Publications by authors named "Djordje Radak"

150 Publications

Association of overweight and obesity with cardiovascular risk factors in patients with atherosclerotic diseases.

J Med Biochem 2020 Jan;39(2):215-223

University of Belgrade, Faculty of Medicine, Institute of Hygiene and Medical Ecology, Belgrade.

Background: The aim of this study was to compare demographic, clinical and biochemical characteristics, including inflammatory markers, according to the nutritional status of patients with verified atherosclerotic disease.

Methods: This cross-sectional study involved 1045 consecutive patients with verified carotid disease or peripheral arterial disease (PAD). Anthropometric parameters and data on cardiovascular risk factors and therapy for hypertension and hyperlipidemia were collected for all participants.

Results: Carotid disease was positively and PAD was negatively associated with body mass index (BMI). Negative association between obesity and PAD was significant only in former smokers, not in current smokers or in patients who never smoked. Overweight and general obesity were significantly related to metabolic syndrome (p < 0.001), lower values of high - density lipoprotein cholesterol (p < 0.001), increased triglycerides (p < 0.001), hyperglycemia (p < 0.001), self-reported diabetes (p < 0.001), hypertension (p < 0.001), high serum uric acid (p < 0.001), increased high sensitivity C-reactive protein (p = 0.020) and former smoking (p = 0.005) after adjustment for age, gender and type of disease. Antihypertensive therapy seems to be less effective in patients who are overweight and obese.

Conclusions: In conclusion, overweight and general obesity were significantly related to several cardiovascular risk factors.
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http://dx.doi.org/10.2478/jomb-2019-0027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526015PMC
January 2020

Effects of Root on Vascular Diseases.

Curr Vasc Pharmacol 2021 ;19(4):359-369

"VINČA" Institute of Nuclear Sciences - National Institute of thе Republic of Serbia, University of Belgrade, Department of Radiobiology and Molecular Genetics, Belgrade, Serbia.

Background: Gentiana lutea (GL), commonly known as yellow gentian, bitter root, and bitterwort, belongs to family Gentianaceae. GL belongs to genus Gentiana, which is a rich natural source of iridoids, secoiridoids, xantones, flavonoids, triterpenoids, and carbohydrates. Medicinal plants from Gentiana species have anti-oxidant, anti-inflammatory, anti-mitogenic, anti-proliferative, and lipidlowering effects, as well as a cardioprotective, hypotensive, vasodilator and anti-platelet activities.

Objective: We reviewed the recent literature related to the effects of Gentiana species, and their active components on vascular diseases.

Methods: Data used for this review were obtained by searching the electronic database [PUBMED/ MEDLINE 1973 - February 2020]. The primary data search terms of interest were: Gentiana lutea, Gentienacea family, phytochemistry, vascular diseases, treatment of vascular diseases, antioxidant, anti-inflammatory, anti-atherogenic.

Conclusion: Gentiana species and their constituents affect many different factors related to vascular disease development and progression. Therefore, Gentiana-based therapeutics represent potentially useful drugs for the management of vascular diseases.
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http://dx.doi.org/10.2174/1570161118666200529111314DOI Listing
January 2021

Effect of Aging and Carotid Atherosclerosis on Multifractality of Dental Pulp Blood Flow Oscillations.

J Endod 2020 Mar 5;46(3):358-363. Epub 2020 Feb 5.

Department of Dental Pharmacology, School of Dental Medicine, University of Belgrade, Belgrade, Serbia.

Introduction: Age-related changes of dental pulp tissue and atherosclerosis of carotid arteries as its feeding arteries could influence the functionality of pulpal circulation. The objective of our study was to evaluate the effect of aging (physiological process) and carotid bifurcation atherosclerosis (pathologic process) on the pulpal microcirculatory system using multifractal analysis of the laser Doppler flowmetry signal.

Methods: Three groups of 10 subjects were enrolled in the study: the young group (healthy subjects, 20-25 years), the middle-aged group (healthy subjects, 50-60 years), and the clinical group (subjects with carotid bifurcation atherosclerosis, 50-60 years). Pulpal blood flow (PBF) signals recorded by laser Doppler flowmetry were assessed by multifractal analysis that estimates Hölder exponents of the signal. PBF levels, the average mean values, and the range of Hölder exponents were obtained.

Results: PBF levels were significantly higher in the young group compared with the middle-aged and clinical groups, and the difference between the middle-aged and clinical groups was not statistically significant. The range of the Hölder exponents was narrower in the middle-aged and clinical groups than in the young group and narrower in the clinical group than in the middle-aged group. The average mean value of Hölder exponents was significantly higher in the young group than in the middle-aged and clinical groups, whereas there was no significant difference between the middle-aged and clinical groups.

Conclusions: Our study investigating the multifractality of the PBF signal showed that the aging process and carotid atherosclerosis could affect the complex structure of PBF oscillations and contribute to a better understanding of pulpal hemodynamics.
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http://dx.doi.org/10.1016/j.joen.2019.12.008DOI Listing
March 2020

Regulation of nitric oxide production in hypothyroidism.

Biomed Pharmacother 2020 Apr 24;124:109881. Epub 2020 Jan 24.

Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia. Electronic address:

Hypothyroidism is a common endocrine disorder that predominantly occurs in females. It is associated with an increased risk of cardiovascular diseases (CVD), but the molecular mechanism is not known. Disturbance in lipid metabolism, the regulation of oxidative stress, and inflammation characterize the progression of subclinical hypothyroidism. The initiation and progression of endothelial dysfunction also exhibit these changes, which is the initial step in developing CVD. Animal and human studies highlight the critical role of nitric oxide (NO) as a reliable biomarker for cardiovascular risk in subclinical and clinical hypothyroidism. In this review, we summarize the recent literature findings associated with NO production by the thyroid hormones in both physiological and pathophysiological conditions. We also discuss the levothyroxine treatment effect on serum NO levels in hypothyroid patients.
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http://dx.doi.org/10.1016/j.biopha.2020.109881DOI Listing
April 2020

Antioxidant enzymes expression in lymphocytes of patients undergoing carotid endarterectomy.

