Early statin treatment of patients with acute coronary syndrome results in vascular changes and improved clinical outcomes. However, the influence of chronic statin treatment on the culprit vessel in acute coronary syndrome is not fully understood. The aim of this study was to investigate the morphologic features of the culprit vessel in acute myocardial infarction by comparing patients with and without chronic statin treatment. We enroled consecutive patients with AMI, who had hyperlipidemia and primary percutaneous coronary intervention guided by intravascular ultrasound within 24 hours of symptom onset. Of 155 patients, 73 patients were stratified to the chronic statin group and 82 to the nonstatin group. Intravascular ultrasound in both the groups showed that positive remodeling was significantly less frequent in the chronic statin group (46.6%) compared with the nonstatin group (70.7%; p = 0.001). Necrotic core area was significantly smaller in the chronic statin group (2.2 ± 1.3 mm 2 ) compared with the nonstatin group (3.2 ± 2.1 mm 2 ; p <0.001). Multivariate logistic regression analysis revealed that chronic statin treatment was significantly associated with less positive remodeling (odds ratio 0.283, 95% confidence interval 0.111 to 0.723, p = 0.008). In conclusion, chronic statin treatment reduced positive remodeling in the culprit lesions of patients with acute myocardial infarction.
Statin is known to reduce cardiovascular events, especially acute coronary syndrome (ACS). In addition, early statin administration in patients with ACS improved clinical outcomes. Although the mechanisms by which statin affects cardiovascular disease are not fully understood, several intravascular ultrasound (IVUS) studies have demonstrated vascular changes caused by statin administration. Hiro et al reported that early statin administration reduced the prevalence of positive vascular remodeling, which is a predictor of poor clinical outcome. Furthermore, early statin administration after ACS altered plaque components such as the amount of necrotic core and fibro-fatty plaque. In contrast, vascular changes in culprit vessels due to chronic statin treatment have not been fully investigated. We hypothesized that chronic statin treatment reduces positive remodeling and alters plaque components in the culprit vessel of patients with ACS. The present study aimed to investigate vascular remodeling and plaque components of the culprit lesion of ACS by comparing patients with ACS with and without chronic statin use.
Methods
We identified patients with acute myocardial infarction (AMI) from hospital records in our medical center from July 2007 to December 2011. The diagnosis of AMI required an elevation of creatine kinase (at least twofold above the normal upper limit), persistent chest pain, and/or ST-segment elevation or depression in the 12-lead electrocardiogram compatible with AMI. Hyperlipidemia was defined as total cholesterol of >220 mg/dl, low-density lipoprotein (LDL) cholesterol of >140 mg/dl, or treatment for hyperlipidemia. Lipid profiles of all patients were measured within 30 minutes of hospital admission.
Patients had to meet all the following inclusion criteria: (1) AMI, (2) percutaneous coronary intervention (PCI) and IVUS study, (3) hyperlipidemia, and (4) within 24 hours from onset. PCI was performed using standard techniques as previously described. Patients were stratified into either a chronic statin group or a nonstatin group based on their treatment before admission. This study was approved by the institutional review board.
The reference diameter, lesion length, stenosis rate, and minimum diameter were calculated by quantitative coronary angiographic analysis. Before stent implantation, a 20-MHz, 2.9Fr IVUS imaging catheter (Eagle Eye; Volcano Corp, Rancho, California) was advanced >10 mm beyond the lesion, and automated pullback was performed to a location of >10 mm proximal to the lesion at a speed of 0.5 mm/s. The grayscale and VH-IVUS images were recorded before stent implantation on a DVD-ROM for off-line analysis.
Qualitative and quantitative analyses of grayscale IVUS images were performed according to the criteria of the American College of Cardiology’s Clinical Expert Consensus Document on IVUS. The proximal and distal reference sites were defined as those with the largest lumen proximal and distal to a stenosis but within the same segment (usually within 10 mm of the stenosis with no major intervening branches), respectively. The remodeling index was defined as the external elastic membrane cross-sectional area at the lesion site divided by the average of the proximal and distal reference external elastic membrane cross-sectional area. Positive remodeling was defined as a remodeling index of >1.05, intermediate remodeling as an index from 0.95 to 1.05, and negative remodeling as an index of <0.95.
