Effects of nicorandil on systemic inflammation and oxidative stress induced by percutaneous coronary intervention in patients with coronary heart disease

Abstract

Objective

The present study investigated the effects of a bolus intracoronary injection of nicorandil on systemic inflammation and oxidative stress induced by percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD).

Methods

Patients undergoing coronary angiography (CAG) were enrolled into the CAG group (n = 30). Patients undergoing PCI were randomly divided into the PCI (n = 30) and PCI + nicorandil groups (n = 30).

Results

Blood taken from patients in the placebo group 24 hours after PCI exhibited significant increases in the expression of inflammatory indicators and mild increases in the expression of anti-inflammatory indicators. The intracoronary injection of nicorandil reversed the elevation of inflammatory indicators and significantly increased the levels of anti-inflammatory indicators in the blood of patients with PCI. Blood taken from patients in the placebo group 24 hours after PCI also displayed significant decreased superoxide dismutase levels and increased malondialdehyde levels. Nicorandil treatment reversed these changes of oxidative stress marker levels.

Conclusions

These results indicated the possible medical application of intracoronary injections of nicorandil for reducing systemic inflammation and oxidative stress in the peripheral blood of patients undergoing PCI.

Keywords

Nicorandil percutaneous coronary intervention inflammation oxidative stress coronary heart disease coronary angiography

Introduction

Coronary heart disease (CHD) has become a major cause of death and disability globally. Percutaneous coronary intervention (PCI) is recognized as one of the most effective and essential methods for patients with acute myocardial infarction (AMI) or unstable angina (UA). Compared with the effects of traditional drug therapy, PCI can more effectively improve coronary blood flow, restore myocardial perfusion, reduce myocardial ischemia or the infarction area, and improve clinical prognoses.^1,2 However, some patients with AMI or UA do not benefit from PCI because of myocardial no-reflow (MNR).³

The absence of MNR, which is also called coronary stent reflux, is considered a manifestation of coronary function disorders during the reperfusion of acute myocardial ischemia. Mechanical injury induced by PCI might increase inflammation and oxidative stress, which may participate in MNR.³ It has been revealed that inflammation and reactive oxygen species (ROS) can cause the constriction of capillaries under ischemic conditions and participate in the phenomenon of MNR.^4,5 Previous research demonstrated that MNR is related to the poor prognosis in patients with AMI after PCI, as typified by cardiac dysfunction, arrhythmia, and myocardial injury.⁶ Thus, it is urgent to identify an effective and feasible therapeutic method for preventing MNR in patients with CHD undergoing PCI. Multiple interventions have been clinically used to rescue MNR, including mechanical methods such as intra-aortic balloon pumping or post-conditioning, and pharmacological agents including adenosine, nitroprusside, verapamil, nicorandil, dipyridamole, epinephrine, and cyclosporine.^7–9

Nicorandil is an ATP-sensitive potassium channel (K_ATP) opener than can improve the dilation of macro- and micro-vessels to protect the myocardium in patients with acute coronary syndrome (ACS).¹⁰ Recently, several studies described the safety of the intravenous or intracoronary injection of nicorandil and its efficacy in improving myocardial perfusion during PCI.^10–13 Nicorandil also reduces the incidence of MNR, thereby reversing the possible poor prognosis of patients undergoing PCI.^10,13 Furthermore, nicorandil administration at the time of primary PCI was associated with reduced rates of major adverse cardiovascular events (MACE) both in the hospital and after discharge.¹⁴ Previous studies demonstrated that nicorandil plays a protective role in ischemia–reperfusion myocardial injury as a K_ATP opener. Nicorandil expanded coronary microcirculation through inducing the opening of K_ATP channels, which are abundantly expressed in arterial smooth muscle cell membranes with a diameter of approximately 100 μm.¹² Meanwhile, nicorandil reduced endothelial function damage caused by the coronary stent-coating drugs paclitaxel and sirolimus by inducing the opening of mitoK_ATP channels, which may exert a protective effect through inhibiting oxidative stress.¹⁵ However, the potential mechanism by which nicorandil reduces MNR during PCI, in addition to dilating coronary arteries, remains unclear. In this study, we investigated the association of a bolus intracoronary injection of nicorandil during PCI with the serum levels of inflammatory and oxidative stress indicators in patients to verify the underlying mechanism by which nicorandil reduces the incidence of MNR.

