Effects of Statins on Endothelial Function in Patients with Coronary Artery Disease

Effects of Statins on Endothelial Function in Patients with Coronary Artery Disease Iana I. Simova, MD; Stefan V. Denchev, PhD; Simeon I. Dimitrov, PhD Clinic of Cardiology, University Hospital Alexandrovska, Sofia, Bulgaria Address for correspondence: Iana I. Simova, MD Clinic of Cardiology University Hospital Alexandrovska Georgi Sofiiski 1 Sofia 1431, Bulgaria ianahr@yahoo.com Background: Flow-mediated dilatation (FMD) of the brachial artery is a method capable of detecting endothelium dysfunction. Statins are generally consent drugs for reducing cardiovascular morbidity and mortality and are shown to improve the systemic endothelial function. Hypothesis: The aim of our study was to assess the endothelial function using FMD of the brachial artery in patients with different degrees of coronary artery stenosis with respect to their treatment with statins. Methods: We evaluated the FMD of 221 patients with coronary arteriography performed, of whom 99 (44.8%) were receiving statins and 122 (55.2%) were not receiving statins. Results: We did not find a statistically significant difference in the FMD values between the patients with and without a statin treatment: 5.57 ± 5.68 and 4.69 ± 4.48, respectively, P =.581. In the subgroup of patients without angiographically visible coronary artery stenoses or with stenoses < 20% (86 patients), patients undergoing statin treatment had a significantly better endothelial function compared to patients without such a treatment: FMD 9.24±6.87 and 6.50±4.51, respectively, P =.047. Conclusions: FMD could not distinguish between the patients who were treated with statin and those not treated with statins with the same demographic, clinical, and angiographic characteristics. The only exception was in the group of patients with a minor coronary disease. had a more pronounced effect in the earlier stages of coronary atherosclerosis. Introduction Some changes in the function of the endothelium are present even in the very early stages of atherosclerosis when no structural impairment in the vessel wall is evident. Flow-mediated vasodilatation of the brachial artery is a method considered capable of detecting the early changes in endothelial function. The method was first described and implemented in clinical practice by Celermajer et al. 1 Statins are generally accepted for reducing cardiovascular morbidity and mortality in coronary artery disease (CAD) patients, and this effect is observed in the patient groups with different levels of baseline low-density lipoprotein (LDL)- cholesterol. 2 They have well-recognized pleotropic effects beside the lipid-lowering action and have been shown to improve the systemic endothelial function in patients with CAD. 3 It is of interest to know how the statin treatment itself, regardless of its direct effects on lipid metabolism, affects the endothelial function in a patient cohort where the level of control of dyslipidemia is not optimal. The aim of our study was to assess the endothelial function using flow-mediated dilatation (FMD) of the brachial artery in patients with different degrees of coronary artery stenosis with respect to treatment with statins. Methods Study Group We investigated 221 patients, admitted to the Clinic of Cardiology, University Hospital Alexandrovska between July 2006 and March 2007. These were patients with angina Received: June 29, 2007 Accepted with revision: September 12, 2007 pectoris or an already established CAD, with positive exercise stress test. Every patient underwent coronary arteriography (CAG) as a part of his/her diagnostic evaluation. The demographic characteristics and distribution of risk factors of patients are presented in Table 1. The clinical characteristics with respect to CHD are presented in Table 2. Only 99 patients (44.8%) from the whole group of 221 patients had been on a statin treatment for at least 1 month at the time of investigation. Only 23 patients (18.9%) of those not receiving a statin treatment (122 patients) did not have dyslipidemia as defined by the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice: Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice total cholesterol 4.5 mmol/l and LDLcholesterol 2.5 mmol/l. 4 This means that 81.1% of the patients in our group with an already known dyslipidemia were untreated. On the other hand, only 10 patients (10.1%) among the patients receiving a statin for at least 1 month (99 patients) had reached their target values. The statin most commonly used in the study was lovastatin (54%), with a mean dose of 36.4 mg (±8.2), followed by atorvastatin (30%), mean dose 13.8 mg (±3.5), and simvastatin (16%), mean dose 27.5 mg (±6.3). Patients were included regardless of their sex and age. Patients who were admitted in our clinic for diagnostic evaluation and treatment who had data available regarding their use of statin were considered eligible. Patients were included in groups with a statin treatment if they had been Clin. Cardiol. 32, 4, 193 198 (2009) 193