Med Hypotheses 2020 Jan 3;134:109419. Epub 2019 Oct 3.

Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.

To remedy carotid artery stenosis and prevent stroke surgical intervention is commonly used, and the gold standard being carotid endarterectomy (CEA). During CEA cerebrovascular hemoglobin oxygen saturation decreases and when this decrease reaches critical levels it leads to cerebral hypoxia that causes neuronal damage. One of the proposed mechanism that affects changes during CEA and contribute to acute brain ischemia (ABI) is oxidative stress. The increased production of reactive oxygen species and reactive nitrogen species during ABI may cause an unregulated inflammatory response and further lead to structural and functional injury of neurons. Antioxidant activity are involved in the protection against neuronal damage after cerebral ischemia. We hypothesized that neuronal injury and poor outcomes in patients undergoing CEA may be results of oxidative stress that disturbed function of antioxidant enzymes and contributed to the DNA damage in lymphocytes.
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http://dx.doi.org/10.1016/j.mehy.2019.109419DOI Listing
January 2020

Endovascular treatment of different types of iliac occlusions-Results from an observational study.

PLoS One 2019 2;14(10):e0222893. Epub 2019 Oct 2.

School of Medicine, Belgrade University, Belgrade, Serbia.

Objective: The aim of this study was to evaluate the results of endovascular therapy on the treatment of different types of iliac occlusions.

Materials And Methods: A bi-center prospective, non-randomized study was conducted on 100 patients (mean age 59.14 ± 8.53; 64 men) who underwent endovascular treatment of iliac occlusive disease between January 2013 and November 2017. We evaluated baseline data, procedure, and follow-up results for the entire group, and according to Trans-Atlantic Inter-Society Consensus (TASC II) classification. The majority of patients (60%) were treated for severe claudication; 56 (56%) patients had TASC B occlusions, 28 patients TASC C, and 16 patients TASC D.

Results: The mean length of the occluded segments was 61.41 ± 35.15 mm. Procedural complications developed in 6 patients (6%). Mean ankle-brachial pressure index increased from 0.40 ± 0.12 preoperatively to 0.82 ± 0.16 postoperatively. The mean follow-up was 33.18 ± 15.03 months. After 1 and 5 years, the primary patency rates were 98% and 75.1%, and the secondary patency rate was 97% respectively. Regarding occlusion complexity there were no statistical significant differences in primary patency rates (TASC B vs. C vs. D: p = 0.19). There were no statistically significant differences in primary patency rates between patients in different clinical stages, as well as between the type of stents, and location of the occlusion.

Conclusion: In our study, endovascular treatment for iliac artery occlusions proved to be a safe and efficient approach with excellent primary and secondary patency rates regardless of the complexity of occlusions defined by TASC II classification. This study is aligned with the notion that in well selected patients, endovascular therapy can be the treatment of choice even in complex iliac lesions if performed by experienced endovascular interventionists in high volume centers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222893PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774573PMC
March 2020

The prevalence of polyvascular disease in patients with carotid artery disease and peripheral artery disease.

Kardiol Pol 2019 10 28;77(10):926-934. Epub 2019 Aug 28.

Institute of Hygiene and Medical Ecology,Faculty of Medicine, University of Belgrade, Belgrade, Serbia

Background: Cardiovascular disease remains the major cause of mortality in the Western World.

Aims: We aimed to assess the prevalence of polyvascular disease in patients with carotid artery disease and peripheral artery disease (PAD), and to determine the risk profile of patients with polyvascular disease.

Methods: The study included 1045 consecutive patients presenting to our department with carotid disease or PAD. Demographic characteristics, anthropometric parameters, and data on cardiovascular risk factors were collected in all patients. On the basis of medical history, patients were classified into those who had only symptomatic carotid disease or symptomatic PAD and those who had symptomatic polyvascular disease.

Results: Carotid disease alone was reported in 366 participants (35%), PAD alone, in 199 (19%), and polyvascular disease, in 480 (46%). Compared with carotid disease, PAD was more often a component of polyvascular disease (P = 0.002) and was combined with a higher number of other atherosclerotic diseases (P = 0.02). Compared with patients with symptomatic atherosclerotic disease in only 1 territory, patients with various types of polyvascular disease more often had hypertension (P from 0.03 to <0.001), dyslipidemia (P <0.001), high‑sensitivity C‑reactive protein levels of 3 mg/l or higher (P = 0.005), and more often were current smokers (P <0.001) or former smokers (P from 0.03 to 0.001).

Conclusions: We showed a high prevalence of symptomatic polyvascular disease in patients with carotid disease or PAD. The risk profile was worse in patients with polyvascular disease than in those with a disease in a single vascular territory.
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http://dx.doi.org/10.33963/KP.14945DOI Listing
October 2019

The Obesity-associated Risk in Open and Endovascular Repair of Abdominal Aortic Aneurysm.

Curr Pharm Des 2019 ;25(18):2033-2037

Vascular Surgery Clinic, "Dedinje" Cardiovascular Institute, Belgrade, Serbia.