Materials and methods

Study population

Patients who were hospitalized in the Department of Cardiology of our hospital because of chest pain and who underwent coronary angiography (CAG) were eligible for study. Patients with ACS included those with acute ST segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and UA. The exclusion criteria were as follows: older than 90 years or younger than 30 years, history of PCI or coronary artery bypass graft, systolic blood pressure <88 mmHg, allergy to nicorandil or clopidogrel/ticagrelor, bleeding history in the prior 3 months, malignant tumors, hepatic impairment, renal insufficiency, primary or secondary thrombocytopenia or platelet dysfunction, moderate-to-severe anemia, and acute heart failure. Patients with NSTEMI are not eligible for stent implantation; thus, they were also excluded.

This study protocol was approved by our Hospital Ethics Committee (approval number: KYLL‑2015266; Approval date: February 25, 2015) and registered with Current Controlled Trials (registration number: ChiCTR1800019349, registration date: November 7, 2018). All enrolled patients provided written informed consent to participate in this trial. Patients who underwent PCI were randomly assigned to the PCI or PCI + nicorandil group on a 1:1 basis. All procedures were performed as standard interventional techniques following current guidelines at the time of intervention.

Outline of the study procedures

CAG was performed in patients to visualize the severity of stenosis in coronary arteries. PCI was then performed if the residual diameter of stenosis was equal to or greater than 75% of the coronary artery diameter. Patients received an intracoronary bolus injection of 2 mg of nicorandil (1 mg/mL) or an equal volume of placebo (2 mL of 0.9% saline) into the coronary ostia 2 mm beyond the occlusion prior to PCI. Peripheral blood samples were collected before CAG and 24 hours after CAG (Figure 1 and Supplementary Figure 1).

Figure 1.

Protocol of the study. Patients with chest pain who underwent CAG were included in this trial. Patients were randomly assigned to receive an intracoronary injection of nicorandil or the same volume of 0.9% saline.

Blood sample collection

Approximately 10 mL of peripheral venous blood samples were collected from all participants before and 24 hours after CAG. All samples were collected in Vacutainer anticoagulant tubes (BD, Franklin Lakes, NJ, USA). Blood samples placed in separate centrifuge tubes were then centrifuged at 3000 × g for 10 minutes to obtain both serum and plasma, which were immediately aliquoted and frozen at −80°C for further analysis. Serum was used to test the expression of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β, IL-1 receptor A (IL-1RA), IL-6, IL-10, IL-13, and superoxide dismutase (SOD). Plasma was used to examine the levels of malondialdehyde (MDA).

Cytokine detection

Enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, Minneapolis, MA, USA) were used to detect the expression of cytokines, including CRP, TNF-α, MCP-1, IL-1β, IL-1RA, IL-6, IL-10, and IL-13, in serum or plasma according to the manufacturer’s instructions. The levels of all cytokines were calculated using the ELISA standard curve, which was produced via serial dilution with the standards. The absorbance of the samples was determined at 450 on a SpectraMax Plus 384 Microplate Reader (Molecular Devices, San Jose, CA, USA).

Measurement of SOD

The expression of SOD was examined using an SOD determination kit (Sigma-Aldrich, St. Louis, MO). All procedures were performed according to the manufacturer’s instructions. The absorbance was read at 450 nm using a microplate reader. Three replicates were conducted for each sample.

Measurement of MDA

MDA levels were examined using a Lipid Peroxidation Assay Kit (Sigma-Aldrich) according to the manufacturer’s instructions. The MDA standard solution was used to create a standard curve. The absorbance was measured at 532 nm using a microplate reader. Each sample performed three replicates.

