Progression of coronary atherosclerosis may lead to angina

Regression of Coronary Atherosclerosis by Simvastatin A Serial Intravascular Ultrasound Study Lisette Okkels Jensen, MD, PhD; Per Thayssen, MD, DMSci; Knud Erik Pedersen, MD, DMSci; Steen Stender, MD, DMSci; Torben Haghfelt, MD, DMSci Background Angiography of the coronary arteries reflects only changes in luminal dimensions. With intravascular ultrasound, cross-sectional images can be obtained and area measurements can be added to calculate volumes of the external elastic membrane (EEM), plaque plus media (P M), and lumen. The aim of this study was to investigate the effect of lipid lowering by simvastatin on coronary atherosclerotic P M as changes in volumes of EEM, P M, and lumen. Methods and Results In 40 male patients with hypercholesterolemia, ischemic heart disease, and a nonsignificant coronary artery lesion in a not previously revascularized coronary artery, serial intravascular ultrasound studies with an ECG-triggered pullback were performed at baseline, after 3 months on a lipid-lowering diet, and after another 12 months on simvastatin 40 mg/d. Mean length of the analyzed atherosclerotic segments was 5.9 3.3 mm. After 12 months on simvastatin, a significant reduction in P M volume of 6.3% (P 0.002) was observed, whereas only a nonsignificant reduction in EEM volume of 1.8% was seen without any concomitant change in lumen volume. A significant reduction in total cholesterol of 31.0% (6.1 0.8 versus 4.2 0.7 mmol/l, P 0.001) and LDL cholesterol of 42.6% (4.0 0.8 versus 2.2 0.6 mmol/l, P 0.001) was obtained. Conclusions Lipid-lowering therapy with simvastatin for 12 months is associated with a significant P M regression in coronary arteries measured as reduction in P M and EEM volumes without any concomitant change in lumen volume. (Circulation. 2004;110:265-270.) Key Words: atherosclerosis plaque remodeling lipids ultrasonics Progression of coronary atherosclerosis may lead to angina pectoris, acute coronary syndromes, or death for cardiac reasons, all of which are frequent causes of mortality and morbidity in the western world. Prevention studies using HMG-CoA reductase inhibitors (statins) have shown a reduction in the incidence of cardiac events 1,2 greater than would be expected from angiographic studies of atherosclerotic regression. In such progression/regression studies, lipidlowering treatments have resulted in only minimal changes in the lumen of coronary arteries, 3 6 first and foremost with a reduction in the angiographically demonstrated progression. An increase in lumen diameter has been established only in a smaller group of patients. For many years coronary angiography (CAG) has been the standard method for the investigation of the anatomy of coronary arteries. In CAG, changes are measured in the vascular lumen and not in the vessel wall, where the atherosclerotic process is located. Pathophysiological studies 7,8 and intravascular ultrasound (IVUS) 9 have shown that atherosclerosis in the coronary arteries is often diffuse and involves long segments of the diseased vessel. IVUS allows crosssectional images and area measurements of external elastic membrane (EEM), plaque plus media (P M), and lumen. 10 12 In several trials, 13 15 a motorized pullback device has been used to generate cross-sectional images for calculations of volumes to evaluate atherosclerotic regression and progression. An approach with an ECG-triggered pullback has been used in a few serial IVUS studies. 16,17 This method has a high level of reproducibility, 18,19 making it suitable for assessing progression and regression of coronary atherosclerosis. The purpose of the present study, using this technique with ECG-triggered pullback, was to evaluate the effect of lipid lowering by simvastatin on coronary atherosclerosis as changes in volumes of EEM, P M, and lumen in a segment including a nonsignificant coronary atherosclerotic lesion by angiography. Methods Subjects From July 2, 1999, to November 1, 2001, 44 male patients with ischemic heart disease, hypercholesterolemia, and an angiographic coronary artery de novo lesion 50% in diameter stenosis in a Received November 6, 2003; de novo received January 7, 2004; revision received March 25, 2004; accepted March 29, 2004. From the Department of Cardiology, Odense University Hospital (L.O.J., P.T., K.E.P., T.H.), Odense, and the Department of Clinical Biochemistry, Gentofte Hospital (S.S.), Gentofte, Denmark. Correspondence to Lisette Okkels Jensen, MD, PhD, Department of Cardiology, Catheterization Laboratorium, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense, Denmark. E-mail okkels@dadlnet.dk 2004 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000135215.75876.41 265

