Previous studies have demonstrated endothelial dysfunction after sirolimus-eluting stent (SES) implantation. The present study evaluated the effect of pioglitazone on endothelial dysfunction after SES implantation in nondiabetic patients. A total of 50 nondiabetic patients who had undergone SES implantation were randomly assigned to the pioglitazone group (n = 25) or the control group (n = 25). Endothelial function was estimated by measuring the coronary vasoreactivity in the reference segment within 15 mm proximal and distal to the SES in response to intracoronary acetylcholine infusion (10 −8 and 10 −7 mol/L) at 9 months of follow-up. Endothelium-independent vasomotion was assessed after an intracoronary bolus of nitroglycerin. Changes in the coronary diameter in response to 10 −8 and 10 −7 mol/L acetylcholine in the segment proximal to the SES were not significantly different between the pioglitazone and control groups. In contrast, in the segment distal to the SES, vasoconstrictions to 10 −8 (−3.0 ± 2.8% vs −7.1 ± 4.5%, p <0.01) and 10 −7 mol/L acetylcholine (−6.2 ± 8.0% vs −13.1 ± 8.9%, p <0.01) were attenuated in the pioglitazone group compared to the control group. Endothelium-independent vasodilation to nitrate did not differ between the 2 groups. Multivariate analysis showed that pioglitazone was an independent predictor improving endothelial dysfunction after SES implantation. In conclusion, pioglitazone might improve endothelial dysfunction after SES implantation in nondiabetic patients.
Previous studies have demonstrated abnormal endothelial function after sirolimus-eluting stent (SES) implantation. Thiazolidinediones, peroxisome proliferator-activated receptor-γ agonists, are used to treat patients with type 2 diabetes mellitus as insulin-sensitizing agents. It has been shown that thiazolidinediones improve endothelial dysfunction independently of glycemic control in animal models and human studies. The present study evaluated the effect of pioglitazone on endothelial dysfunction after SES implantation in nondiabetic patients.
Methods
The institutional review boards at Chiba University Hospital approved the present open-label randomized study, and all patients provided written informed consent. The present study was registered at the University Hospital Medical Information Network Clinical Trials Registry in Japan, according to a statement from the International Committee of Medical Journal Editors in 2004, as registry identification University Hospital Medical Information Network Clinical Trials number 000000899.
A total of 50 nondiabetic patients who had been diagnosed with stable or unstable angina and treated with a SES for a de novo single lesion were enrolled. The nondiabetic state was determined by no history of diabetes mellitus and an assessment of the fasting plasma glucose with a level <126 mg/dl, and hemoglobin A1c level of <5.6%. The major criteria for exclusion were recent myocardial infarction (within the previous 48 hours), a history of coronary artery vasospasm, an ejection fraction of <40%, a target lesion in an unprotected left main coronary artery or a vessel with thrombus, severe calcified lesion, the presence of a >50% stenosis, except for a culprit lesion in the target vessel, a reference diameter of <2.5 or >4.0 mm, previous percutaneous coronary intervention in the target vessel, a contraindication to SES, and serious medical conditions. Intravascular ultrasound (IVUS)-guided stenting was performed in all patients. Stent implantation was performed according to current guidelines. All stents were implanted to fully cover the lesion. Pre- and postdilation were performed, if necessary. Special care was taken to avoid geographic miss. In all patients, optimal stent expansion without residual stenosis and dissection of stent edge was confirmed by IVUS. After percutaneous coronary intervention, the patients continued a regimen of aspirin (100 mg/day) plus clopidogrel (75 mg/day) during 9 months of follow-up. The medications used before intervention were continued and were not changed during follow-up.