Statistical analysis

All experiments were repeated three times, and the values were averaged. Data were presented as the mean ± standard error of the mean. SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA) was used for data analysis. Comparisons between two groups were assessed using a two-sided unpaired Student t-test for normally distributed variables. Comparison of ≥3 groups were performed via one-way analysis followed by post hoc analysis with Dunnett’s multiple comparison test as appropriate. All data in this study were identified to follow a normal Gaussian distribution after a normality test. P < 0.05 indicated statistical significance.

Results

Patient baseline characteristics

Ninety patients were enrolled, 30 of whom underwent CAG without PCI. The other 60 patients were randomly divided into the PCI and PCI + nicorandil groups on a 1:1 basis. The baseline characteristics of patients in the three groups are presented in Table 1. There were no differences in age, sex, body mass index, systolic blood pressure, diastolic blood pressure, heart rate, and cardiovascular risk factors, including the percentage of smokers and histories of diabetes, hypertension, and hyperlipidemia, among the groups. In addition, white blood cells and platelet counts and hemoglobin, alanine transaminase, aspartate aminotransferase, creatinine, blood urea nitrogen, fasting blood glucose, and lipid levels were similar among the groups (Table 2).

Table 1.

Clinical characteristics of the study population.

Characteristics	CAG group (n = 30)	PCI group (n = 30)	PCI + nicorandil group (n = 30)	P
Male, n	21	22	22	>0.05
Age (years)	59.33 ± 16.46	57.93 ± 18.03	55.90 ± 17.05	>0.05
BMI (kg/m²)	25.7 ± 4.49	24.80 ± 4.91	24.28 ± 4.01	>0.05
Cardiovascular risk factors
Hypertension, n	18	19	18	>0.05
Diabetes, n	15	16	17	>0.05
Smoking, n	10	9	11	>0.05
Systolic BP (mmHg)	139.5 ± 12.1	140.5 ± 13.5	142.7 ± 11.2	>0.05
Diastolic BP (mmHg)	82.8 ± 12.1	79. 9 ± 10.5	81.7 ± 13.5	>0.05
Heart rate (bpm)	77.2 ± 12.2	76.2 ± 12.6	74.1 ± 15.0	>0.05

BMI, body mass index; BP, blood pressure; CAG, coronary angiography; PCI, percutaneous intervention.

Table 2.

Hematological indicators of participants in the three groups.

Parameters	CAG group (n = 30)	PCI group (n = 30)	PCI + nicorandil group (n = 30)	P
WBC (10⁹/L)	6.00 ± 1.86	6.64 ± 1.87	6.25 ± 1.76	>0.05
Hemoglobin (g/L)	151.20 ± 13.86	150.93 ± 11.74	155.30 ± 11.23	>0.05
Platelet (10⁹/L)	194.43 ± 64.09	196.17 ± 61.92	203.9 ± 65.18	>0.05
ALT (U/L)	29.13 ± 13.08	28.6 ± 13.79	28.63 ± 11.79	>0.05
AST (U/L)	26.83 ± 7.19	27.53 ± 8.08	27.73 ± 8.36	>0.05
Creatinine (μmol/L)	84.28 ± 11.94	80.78 ± 14.89	87.16 ± 12.97	>0.05
BUN (mmol/L)	5.61 ± 1.49	5.33 ± 1.59	5.64 ± 1.43	>0.05
FBG (mmol/L)	6.10 ± 2.29	6.08 ± 2.32	6.78 ± 3.33	>0.05
TC (mmol/L)	3.92 ± 0.96	4.20 ± 0.94	3.75 ± 0.10	>0.05
TG (mmol/L)	1.35 ± 0.66	1.48 ± 0.63	1.40 ± 0.62	>0.05
LDL-C (mmol/L)	2.46 ± 0.80	2.69 ± 0.78	2.35 ± 0.84	>0.05
HDL-C (mmol/L)	1.18 ± 0.21	1.21 ± 0.27	1.16 ± 0.25	>0.05

WBC, white blood cell; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FBG, fasting blood glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CAG, coronary angiography; PCI, percutaneous coronary intervention.