The rising pandemic of obesity in modern society should direct attention to a more comprehensive approach to abdominal aortic aneurysm (AAA) treatment in the affected population. Although overweight patients are considered prone to increased surgical risk, studies on the subject did not confirm or specify the risks well enough. Associated comorbidities inevitably lead to a selection bias leaning towards endovascular abdominal aortic repair (EVAR), as a less invasive treatment option, which makes it hard to single out obesity as an independent risk factor. The increased technical difficulty often results in prolonged procedure times and increased blood loss. Several smaller studies and two analyses of national registries, including 7935 patients, highlighted the advantages of EVAR over open repair (OR) of abdominal aortic aneurysm, especially in morbidly obese population (relative risk reduction up to 47%). On the other hand, two other studies with 1374 patients combined, concluded that EVAR might not have an advantage over OR in obese patients (P = 0.52). Obesity is an established risk factor for wound infection after both EVAR and OR, which is associated with longer length of stay, subsequent major operations, and a higher rate of graft failure. Percutaneous EVAR technique could present a promising solution to reducing this complication. EVAR seems like a more feasible treatment option than OR for obese patients with AAA, due to lower overall morbidity and mortality rates, as well as reduced wound-related complication rates. However, there is a clear lack of high-quality evidence on the subject, thus future prospective trials are needed to confirm this advantage.
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http://dx.doi.org/10.2174/1381612825666190710112844DOI Listing
March 2020

Glutathione "Redox Homeostasis" and Its Relation to Cardiovascular Disease.

Oxid Med Cell Longev 2019 9;2019:5028181. Epub 2019 May 9.

Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.

More people die from cardiovascular diseases (CVD) than from any other cause. Cardiovascular complications are thought to arise from enhanced levels of free radicals causing impaired "redox homeostasis," which represents the interplay between oxidative stress (OS) and reductive stress (RS). In this review, we compile several experimental research findings that show sustained shifts towards OS will alter the homeostatic redox mechanism to cause cardiovascular complications, as well as findings that show a prolonged antioxidant state or RS can similarly lead to such cardiovascular complications. This experimental evidence is specifically focused on the role of glutathione, the most abundant antioxidant in the heart, in a redox homeostatic mechanism that has been shifted towards OS or RS. This may lead to impairment of cellular signaling mechanisms and elevated pools of proteotoxicity associated with cardiac dysfunction.
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http://dx.doi.org/10.1155/2019/5028181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532282PMC
December 2019

IL-33/IL-33R in various types of carotid artery atherosclerotic lesions.

Cytokine 2019 08 24;120:242-250. Epub 2019 May 24.

Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia. Electronic address:

Objective: Inflammation plays a crucial role in the progression of atherosclerotic plaques. The aim of the study was to investigate serum levels and expression of Interleukin-33 (IL-33) and ST2 receptor in atherosclerotic plaques and to analyze correlation with the type of the carotid plaques in patients with carotid disease.

Methods: This study included 191 consecutive patients submitted for carotid endarterectomy (CEA). Preoperative serum levels of IL-33 and soluble ST2 (sST2) were measured. Atherosclerotic plaques obtained during surgery were initially histologically classified and immunohistochemical analyzes of IL-33, IL-33R, CD68 and alpha-SMA expression was performed. Ultrasound assessment of the level of carotid stenosis in each patient was performed prior to carotid surgery. Demographic and clinical data such as gender, age, smoking status, blood pressure, glycaemia, hemoglobin and creatinine levels, and comorbidities were collected and the comparisons between variables were statistically evaluated.

Results: Serum levels of IL-33 (35.86 ± 7.93 pg/ml vs.12.29 ± 1.8 pg/ml, p < 0.05) and sST2 (183 ± 8.03 pg/ml vs. 122.31 ± 15.89 pg/ml, p < 0.05) were significantly higher in the group of CEA patients vs. healthy subjects. We demonstrated abundant tissue expression of IL-33 and ST2 in atherosclerotic carotid artery lesions. The levels of IL-33 and IL-33R expression were significantly higher in vulnerable plaques and significantly correlated with the degree of inflammatory cells infiltration in these plaques (R = 0.579, p = 0.049). Immunohistochemical analysis also revealed that cells responsible for IL-33 expression are not only mononuclear cells confined to inflammatory atherosclerotic lesions, but also smooth muscle cells which gained phenotypic characteristics of foam cells and were loaded with lipid droplets.

Conclusion: The obtained results confirm the importance of IL-33/ST2 axis in the process of atherosclerosis, and indicate its ambiguous function in immune response, whether as proinflammatory cytokine in advanced atherosclerotic lesions, or as profibrotic, in early lesions.
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http://dx.doi.org/10.1016/j.cyto.2019.05.010DOI Listing
August 2019

Surgical Treatment of Proximal Segmental Occlusion of the Internal Carotid Artery.

Surg Res Pract 2019 2;2019:2976091. Epub 2019 Jan 2.

Department of Vascular Surgery, Institute for Cardiovascular Disease "Dedinje", Belgrade, Serbia.

Purpose: To present the feasibility, safety, and efficacy of carotid endarterectomy in patients with type II internal carotid artery occlusions, including the long-term outcomes.

Methods: From March 2008 to August 2015, 74 consecutive patients (48 men with a mean age of 65.1 ± 8.06 years) underwent carotid endarterectomy because of internal carotid artery (ICA) segmental occlusions. These were verified with preoperative carotid duplex scans (CDS) and CT angiography (CTA). Also, brain CT scanning was performed in all these patients. The indication for treatment was made jointly by a vascular surgeon, neurologist, and an interventional radiologist in a multidisciplinary team (MDT) context. After successful treatment, all the patients were followed-up at 1, 3, 6, and 12 months, then every 6 months thereafter.