Grayscale plaque type was classified as hypo-echoic, hyper-noncalc, hyper-calc, or mixed. Lesions with plaque rupture on IVUS were defined as lesions with fissure or dissection. Calcium was identified when the lesion echogenicity was brighter than the adventitia with an acoustic shadowing arc of >90°. VH-IVUS automatically classified the plaque into 4 components: fibrous (labeled green), fibro-fatty (labeled yellow), necrotic core (labeled red), and dense calcium (labeled white).
We compared risk factors, medical history, angiographic findings, and PCI procedural variables between the statin and nonstatin groups. Quantitative data are presented as mean ± SD for continuous variables and as the number of patients (percentage) for categorical variables. The Kolmogorov-Smirnov test was performed to determine whether the continuous variables were normally distributed. Normally distributed continuous variables were compared using an unpaired Student t test. Otherwise, continuous variables were compared using a Mann-Whitney U test. Categorical variables were compared using a chi-square test. Multivariate logistic regression analysis was performed to investigate the association between chronic statin treatment and vascular remodeling after controlling for confounding factors. Positive remodeling was used as a dependent variable, and chronic statin treatment was used as the independent variable. Other known factors such as age, male gender, hypertension, diabetes, smoking, calcium channel blocker use on admission, LDL cholesterol, and high-density lipoprotein cholesterol were used as independent variables. These factors have been shown to be relevance to vascular remodeling in previous studies. The odds ratios and the 95% confidence intervals were calculated. A p value of <0.05 was considered to indicate statistical significance. All analyses were performed using statistical software SPSS 16.0/Windows (SPSS Inc., Chicago, Illinois).
Results
In our medical center, a total of 785 patients with AMI were admitted during the study period. We excluded 215 patients who did not undergo PCI and IVUS and 364 patients who did not have hyperlipidemia. We also excluded 51 patients who were not within 24 hours of symptom onset. There were 155 patients who met the study inclusion criteria and were included in the final analysis. Of the 155 patients, 73 patients were stratified to the chronic statin group and 82 to the nonstatin group.
The patient characteristics are listed in Table 1 . Compared with the nonstatin group, the chronic statin group was older, and the prevalence of previous MI or PCI was greater in the chronic statin group. The chronic statin group had lower total and LDL cholesterol levels. Moreover, the number of medications used in the chronic statin group was larger. There were fewer current smokers in the chronic statin group.
| All n = 155 | Statin Use | p Value | ||
|---|---|---|---|---|
| Yes n = 73 | No n = 82 | |||
| Age (yrs) | 64.0 ± 12.3 (155/155) | 67.6 ± 11.2 (73/73) | 60.9 ± 12.5 (82/82) | <0.001 |
| Men | 117/155 (75.5) | 52/73 (71.2) | 65/82 (79.3) | 0.246 |
| Hypertension | 109/155 (70.3) | 53/73 (72.6) | 56/82 (68.3) | 0.558 |
| Diabetes mellitus | 51/155 (32.9) | 23/73 (31.5) | 28/82 (34.1) | 0.727 |
| Current smoker | 54/155 (34.8) | 19/73 (26.0) | 35/82 (42.7) | 0.030 |
| Former smoker | 47/155 (30.3) | 26/73 (35.6) | 21/82 (25.6) | 0.176 |
| Previous myocardial infarction | 16/155 (10.3) | 14/73 (19.2) | 2/82 (2.4) | <0.001 |
| Previous percutaneous coronary intervention | 15/155 (9.7) | 14/73 (19.2) | 1/82 (1.2) | <0.001 |
| Previous coronary artery bypass graft | 4/155 (2.6) | 2/73 (2.7) | 2/82 (2.4) | 0.645 |