266 Circulation July 20, 2004 coronary artery that had not previously been revascularized were enrolled. Exclusion criteria were acute coronary syndromes, heart failure, diabetes mellitus, or lipid-lowering drugs. All patients provided written, informed consent, and the local institutional review board (The Scientific Ethics Committee for the Counties of Vejle and Funen, Denmark) approved the protocol (case no. 96/291). Study Design The study was performed as an open non placebo-controlled serial investigation in which every patient acted as his own control. Patients were included if serum cholesterol exceeded 5.0 mmol/l, LDL cholesterol was 3.5 mmol/l, and CAG showed a de novo nonsignificant coronary lesion ( 50% in diameter stenosis). At baseline, all patients underwent CAG and IVUS with ECGtriggered pullback of the study lesion. After this, the patients received dietary guidance by a clinical dietitian and were followed up on dietary treatment for 3 months. At that time, CAG and IVUS with ECG-triggered pullback were repeated if total cholesterol was 5.0 mmol/l and LDL cholesterol was 3.0 mmol/l, and additional therapy with simvastatin 40 mg/d was initiated. The purpose of the simvastatin treatment was to achieve a total cholesterol level of 5.0 mmol/l and an LDL cholesterol level of 3.0 mmol/l. If this was not achievable on 40 mg/d, the dose was increased to 80 mg/d on the basis of control measurements of cholesterol after 1 or 3 months of simvastatin therapy. After 15 months, the CAG and IVUS with ECG-triggered pullback were repeated on the study lesion. Dietary Guidance Overall, an energy intake corresponding to normal weight was recommended, with an energy distribution of 55% to 60% from complex carbohydrates, 10% to 15% from protein, and 30% from fat (distributed between no more than 10% saturated fat, no more than 10% polyunsaturated fat, and at least 10% monounsaturated fat). It was further recommended that the daily intake of fruit and vegetables should be at least 600 g and that the weekly intake of fish should be 300 g chosen in such a way that 1 g n-3 fatty acid was ingested each day. The Eating Pattern Assessment Tool 20 was used for dietary recording purposes. Invasive Procedure Under local anesthesia, CAG was performed via a 7F guiding catheter using the femoral approach. Subsequently, the IVUS catheter was introduced over a guidewire preceded by 5000 IU heparin and 200 g nitroglycerin IC just before the IVUS procedure. The latter was repeated just before each pullback recording. Intravascular Ultrasound A cardiovascular imaging system with a 30-MHz, 2.9F IVUS catheter (UltraCross, CardioVascular Imaging System) was used. The distal part of the IVUS catheter is a sheath in which the transducer can be moved longitudinally without doing any damage to the vessel wall and without artifacts from the guidewire. The transducer is rotated at 1800 rpm, producing cross-sectional images. The image acquisition was ECG-gated; the technique has been described previously in detail. 21 Series of cross sections spaced exactly 0.2 mm apart were analyzed offline for each IVUS study. For each cross-sectional image, the cross-sectional areas (CSAs) of the lumen and EEM were calculated. P M CSA was defined as EEM CSA lumen CSA. In the first study, an image slice was selected for each patient, and the distance from this image slice to the closest side branch was measured. The second and third studies were screened to identify this fiduciary point, and the previously measured distance was used to identify the corresponding image slices. The IVUS analyses were performed with the investigator blinded both with regard to the time of investigation and to patients. To assess the reliability of the changes in volumes, 2 pullbacks were performed at baseline in 20 patients. TABLE 1. Characteristics of Study Patients Baseline