Results: The most common symptom at presentation was transient ischaemic attack (TIA) in 49 patients (66.2%), followed by stroke in the past six months in the 17 remaining patients (23%). Revascularisation of the ICA with endarterectomy techniques was performed successfully in all the patients with an average clamp time of 11.9 min. All the procedures were performed under general anaesthesia in combination with a superficial cervical block. The early complication rate was 8.1% and included two cardiac events (2.7%) (one rhythm disorder and one acute coronary syndrome), three TIAs (4.1%), and one intracerebral hemorrhage (1.3%). Only one patient with the intracerebral hemorrhage died 5 days after surgery giving a postoperative mortality of 1.3% for this series. During the follow-up period (mean 50.4 ± 31.3 months), the primary patency rates at 1, 3, 5, and 7 years were 98.4%, 94.9%, 92.9%, and 82.9%, respectively. Likewise, the survival rates were 98.7%, 96.8%, 89%, and 77.6%, respectively. Ultrasound Doppler controls during follow-up detected 8 ICA restenoses; however, only 3 of these patients required further endovascular treatment.

Conclusions: Carotid endarterectomy of internal carotid artery (ICA) segmental occlusion is a safe and effective procedure associated with acceptable risk and good long-term results. Therefore, the current guidelines which do not recommend carotid endarterectomy in this patient group should be reassessed, with the requirement for ongoing large-scale randomized controlled trials to compare CEA with best medical therapy in this patient cohort.
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http://dx.doi.org/10.1155/2019/2976091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334308PMC
January 2019

Genetic Markers for Coronary Artery Disease.

Medicina (Kaunas) 2018 May 28;54(3). Epub 2018 May 28.

Laboratory of Radiobiology and Molecular Genetics, Institute of Nuclear Science Vinca, University of Belgrade, 11000 Belgrade, Serbia.

Coronary artery disease (CAD) and myocardial infarction (MI) are recognized as leading causes of mortality in developed countries. Although typically associated with behavioral risk factors, such as smoking, sedentary lifestyle, and poor dietary habits, such vascular phenotypes have also long been recognized as being related to genetic background. We review the currently available data concerning genetic markers for CAD in English and non-English articles with English abstracts published between 2003 and 2018. As genetic testing is increasingly available, it may be possible to identify adequate genetic markers representing the risk profile and to use them in a clinical setting.
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http://dx.doi.org/10.3390/medicina54030036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122104PMC
May 2018

Cyanoacrylate Embolization: A Novelty in the Field of Varicose Veins Surgery.

Ann Vasc Surg 2019 Feb 10;55:285-291. Epub 2018 Aug 10.

Vascular surgery Clinic, "Dedinje" Cardiovascular Institute, Belgrade, Serbia.

In the past 2 decades, varicose veins surgery went through a great turbulence and various innovations. A number of new techniques have been introduced with a goal to increase the success rate, reduce the periprocedural complications and, overall, to improve patients' quality of life. The latest of them, named cyanoacrylate embolization (CAE) technique, threatens to shake the glory of the currently well-established endovenous methods. We have analyzed all previous studies by searching MEDLINE base using PubMed. Although the idea of using n-butyl cyanoacrylate (NBCA) glue in medical purposes was not new, the very first in vivo and animal experiments using NBCA for vein closure were conducted just at the beginning of this millennium. The results of these studies gave warranty to begin with the first interventions in humans. Early studies reported very high success rates of more than 90%, with the longest follow-up period of 36 months. There were no major adverse events reported, while the minor ones-mostly phlebitic reactions-were defined as mild to moderate. The newest head-to-head studies showed that CAE is a noninferior technique to other endovenous methods, with higher occlusion rates and fewer adverse events. Short procedure time and no need for tumescent anesthesia or compressive stockings reduce patients' discomfort to the minimum and definitely seem to be a step forward answering the modern "walk in-walk out surgery" demands. As an easily handling technique, CAE undoubtedly pierces its path to the top of varicose veins surgery but more head-to-head clinical trials with longer follow-up periods are necessary to obtain a plain picture.
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http://dx.doi.org/10.1016/j.avsg.2018.06.009DOI Listing
February 2019

The Effect of Vacuum-Assisted Closure Therapy on Methicillin-Resistant Staphylococcus aureus Wound Biofilms.

Adv Skin Wound Care 2018 Aug;31(8):361-364

In Belgrade, Serbia, Ivana Ćirković, MD, PhD, is Professor of Microbiology, Institute of Microbiology, University of Belgrade; Dario Jocić, MD, MS, is a vascular surgeon, Institute of Cardiovascular Diseases; Dragana D. Božić, MD, PhD, is Professor of Microbiology, Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade; Slobodanka Djukić, MD, PhD, is Professor of Microbiology, Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade; Neda Konstantinović, MD, is a medical doctor, Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade; and Djordje Radak, MD, PhD, is Chief of Vascular Surgery, Institute of Cardiovascular Diseases, and Professor of Surgery, Faculty of Medicine, University of Belgrade. Acknowledgments: This research was supported by the Ministry of Education, Science and Technological Development, Republic of Serbia (project no. ON175039).

Biofilm-associated wound infections are a major global health issue, and methicillin-resistant Staphylococcus aureus (MRSA) is among the greatest therapeutic challenges. Vacuum-assisted closure (VAC) therapy is now being revisited as an alternative treatment for both acute and chronic wounds. However, data supporting the concept of its antibiofilm effect remain limited. Using quantitative biofilm-forming assay and a range of genotypic methods (spa, SCCmec, and agr typing), study authors showed that VAC therapy can significantly prevent biofilm formation (P < .01) of a range of MRSA wound isolates differing widely in their biofilm-forming abilities and genetic background. The best effect was presented on CC5-MRSA-SCCmecI-agrII, a dominant MRSA clone among wound isolates worldwide. An assessment of effects of different protocols on dressing changes (1 or 2 times per week) demonstrated significantly greater antibiofilm activity (P < .05) of 3-day dressing changes. These findings support the use of VAC therapy as a topical antibiofilm treatment for the effective management of wound healing.
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http://dx.doi.org/10.1097/01.ASW.0000540070.07040.70DOI Listing
August 2018

Scoring system to predict early carotid restenosis after eversion endarterectomy by analysis of inflammatory markers.