Effect of nicorandil on pro-inflammatory cytokine levels after PCI

We tested the expression of pro-inflammatory cytokines, including CRP, TNF-α, MCP-1, IL-1β, and IL-6, in the venous blood of patients before and 24 hours after CAG. We found no significant differences in the expression of all pro-inflammatory cytokines among the three groups before CAG. In the PCI group, the expression of pro-inflammatory cytokines, including CRP, TNF-α, IL-1β, and IL-6, was markedly elevated 24 hours after PCI compared with that after CAG (all P < 0.05, Figure 2a–2d). Furthermore, patients in the PCI + nicorandil group displayed significant reductions in the expression of these inflammatory factors 24 hours after PCI compared with the findings in the PCI group (all P < 0.05, Figure 2a–2d). However, MCP-1 expression did not differ among the groups either before or after CAG (Figure 2e). Nicorandil may alleviate inflammation by reducing the upregulation pro-inflammatory indicators induced by PCI.

Figure 2.

Effect of nicorandil on pro-inflammatory cytokine levels. (a) CRP levels in the three groups before and 24 hours after CAG. (b) IL-1β levels in the three groups before and 24 hours after CAG. (c) IL-6 levels in the three groups before and 24 hours after CAG. (d) TNF-α levels in the three groups before and 24 hours after CAG. (e) MCP-1 levels in the three groups before and 24 hours after CAG. Values are expressed as the mean ± standard error of the mean. *P < 0.05, **P < 0.01.

Effect of nicorandil on anti-inflammatory cytokine levels after PCI

We also tested the expression of anti-inflammatory cytokines, including IL-1RA, IL-10, and IL-13, in the venous blood of patients before and 24 hours after CAG. We found no significant difference in the expression of all anti-inflammatory cytokines among the three groups of patients before CAG. In the PCI group, the expression of anti-inflammatory cytokines, including IL-1RA, IL-10, and IL-33, was mildly increased 24 hours after PCI versus that after CAG (all P < 0.05, Figure 3a–3c). Patients in the PCI + nicorandil group displayed significantly elevated expression of anti-inflammatory factors 24 hours after PCI compared with the findings in the PCI group (all P < 0.01, Figure 3a–3c). Nicorandil may alleviate inflammation by upregulating anti-inflammatory indicators in patients who underwent PCI.

Figure 3.

Effect of nicorandil on anti-inflammatory cytokine levels. (a) IL-1RA levels in the three groups before and 24 hours after CAG. (b) IL-10 levels in the three groups before and 24 hours after CAG. (c) IL-13 levels in the three groups in three groups before and 24 hours after CAG. Values are expressed as the mean ± standard error of the mean. *P < 0.05, **<0.01.

Effect of nicorandil on oxidative stress after PCI

We further tested the levels of oxidative stress indicators, including SOD and MDA, in the venous blood of patients before and 24 hours after CAG. We identified no differences in the levels of SOD and MDA among the three groups before CAG. The expression of SOD was reduced in patients 24 hours after PCI versus that after CAG (P < 0.01, Figure 4a), and nicorandil treatment significantly increased the expression of SOD 24 hours after PCI (P < 0.01, Figure 4a). Conversely, MDA levels were increased in patients 24 hours after PCI (P < 0.01 vs. 24 hours after CAG, Figure 4b), and this change was significantly reversed by nicorandil treatment (P < 0.01 vs. 24 hours after PCI, Figure 4b). These results indicated that nicorandil treatment reduces ROS levels, thereby improving oxidative stress in patients who underwent PCI.

Figure 4.

Effect of nicorandil on the levels of oxidative stress indicators. (a) Levels of SOD in the three groups before and 24 hours after CAG. (b) Levels of MDA in the three groups before and 24 hours after CAG. Values are expressed as the mean ± standard error of the mean. **P < 0.01.

Discussion

The present investigation found that an intracoronary injection of nicorandil alleviated the inflammatory reaction and oxidative stress in the peripheral blood in patients 24 hours after PCI. We found that an intracoronary bolus injection of nicorandil could significantly decrease the expression of pro-inflammatory cytokines and elevate that of anti-inflammatory indicators in patients 24 hours after PCI compared with the findings in patients who underwent PCI alone. Meanwhile, oxidative stress, which was enhanced following PCI, was alleviated in patients who received nicorandil. These results indicated that nicorandil might prevent MNR by regulating inflammatory responses and oxidative stress induced by PCI.

