The effects of atorvastatin therapy on endothelıal function in patients with coronary artery disease

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Background Statins improve the endothelial function in patients with coronary artery disease (CAD). However, they contribute to the substantial decrease in coronary heart disease by reducing plasma cholesterol levels. They also, reduce oxidative

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  BioMed   Central Page 1 of 5 (page number not for citation purposes) Cardiovascular Ultrasound Open Access Technical notes The effects of atorvastatin therapy on endothel   al function in patients with coronary artery disease  AhmetYildiz* 1 , M AkifCakar  2 , MuratBaskurt  2 , Bar  õ sOkcun 2 , DenizGuzelsoy  2  and UgurCoskun 2  Address: 1 Department of Cardiology, Gazi Hospital, İ zmir, Turkey and 2 Department of Cardiology, Institute of Cardiology, İ stanbul University, İ stanbul, Turkey Email: AhmetYildiz*-drayildiz@yahoo.com; M AkifCakar-makifcakar@yahoo.com; MuratBaskurt-drmuratbaskurt@yahoo.com; Bar  õ sOkcun-drabaris_2000@yahoo.com; DenizGuzelsoy-denizguzelsoy@yahoo.com; UgurCoskun-ucoskun1@yahoo.com* Corresponding author Abstract Background: Statins improve the endothelial function in patients with coronary artery disease(CAD). However, they contribute to the substantial decrease in coronary heart disease by reducingplasma cholesterol levels. They also, reduce oxidative stress, stabilize the atherosclerotic plaqueand inhibit inflammatory response. These functions of statins have been briefly described aspleiotropic effects. The aim of our study was to evaluate the effect of atorvastatin therapy onendothelial functions in patients with CAD. Methods: Fourty-nine patients (40 men, 9 women, mean age 59 +/- 11 years) with diagnosed CADwere selected as the study group. The patients were given 10 mg/day atorvastatin for 12 weeks. If the target cholesterol levels has not been achieved 6 weeks after the treatment, then the dailyatorvastatin dosage has been increased. The endothelial function was evaluated by flow mediateddilatation (FMD) of the brachial artery. Results: It has been figured out that 12 weeks later, atorvastatin caused a statistically significantdecrease in the plasma levels of LDL-cholesterol and total cholesterol (p < 0,0001). Meanwhile, itwas determined that the FMD got statistically significant improved 12 weeks after the atorvastatintherapy (8,1%–4,2%, p < 0,001). However there was no statistically significant change in non-endothelium dependent dilatation (NID). Conclusion: Endothelium derived vasodilatation (EBD), which was non-invasively detected viabrachial artery ultrasonography, had statistically significant improvment within 12 weeks of atorvastatin therapy whereas non-endothelium dependent dilatation (NID) had no change. Introduction  The endothelium plays a vital role on the process of atherosclerosis; and it functions as a barrier between theblood and wall of the vessel [1,2]. Hypercholesterolemiais highly associated with impaired endothelial function.Endothelial dysfunction (ED) has a predictive value about the future cardiovascular events [3]. ED is reversible dur-ing the early stages of atherosclerosis. Some of the sys-temic markers of inflammation such as C-reactive protein(CRP) may also have predictive value for the future cardi- Published: 30 December 2007 Cardiovascular Ultrasound   2007, 5 :51doi:10.1186/1476-7120-5-51Received: 27 September 2007Accepted: 30 December 2007This article is available from: http://www.cardiovascularultrasound.com/content/5/1/51© 2007 Yildiz et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the srcinal work is properly cited.  Cardiovascular Ultrasound   2007, 5 :51http://www.cardiovascularultrasound.com/content/5/1/51Page 2 of 5 (page number not for citation purposes) ovascular events in healty subjects, in elder patients and inindividuals with high risk. The serum level of CRP isdirectly correlated with the presence and severity of coro-nary, cerebral and peripheral arterial atherosclerosis [4].Beyond their lipid lowering effects, statins may improveendothelial function, reduce CRP and the risk of cardio- vascular events. The endothelial function can be non-invasively evaluated by FMD of the brachial artery. Theaim of our study was to evaluate the effects of atorvastatintherapy on serum lipid levels and to evaluate the effect of atorvastatin on endothelial function assessed by FMD of brachial artery in patients with