Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism Accepted Manuscript Clinical Study on efficacy of allopurinol in patients with acute cor[.]
Accepted Manuscript Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism Ying Huang, Chunya Zhang, Zhiqing Xu, Jinghua Shen, Xiaogang Zhang, Huanhua Du, Kanjian Zhang, Daifu Zhang PII: S1109-9666(16)30319-0 DOI: 10.1016/j.hjc.2017.01.004 Reference: HJC 113 To appear in: Hellenic Journal of Cardiology Received Date: 14 November 2016 Revised Date: 30 December 2016 Accepted Date: January 2017 Please cite this article as: Huang Y, Zhang C, Xu Z, Shen J, Zhang X, Du H, Zhang K, Zhang D, Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism, Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism Ying Huang*, Chunya Zhang, Zhiqing Xu, Jinghua Shen, Xiaogang Zhang, Huanhua Du, Kanjian Zhang, Daifu Zhang* Pudong New Area People’s Hospital ShangHai 201200 China *Corresponding authors: Daifu Zhang PR RI PT Department of Cardiology Email: zep941@163.com, Tel: +86-021-58951990*2326 SC Ying Huang Email sunllmm2007@126.com, Tel: +86-021-58951990*2326 N0 490 Chuanhuan Road,Chuansha Town,Shanghai Pudong New Area,ShangHai 201200 PR China M AN U Address [Abstract] Objective: To investigate the therapeutic effect of allopurinol treatment on acute coronary syndrome and to elucidate its possible mechanism Methods: Patients with acute coronary syndrome (n=100) were recruited as research subjects in our TE D hospital The patients were randomly divided into two groups (allopurinol group, n = 50) and control group, n= 50) These two groups were treated with conventional antiplatelet, anticoagulation and anti-ischemic therapy, while allopurinol was added to The biochemical indexes such as EP allopurinol group based on conventional treatment serum creatinine, uric acid, BNP, blood glucose and blood lipid were compared between the two groups Indicators of oxidative stress and inflammatory response AC C (MDA, OX-LDL, NO, hs-CRP and TNF-α) as well as cardiovascular events during 2-years follow-up were recorded Results: On admission, there is no difference in serum creatinine, uric acid, BNP, blood glucose and lipid levels between the two groups (P > 0.05), and after month of treatment, these levels are better in patients in the allopurinol group than the control group (P < 0.05) After treatment on day 14, month, months, months, year and years follow-up, MDA, OX-LDL and hs-CRP, TNF-α in both groups have decreased, however data from the allopurinol group are significantly lower than the control group (P < 0.05) Additionally, compared with control group, allopurinol treatment significantly elevated the level of ACCEPTED MANUSCRIPT NO (P < 0.05) The total effective rates of allopurinol group are much higher than the control group both in angina pectoris (93.2% and 76% respectively) and ECG (96% and 82% respectively) Patients in allopurinol group (n=40) and control group (n=41) received stent implantation and there is no statistical difference between them The RI PT incidence of cardiovascular events during 2-years follow-up in allopurinol group is 10% while it is 30% in the control group Conclusion: Allopurinol has remarkable effect in the treatment of ACS and can improve the Oxidative Stress and inflammatory reaction indicators of patients The protective mechanism of allopurinol SC might be achieved by suppressing the secretion and release of inflammatory mediators TNF-α, hs-CRP and OX-LDL, MDA and increasing level of NO M AN U [Keywords] allopurinol; acute coronary syndrome; cardiovascular events; clinical efficacy Introduction With the increasing incidence of acute coronary syndrome (ACS), it has become a serious threat to human health [1] At present, the main treatments for ACS include TE D anticoagulant and antiplatelet drugs, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) [2-6] Despite certain curative effect, clinical cardiovascular events such as angina pectoris (AP) and myocardial reinfarction are EP reported [7-9] The focus of this research is to explore other therapy approaches that could further lower the occurrence of cardiovascular events and this article aims to evaluate the effects of the prototypical xanthine oxidase (XO) inhibitor (allopurinol) AC C in treating ACS and reducing cardiovascular events, as well as illustrate its possible mechanism Study Overview and Methods Overview 100 patients (60 males and 40 females) with ACS were screened for the research from June 2013 to June 2014 in Pudong New Area People’s Hospital, and they ranged in age from 30 to 70 years with an average