J Vasc Surg 2018 07 1;68(1):118-127. Epub 2018 Mar 1.

Clinic for Vascular Surgery, University Hospital Zurich, Zurich, Switzerland; Medical Faculty, University of Zurich, Zurich, Switzerland.

Background: Inflammation is one of the mechanisms that leads to carotid restenosis (CR). The aim of this study was to examine the influence of increased values of inflammation markers (high-sensitivity C-reactive protein [hs-CRP], C3 complement, and fibrinogen) on CR development after eversion carotid endarterectomy (CEA).

Methods: A consecutive 300 patients were included in the study, in which eversion CEA was performed between March 1 and August 1, 2010. Demographic data, atherosclerosis risk factors, comorbidities, and ultrasound plaque characteristics were listed in relation to potential risk factors for CR. Serum concentrations of hs-CRP, fibrinogen, and C3 complement were taken just before surgery (6 hours); 48 hours after CEA; and during regular checkups at 1 month, 6 months, 1 year, and 2 years. An "inflammatory score" was also created, which consisted of six predictive values of inflammatory markers (hs-CRP just before and just after CEA, fibrinogen just before and just after CEA, and C3 complement just before and just after CEA) with a maximum score of 6 and a minimum score of 0. At every follow-up visit to the outpatient clinic, ultrasound assessment of the carotid artery for restenosis was done.

Results: Our results showed an increased risk of early CR within 1 year in patients with increased hs-CRP before CEA (6 hours) and increased fibrinogen 48 hours after surgery and in patients not taking aspirin after CEA. Sex was determined to be an independent predictor of CR, with female patients having a higher risk (P = .002). Male patients taking aspirin with an inflammatory score >2 had an increased risk for restenosis compared with male patients with inflammatory score <2. Not taking aspirin after CEA and fibrinogen (48 hours) were the strongest predictors, and the Fisher equation incorporating these predictors was used to predict CR. A computer program was created to calculate whether the patient was at high or low risk for CR by selecting whether the patient was taking aspirin (yes or no) and whether fibrinogen was increased 48 hours after CEA (yes or no) and to display the recommended therapeutic algorithm consisting of aspirin, clopidogrel, cilostazol, and statins.

Conclusions: Increased hs-CRP before CEA, increased fibrinogen 48 hours after CEA, and not taking aspirin were the main predictors of early CR. With the clinical implementation of the Fisher equation, it is possible to identify patients at high risk for early CR and to apply an aggressive therapeutic algorithm, finally leading to a decreased CR rate.
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http://dx.doi.org/10.1016/j.jvs.2017.09.054DOI Listing
July 2018

The Significance of Pain in Chronic Venous Disease and its Medical Treatment.

Curr Vasc Pharmacol 2019 ;17(3):291-297

Laboratory of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.

Chronic venous disease (CVeD) is a highly prevalent condition in the general population, and it has a significant impact on quality of life. While it is usually manifested by obvious signs, such as varicose veins and venous ulcers, other symptoms of the disease are less specific. Among the other symptoms, which include heaviness, swelling, muscle cramps and restless legs, pain is the symptom that most frequently compels CVeD patients to seek medical aid. However, there is a substantial discrepancy between pain severity and clinically detectable signs of CVeD, questioned by several opposing studies. Further evaluation is needed to clarify this subject, and to analyse whether pain development predicts objective CVeD progression. General management of CVeD starts with advising lifestyle changes, such as lowering body mass index and treating comorbidities. However, the mainstay of treatment is compression therapy, with the additional use of pharmacological substances. Venoactive drugs proved to be the drugs of choice for symptom alleviation and slowing the progression of CVeD, with micronized purified flavonoid fraction being the most effective one. Interventional therapy is reserved for advanced stages of the disease.
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http://dx.doi.org/10.2174/1570161116666180209111826DOI Listing
May 2020

A Novel Antegrade Approach for Simultaneous Carotid Endarterectomy and Angioplasty of Proximal Lesions in Patients with Tandem Stenosis of Supraaortic Arch Vessels.

Ann Vasc Surg 2017 Oct 24;44:368-374. Epub 2017 May 24.

Vascular Surgery Clinic, "Dedinje" Cardiovascular Institute, Belgrade, Serbia; School of Medicine, Belgrade University, Belgrade, Serbia.

Background: To date, all published studies analyzing simultaneous treatment of carotid and proximal atherosclerotic lesions are describing retrograde approach and several technical variations. In the presented study, for the first time, antegrade approach is described for simultaneous carotid endarterectomy (CEA) and associated brachiocephalic trunk (BCT) or common carotid artery (CCA) angioplasty in the hybrid operating room.

Methods: From January 2012 till January 2016, antegrade hybrid procedures were performed in 18 patients. All patients were admitted to our institute for elective supraaortic arch multidetector computed tomography angiography when significant simultaneous proximal and distal supraaortic arch lesions were revealed. After surgical exposure of carotid arteries, proximal lesions were crossed by antegrade approach. Prior to stent placement, internal carotid artery (ICA) is clamped at its origin with the guidewire placed in the external carotid artery (ECA). After primary stenting and control arteriography, CCA and ECA are clamped and the ICA clamp moved more distally. An arteriotomy is performed in the CCA, with flushing of possible debris and thrombus before performance of the eversion CEA, once again flushing before completion of the anastomosis. Follow-up ranged from 6 to 36 months with average follow-up of 22.15 ± 11.31 months.

Results: All procedures went uneventfully. Out of 18 patients, 11 were males and 7 females, mean age 66.6 ± 3.82 years. In 10 patients (55.5%), simultaneous CEA and CCA angioplasty was performed, in 7 patients (38.9%) CEA and BCT angioplasty, and in 1 patient (5.5%) tubular graft interposition between the CCA and the ICA and CCA angioplasty. In 6 patients (33.3%), CCA/BCT balloon angioplasty alone was performed simultaneously with CEA. None of the patient had postoperative transient ischemic attack, stroke, hematoma, dissection, myocardial infarction, or ischemia in the early postoperative period and during the follow-up. There were no lethal outcomes, neither in the early postoperative course nor during the follow-up.