diagnosed CAD. Materials and methods Study population Fourty-nine patients (40 men, 9 women, mean age 59 +/-11 years) with diagnosed CAD were selected as the study group. The inclusion cirteria for the study were describedas; having coronary artery lesions on coronary angiogra-phy or previous myocardial infarction onset of which wasolder then 6 months, having a LDL-cholesterol levelhigher then 130 mg/dl and triglyceride level lower then300 mg/dl and for diabetic population having a fasting glucose level lower then 180 mg/dl and HbA1c levelbelow 8%. Our exclusion criteriae were; having a lipidlowering drug therapy for the last two months, undergo-ing any surgical operation within last 6 months, having ananticoagulant therapy, renal or hepatic failure, uncon-trolled systemic hypertension (systolic>160 mmHg,diastolic > 100 mmHg), having a myocardial infarction,unstable angina, stroke, angioplasty and/or coronary artery bypass surgery within the period of last 6 months. Ten of 59 patients were excluded from the study due to thediscordance in the treatment. Study design  All of the patients were evaluated at the begining of thestudy and at the 6th and 12th week of the study. Any patient who had not been taking aspirin therapy wasgiven 300 mg aspirin daily and study was started two weeks later. 1) Initial evaluation  At the beginning of the study a detailed medical history  was obtained, demographic data including the heightsand weights of the patients was collected and a detailedphysical examination was performed. For analysing thefasting glucose level, lipid profile, liver functional tests,fibrinogen and CRP, blood samples were taken. For theassesment of the endothelial function before the treat-ment, brachial arterial ultrasonography which is a non-invasive test was performed. Later on all of the patients were given NCEP step 2 diet. Special attention was paidon not to change any other drug therapy that the patient has already been receiving. Atorvastatin dosage wasordered as 10 mg per day for patients whose initial LDL cholesterol levels were below 180 mg/dl and 20 mg per day for patients whose initial LDL levels were above 180mg/dl. 2) 6th week evaluation  The patients whose hepatic functional tests were twotimes higher then their initial levels were excluded fromthe study. The aim of the therapy was to achieve either a30% decrease in the level of LDL cholesterol or a levelunder 125 mg/dl. When the expected level of LDL choles-terol was not reached then the atorvastatin dosage wasincreased to 20 mg per day for patients receiving 10 mg per day and to 30 mg per day for patients receiving 20 mg per day. 3) 12th week evaluation Blood samples were taken for the re-measurement of fast-ing glucose level, lipid profile, liver functional tests,fibrinogen and CRP and brachial arterial ultrasonography  was repeated. The vasomotor function of brachial artery can be evalu-ated by brachial arterial ultrasonography and this methodis well correlated with coronary artery vasomotor function[5]. So, we preferred to perform brachial arterial ultra-sonography for assessing the endothelial function. Theprotocol for the flow mediated dlation is performedaccording to guidelines, by Corretti. M.C. et al. [6] Themedications such as nitrates, calcium antagonists, angi-otensin converting enzyme inhibitors and beta blockershave been discontinued one day before the examination. The patients were wanted to lay down in supine position. Two-dimensional images of 10–20 mm slices of the right brachial artery were obtained via 8,5 MHz linear trans-ducer. Later on, the largest diameter of the artery wasmeasured during systole via M-mode imaging. The meas-urements were repeated three times and the arithmetic medians were calculated. After the measurement, 250mmHg pressure was applied to the same upper extremity  with a cuff for 5 minutes. After loosening the cuff, theultrasonographic views were recorded for 3 minutes andthe largest diameter of the vessel in systole was measured(Endothelium dependent vasodilatation-EDV) (Reactivehyperemia). After the diameter of the vessels returned totheir resting state (10 minutes later), the patient was given2,5 mg sublingual nitroglyicerin spray and then theimages were recorded for 5 minutes and the largest diam-eter of the vessel during systole was reached (Vasodilata-tion independent from endothelium-NID).Rates of EDV and NID were obtained in percentageaccording to the ratio between the arterial diametersmeasured at rest and arterial diameters measured after   Cardiovascular Ultrasound   2007, 5 :51http://www.cardiovascularultrasound.com/content/5/1/51Page 3 of 5 (page number not for citation purposes) reactive hyperemia and application of nitroglyicerin. Thecalculation was made according to the formula below.