Objectives: To investigate serum levels of some inflammatory markers (CRP-hs, C3, C4, and Interleukin (IL)-6 in patients with acute coronary syndrome (ACS). Subjects and Methods: Serum levels of CRP-hs, C3, C4, and IL-6 in blood samples taken from 100 patients with ACS (on hospital admission, and at 6 months after treatment) and 50 healthy people (served as normal controls) were quantified using immuno-chemiluminescense technique.
Journal of military pharmaco-medicine no1-2018 RESEARCH ON CHANGES IN LEVELS OF NON-SPECIFIC INFLAMMATORY MARKERS IN PATIENTS WITH ACUTE CORONARY SYNDROME Nguyen Thi Thanh Thuy*; Pham Nguyen Vinh**; Pham Manh Hung*** SUMMARY Objectives: To investigate serum levels of some inflammatory markers (CRP-hs, C3, C4, and Interleukin (IL)-6 in patients with acute coronary syndrome (ACS) Subjects and Methods: Serum levels of CRP-hs, C3, C4, and IL-6 in blood samples taken from 100 patients with ACS (on hospital admission, and at months after treatment) and 50 healthy people (served as normal controls) were quantified using immuno-chemiluminescense technique Results: Serum levels of CRP-hs, C3, C4, and IL-6 were significantly higher in patients with ACS compared to those in controls After months of conventional treatment, CRP-hs and IL-6 levels significantly decreased compared to those before treatment Conclusions: Serum level of IL-6 CRP-hs in patients with ACS reflected the treatment response, and thus, may serve as biomarkers for treatment evaluation in patients with ACS * Keywords: Coronary artery disease; Acute coronary syndrome; Inflammatory markers INTRODUCTIONS Coronary artery disease (CAD) is one of the diseases that has increased in prevalence and become more common in developed as well as developing countries, including Vietnam The disease is believed to account for a large number of death in hospital inpatients CAD includes ACS and stable coronary artery disease Pathogenesis of CAD involves artherosclerosis with damaged vessel wall of the coronary arteries, leading to vessel occlusion by thrombosis, and eventually, myocardial infarction [3, 8] Recent data showed that inflammation plays an important role in initiation as well as progression of ACS [6, 7]; investigation of level of inflammatory markers in serum of patients with ACS would be of importance in elucidating the pathogenesis of the disease Among the inflammatory markers, CRP-hs has been proven to be associated with the risk of cardiovascular events In addition to CRP, however, some other inflammatory markers may be involved in pathogenesis of the disease In the present study, we investigated the changes in serum level of complement C3, C4 and IL-6 in patients with acute coronary syndrome after treament, in order to determine a relationship between the inflammatory markers and the disease progression * Institute of Heart , Hochiminh City ** Pham Ngoc Thach Medical College *** Vietnam General Association of Medicine and Pharmacy Corresponding author: Nguyen Thi Thanh Thuy (thuylabo@yahoo.com) Date received: 03/11/2017 Date accepted: 18/12/2017 163 Journal of military pharmaco-medicine no1-2018 SBJECTS AND METHODS Subjects The study has been carried out on 100 patients with ACS, who hospitalized and treated at Institute of Heart, Hochiminh City during the period from October 2011 to October 2013, and 50 healthy people without ACS who have undergone medical examination at the Hospital at the same period of time, serving as controls * Inclusion criteria for patients: - Patients who were confirmatorily diagnosed to have ACS, and were indicated to undergo emergent coronary intervention - Patients who had one or more occluded coronary artery branches and were indicated to undergo coronary artery bypass surgery or coronary intervention - Patients with ACS who were indicated to undergo treatment by internal medicine * Exclusion criteria for patients: - Patients who were infected - Patients who had concurrent inflammatory diseases, such as arthritis, goute, bronchitis, etc * Selection criteria for controls: Healthy people who had periodical medical examination at the hospital during the period of the study, without cardiovascular diseases Methods * Study design: This is a prospective study, in which the patients’ samples were taken times: first time at hospital admission, and