| Cerebrovascular disease | 10/155 (6.5) | 5/73 (6.8) | 5/82 (6.1) | 0.552 |
| Peripheral artery disease | 5/155 (3.2) | 3/73 (4.1) | 2/82 (2.4) | 0.445 |
| Killip | 0.022 | |||
| I | 133/155 (85.8) | 63/73 (86.3) | 70/82 (85.4) | |
| II | 10/155 (6.5) | 1/73 (1.4) | 9/82 (11.0) | |
| III | 6/155 (3.9) | 4/73 (5.5) | 2/82 (2.4) | |
| IV | 6/155 (3.9) | 5/73 (6.8) | 1/82 (1.2) | |
| Cardiac arrest on out of hospital | 0/155 (0) | 0/73 (0) | 0/82 (0) | 1.000 |
| ST-elevation myocardial infarction | 133/155 (85.8) | 63/73 (86.3) | 70/82 (85.4) | 0.868 |
| Heart rate on admission (beats/min) | 79.5 ± 20.7 (155/155) | 79.5 ± 22.4 (73/73) | 79.5 ± 19.3 (82/82) | 0.978 |
| Systolic blood pressure (mm Hg) | 136.0 ± 31.6 (155/155) | 133.6 ± 32.0 (73/73) | 138.2 ± 31.2 (82/82) | 0.249 |
| Diastolic blood pressure (mm Hg) | 80.8 ± 17.6 (155/155) | 78.2 ± 18.4 (73/73) | 83.1 ± 16.7 (82/82) | 0.081 |
| Ejection fraction on admission (%) | 48.5 ± 11.2 (130/155) | 48.4 ± 12.3 (58/73) | 48.6 ± 10.4 (72/82) | 0.927 |
| Body mass index (kg/m 2 ) | 24.0 ± 4.0 (155/155) | 23.5 ± 3.5 (73/73) | 24.4 ± 4.3 (82/82) | 0.186 |
| Total cholesterol (mg/dl) | 201.8 ± 50.0 (155/155) | 173.8 ± 42.6 (73/73) | 226.7 ± 42.5 (82/82) | <0.001 |
| LDL cholesterol (mg/dl) | 131.5 ± 41.8 (155/155) | 104.8 ± 36.7 (73/73) | 155.2 ± 30.3 (82/82) | <0.001 |
| High-density lipoprotein cholesterol (mg/dl) | 45.1 ± 12.7 (155/155) | 43.3 ± 11.1 (73/73) | 46.7 ± 13.8 (82/82) | 0.197 |
| Triglyceride (mg/dl) | 126.0 ± 90.2 (155/155) | 111.2 ± 62.0 (73/73) | 139.2 ± 108.1 (82/82) | 0.291 |
| Hemoglobin A1c (%) | 6.18 ± 1.43 (155/155) | 5.99 ± 0.95 (73/73) | 6.35 ± 1.74 (82/82) | 0.936 |
| Maximum creatine kinase (U/L) | 2,839 ± 3,032 (155/155) | 2,766 ± 3,329 (73/73) | 2,903 ± 2,760 (82/82) | 0.798 |
| White blood count (/μl) | 10,553 ± 3,567 (155/155) | 10,299 ± 3,255 (73/73) | 10,779 ± 3,839 (82/82) | 0.300 |
| Hemoglobin (g/dl) | 13.9 ± 1.9 (155/155) | 13.3 ± 1.70 (73/73) | 14.5 ± 1.87 (82/82) | <0.001 |
| Platelet (/μl) | 28.5 ± 8.1 (155/155) | 26.9 ± 8.8 (73/73) | 29.9 ± 7.2 (82/82) | 0.020 |
| C-reactive protein (mg/dl) | 0.56 ± 1.40 (155/155) | 0.55 ± 1.48 (73/73) | 0.56 ± 1.34 (82/82) | 0.845 |
| Creatinine (mg/dl) | 0.80 ± 0.27 (155/155) | 0.85 ± 0.30 (73/73) | 0.75 ± 0.24 (82/82) | 0.024 |
| Medical therapy on admission | ||||
| Angiotensin receptor blocker or angiotensin-converting enzyme inhibitor | 70/151 (46.4) | 37/70 (52.9) | 33/81 (40.7) | <0.001 |
| Beta blocker | 15/151 (9.9) | 11/70 (15.7) | 4/81 (4.9) | 0.027 |
| Calcium channel blocker | 47/151 (31.1) | 30/70 (42.9) | 17/81 (21.0) | 0.004 |
| Aspirin | 34/151 (22.5) | 26/70 (37.1) | 8/81 (9.9) | <0.001 |
| Thienopyridine | 8/151 (5.3) | 5/70 (7.1) | 3/81 (3.7) | 0.282 |
Angiographic findings and lesion characteristics are listed in Table 2 . Compared with the nonstatin group, single-vessel disease was less frequent in the chronic statin group. The IVUS findings are listed in Table 3 . Compared with the nonstatin group, positive remodeling was less frequent in the chronic statin group. The remodeling index was smaller in the chronic statin group. Compared with the nonstatin group, necrotic core area was less, and fibro-fatty area was greater in the chronic statin group. The initial and final Thrombolysis in Myocardial Infarction flow grade, type of procedure, and stent type were not different between the 2 groups. Moreover, in-hospital outcomes were not different between the 2 groups. The results of multivariate logistic regression analysis are listed in Table 4 . Chronic statin use on admission was significantly associated with less positive remodeling after controlling for confounding risk factors (odds ratio 0.283, 95% confidence interval 0.111 to 0.723, p = 0.008).