Conclusions: Antegrade approach for simultaneous treatment of proximal CCA/BCT and distal carotid lesions with temporary ICA clamping is safe and feasible procedure that should be thought of in the future in addition to already described retrograde approach.
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http://dx.doi.org/10.1016/j.avsg.2017.05.023DOI Listing
October 2017

Vascular Age as a Predictor of Side Effects After Facial Lipofilling.

Aesthetic Plast Surg 2017 Jun 4;41(3):729-737. Epub 2017 Apr 4.

Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Visegradska 26, Belgrade, 11000, Serbia.

Background: Vascular age (VA) represents chronological age adjusted for an individual's atherosclerotic burden. Keeping in mind the fact that facial vascularization could influence the success of esthetic interventions, we aimed to investigate the predictive value of VA in development of side effects following facial lipofilling.

Methods: In the period from October 1, 2014, to October 1, 2015, 106 consecutive subjects who underwent a facial lipofilling were included in the study. The VA was calculated using two approaches: Systematic Coronary Risk Evaluation (SCORE) project equations and means of vascular parameters assessed by color duplex sonographic examinations. The data regarding facial lipofilling-related complications (pain, edema and/or hematoma) have been collected during the regular checkups over 2 weeks after intervention.

Results: The average chronological age of the participants was 50.9 ± 9.4 years. Estimation of VA using vascular sonographic parameters revealed the value of 45.4 ± 29.1 years, whereas the assessment of VA using SCORE equations showed that the mean age was 53.7 ± 12.7 (p = 0.006). The total frequency of these complications was as follows: 6.6% for hematoma, 15.1% for edema (13.2% mild edema and 1.9% severe edema) and 20.8% for local facial pain (17.0% mild pain and 3.8% severe pain). The multivariate logistic regression models showed that VA had statistically significant (p < 0.01) independent prognostic value for facial lipofilling-related appearance of hematoma and pain.

Conclusions: The results of our study revealed that advanced VA has an independent predictive role in the appearance of complications following facial plastic surgery.

Level Of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-017-0852-9DOI Listing
June 2017

Awareness and knowledge of cardiovascular disease risk factors among medical students.

Wien Klin Wochenschr 2017 Jul 29;129(13-14):458-463. Epub 2017 Mar 29.

Department of Vascular Surgery, Dedinje Cardiovascular Institute, Belgrade, Serbia.

Background: The aim of this study was to assess the knowledge and attitude of medical students in relation to cardiovascular disease (CVD) risk factors as well as to assess the impact of medical education on their knowledge and recognition of the importance of implementation of preventive measures.

Methods: This cross-sectional study included 514 students in the second year of studying at the Faculty of Medicine in Belgrade, Serbia (younger students response rate 79.57%) and 511 students in the last year of education (older students response rate 90.21%). For data collection, an anonymous self-administered questionnaire was used, which included two types of questions about CVD risk factors and questions about the student's attitude.

Results: Older students knew significantly more about CVD risk factors than students who were at the beginning of their medical studies; however, more than half of the older students did not know the correct answers about CVD risk factors. The only exceptions were questions about "bad" and "good" cholesterol, metabolic syndrome (MSy) and lipid lowering therapy in high risk subjects. Physical inactivity, obesity, type 2 diabetes, smoking and hypertension were not ranked highly enough as important CVD risk factors. Compared groups of students did not significantly differ in attitude scores. The majority of them recognized CVD as the leading cause of death, had normal weight and knew their own blood pressure.

Conclusion: Knowledge of medical students from Belgrade about CVD risk factors should be improved.
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http://dx.doi.org/10.1007/s00508-017-1192-0DOI Listing
July 2017

Carotid endarterectomy has significantly lower risk in the last two decades: should the guidelines now be updated?

J Cardiovasc Surg (Torino) 2018 Aug 9;59(4):586-599. Epub 2017 Feb 9.

Vascular Surgery Clinic, "Dedinje" Cardiovascular Institute, Belgrade, Serbia -

Carotid endarterectomy (CEA) carries a significant risk of procedural stroke and death Guidelines recommend keeping this risk below 6% and below 3% for symptomatic and asymptomatic patients respectively. After analyzing our Institute's CEA results during the past 25 years, we found the rate of postoperative complications was now well below Guideline thresholds. Accordingly, we studied temporal changes in procedural risks in randomized controlled trials (RCTs) and in large observational studies in order to compare these against Guidelines. We found a clear temporal trend towards improving procedural outcomes, which can be explained by improvements in medical therapy, more appropriate timing of CEA, the use of local anesthesia and the use of peroperative cerebral monitoring as well as improving surgical techniques. An update of current guidelines should now be undertaken, since our findings are not unique and are supported by other studies in this review.
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http://dx.doi.org/10.23736/S0021-9509.17.09742-7DOI Listing
August 2018

Should We be Concerned About the Inflammatory Response to Endovascular Procedures?

Curr Vasc Pharmacol 2017 ;15(3):230-237

Institute of Nuclear Sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, P.O.Box 522, 11000 Belgrade, Serbia.

