients of all ages, and with STEMI only. Another study conducted by Yang et al.¹ proposed that SII was an independent predictor of adverse events in CAD patients, including stable angina pectoris, non-STEMI, and STEMI patients.¹ In recent studies, the prognostic value of SII was reported to be better than PLR and NLR.³⁴ To avoid multicollinearity and interaction, we did not put NLR and PLR in the Cox regression models with SII. However, in concordance with the abovementioned studies, AUC calculated from ROC analysis and model fit comparisons including -2LL, AIC, BIC, and NagelkarkeR² demonstrated that SII might fit better than NLR and PLR for risk stratification of STEMI patients undergoing pPCI.

Because the early prediction of adverse events in high-risk patients with STEMI undergoing pPCI is crucial for treatment and follow-up strategies, high SII might serve a role in the risk classification and treatment assignment for these patients.

The relatively small sample size and retrospective and single-center design were the major limitations of this study. In addition, we collected data from an eight-year period, from hospital records, so there might be selection bias due to unmeasured confounding variables affecting adverse events and exclusion of patients with missing variables. The platelet, neutrophil, and lymphocyte counts were recorded only once upon admission. The in-hospital or follow-up measurements were not recorded, and the impacts of changes of these variables on adverse cardiovascular events remained uncertain. Large randomized controlled trials could provide more definitive evidence about the predictive ability of SII for clinical adverse events in patients with STEMI.

This study identified that high SII was independently related to adverse cardiovascular events, including cardiac death, nonfatal MI, nonfatal stroke, hospitalization for heart failure, revascularization, and composite MACE in patients with STEMI after pPCI. Furthermore, the risk prediction of MACE was improved by adding SII to traditional risk factors. SII was superior to NLR and PLR in the prediction of adverse events in STEMI patients after pPCI. Finally, SII is an easily calculable predictor that could be used to detect high-risk patients with STEMI undergoing pPCI.