Characteristics Number 40 Age, y 57.7 8.8 Hypertension, % 22.5 Previous myocardial infarction, % 22.5 Previous PCI, % 82.5 No PCI, % 17.5 PCI in 1 vessel, % 70.0 PCI in 2 vessels, % 12.5 PCI in 3 vessels, % 0 No angina pectoris, % 85.0 CCSC 1 10.0 CCSC 2 5.0 CCSC 3 0 CCSC 4 0 Left ventricle ejection fraction, % 71.1 8.8 Smoking Yes, % 42.5 No, % 22.5 Previously, % 35.5 Body mass index, kg/m 2 (median, range) 27.4 3.5 Medicine Aspirin, % 97.5 Clopidogrel, % 2.5 -Blocker, % 50.0 Calcium antagonist, % 20.0 ACE inhibitor, % 7.5 Angiotensin II antagonist, % 2.5 Diuretics, % 7.5 Lipid-lowering drugs, % 0 PCI indicates percutaneous coronary intervention. Quantitative Coronary Angiography Siemens HICOR biplane catheterization equipment was used for CAG. The computer-based ACOM.PC V3.1 (Siemens Medical Systems, Inc) was used for QCA analysis. Quantitative analysis was performed offline, with the investigators blinded with regard to the time of the study and to patient identification. Statistical Analysis The data analysis was performed using the statistical program SPSS 11.5. Results are presented as mean SD or expressed as percentages unless otherwise indicated. Two-way ANOVA with 3 repeated measurements was used to test whether there was a significant change in measurements over time. If this test was significant, a paired t test was used to compare the values between the relevant times. Percentage differences was tested with a t test. Univariate multiple linear regression analysis was used to investigate the influence of factors on P M volume. A probability value of P 0.05 was considered significant. Results The clinical features at baseline are shown in Table 1. During the study period, there were no changes in prescriptions of medication, and the patients did not change smoking status.

Jensen et al Coronary Plaque Regression by Simvastatin 267 TABLE 2. Lipids Baseline 3 Months 15 Months P (2-Way ANOVA) Cholesterol, mmol/l 6.2 0.88 6.2 0.86 4.2 0.76* 0.001 LDL cholesterol, mmol/l 4.1 0.79 4.0 0.68 2.2 0.57* 0.001 HDL cholesterol, mmol/l 1.3 0.25 1.4 0.34 1.4 0.35 0.001 Triglycerides, mmol/l 1.8 0.87 1.8 1.00 1.2 0.75* 0.001 *P 0.001, 15 vs 3 months. P 0.017, 3 months vs baseline. Lipids Dietary recording at baseline and after 3 months showed a significant reduction in Eating Pattern Assessment Tool 20 score (22 versus 17; P 0.001), indicating a reduction in the fat energy percentage. At baseline, at 3 months, and after 15 months, there was no significant difference in body mass index (27.7 3.7 versus 27.9 3.7 versus 28.0 4.1 kg/m 2 ; P NS). After the dietary period, all the patients primarily included met the criteria for being able to continue in the study (total cholesterol 5.0 mmol/l and LDL cholesterol 3.0 mmol/l) and started treatment with simvastatin tablets 40 mg/d immediately after the end of all the investigations at 3 months. In 2 patients, the therapeutic objective of LDL cholesterol 3.0 mmol/l was not met after 3 months of simvastatin treatment, and dose adjustment to 80 mg/d was performed. There were no drug-related side effects or significant changes in the enzymes alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, or creatine kinase. As can be seen from Table 2, lipids changed significantly in the 3 measurements according to the 2-way ANOVA. After 3 months on dietary therapy, there was no significant change in cholesterol, LDL cholesterol, or triglycerides but a significant increase of 5.5% in HDL cholesterol (1.28 0.25 versus 1.37 0.34 mmol/l; P 0.017). After 12 months of treatment with simvastatin, there was a significant reduction of 31.0% in cholesterol, 42.6% in LDL cholesterol, and 22.5% in triglycerides (P 0.001). In 80% of the patients, LDL cholesterol was 2.6 mmol/l. QCA Data Neither the percentage coronary artery diameter lesion, minimal lumen diameter, mean segment diameter, nor reference diameter changed significantly between the angiograms at baseline, after 3 months, and after 15 months (Table 3). IVUS Measurements Of 44 patients, 40 underwent all 3 IVUS investigations. In 1 patient, the referring hospital started therapy with simvastatin before the planned second IVUS investigation, and 3 patients were eliminated from the study because of poor technical quality of the IVUS imaging, lack of identification of the