of (56.3±5.2) years Patients had (3.6±1.5) seizures within 48 hours of admission, and 30 cases were ST-segment elevation myocardial infarction (STEMI), 42 were non-ST elevation myocardial infarction ACCEPTED MANUSCRIPT (NSTEMI) and 28 were unstable AP Exclusion criteria were: patients involved in other clinical trials; revascularization surgery within months; hepatic or renal insufficiency; significant reduction in blood cell counts; allergic to allopurinol Participants were randomly divided into two groups of 50 cases (allopurinol group RI PT and control group), and there is no significant difference between the groups All the patients signed the informed consents The study was approved by the ethics committee of Pudong New Area People’s Hospital SC Methods Both groups were given conventional antiplatelet, anticoagulant and anti-ischemia M AN U treatments Patients in allopurinol group received additional allopurinol based on conventional treatment, which consists of a large daily dose of allopurinol 600mg during ACS acute phase (within 14 days) and followed by 200 mg daily until the completion of 4-weeks course Allopurinol was provided by Shanghai Sine Wanxiang Pharmaceuticals Co., Ltd and its national medicine permission number is H31020334 TE D Monitored Indicators The biochemical indicators such as serum creatinine (SCr), uric acid (UA), B-type natriuretic peptide (BNP), blood glucose (GLU) and blood lipid were EP compared in patients from both groups upon admission and after month treatment Malondialdehyde (MDA), oxidized low-density lipoprotein (OX-LDL), nitric oxide (NO), high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor alpha AC C (TNF-α) in groups were tested before hospitalization, on day 14 and month treatment, and on month 3, 6, 12, 24 follow-up The therapeutic effects on angina pectoris and electrocardiogram (ECG) after month treatment were evaluated The number of stent placements in the groups were compared Patients were followed up every week for years after discharge to assess cardiovascular events.‐ Evaluation Criteria on Therapeutic Effect (1) For AP evaluation, the following observations are taken into account : Remarkable effective: AP attack disappeared or nearly disappeared, or reduction in ACCEPTED MANUSCRIPT frequency ≥ 80% Effective: Improvement on AP symptoms and frequency decreased by 50% - 80% Ineffective: Reduction in frequency of AP ≤ 50% or no decrease on seizures (2) ECG evaluation: Remarkable effective: ST segment and T wave indicate and negative T wave Effective: Improvement on ST segment depression RI PT normality or near normality Ineffective: No change on ST segment depression or negative T wave Statistical Considerations‐ ‐ SC Data analysis were performed using statistical software SPSS version 20.0 (IBM, City of New York, USA) Enumeration data were expressed as percentage and compared M AN U by χ2 test, while measurement data were expressed as mean and standard deviation and compared with t-test A significant difference exists if p-value is less than 0.05 Results Comparison of Biochemical Indicators Table I indicates that the levels of serum creatinine, uric acid, BNP, blood glucose TE D and blood lipid show no statistically significant difference (P > 0.05) in the allopurinol group compared to the control group on admission but they have greatly improved after month of treatment (P < 0.05) Table I Comparison of biochemical indicators between groups BNP (pg/ml) GLU (mmol/L) Blood Lipid (mg/dL) 162.3± 583.6± 224.2± 5.3± 182.7± 28.6 34.2 37.8 0.6 27.2 month 128.5± 473.2± 142.4± 4.8± 173.3± treatment 17.3 45.6 26.7 0.5 21.1 163.7± 584.2± 225.1± 5.4± 183.1± 31.2 35.6 41.3 0.7 25.6 month 101.6± 414.7± 102.6± 4.1± 150.5± treatment 15.4* 40.8* 18.7* 0.4* 17.4* EP UA (µmol/L) Time Point AC C Group SCr (µmol/L) On admission Control Group On admission Allopurinol Group ACCEPTED MANUSCRIPT Asterisks indicate a significant difference between allopurinol group and control group after month treatment (P < 0.05) RI PT Comparison of Oxidative Stress Indicators Figures and demonstrate that on day 14 and month treatment, and month 3, 6, 12, 24 follow-up, there is a reduction on MDA and OX-LDL in patients from control group, but obviously to a lesser extent when compared with the allopurinol group (P < SC 0.05) As shown in Figure 3, allopurinol treatment significantly elevated the level of NO, compared with control group (P < 0.05) ‐ M AN U ‐ Comparison of Inflammatory Reaction Indicators As shown in figures 4-5, indicators on day 14 and month after treatment and month 3, 6, 12 and 24 follow-up exhibits a declining trend on the level of hs-CRP and TNF-α in both groups, and data in allopurinol group is obviously lower than the control TE D group (P < 0.05).