Recent studies revealed that inflammation and oxidative stress may be essential for the mechanism of MNR in patients with ACS after PCI.¹⁶ After the reperfusion of myocardial ischemia, myocardial inflammatory factors and ROS, both of which caused myocardial injury and cardiac dysfunction,¹⁷ were detected. On the one hand, PCI induced the shedding of atherosclerotic plaques, thereby potentially inducing myocardial inflammation,¹⁸ which has been considered an important cause of significant ventricular dysfunction.^3,19 The release of massive amounts of inflammatory mediators, such as TNF-α and IL-1β, plays an important role in the development and progression of MNR.²⁰ On the other hand, ROS were generated and released after reperfusion because of damage of the mitochondrial respiratory chain.²¹ The accumulation of ROS in the body caused oxidative damage, which may further aggravate MNR.²²

In this study, we investigated a cohort of patients undergoing either CAG or PCI with or without an intracoronary injection of nicorandil and examined the changes of serum pro-inflammatory and anti-inflammatory cytokines between before and 24 hours after intervention. The results indicated that the serum levels of pro-inflammation cytokines, excluding MCP-1, rose sharply 24 hours after PCI. These results indicated the presence of systemic inflammation in patients who underwent PCI, reflecting a short inflammatory response of the body to invasive procedures.²³ Surprisingly, we also found mild increases in the serum levels of the anti-inflammatory indicators IL-1RA, IL-10, and IL-13. This suggests the presence of an underlying feedback mechanism of the body to counteract pro-inflammatory stimulation.^24,25 Previous research found that an intracoronary bolus of nicorandil could improve the instantaneous increases of inflammation and oxidative stress in the coronary blood of patients with ACS during PCI.²¹ This investigation demonstrated that an intracoronary injection of nicorandil could further ameliorate the inflammatory and oxidative reactions in peripheral blood, which supported the need for a longer treatment period for nicorandil.

Nicorandil is a nitrate-like and ATP-sensitive potassium channel opener that can dilate coronary arteries and participate in ischemic pre-conditioning for cardioprotection.²⁶ Studies demonstrated the anti-inflammatory properties of nicorandil.^21,27 Intracoronary nicorandil has proven safe clinically.^10–13 This trial found that nicorandil significantly reduced the levels of pro-inflammatory indicators, including CRP, IL-1β, IL-6, and TNF-α, 24 hours after PCI. Furthermore, the drug also elevated the levels of anti-inflammatory cytokines, including IL-1RA, IL-10, and IL-13, 24 hours after PCI. Thus, the use of nicorandil during PCI may be effective for reducing the inflammatory reaction, thereby protecting against MNR.

K_ATP regulates the production of ROS, and nicorandil can reduce oxidative stress by preventing endothelial function damage caused by the coronary stent-coating drugs sirolimus and paclitaxel in vivo.^21,28 SOD and MDA levels directly reflect the levels of ROS. Our results revealed that blood taken from patients 24 hours after PCI displayed significantly increased SOD levels and decreased MDA levels. Nicorandil treatment reversed the induction of oxidative stress in the blood of patients with PCI. Thus, the use of nicorandil during PCI may be effective for reducing the oxidative stress and preventing MNR.

Previous studies reported that the phenomenon of MNR was believed to be associated with impaired cardiac microvascular function including microcirculatory barrier function, endothelial damage, inflammation, and increased oxidative stress.²⁹ The release of both pro-inflammatory mediators, such as TNF-α and IL-1β, and ROS plays an important role in the development and progression of MNR.³⁰ We found that nicorandil could improve inflammation and oxidative stress, which may participate in MNR, in addition to its effect on vasodilation in this trail. Thus, the suppression of MNR by nicorandil might occur through the inflammatory pathway. Necessary animal and cell experiments should be performed to further confirm the relationship of the inflammatory pathway induced by nicorandil and the reduction of MNR.