second 164 time at months after treatment, either by internal medicine or coronary intervention - Group 1: 100 patients with CAD - Group 2: 50 healthy people without cardiovascular diseases, serving as control group Among the CAD patients, 37 patients were followed for months after treatment at Institute of Heart Diseases, Hochiminh City * Studied parameters: - Serum level of inflammatory markers C3, C4, IL-6, and CRP-hs at hospital admission, measured by immunochemiluminescence assay (for C3, C4 and IL-6) or immunoturbidimetric method (for CRP-hs), using reagents from Roche Diagnostics - Data analysis: by STATA 12 statistical software RESULTS AND DISCUSSIONS Patients’ characteristics Among 100 CAD patients involved in the study, 66 (66%) were male The average age of the patients was 63.67 ± 11.7, which was believed to be the age of most prevalent of CAD, according to recent papers [9, 10] Among 37 patients being followed up after treatment, the average age of the patients was 63.0 ± 11.29, with 24/37 (65%) were male 15/37 patients (40.54%) had elevated ST on ECG; 18/37 patients (48.65%) had non-ST elevation, and 4/37 patients (10.8%) had ACS Journal of military pharmaco-medicine no1-2018 Serum levels of C3, C4 Table 1: Serum levels of C3 and C4 Patients group (n = 100) Control group (n = 50) p Mean ± SD Mean ± SD C3 (mg/dL) 130.326 ± 26.4 99.056 ± 17.9 < 0.001 C4 (mg/dL) 31.41 ± 9.01 22.332 ± 7.4 < 0.001 Serum levels of C3 and C4 in patient group were significantly higher than those in control group (p < 0.001) Serum levels of IL-6 and CRP-hs The levels of IL-6 and CRP-hs in serum samples from the CAD patients did not show a standard Gauss’s distribution pattern The median and 25, 75 percentile values of the IL-6 and CRP-hs levels were presented in table Table 2: Serum levels of IL-6 and CRP-hs IL-6 (pg/mL) CRP-hs (mg/L) Patient group (n = 100) Control group (n = 50) p Median [25%; 75%] Median [25%; 75%] 13.885 [6.11; 42.105] 1.5 [1.5; 1.65] < 0.001 7.6 [2.5; 31.25] 0.8 [0.3; 1.3] < 0.001 Median values of CRP and IL-6 levels in serum from patients were significantly higher than those from controls (p < 0.001) Relationship between levels of inflammatory markers C3, C4, IL-6 and CRP and patients’ status There was a significant relationship between serum levels of CRP and C4, IL6 (p < 0.001) However, no relationship between CRP and C3 levels was observed (p = 0.065) It was revealed by our data presented in this study that levels of C3, C4, IL-6 and CRP significantly elevated in patients with ACS, and there was close relationship between these parameters These results were in agreement with data published previously [8, 9]; particularly, the increase of serum IL-6 was also recently reported by Vu Tien Thang [5] IL-6 is a proinflammatory cytokine which has been intensively studied in recent years Serum level of IL-6 is elevated in various inflammatory diseases, including infection Although not a specific marker for ACS, the elevation of IL-6 may suggest a close relationship between inflammatory response and ACS By deeper researching, several authors have proposed a hypothesis that the inflammatory factors present in ACS may lead to artherosclerotic plaque rupture, which eventually causes myocardial infarction However, conclusive studies are needed, 165 Journal of military pharmaco-medicine no1-2018 since the myocardial ischemia as well as necrosis caused by myocardial infarction may trigger an inflammatory response On the other hand, it was believed by several other authors that changes in level of some inflammatory markers may help evaluating the disease's progression as well as prognosis, and thus, determination of inflammatory markers in serum maybe helpful in management of ACS [11] Serum levels of C3, C4 before and after treatment Table 3: Serum levels of C3 and C4 Before treatment After treatment p (n = 37) (n = 37) C3 (mg/dL) 133.86 ± 28.08 132.73 ± 22.4 0.7430 C4 (mg/dL) 32.7 ± 10.3 31.8 ± 7.8 0.3869 Serum levels of C3 and C4 after treatment and those before treatment were not significantly different (p = 0.7430 and 0.3869 for C3 and C4 levels, respectively) Serum levels of IL-6 and CRP-hs before and after treatment Table 4: Serum levels of IL-6 and CRP-hs IL-6 (pg/mL) CRP-hs (mg/L) Before treatment After treatment (n = 37) (n = 37) Median [25%; 75%] Median [25%; 75%] 16.59 [7.42; 45.69] 3.99 [2.89; 6.29] < 0.001 8.7 [3.4; 26.5] 1.3 [0.8; 3.5] < 0.001 Serum levels of IL-6 and CRP-hs after treatment significantly lower than those before treatment (p < 0.001), which was in agreement with data from Vu Tien Thang [4] A significant decrease in IL-6, CRP levels after treatment which was not similarly observed with C3 and C4 levels suggested a more specific association of IL-6 and CRP-hs levels in ACS than C3 and C4, and this requires further studies for more conclusive data Regarding the sources and roles of inflammatory factors, IL-6 stimulates 166 p hepatocytes to produce acute phase proteins, including CRP, during the acute phase of inflammatory repsonse IL-6 level is early elevated in most patients Previous studies indicated that serum IL-6 level elevated during the first days and then quickly declined; meanwhile, CRP level elevated later and remained high for longer time Serum C3 and C4 levels elevated during acute phase and declined after treatment, yet not significantly The increase in CRP, IL-6, C3 and C4 levels was in agreement with data previously published [8, 12] Journal of military pharmaco-medicine no1-2018 After months of treatment, a decline of all investigated inflammatory markers was observed in all ACS patient groups The severity of inflammation was likely to decrease due to effective anti-inflammatory therapy using both statin and aspirin CONCLUSIONS - There was a significant elevation in serum levels of C3, C4, IL-6 and CRP in patients with acute coronary syndrome - There was a significant relationship between the elevation of C4, IL-6 level and that of CRP, but not with the elevation of C3 and CRP - After treatment, IL-6 and CRP-hs levels significantly declined, but C3 and C4 levels did not REFERENCES Trương Quang Bình, Đặng Vạn Phước Lịch sử, dịch tễ học tầm quan trọng bệnh động mạch vành Bệnh động mạch vành thực hành lâm sàng Nhà xuất Y học 2006, tr.1-12 Trương Phi Hùng Nghiên cứu nồng độ C-reactive protein máu bệnh nhân hội chứng mạch vành cấp Trường Đại học Y Dược TP Hồ Chí Minh Luận văn Bác sỹ Nội trú 2005 Trần Thị Kim Thanh Khảo sát nồng độ hs-CRP nhồi máu tim cấp Hội nghị Khoa học kỹ thuật Bệnh viện Cấp cứu Trưng Vương 2008 Vũ Tiến Thăng, Nguyễn Oanh Oanh, Đặng Lịch Nghiên cứu nồng độ IL-6 IL-10 bệnh nhân nhồi máu tim cấp Tạp chí Y học Việt Nam 2015, số1, tập 426, tr.1-3 Phạm Nguyễn Vinh, Hồ Huỳnh Quang Trí Nhồi máu tim cấp: chẩn đốn điều trị Bệnh học tim mạch, tập Tái lần4 Nhà xuất Y học 2008, tr.78- 97 Januzzi James L Xét nghiệm chất điểm sinh học chẩn đoán phân tầng nguy hội chứng động mạch vành cấp Tài liệu Hội thảo Tim mạch thường niên lần thứ Roche Diagnostic 2010 Anil Palikhe, Juha Sinisalo, Mikko Seppanen Serum complement C3/C4 ratio, a novel marker for recurrent cardiovascular events American Journal of Cardiology 2007, 11, pp.890-895 A.L Pasqui, M Di Renzo, A Auteri Cytokines in acute coronary syndromes International Journal of Cardiology 2005, 105, pp.355-356 Biasucci L.M, Angiolillo D.J Inflammation in acute coronary syndromes: Mechanisms and clinical implications Rev Esp Cardiol 2004, 57, pp.433-436 10 Biswas S, Ghoshal P.K, Mandal S.C, Mandal N Relation of anti- to pro-inflammatory cytokine ratios with acute myocardial infarction Korean J Intern Med 2010, 25 (1), pp.44-50 11 Erling Falk, Masataka Nakano, Jacob Fog Bentzon, Aloke v Finn Renu Virmani Update on acute coronary syndromes: the pathologists’ view European Heart Journal 2013, 34, pp.719-728 12 Juan Carlos Kaski, Jose Maria cruz Fernandez Inflammation markers and risk stratification in patients with acute coronary syndromes Design of the SIESTA Study Rev Esp Cardiol 2003, 56, 4, pp.389-395 167 ... effective anti -inflammatory therapy using both statin and aspirin CONCLUSIONS - There was a significant elevation in serum levels of C3, C4, IL-6 and CRP in patients with acute coronary syndrome -... Auteri Cytokines in acute coronary syndromes International Journal of Cardiology 2005, 105, pp.355-356 Biasucci L.M, Angiolillo D.J Inflammation in acute coronary syndromes: Mechanisms and clinical... more conclusive data Regarding the sources and roles of inflammatory factors, IL-6 stimulates 166 p hepatocytes to produce acute phase proteins, including CRP, during the acute phase of inflammatory