Clinical Investigations continued Table 1. Demographic Characteristics of the Patients and Distribution of Risk Factors Clinical Variable Unit Distribution All cases n = 221 (100%) Female gender Number (percent) 106 (48%) Age (years) Mean (± standard 59.6 (±9.6) deviation) Body mass index (BMI) Mean (± standard 28.38 (±4.01) deviation) Arterial hypertension Number (percent) 188 (85.1%) Diabetes mellitus Number (percent) 51 (23.1%) Current smokers Number (percent) 36 (16.3%) Past smokers Number (percent) 119 (53.8%) Table 2. Clinical Characteristics of the Patients Clinical Variable Unit Distribution All cases n = 221 (100%) Angina pectoris Number (percent) 183 (82.8%) History of myocardial Number (percent) 84 (38%) infarction (MI) Duration of statin Mean (± standard 8.5 (±3.1) treatment (months) deviation) Patients were considered with a history of myocardial infarction (MI), if they had a MI for at least one month before the inclusion. Patients with a more recent MI had been excluded. The mean time elapsed from MI was 15.6±6.7months. receiving this kind of treatment for at least 1 month. Patients presenting with acute coronary syndrome, and patients with hemodynamically significant valvular disease, and patients with previously performed coronary interventions or surgical revascularization were excluded. Ethics All patients signed an informed consent for FMD measurement. The investigation protocol was approved by the local ethical committee. Flow-Mediated Brachial Artery Dilatation FMD was accomplished according to the guidelines for the ultrasound assessment of endothelial-dependent flowmediated vasodilation of the brachial artery. 5 The inter- and intraobserver variability of the method was evaluated on a sample of 40 patients with a correlation coefficient > 0.92, p <.001. 6 FMD was done in the morning between 7 and 9 AM. In the evening prior to the study, the patient was asked to refrain from eating or drinking alcoholic beverages, and to avoid smoking after 8 PM. Long-acting nitrates were not allowed for 24 hours. On the morning before the study, the patient was asked not to consume anything but water, not to smoke, to postpone taking his/her prescribed medication until after the study, and to refrain from any vigorous physical activity. The investigation started with the taking of the blood pressure on the dominant arm after a 15-minute rest in a quiet and temperate room. Then the cuff of the sphygmomanometer was placed on the forearm of the same arm with the patient in a supine position, and a longitudinal image of the brachial artery was obtained with optimal visualization of the intima using a linear array transducer 3 11 MHz and a Sonos 5500 echocardiograph. A 5- to 10 second recording on a video cassette recorder (VCR) of the baseline state of the brachial artery was done. The cuff was inflated to a pressure of 200 mm Hg or 50 mm Hg above the systolic arterial pressure of the given patient, whichever was higher, and maintained as such for 5 minutes. A new recording on the VCR was done during the last 30 seconds of the ischemic phase (with cuff inflated) and then 120 seconds after the cuff deflation. The whole image was electrocardiogram (ECG)-gated. Measurement The analysis was made off-line. Two parameters were taken: the baseline diameter of the brachial artery and the maximum postischemic stimulus diameter of the artery. All measurements were done in the end-diastole (the beginning of the R on the ECG) from the endothelial to the endothelial surface along a line perpendicular to the artery s long axis. The FMD was measured in terms of percentage and derived by the formula given here: FMD (%) = ([postischemic diameter of the brachial artery-baseline diameter] / baseline diameter) 100. Statistics Continuous variables were presented as mean ± standard deviation. Categorical variables were presented in terms of percentage. The distribution of the data within groups was tested with the Kolmogorov Smirnov test. With normal distribution an independent samples t test to compare means for FMD was used. When the distribution was not normal the Mann-Whitney U test was used. The distribution of risk factors and clinical variables between the groups was compared with the chi-square test. A two-tailed p value <.05 was considered significant. All tests were performed with SPSS 13 for Windows (SPSS, Inc., Chicago, IL). 194 Clin. Cardiol. 32, 4, 193 198 (2009)