reference point, or breakdown of the ECG-gated pullback. In 40 patients, all 3 IVUS scans were available for analysis. At baseline, the average length of the segment analyzed was 5.9 3.3 mm. The mean minimum lumen diameter was 2.6 0.6 mm, and the average diameter of the proximal and distal reference segment was 3.5 0.6 mm. During the 15-month period of observation, the withinsubject change in P M volume changed significantly (2-way ANOVA, P 0.001). Compared with baseline, the mean (SD) change in absolute P M volume was 0.3 mm 3 (4.35 mm 3 ) (P NS) after 3 months of diet (Table 4). Compared with 3 months, the mean (SD) change in P M volume was 3.6 mm 3 (5.71 mm 3 )(P 0.001) after 12 months of simvastatin therapy (at 15 months). The relative change in P M volume was 6.3% (P 0.002). The within-subject change in EEM volume changed significantly (2-way ANOVA, P 0.001). Compared with baseline, the mean (SD) change in absolute EEM volume was 2.4 mm 3 (7.58 mm 3 )(P NS) after 3 months of diet (Table 4). Compared with 3 months, the mean (SD) change in EEM volume was 1.9 mm 3 (8.97 mm 3 )(P NS) after 12 months of simvastatin therapy (at 15 months). The relative change in EEM volume was 1.8% (P NS). In contrast, no corresponding significant changes in lumen volume were observed (2-way ANOVA, 44.5 29.90 versus 42.4 30.35 versus 44.1 31.06 mm 3 ; P NS). No direct effect of simvastatin on EEM volume in a normal coronary artery wall without plaque was demonstrated, because there was no significant difference (2-way ANOVA) in EEM volume with a segment length of 1 mm for the 3 IVUS scans (10.6 2.2 versus 10.9 2.5 versus 10.5 2.8 mm 3, P NS). To assess the reliability of the changes in volumes, 2 pullbacks were performed at baseline in 20 patients (Table 5). With univariate multiple linear regression analysis, no independent predictors for relative volume change were found for P M (between the second and third investiga- TABLE 3. Angiographic Variables Baseline 3 Months 15 Months P (2-Way ANOVA) Minimal lumen diameter, mm 2.18 0.58 2.13 0.55 2.18 0.57 0.610 Mean segment diameter, mm 2.95 0.59 2.91 0.55 2.90 0.58 0.575 Reference diameter, mm 3.24 0.68 3.06 0.62 3.13 0.61 0.661 Stenoses, % 32.2 9.6 30.3 10.3 30.7 9.6 0.125

268 Circulation July 20, 2004 TABLE 4. Total Plaque Media and EEM Volumes in the Target Lesion and Change in Percentage of Plaque Media and EEM Plaque Media EEM Baseline, mean (SD), mm 3 45.8 (30.96) 90.3 (58.00) 3 months, mean (SD), mm 3 45.6 (31.34) 87.9 (58.55) 15 months, mean (SD), mm 3 41.9 (27.60) 86.0 (55.80) P (2-way ANOVA) 0.001 0.001 Baseline, median (IQR), mm 3 37.8 (27.5 to 53.8) 70.5 (56.03 to 104.10) 3 months, median (IQR), mm 3 37.8 (27.2 to 55.2) 68.7 (53.11 to 104.01) 15 months, median (IQR), mm 3 34.4 (25.2 to 51.3) 68.8 (51.22 to 99.73) Change from baseline to 3 months, mm 3 Mean (SD) 0.3 (4.35) 2.4 (7.58) 95% CI for the difference 1.13 to 1.64 0.06 to 4.79 P 0.711 0.055 Change from 3 to 15 months, mm 3 Mean (SD) 3.6 (5.71) 1.9 (8.97) 95% CI for the difference 1.75 to 5.41 0.98 to 4.76 P 0.001 0.192 Mean change from baseline to 3 months, % 0.4 3.1 95% CI for difference 2.86 to 3.61 0.32 to 5.83 P 0.816 0.03 Mean change from 3 to 15 months, % 6.3 1.8 95% CI for difference 2.40 to 10.09 1.15 to 4.69 P 0.002 0.229 IQR indicates interquartile range. tions), EEM, or lumen (age, length of the segment analyzed, LDL, HDL, and smoking as covariates). Discussion In a 15-month observation period encompassing 12 months of treatment with simvastatin 40 mg/d preceded by a 3-month dietary guidance period, coronary artery remodeling with a significant P M regression and a small reduction in EEM volume are found, but without any change in lumen volume as assessed by ECG-gated IVUS. No significant change in absolute value of either P M volume, lumen volume, or EEM volume was observed during the 3-month period on dietary treatment alone, but the data are the only short-term variability data for IVUS available from any source. Recent IVUS studies have demonstrated changes in coronary atherosclerosis with different antiatherosclerotic treatment strategies, 14,15,22,23 but other studies have not shown regression by IVUS with statins after 12 to 24 months of statin treatment. 