This study had several limitations, including the small sample sizes of the three groups. We initially assessed and assured the normality of the data distribution and then performed power analysis through PASS based on the levels of CRP, IL-1β, IL-6, TNF-α, IL-1RA, IL‑33, SOD, and MDA. The value of 1 − β exceeded 0.8 among the three groups of patients based on the aforementioned data. Second, we reviewed the MACE of the enrolled patients during hospitalization. No patients experienced in-hospital MACE, including cardiac death, non-fatal myocardial infarction, and repeat revascularization. However, we lack the follow-up data and records of adverse reactions of patients enrolled in this investigation. Further investigations are indeed necessary and urgent to obtain more detailed in-hospital and follow-up data and records of adverse reactions based on the use of nicorandil in patients during PCI.

In conclusion, our investigation revealed that an intracoronary injection of nicorandil alleviates inflammation and oxidative stress in patients with CHD after PCI. Thus, nicorandil might regulate inflammatory responses and oxidative stress to improve coronary microcirculation in addition to its dilatory effects on coronary arteries to prevent coronary no-reflow.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605211058873 - Supplemental material for Effects of nicorandil on systemic inflammation and oxidative stress induced by percutaneous coronary intervention in patients with coronary heart disease

Supplemental material, sj-pdf-1-imr-10.1177_03000605211058873 for Effects of nicorandil on systemic inflammation and oxidative stress induced by percutaneous coronary intervention in patients with coronary heart disease by Yulong Zong, Jie Li, Xinghua Xu and Xingli Xu in Journal of International Medical Research

Footnotes

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgements

We thank all patients, researchers, doctors, and nurses involved in this study.

Authors’ contributions

YZ, JL, and LL conceived, designed, and performed the experiments. LK, LC, XX, and LL collected and analyzed the data. All authors contributed to the interpretation of data and drafting or revision of the paper. All authors read and approved the manuscript and agreed to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work is appropriately investigated and resolved.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and publication of this article: This work was supported by grants from the National Natural Science Foundation of China (No. 82100439), the Science Foundation Project in Sichuan Province (No. 2021YJ0216), and the Innovation Project of University Students in Shandong First Medical University (S202010439123).

Supplemental material

Supplemental material for this article is available online.

References

Wassie

Lee

Sun

, et al. Single vs Serial Measurements of Cardiac Troponin Level in the Evaluation of Patients in the Emergency Department with Suspected Acute Myocardial Infarction. JAMA Netw Open 2021; 4: e2037930.

Scholz

Lengenfelder

Jacobshagen

, et al. Long-term effects of a standardized feedback-driven quality improvement program for timely reperfusion therapy in regional STEMI care networks. Eur Heart J Acute Cardiovasc Care 2020: 2048872620907323.

Yang

Cong

, et al. A nomogram for predicting the risk of no-reflow after primary percutaneous coronary intervention in elderly patients with ST-segment elevation myocardial infarction. Ann Transl Med 2021; 9: 126.

Doll

Hira

Kearney

, et al. Management of Percutaneous Coronary Intervention Complications: Algorithms From the 2018 and 2019 Seattle Percutaneous Coronary Intervention Complications Conference. Circ Cardiovasc Interv 2020; 13: e008962.

Wang

Toan

and Zhou

New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury.

Angiogenesis 2020; 23: 299–314.

Ndrepepa

Tiroch

Fusaro

, et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol 2010; 55: 2383–2389.

Barzyc

Łysik

Słyk

, et al. Reperfusion injury as a target for diminishing infarct size. Med Hypotheses 2020; 137: 109558.

Sheng

Ding

, et al. Intracoronary infusion of alprostadil and nitroglycerin with targeted perfusion microcatheter in STEMI patients with coronary slow flow phenomenon. Int J Cardiol 2018; 265: 6–11.

Muller

Trana

and Eeckhout

Myocardial no-reflow treatment. Curr Vasc Pharmacol 2013; 11: 278–285.

10.

Wong

Puri

Richardson

, et al. Myocardial ‘no-reflow'–diagnosis, pathophysiology and treatment. Int J Cardiol 2013; 167: 1798–1806.

11.