| All n = 155 | Statin Use | p Value | ||
|---|---|---|---|---|
| Yes n = 73 | No n = 82 | |||
| Culprit coronary lesions | 0.258 | |||
| Right | 55/155 (35.5) | 32/73 (43.8) | 23/82 (28.0) | |
| Left anterior descending | 78/155 (50.3) | 31/73 (42.5) | 47/82 (57.3) | |
| Left circumflex | 19/155 (12.3) | 9/73 (12.3) | 10/82 (12.2) | |
| Left main | 1/155 (0.6) | 0/73 (0) | 1/82 (1.2) | |
| Saphenous vein graft | 2/155 (1.3) | 1/73 (1.4) | 1/82 (1.2) | |
| Number of narrowed coronary arteries | 0.021 | |||
| 1 | 92/155 (59.4) | 40/73 (54.8) | 52/82 (63.4) | |
| 2 | 45/155 (29.0) | 19/73 (26.0) | 26/82 (31.7) | |
| 3 | 18/155 (11.6) | 14/73 (19.2) | 4/82 (4.9) | |
| Multivessel disease | 63/155 (40.6) | 33/73 (45.2) | 30/82 (36.6) | 0.275 |
| In-stent restenosis lesions | 3/155 (1.9) | 3/73 (4.1) | 0/82 (0.0) | 0.102 |
| Thrombus | 68/155 (43.9) | 27/73 (37.0) | 41/82 (50.0) | 0.103 |
| Ostial lesion | 9/155 (5.8) | 3/73 (4.1) | 6/82 (7.3) | 0.309 |
| Bifurcation lesion | 7/155 (4.5) | 2/73 (2.7) | 5/82 (6.1) | 0.272 |
| Reference diameter (mm) | 2.83 ± 0.72 (155/155) | 2.77 ± 0.75 (73/73) | 2.89 ± 0.69 (82/82) | 0.193 |
| Percent stenosis rate | 87.8 ± 14.1 (155/155) | 88.2 ± 14.1 (73/73) | 87.5 ± 14.2 (82/82) | 0.763 |
| Minimum diameter (mm) | 0.34 ± 0.40 (155/155) | 0.31 ± 0.37 (73/73) | 0.37 ± 0.42 (82/82) | 0.358 |
| Lesion length (mm) | 10.8 ± 4.5 (155/155) | 10.9 ± 4.9 (73/73) | 10.7 ± 4.3 (83/83) | 0.755 |
| All n = 155 | Statin Use | p Value | ||
|---|---|---|---|---|
| Yes n = 73 | No n = 82 | |||
| Grayscale | ||||
| Remodeling | 0.001 | |||
| Positive | 92/155 (59.4) | 34/73 (46.6) | 58/82 (70.7) | |
| Intermediate | 36/155 (23.2) | 27/73 (37.0) | 9/82 (11.0) | |
| Negative | 27/155 (17.4) | 12/73 (16.4) | 15/82 (18.3) | |
| Remodeling index | 1.11 ± 0.21 (155/155) | 1.08 ± 0.16 (73/73) | 1.16 ± 0.24 (82/82) | 0.032 |
| Plaque rupture | 20/155 (12.9) | 6/73 (8.2) | 14/82 (17.1) | 0.101 |
| Calcium | 37/155 (23.9) | 18/73 (24.7) | 19/82 (23.2) | 0.828 |
| Grayscale plaque type | 0.570 | |||
| Hypo-echoic | 109/155 (70.3) | 54/73 (74.0) | 55/82 (67.1) | |
| Hyper-noncalc | 7/155 (4.5) | 4/73 (5.5) | 3/82 (3.7) | |
| Hyper-calc | 11/155 (7.1) | 5/73 (6.8) | 6/82 (7.3) | |
| Mixed | 28/155 (18.1) | 10/73 (13.7) | 18/82 (22.0) | |
| Proximal | ||||
| Proximal external elastic membrane (mm 2 ) | 17.8 ± 6.3 (155/155) | 18.4 ± 6.9 (73/73) | 17.2 ± 5.6 (82/82) | 0.121 |