% change = (D2-D1)/D1 × 100%D1 was the initial diameter while D2 was the diameter measured after atorvastatin therapy. Plasma lipid and C-Reactive Protein levels Lipid profiles and hepatic functional tests of the patients were analyzed at the beginning, at the sixth week and at third month of the therapy. The total cholesterol levels were measured by Technicon Opera autoanalyser by using trading kit (biotrol) after it dissolved. CRP was checked by using high sensitive Dade Behring kit on Dade Behring Nephhelometer 100 device. Dilution was applied to highlevels. CRP levels under 0,34 mg/L were accepted as nor-mal while the levels higher were accepted as pathological. Statistical analysis In our study, quantitive factors were indicated as aritmetic means +/- standard deviation and qualitative factors wereindicated as percentage. Matched t test was used for thecomparison of the brachial arterial diameters. The totalcholesterol level was evaluated via Pearson correlationanalysis according to the % change between LDL andEBD. The correlation was considered as statistically signif-icant for whom the coefficient of correlation was higher then 0,05. The SPSS 11,0 package statistics program wasused for statistical work. Results  The demographical characteristics, coronary angiographic findings and the medications have been summarised in Table 1. Initially, 10 mg atorvastatin was given to 41patients (83,6%) and 20 mg to 8 patients (16,3%) and thedosages were increased substantially according to the con-trol levels at the sixth week of the therapy. No significant increase was seen in the liver functional tests in any con-trol evaluation. Effects of atorvastatin on serum lipid and CRP levels It has been seen that the total cholesterol and LDL choles-terol levels got significantly decreased at the third monthof the atorvastatin therapy. The total decrease was 32,4%for total cholesterol level and was 42,3% for LDL choles-terol level. The triglyceride levels and HDL cholesterol lev-els were not changed significantly. With atorvastatintreatment, the rate of decreament in fibrinogen levels was8,2 % (p < 0,05) while it was 31,6 % (p < 0,001) in CRPlevels. The results of brachial arterial ultrasonography   The brachial artery diameter was 3,81 +/- 0,43 mm at rest-ing state before treatment. At the third month of the ator- vastatin therapy, the new resting diameter was 3,82 +/-0,43 mm and the change had no statistically significant meaning (p > 0,05). The dilatation formed in brachialartery during hyperemia caused by cuff pressure (EDV) was measured as 4,25 +/- 1,7 % at the beginning of thetherapy and 8,16 +/- 1,84 after 3 months of atorvastatintherapy. The EDV values were increased significantly after three months of the therapy (p < 0,0001). When com-pared with the beginning of the therapy, it has been seenthat after application of 2,5 mg sublingual nitroglycerinthe vasodilatation independent from endothelium (NID)did not get changed significantly after 3 months (8,74 +/-2,58% vs 8,73 +/- 2,34, p > 0,05). Discussion In recent years the trials mainly have focused on non-inva-sive detection of endothelial dysfunction which has beenaccepted as an early sign of atherosclerosis. This non-inva-sive method is based on determination of EDV and NID via high resolution ultrasonography of brachial artery [7,8]. There are several agents which affect endothelial func-tions. Among these agents, Angiotensin Converting Enzyme (ACE) inhibitors are the most widely knownagents bearing such an endothelial activity [9,10].It has been figured out that hypercholesterolemia causesno impairment on endothelial functions in premenopau-sal women. This has been considered to be due to the pos-itive effects of estrogen on endothelial functions. It hasbeen reported that the endothelial functions could beimproved by the use of aspirin in athersclerotic patientsand this has been considered to be associated with the Table 1: The demographical and angiographic characteristics of patients Age (year)59. 33 ± 11. 20Sex(men, n=)40 (% 81. 6)(women, n=)9 (% 18. 4)BMI(kg/m 2 )27. 50 ± 3. 41Hypertension23 (%. 47)Diabetes12 (% 24. 5)Smoking18 (% 36. 7)Family history13 (% 26. 5)The diameter of Brachial artery(men)3.87 ± 0.41(women)3.56 ± 0.41EF %48. 