Matsumoto

Mikuri

Masaki

, et al. Feasibility of intracoronary nicorandil for inducing hyperemia on fractional flow reserve measurement: Comparison with intracoronary papaverine. Int J Cardiol 2020; 314: 1–6.

12.

Wang

, et al. Intracoronary application of nicorandil regulates the inflammatory response induced by percutaneous coronary intervention. J Cell Mol Med 2020; 24: 4863–4870.

13.

Soukoulis

Boden

Smith

Jr , et al. Nonantithrombotic medical options in acute coronary syndromes: old agents and new lines on the horizon. Circ Res 2014; 114: 1944–1958.

14.

Zhou

, et al. Cardiovascular events associated with nicorandil administration prior to primary percutaneous coronary intervention in patients with acute ST-segment elevated myocardial infarction: a systematic review and meta-analysis. Expert Opin Drug Saf 2019; 18: 537–547.

15.

Serizawa

Yogo

Aizawa

, et al. Paclitaxel-induced endothelial dysfunction in living rats is prevented by nicorandil via reduction of oxidative stress. J Pharmacol Sci 2012; 119: 349–358.

16.

Kopetz

Penno

MAS

Hoffmann

, et al. Potential mechanisms of the acute coronary syndrome presentation in patients with the coronary slow flow phenomenon – insight from a plasma proteomic approach. Int J Cardiol 2012; 156: 84–91.

17.

Sun

, et al. Role of high mobility group A1/nuclear factor-kappa B signaling in coronary microembolization-induced myocardial injury. Biomed Pharmacother 2018; 105: 1164–1171.

18.

Dörge

Schulz

Belosjorow

, et al. Coronary microembolization: the role of TNF-alpha in contractile dysfunction. J Mol Cell Cardiol 2002; 34: 51–62.

19.

Liu

, et al. Effects of atorvastatin on PDCD4/NF-κB/TNF-α signaling pathway during coronary microembolization of miniature pigs. Exp Mol Pathol 2015; 99: 564–569.

20.

Zhao

, et al. Altered expression of pro- and anti-inflammatory cytokines is associated with reduced cardiac function in rats following coronary microembolization. Mol Cell Biochem 2010; 342: 183–190.

21.

Liu

, et al. Impact of intracoronary nicorandil before stent deployment in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Exp Ther Med 2020; 19: 137–146.

22.

Ikonomidis

Vlastos

Andreadou

, et al. Vascular conditioning prevents adverse left ventricular remodelling after acute myocardial infarction: a randomised remote conditioning study. Basic Res Cardiol 2021; 116: 9.

23.

Pepys

and Baltz

ML.

Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol 1983; 34: 141–212.

24.

Shimada

Immune system and atherosclerotic disease: heterogeneity of leukocyte subsets participating in the pathogenesis of atherosclerosis.

Circ J 2009; 73: 994–1001.

25.

Kim

Kwak

Kwon

, et al. Analysis of plasma multiplex cytokines and increased level of IL-10 and IL-1Ra cytokines in febrile seizures. J Neuroinflammation 2017; 14: 200.

26.

Testai

Rapposelli

Martelli

, et al. Mitochondrial potassium channels as pharmacological target for cardioprotective drugs. Med Res Rev 2015; 35: 520–553.

27.

El-Kashef

DH.

Nicorandil ameliorates pulmonary inflammation and fibrosis in a rat model of silicosis.

Int Immunopharmacol 2018; 64: 289–297.

28.

Ekeløf

Jensen

Rosenberg

, et al. Reduced oxidative stress in STEMI patients treated by primary percutaneous coronary intervention and with antioxidant therapy: a systematic review. Cardiovasc Drugs Ther 2014; 28: 173–181.

29.

Movahed

and Butman

SM.

The pathogenesis and treatment of no-reflow occurring during percutaneous coronary intervention. Cardiovasc Revasc Med 2008; 9: 56–61.

30.

Jiang

, et al. Protective Effect of Nicorandil on Cardiac Microvascular Injury: Role of Mitochondrial Integrity. Oxid Med Cell Longev 2021; 2021: 4665632.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.04 MB