Endovascular surgery represents a minimally invasive procedure for the treatment of occlusive and aneurysmal arterial disease. However, it is followed by inflammatory response, with a rise in specific inflammatory biomarkers, such as C-reactive protein, serum amyloid A and fibrinogen. Shear stress during balloon inflation and vascular injury represents triggering events for the inflammatory process, stimulating the production of proinflammatory molecules and activation of circulating monocytes. The current literature indicates that stent implantation induces more prominent inflammatory reaction. Additionally, it has been shown that muscular arteries of femoropopliteal segment react to a greater extent to stent implantation, compared with elastic carotid or iliac arteries. The endovascular treatment of thoracic and abdominal aortic aneurysm is frequently followed with post-implantation inflammatory syndrome. Most recent findings point out that stent graft material plays a significant role in the inflammatory response, representing a challenge for clinicians. Future studies should consider the pathophysiology of the inflammatory response associated with endovascular procedures as well as predictors and risk factors including preventive strategies and therapeutic algorithms. Although the potential role of anti-inflammatory drugs after endovascular procedures has been observed, it needs to be validated in upcoming trials. The Neutrophil Lymphocyte Ratio, platelet count, Platelet-to-Lymphocyte Ratio and other biomarkers should be considered in future trials to assess the inflammatory response after endovascular procedures. Inflammatory markers may also become therapeutic targets.
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http://dx.doi.org/10.2174/1570161115666170105121900DOI Listing
December 2017

Apoptosis and Acute Brain Ischemia in Ischemic Stroke.

Curr Vasc Pharmacol 2017 ;15(2):115-122

Laboratory of Radiobiology and Molecular Genetics, Institute Vinca, University of Belgrade, P.O.Box 522, 11000 Belgrade, Serbia.

Apoptosis may contribute to a significant proportion of neuron death following acute brain ischemia (ABI), but the underlying mechanisms are still not fully understood. Brain ischemia may lead to stroke, which is one of the main causes of long-term morbidity and mortality in both developed and developing countries. Therefore, stroke prevention and treatment is clinically important. There are two important separate areas of the brain during ABI: the ischemic core and the ischemic penumbra. The ischemic core of the brain experiences a sudden reduction of blood flow, just minutes after ischemic attack with irreversible injury and subsequent cell death. On the other hand, apoptosis within the ischemic penumbra may occur after several hours or days, while necrosis starts in the first hours after the onset of ABI in the ischemic core. ABI is characterized by key molecular events that initiate apoptosis in many cells, such as overproduction of free radicals, Ca2+ overload and excitotoxicity. These changes in cellular homeostasis may trigger either necrosis or apoptosis, which often depends on cell type, cell age, and location in the brain. Apoptosis results in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells. This review focuses on recent findings based on animal and human studies regarding the apoptotic mechanisms of neuronal death following ABI and the development of potential neuroprotective agents that reduce morbidity. The effects of statins on stroke prevention and treatment as well as on apoptotic mediators are also considered.
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http://dx.doi.org/10.2174/1570161115666161104095522DOI Listing
December 2017

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats.

Curr Vasc Pharmacol 2017 ;15(5):491-500

Institute of Nuclear Sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, P.O. Box 522, 11000 Belgrade. Serbia.

Background: Overexpression of inducible nitric oxide synthase (iNOS) is a key link between high-fat (HF) diet induced obesity and cardiovascular disease. Oestradiol has cardioprotective effects that may be mediated through reduction of iNOS activity/expression.

Methods: In the present study, female Wistar rats were fed a standard diet or a HF diet (42% fat) for 10 weeks. iNOS gene and protein expressions were measured in heart tissue. HF-fed rats exhibited a significant increase in cardiac iNOS mRNA by 695% (p<.05), iNOS protein level by 248% (p<0.01), without changes in nitrate/nitrite levels. Expression of CD36 protein in plasma membranes was increased by 37% (p<0.05), while the concentration of free fatty acids (FFA) was reduced by 25% (p<0.01) in HF-fed rats. Expression of the p50 subunit of nuclear factor-kB (NFkB-p50) in heart was increased by 77% (p<0.01) in HF-fed rats. Expression of protein kinase B (Akt) and extracellular signalregulated kinases 1/2 (ERK1/2) were unchanged between the groups. There was a significant increase in the ratio of phospho-Akt/total Akt but not for phospho-ERK1/2/total ERK1/2 in HF-fed rats. Estrogen receptor-α levels (by 50%; p<0.05) and serum oestradiol concentrations (by 35%; p<0.05) were shown to be significantly reduced in HF-fed rats.

Results And Conclusion: Our results revealed that a HF diet led to increased iNOS expression, most likely via a mechanism involving Akt and NFκB-p50 proteins. Decreased levels of oestradiol and ERα protein in the HF-fed group, in combination with increased iNOS levels are consistent with the hypothesis that oestradiol has a cardioprotective effect through its ability to regulate iNOS expression.
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http://dx.doi.org/10.2174/1570161114666161025101303DOI Listing
May 2018

Negative-pressure wound therapy for deep groin vascular infections.

Srp Arh Celok Lek 2016 Nov-Dec;144(11-12):621-5

Introduction: Infection of synthetic graft in the groin is a rare but devastating complication. When it occurs, several possibilities of treatment are available. Extra-anatomic reconstruction and in-situ implantation of new, infection resistant grafts are associated with high mortality and morbidity. Therefore, more conservative approach is needed in some cases. Negative-pressure wound therapy is one of the options in treating such patients.

Objective: The aim of this study was to assess the outcome for deep groin vascular graft infection treated with negative-pressure wound therapy.

Methods: Seventeen patients (19 wounds), treated for Szilagyi grade III groin infections between October 2011 and June 2014, were enrolled into this observational study.

Results: Majority of the wounds (11/19) were healed by secondary intention, and the rest of the wounds (8/19) were healed by primary intention after initial negative-pressure wound therapy and graft substitution with silver-coated prostheses or autologous artery/vein implantation. No early mortality was observed. Minor bleeding was observed in one patient. Reinfection was noted in three wounds. Only one graft occlusion was noted. Late mortality was observed in three patients.