| Proximal lumen (mm 2 ) | 7.9 ± 4.3 (155/155) | 8.2 ± 5.2 (73/73) | 7.6 ± 3.3 (82/82) | 0.299 |
| Proximal plaque (mm 2 ) | 9.9 ± 3.8 (155/155) | 10.2 ± 4.2 (73/73) | 9.6 ± 3.4 (82/82) | 0.300 |
| Lesion | ||||
| Lesion external elastic membrane (mm 2 ) | 18.1 ± 6.6 (155/155) | 17.9 ± 6.1 (73/73) | 18.3 ± 7.0 (82/82) | 0.894 |
| Lesion lumen (mm 2 ) | 2.5 ± 0.5 (155/155) | 2.5 ± 0.5 (73/73) | 2.4 ± 0.6 (82/82) | 0.364 |
| Lesion plaque (mm 2 ) | 15.6 ± 6.5 (155/155) | 15.4 ± 5.9 (73/73) | 15.8 ± 6.9 (82/82) | 0.993 |
| Distal | ||||
| Distal external elastic membrane (mm 2 ) | 14.9 ± 5.5 (155/155) | 15.3 ± 6.1 (73/73) | 14.6 ± 4.8 (82/82) | 0.326 |
| Distal lumen (mm 2 ) | 6.1 ± 5.8 (155/155) | 5.6 ± 2.5 (73/73) | 6.6 ± 7.7 (82/82) | 0.252 |
| Distal plaque (mm 2 ) | 9.2 ± 4.5 (155/155) | 9.7 ± 5.3 (73/73) | 8.7 ± 3.6 (82/82) | 0.126 |
| Percent plaque volume | ||||
| Percent proximal plaque volume | 56.3 ± 11.6 (155/155) | 56.5 ± 13.4 (73/73) | 56.2 ± 9.9 (82/82) | 0.878 |
| Percent distal plaque volume | 60.7 ± 11.5 (155/155) | 62.2 ± 11.3 (73/73) | 59.3 ± 11.5 (82/82) | 0.120 |
| Percent lesion plaque volume | 85.0 ± 5.1 (155/155) | 84.7 ± 5.1 (73/73) | 85.3 ± 5.1 (82/82) | 0.512 |
| Virtual histology | ||||
| External elastic membrane area (mm 2 ) | 18.9 ± 71 (150/155) | 18.8 ± 6.7 (72/73) | 19.0 ± 7.4 (78/82) | 0.778 |
| Lumen area (mm 2 ) | 2.8 ± 0.6 (150/155) | 2.8 ± 0.6 (72/73) | 2.9 ± 0.6 (78/82) | 0.622 |
| Lesion plaque area (mm 2 ) | 16.0 ± 7.1 (150/155) | 16.0 ± 6.6 (72/73) | 16.0 ± 7.6 (78/82) | 0.579 |
| Percent plaque area | 83.2 ± 6.2 (150/155) | 83.5 ± 5.9 (72/73) | 83.1 ± 6.5 (78/82) | 0.696 |
| Necrotic core area (mm 2 ) | 2.7 ± 1.8 (149/155) | 2.2 ± 1.3 (72/73) | 3.2 ± 2.1 (77/82) | <0.001 |
| Percent necrotic core area | 21.6 ± 11.3 (149/155) | 17.3 ± 8.2 (72/73) | 25.7 ± 12.3 (77/82) | <0.001 |
| Dense calcium area (mm 2 ) | 0.7 ± 0.8 (149/155) | 0.6 ± 0.8 (72/73) | 0.7 ± 0.7 (77/82) | 0.401 |
| Percent dense calcium area | 5.8 ± 6.6 (149/155) | 5.5 ± 6.7 (72/73) | 6.0 ± 6.6 (77/82) | 0.536 |
| Fibrous area (mm 2 ) | 7.5 ± 4.0 (149/155) | 7.6 ± 3.7 (72/73) | 7.4 ± 4.4 (77/82) | 0.410 |
| Percent fibrous area | 57.6 ± 10.5 (149/155) | 59.2 ± 9.2 (72/73) | 56.1 ± 11.5 (77/82) | 0.065 |
| Fibro-fatty area (mm 2 ) | 2.1 ± 2.2 (149/155) | 2.5 ± 2.1 (72/73) | 1.8 ± 2.1 (77/82) | 0.002 |
| Percent fibro-fatty area | 14.8 ± 10.2 (149/155) | 17.9 ± 10.0 (72/73) | 11.9 ± 9.7 (77/82) | <0.001 |
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