‐ ‐ Comparison of Efficacy on Angina Pectoris EP Table II demonstrates that after month treatment, the total effective rate of angina pectoris in allopurinol group is 93.2%, which is significantly better than the control AC C group (76%) Table II Comparison of efficacy on Angina Pectoris between groups Group Remarkable n Total Effective Effective Ineffective Effective Rate (%) Allopurinol Group 50 32 16 96* Control Group 50 17 21 12 76 Asterisk indicates a significant difference between allopurinol group and control group (P < 0.05) ACCEPTED MANUSCRIPT Comparison of ECG Effect‐ ‐ Table III shows that the total effective rate of ECG in allopurinol group is evidently higher and achieves 96% after month of treatment compared to control Table III Comparison of ECG effect between groups Total Effective Remarkable Group RI PT group (82%) n Effective Effective Ineffective Rate % 50 30 18 Control Group 50 15 26 96* SC Allopurinol Group 82 M AN U Asterisk indicates a significant difference between allopurinol group and control group (P < 0.05) Comparison of PCI and Cardiovascular Events TE D Patients received stent implantation (n=40 in allopurinol group and n=41 in the control group, respectively and no statistical difference was found between the groups Table IV shows that during 2-years follow-up, the incidence of cardiovascular EP events in control group is 30%, whereas it is only 10% in allopurinol group Table IV n AP AC C Group Comparison of cardiovascular events in groups CVEI MI CI STCS LT RVS CVD (%) Allopurinol 50 1 1 10* 50 2 30 Group Control Group Discussion ACCEPTED MANUSCRIPT Plaque disruption and thrombosis play critical roles in the patho-anatomical mechanism of ACS, where oxidative stress injury, endothelial dysfunction and inflammatory reaction are important parts of the development (10, 11) Recent studies show that oxidative stress (OS) is recognized as an independent risk factor for RI PT atherosclerosis (AS), and it can promote the occurrence and development of AS by oxygenation of lipoproteins and inducing gene expression of inflammatory mediators Research by Rajendra NS et al (12) concluded that endogenous xanthine oxidase is the major cause of vascular tissue OS as well as vascular dysfunction XO is mostly SC produced by vascular endothelial cells, it needs molecular oxygen as electron acceptor to obtain reactive oxygen species (ROS) by cascade reactions and OX-LDL Lipid M AN U peroxides such as MDA are generated by lipid peroxidation of ROS with polyunsaturated fatty acids in biomembrane, which can induce a series of harmful responses like apoptosis, endothelial dysfunction and mechanoenergetic uncoupling in heart And uric acid, the major product of XO, increases the oxygen consumption as it is tri-oxy-purine (13, 14) Endothelial dysfunction is the initial factors resulting in as well as induces TE D atherosclerosis cardiovascular events Decreased endothelium-dependent vasodilatation (EDV) and NO indicate the impairment of vascular endothelial function Numerous studies (15-17) suggest that EP inflammatory reaction also plays a vital role in the development of coronary atherosclerosis As the initial factor of AS, inflammation can result in regional neutrophil and monocyte infiltration and lipidosis, which is the principal cause of AC C coronary plaque disruption and hemorrhage, thrombosis and ACS hs-CRP is an acute-phase protein of hepatic origin induced by cytokine (such as interleukin-6) after tissue injury or acute and chronic inflammation, and it is positively correlated with the degree of inflammation and injury Since hs-CRP can reflect the inflammatory status accurately and reliably, it is acting as the clinical indicator for therapeutic effect and observation as well as the independent predictor of ACS (18) TNF-α is an important mediator involved in systemic inflammation, which will induce immunoregulation at low level and pathological lesions at high level It has been verified that TNF-α plays a crucial role in the pathogenesis of ACS (19) ACCEPTED MANUSCRIPT Oxidative stress leads to endothelial dysfunction and inflammatory reaction, while in turn this dysfunction and reaction can aggravate OS injury Allopurinol is a typical xanthine oxidase inhibitor whose research and application are mostly related to hyperuricemia and chronic gout, however, recent studies RI PT demonstrate that it can also be used for the treatment of cardiovascular