39 ± 7. 37Previous MI33/49Coronary angiography.44/49One vessel13/49Multivessel32/49Previous revascularization (CABG or PCI)33/49EF:Ejection fraction  Cardiovascular Ultrasound   2007, 5 :51http://www.cardiovascularultrasound.com/content/5/1/51Page 4 of 5 (page number not for citation purposes) inhibition of constructor substance formation by aspirin via the cyclooxygenase pathway [11].Hypercholesterolemia is the most important risk factor inthe development of coronary atherosclerosis [12]. Thedeterioration of endothelium dependent on vasodilata-tion has been found to be related with hypercholestero-lemia [12-15]. The oxidized LDL, which gets increased in hypercholeste-rolemia and atherosclerosis cause impairment of endothelial vasodilatation by decreasing NO synthaseactivity [16]. The deterioration of EBD takes place beforethe formation of atherosclerotic lesions [12-14]. Hyperc-holesterolemia causes deteriation of EBD and then myo-cardial perfusion decreases [12-17]. Statins enhance theendothelial vasodilator and fibrinoliytic capacity by low-ering the oxidized LDL. The use of statins in patients with CAD and hyperlipi-demia results in improvement of both endothelial func-tions of coronary arteries and myocardial perfusion [18-21]. The main causative substrate for this improvement isendothelium derived relaxing factor (EDRF = NO). Within 24 weeks of fluvastatin therapy, an increase in theforearm blood flow through plethysmography has beendetected in hyperlipidemic patients with an inverse ratioof LDL levels [22]. The same benefical effect has been alsoreported with 4 weeks of simvastatin therapy [23]. InRECIFE study, improvement in endothelial functions withpravastatin use (40 mg/d) has been shown in such a short time as 6 weeks [24].In a study, Anderson et al. randomized 49 patients intothree groups with average serum cholesterol levels of 209+/- 33 mg/dl [25]. At the end of the first year, a significant improvement in the coronary artery dilatation by Ach hasbeen observed. Consequently, the authors indicated that an improvement in endothelial functions could beobtained in patients with CAD and unfavorable cardiac events could be reduced with the combination of choles-terol lowering therapy with antioxidant therapy.In our study we hold a group that contained patients withhigh risk (diagnosed CAD, 30% incidence of diabetesmellitus) and we examined the effect of atorvastatin onendothelial functions, by evaluating the EDV and NID onbrachial artery before and after 12 weeks of atorvastatintherapy. At the end of 12 weeks, LDL cholesterol levelsshowed a decrease of 42,3 % and endothelium dependent  vasodilatation showed a 92% increase. We found no sig-nificant change in NID with atorvastatin therapy. Our results were similar to the other statin studies (RECIFEetc.) [24]. However. the method we used is a very simplemethod highlighting the general status of the circulatory system. Because it depends on ultrasonography, the exam-ination requires experience. As a result, in the adults who have normal vascular func-tion, a marked improvement in endothelial functions with 80 mg/day atorvastatin therapy was observed within24 hours and this improvement came out before choles-terol lowering activity. However, it has been seen that vas-cular functions deteriorated acutely irrespective of cholesterol levels after cessation of atorvastatin therapy [26]. Conclusion Statins have cholesterol lowering effects and recover endothelial dysfunction which contributes to atheroscle-rosis in patients with hypercholesterolemic ischemic car-diac disease. The improvement in endothelial functionsmay play a significant role in reducing the risk of futurecoronary events. It is important to use statins for a long time, because of rapid deterioration of endothelial func-tions occurs shortly after cessation of statin therapy. 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Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central yours — you keep the copyright Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp BioMed central Cardiovascular Ultrasound   2007, 5 :51http://www.cardiovascularultrasound.com/content/5/1/51Page 5 of 5 (page number not for citation purposes) 11.Husain S, Andrews NP, Mulcahy D, Panza JA, Quyyumi AA: Aspirinimproves endothelial dysfunction in atherosclerosis.   Circula-tion   97(8): 716-720. 12.Brown BG, Zhao XQ, Sacco DE, Albers JJ: Lipid lowering andplaque regression. 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