Table 3. Distribution of Patients According to Statin Treatment and Percent Stenosis of the Coronary Arteries 1 p = 0.047 No Treatment Statin Treatment 1 %stenosis n= 122 n = 99 <20% 53 33 20 49% 13 11 50% 56 55 Mean FMD 8.00 6.00 6,50 9,24 7.00 p = 0.581 6.00 Error bar.: 95.00% CI 5.00 Mean FMD 3.00 1.00 4,693 5,566 Error bar.: 95.00% CI Figure 1. Mean FMD values in patients without statin treatment and those with such treatment for the whole study population. CI = confidence interval; FMD = flow-mediated dilatation. Results Patients The 221 patients were divided into groups according to their treatment status with statins and the degree of coronary artery stenosis (Table 3). The mean FMD values for the entire groups of statintreated (99 patients) and statin-untreated (122 patients) patients were not significantly different (Figure 1). If patients with coronary artery stenoses < 20% were divided into groups according to their statin treatment (33 patients) or with no statin treatment (53 patients), and the mean values for FMD were compared for the two groups, there would be a statistically significant difference in the FMD values indicating a better endothelial function for those patients receiving this type of medication (Figure 2). The risk factors for atherosclerosis, the presence of angina pectoris, and treatment with ACE inhibitors or calcium channel blockers, which could affect the values for the FMD, were equally distributed between the groups treated and not treated with statins for the entire group of patients and for the subgroup with stenosis < 20% (Tables 4 and 5). There was one exception patients with a previous Figure 2. Mean FMD values in patients without statin treatment and those with such treatment for the subgroup with stenoses < 20%. CI = confidence interval; FMD = flowmediated dilatation. myocardial infarction (MI) were more likely to be treated with statins than those without MI. In the 110 patients with stenoses < 50% on CAG, including the former group, there was no statistically significant difference in the endothelial function between the patients receiving (44 patients) and those not receiving (66 patients) a statin (Figure 3). When patients presented with a significant ( 50%) coronary artery stenosis, there again was not much of a significant difference in endothelium-dependent vasodilatation between the group with (55 patients) and those without (56 patients) statin treatment (Figure 4). Discussion Dyslipidemia is a well-known major atherosclerotic risk factor. Guidelines relevant for the European practice recommend that the total cholesterol and LDL-cholesterol should be reduced to a level below 5 mmol/l and 3 mmol/l, respectively, with more stringent goals of total cholesterol < 4.5 mmol/l and LDL-cholesterol < 2.5 mmol/l for patients with cardiovascular disease and diabetes. 4 However the implication of these recommendations is far from optimal, which leaves a major part of patients with dyslipidemia undertreated both in Europe and in the United States. According to different surveys that included a large number of patients, 7 the NCEP/ATP III lipid goal 8 has been achieved only in a minority of the study group, and the proportion of patients receiving statin treatment also varies within individual countries. 9 Only 44.8% in our study group of 221 patients were receiving statin treatment at the time of investigation, and only 10.1% of them had achieved the target values. Clin. Cardiol. 32, 4, 193 198 (2009) 195

Clinical Investigations continued Table 4. Distribution of Risk Factors and Clinical Characteristics for the Whole Group of Patients According to a Statin Treatment Status Clinical Variable Without Statin Treatment With Statin Treatment Significance Number 122 (55.2%) 99 (44.8%) Female gender n (%) 51 (41.8%) 55 (55.5%) 0.057 Age mean ± SD 59.85 (±9.05) 56.83 (±9.61) 0.113 BMI mean ± SD 28.43 (±4.25) 28.32 (±3.71) 0.842 Arterial hypertension n (%) 106 (86.9%) 82 (82.8%) 0.400 Diabetes mellitus n (%) 26 (21.3%) 25 (25.3%) 0.489 Active smokers n (%) 19 (15.6%) 17 (17.2%) 0.749 Former smokers n (%) 62 (50.8%) 57 (57.6%) 0.316 Angina pectoris n (%) 105 (86.1%) 78 (78.8%) 0.154 Myocardial infarction n (%) 36 (29.5%) 48 (48.5%) 4 Treatment with ACE inhibitor n (%) 105 (86.1%) 91 (91.9%) 0.278 Treatment with calcium channel blockers n (%) 30 (24.6%) 24 (24.2%) 0.892 Table 5. Distribution of Risk Factors and Clinical Characteristics in Patients Without Visible Coronary Artery Lesions on CAG According to Statin Treatment Status Clinical Variable Without Statin Treatment With Statin Treatment Significance Number 53 (61.6%) 33 (38.4%) Female gender n (%) 36 (67.9%) 27 (81.8%) 0.157 Age mean ± SD 61.7 (±9.47) 57.33 (±8.94) 0.053 BMI mean ± SD 29.38 (±4.5) 27.55 (±3.22) 0.056 Arterial hypertension n (%) 46 (86.8%) 29 (87.9%) 0.883 Diabetes mellitus n (%) 10 (18.9%) 5 (15.2%) 0.659 Active smokers n (%) 6 (11.3%) 8 (24.2%) 0.114 Former smokers n (%) 16 (30.2%) 14 (42.4%) 0.247 Angina pectoris n (%) 48 (90.6%) 31 (93.9%) 0.578 Myocardial infarction n (%) 2 (3.8%) 5 (15.2%) 0.061 Treatment with ACE inhibitor n (%) 48 (90.6%) 30 (90.9%) 0.921 Treatment with calcium channel blockers n (%) 15 (28.3%) 8 (24.2%) 0.586 This reflects the undertreatment in such patients who are generally considered as candidates for statin therapy. The correlation between statin treatment and endothelial function has been a subject of interest for many investigators. A REVERSAL trial substudy evaluated the effect of intensive and moderate cholesterol lowering with statins in CAD patients with low LDL-cholesterol, and it has been proven to effect a significant improvement in endothelial function during the statin treatment. 