disease including heart failure and stable coronary heart disease (CHD) Farquharson et al (20) suggested that allopurinol contributes to inhibit oxidative stress and improve endothelial function efficiently Research by Cappola et al (21) demonstrates SC that short-term infusion of allopurinol into the coronary circulation can enhance myocardial efficiency in patients with dilated cardiomyopathy (referred for elective M AN U coronary angiography) and will not increase the oxygen cost Some scholars (22) argue that allopurinol can improve OS indicators of patients with chronic stable CHD Clozel (23) found that short-term or long-term allopurinol treatment can increase cardiac output and has no impact on blood pressure from animal experiments However, at present there is no report regarding the curative effect of large-dose TE D allopurinol on ACS in the world (24-26) This research study indicates that after month treatment, the levels of SCr, UA, BNP, GLU and blood lipid are better in patients of the allopurinol group than the control EP group (P < 0.05) There is a decrease on MDA, OX-LDL, hs-CRP and TNF-α and an increase of NO in patients of both groups, however the levels in the allopurinol group are significantly lower than the control group (P < 0.05) The total effective rates are AC C obviously higher in the allopurinol group than in control group both for angina pectoris (93.2% and 76% respectively) and ECG (96% and 82% respectively) 40 patients in allopurinol group and 41 in control group received stent implantation and there is no significant statistical difference between the groups.‐Data collected during 2-years follow-up shows that the incidence of cardiovascular events in allopurinol group is 10%, which is clearly lower than the control group (30%) The possible mechanism is that allopurinol can inhibit the activity of xanthine oxidase and relieve oxidative stress (27-30) Allopurinol also contributes to prompting activity of nitric oxide synthase and the balance of NO and ROS as well as the reduction on lipid ACCEPTED MANUSCRIPT peroxidation of oxyradical, which result in the enhancement of vascular endothelial function and the suppression of inflammatory reaction And it can protect cardiac muscle cell and the structure and function of vascular endothelium, and exhibit improvement on myocardial ischemia, myocardial contractile RI PT and diastolic function (31-33) In conclusion, allopurinol has remarkable effect in the treatment of ACS and can improve the OS and inflammatory reaction indicators of patients The protective mechanism of allopurinol on ACS might be achieved by suppressing the secretion and release of inflammatory mediators TNF-α, hs-CRP and SC OX-LDL, MDA and increasing the level of NO Acknowledgements: M AN U This study was supported by Shanghai Pudong New Area Science and Technology Development Fund Project (Project Number: PKJ2012-Y15) References [1] Andrikopoulos G, Terentes-Printzios D, Tzeis S, Vlachopoulos C, Varounis C, TE D Nikas N, Lekakis J, Stakos D, Lymperi S, Symeonidis D, Chrissos D, Kyrpizidis C, Alexopoulos D, Zombolos S, Foussas S, Kapparanidis A, Oikonomou K, Vasilikos V, Andronikos P, Dermitzakis A, Richter D, Fragakis N, Styliadis I, Mavridis S, EP Stefanadis C, Vardas P: Epidemiological characteristics, management and early outcomes of acute coronary syndromes in Greece: The PHAETHON study Hellenic J Cardiol 2016;57:157-166 AC C [2] Cannon, CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS at 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ECG effect between groups M AN U Table IV Comparison of cardiovascular events in groups Where CI is cardiac insufficiency, STCS is subacute thrombosis in coronary stent, LT is late thrombosis, RVS is revascularization surgery, CVD is cardiovascular deaths and CVEI is incidence of cardiovascular events Asterisk indicates a significant difference between allopurinol group and control EP TE D group (P < 0.05) ‐ ‐ AC C ‐ AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ...ACCEPTED MANUSCRIPT Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism Ying Huang*, Chunya Zhang, Zhiqing Xu, Jinghua Shen, Xiaogang... treatment of ACS and can improve the OS and inflammatory reaction indicators of patients The protective mechanism of allopurinol on ACS might be achieved by suppressing the secretion and release of inflammatory... atherosclerosis As the initial factor of AS, inflammation can result in regional neutrophil and monocyte infiltration and lipidosis, which is the principal cause of AC C coronary plaque disruption and hemorrhage,