22 Using a method similar to that TABLE 5. Differences of Plaque Media, EEM, Lumen Volumes in 2 Pullbacks at Baseline Mean, mm 3 (SD) 95% CI for Difference P Plaque media 0.1 (1.55) 0.79 to 0.66 0.854 EEM 0.4 (2.16) 1.43 to 0.59 0.396 Lumen 0.4 (1.90) 1.28 to 0.50 0.369 of the present study, Schartl et al 22 found an increase in both P M volume and EEM volume after 12 months of treatment with either atorvastatin or ordinary lipidlowering treatment, with the least progression in the atorvastatin group. This indicates a persistent plaque progression and positive remodeling process, 24 whereas the results in the present study, in which P M regression was observed, indicate that the positive remodeling process may be reversible. However, the 2 studies differ from one another in many ways with regard to patients and methods. In the study by Schartl et al, 22 11% of the patients were on statin therapy before inclusion; 15% of the patients had diabetes mellitus type II; and in 92% of the patients, the study lesion was on the same vessel that had undergone percutaneous coronary intervention. All such patients were excluded in the present study. Furthermore, they did not use the same length of segment analyzed at follow-up. One study demonstrated a positive linear relation between LDL cholesterol and annual changes in P M size studying the left main coronary artery. 15 This has also been found with B-mode ultrasound of the carotid artery 25,26 and might be taken as an expression of remodeling, indicating that in patients already receiving statin therapy at the time of inclusion in a study, some degree of remodeling already had taken place when the primary therapy was initiated. Corti et al 27 used MRI to assess the effect of simvastatin on atherosclerotic plaque in the carotid artery and aorta.

Jensen et al Coronary Plaque Regression by Simvastatin 269 With a reduction in cholesterol and LDL cholesterol similar to that in the present study, they found that simvastatin therapy for 12 months brought about significant regression of atherosclerotic plaque; in accordance with the present study, they found a reduction in the thickness of the vessel wall and vascular area without changes in lumen. Maximal thickness of the vessel wall decreased after 12 months, whereas the smallest thickness remained unchanged, confirming that simvastatin treatment causes the atherosclerotic plaque to shrink without any direct effect on a normal vessel wall. The authors established in a later study that this regression continues with continued treatment for up to 24 months. 28 Limitations The present study was not performed as a randomized, placebo-controlled study. The reason for this is that it would be unethical to withhold lipid-lowering treatment from patients with documented ischemic heart disease and hypercholesterolemia. To compensate for this lack of a control group, the study was designed as a 3-month period on diet alone followed by a 12-month period on continued diet simvastatin treatment. Although a 3-month diet period may be too short to serve as a true control period, the data provide the short-term variability data for IVUS available from any source and thereby helpful in separating the effect of simvastatin from the natural history of the disorder. The patients were not included in a true consecutive manner, and some degree of selection bias may therefore be present; nevertheless, they were selected consecutively among all patients with stable angina pectoris who underwent a CAG or percutaneous coronary intervention and fulfilled inclusion and exclusion criteria. In IVUS, the circumference, area, and volume of the EEM cannot be measured reliably at points from which large side branches originate or in areas with a high calcium content owing to an acoustic shadow. To minimize this weakness, only segments without side branches and with minimal calcification (maximal 90 in 5 consecutive images) have been chosen, and this explains the relatively short length of analyzed segments. The precision of the ECG-gated pullback allowed very reliable data to be generated from a fairly short pullback. Furthermore, the aim of the study was to analyze only segments with coronary atherosclerotic changes by angiography, and not an entire coronary artery or a large part thereof without angiographic changes. 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