Conclusion: Negative-pressure wound therapy seems to be safe for groin vascular graft infections and comfortable for both patient and surgeon. However, the rate of persistent infection is high. This technique, in our opinion, can be used as a “bridge” from initial wound debridement to definitive wound management, when good local conditions are achieved for graft substitution, either with new synthetic graft with antimicrobial properties or autologous artery/vein. In selected cases of deep groin infections it can be used as the only therapeutic approach in wound treatment.
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May 2018

Regarding "Retrograde stenting of proximal lesions with carotid endarterectomy increases risk".

J Vasc Surg 2016 11;64(5):1546-1547

Vascular Surgery Clinic, "Dedinje" Cardiovascular Institute, Belgrade, Serbia; School of Medicine, Belgrade University, Belgrade, Serbia.

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http://dx.doi.org/10.1016/j.jvs.2016.05.091DOI Listing
November 2016

Link between Metabolic Syndrome and Insulin Resistance.

Curr Vasc Pharmacol 2017 ;15(1):30-39

Institute of Nuclear Sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, P.O.Box 522, 11000 Belgrade, Serbia.

Metabolic syndrome (MetS) is a leading public health and clinical challenge worldwide. MetS represents a group of interrelated risk factors that predict cardiovascular diseases (CVD) and diabetes mellitus (DM). Its prevalence ranges between 10 and 84%, depending on the geographic region, urban or rural environment, individual demographic characteristics of the population studied (sex, age, racial and ethnic origin), as well as the criteria used to define MetS. Persons with MetS have higher mortality rate when compared with people without MetS, primarily caused by progressive atherosclerosis, accelerated by pro-inflammatory and pro-coagulation components of MetS. Considering the high prevalence of metabolic disorders (glucose metabolism disorder, hypertension, dyslipidaemia, obesity etc.), preventive healthcare should focus on changing lifestyle in order to reduce obesity and increase physical activity. This narrative review considers the available evidence from clinical and experimental studies dealing with MetS, and current treatment options for patients with insulin resistance and MetS.
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http://dx.doi.org/10.2174/1570161114666161007164510DOI Listing
October 2017

Rare case of inferior mesenteric artery aneurysm with associated pelvic arteriovenous malformation.

ANZ J Surg 2018 11 9;88(11):1202-1203. Epub 2016 Oct 9.

Vascular Surgery Clinic, 'Dedinje' Cardiovascular Institute, Belgrade, Serbia.

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http://dx.doi.org/10.1111/ans.13788DOI Listing
November 2018

Treatment of stump complications after above-knee amputation using negative-pressure wound therapy.

Srp Arh Celok Lek 2016 Sep-Oct;144(9-10):503-6

Introduction: The stump wound complications after above-knee amputation lead to other problems, such as prolonged rehabilitation, delayed prosthetic restoration, the increase in total treatment cost and high mortality rates.

Objective: To evaluate the safety and outcomes of negative-pressure wound therapy (NPWT) using Vacuum-Assisted Closure (VAC®) therapy in patients with stump complication after above-knee amputation (AKA).

Methods: From January 2011 to July 2014, AKA was performed in 137 patients at the University Cardiovascular Clinic. Nineteen (12.4%) of these patients (mean age 69.3 ± 9.2 years) were treated with NPWT. The following variables were recorded: wound healing and hospitalization time, rate of NPWT treatment failure, and mortality.

Results: AKA was performed in 17 (89.5%) patients after the vascular or endovascular procedures had been exhausted, while urgent AKA was performed in two (10.5%) patients due to uncontrolled infection. The time before NPWT application was 3.1 ± 1.9 days and the duration of the NPWT use ranged from 15 to 54 days (mean 27.95 ± 12.1 days). During NPWT treatment, operative debridement was performed in 12 patients. All the patients were kept on culture-directed intravenous antibiotics. The average hospital length of stay was 34.7 days (range 21–77 days). There were four (20.9%) failures during the treatment which required secondary amputation. During the treatment, one (5.3%) patient died due to multi-organ failure after 27 days.

Conclusions: The use of NPWT therapy in the treatment of AKA stump complication is a safe and effective procedure associated with low risk and positive outcome in terms of wound healing time and further complications.
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April 2018

Clopidogrel High On-Treatment Platelet Reactivity in Patients with Carotid Artery Stenosis Undergoing Endarterectomy. A Pilot Study.

Curr Vasc Pharmacol 2016 ;14(6):563-569

Faculty of Pharmacy, University of Belgrade, Serbia, Vojvode Stepe 450, 11000 Belgrade, Serbia..

Objectives: A considerable number of patients do not achieve an adequate response to clopidogrel. Our study aimed to evaluate genetic and non-genetic factors as possible risks for clopidogrel high on-treatment platelet reactivity (HTPR) in patients (n=112) with carotid artery stenosis undergoing endarterectomy (CEA).

Methods: Using multiple-electrode impedance aggregometry (MEA) the antiplatelet effectiveness of clopidogrel was measured after 24 h, 7 and 30 days of clopidogrel treatment, which was introduced after elective CEA at a dose of 75 mg daily, for at least 30 days.

Results: HTPR was observed among 25% patients after clopidogrel therapy for 30 days. Further analysis showed that 53.3% of patients carrying the CYP2C19*2 gene variant had clopidogrel-HTPR, while in the wild type group there were 14.6% (p<0.001). Multivariate logistic regression analysis identified the CYP2C19*2 variant allele (OR 4.384; 95% CI 1.296-14.833, p=0.017) and high total cholesterol level (OR 2.090; 95% CI 1.263-3.459, p=0.004) as the only independent risk factors for clopidogrel-HTPR.

Conclusion: The CYP2C19*2 gene variant and high total cholesterol level were major factors for clopidogrel- HTPR in patients with carotid artery stenosis undergoing CEA.
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http://dx.doi.org/10.2174/1570161114666160714103148DOI Listing
October 2017
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