10 Our study showed that in a group of patients with angina pectoris or with an already established CAD, those receiving a statin treatment did not have a better endothelial function compared to patients without a statin treatment. It must be noted, however, that only 10.1% of our patients had achieved the target lipid levels at the time of investigation. That means, we assume, that the pleiotropic effects of statins alone are not enough to improve the endothelial function. Another possible explanation could be that the duration of 196 Clin. Cardiol. 32, 4, 193 198 (2009)

Mean FMD 1 1 8.00 6.00 p = 0.084 6,426 8,413 Error bar: 95.00% CI Figure 3. Mean FMD values in patients without statin treatment and those with such treatment for the subgroup with stenoses < 50%. Mean FMD 5.00 3.00 1.00 p = 0.332 2,649 3,288 Error bar: 95.00% CI Figure 4. Mean FMD values in patients without statin treatment and those with such treatment for the subgroup with stenosis 50%. CI = confidence interval; FMD = flow-mediated dilatation. statin treatment was not long enough for the potentially beneficial effect of statins on endothelial function to take place. On the other hand, patients in the statin group might have had a worse baseline FMD, which had been improved after statins had been initiated. However, the endothelial function was significantly better in the subgroup of patients without angiographically visible coronary stenoses or with stenoses < 20% when the patients were receiving a statin. There was not much of a statistically significant difference in the distribution of demographic and clinical variables between these two groups of patients, which could have influenced the brachial artery response and, therefore, the greater FMD values could possibly be attributed to the statin treatment itself. TheFMDvaluesweredistinctlydecreasedinthegroup of patients with angiographically significant CAD, but again regardless of the statin treatment status. Of interest is that in our study group, the beneficial effect of statins on endothelial function was only evident in patients with minor CAD. One possible explanation could be that the pleiotropic and anti-inflammatory effects of statins could be more pronounced when the endothelium is not severely damaged, as it is in those cases with earlier atherosclerosic changes in coronary arteries. Another explanation could be that a beneficial effect on endothelial function was present during statin treatment in patients with significant coronary stenoses, but the methods used in detecting them, the FMD was not sensitive enough. Our results are in contradiction to the findings of Vogel et al, 10 but it should be noted that the patient group in the REVERSAL trial has a low LDL-cholesterol level at baseline and that most of our patients do not reach their target lipid levels even during a statin treatment. In future endeavors, we contemplate examining meticulously the interaction between dyslipidemia, statin treatment, and the endothelial function including examining larger patient cohorts as well as prospectively following patient groups, randomized to statin or placebo. In our opinion, it is of importance to investigate the effects of statins with respect to the patients gender and the presence or absence of diabetes mellitus. Our study was retrospective and observational, therefore a selection bias cannot be excluded. As already mentioned, the group in which the target lipid goals were reached was of a relatively small size, and we did not have information about the baseline FMD of the patients. Conclusion On the basis of the results obtained in our study, we conclude that FMD cannot distinguish between patients treated with statins and those not treated with statins using the same demographic, clinical, and angiographic characteristics. An exception is seen in the group of patients with minor coronary disease. has a more pronounced effect in the earlier stages of coronary atherosclerosis. References 1. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111 1115. 2. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383 1389. 3. Jarvisalo MJ, Toikka JO, Vasankari T, et al. HMG CoA reductase inhibitors are related to improved systemic endothelial function in coronary artery disease. Atherosclerosis. 1999;147:237 242. Clin. Cardiol. 32, 4, 193 198 (2009) 197

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