After the patients provided written informed consent, randomization was done with a sequentially numbered, opaque, sealed envelope in a 1:1 ratio. All patients were prospectively recruited from the Department of Cardiology at Chiba University Hospital. The patients were assigned to the pioglitazone group (n = 25) or the control group (n = 25). If allocated, we gave patients pioglitazone 15 mg/day for the initial 2 weeks and 30 mg/day thereafter. We saw patients monthly for the first 2 months and then every 2 months until follow-up angiography. The assessment of concentrations of fasting plasma glucose, hemoglobin A1c, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, malondialdehyde LDL, high-sensitive C-reactive protein, high-molecular-weight adiponectin, and brain natriuretic peptide was performed at baseline and 9 months of follow-up.
Follow-up coronary angiography was performed 9 months after SES implantation. Endothelial function was estimated by measuring the coronary vasoreactivity in response to acetylcholine (Ach) infusion into the target coronary artery at 9 months of follow-up. All antianginal agents that influence vasomotor tone, including long-acting nitrates, calcium channel blockers, and β blockers, were withheld for ≥48 hours before follow-up angiography, except for sublingual nitroglycerin as needed. After baseline coronary angiography, serial Ach infusion (10 −8 and 10 −7 mol/L) into the target coronary artery through the 4Fr Judkins catheter for 2 minutes at each concentration was performed at an infusion rate of 2.0 ml/min. Subsequently, endothelium-independent vasomotion was assessed after an intracoronary bolus of nitroglycerin (200 μg).
Using a computer-assisted, automated, edge-detection algorithm (CMS, MEDIS, Leiden, The Netherlands), off-line quantitative analysis of coronary angiography was performed by an experienced cardiologist (H.K.), who was unaware of the treatment group assignment. Two orthogonal views with less foreshortening or without overlapping of side branches were selected. The minimum lumen diameter in the reference segments within 15 mm proximal and distal to the SES was measured. It was measured 3 times for each projection. The mean minimum lumen diameter was averaged for 2 projections. In addition, a reference angiographically normal segment in another vessel was measured, if the SES was implanted in the left coronary artery. If the intervened vessel was the right coronary artery, an angiographically normal segment as far as possible from the stented vessel segment was measured as the reference. Changes in the coronary diameter in response to Ach and nitrate infusion are expressed as the percentage of changes versus the baseline angiographic findings. The primary end point was the change in the coronary diameter in response to 10 −7 mol/L Ach in the segment distal to the SES. The secondary end points were the changes in coronary diameter in response to 10 −8 mol/L Ach in a segment distal to the SES and in response to 10 −8 and 10 −7 mol/L Ach in the segment proximal to the SES.
IVUS was performed after administration of 200 μg of intracoronary nitroglycerin using the 40-MHz IVUS catheter (Boston Scientific, Natick, Massachusetts) with an automated pullback at 0.5 mm/s. According to the Clinical Expert Consensus Documents, quantitative IVUS analysis was performed using commercially available planimetry software (echoPlaque, INDEC Systems, Mountain View, California).
In a previous study, the change in the coronary diameter in response to 10 −7 mol/L Ach in a segment distal to the SES was −17.5 ± 12.5%. We expected pioglitazone to achieve a 60% reduction in the change in coronary diameter in response to 10 −7 mol/L Ach in a segment distal to the SES. We estimated that 50 patients were required for a power of 80% and an α level of 0.05, assuming an angiographic follow-up rate of 92%.
Statistical analysis was performed with StatView, version 5.0, software (SAS Institute, Cary, North Carolina). Data are expressed as the mean ± SD or frequency (%). Comparisons within groups were performed by analysis of variance for repeated measurements. For intergroup comparisons, an unpaired Student’s t test was applied. Categorical variables were analyzed using the chi-square test or Fisher’s exact test. A value of p <0.05 was considered significant. Univariate analysis was performed using linear regression analysis of rank-transformed outcomes. Including only variables with a p value of <0.1 on univariate analysis, multivariate analysis was performed using multiple linear regression analysis of rank-transformed outcomes.
Results
The baseline patient, angiographic, and procedural characteristics were similar between the 2 groups ( Tables 1 and 2 ). The baseline and follow-up laboratory data and blood pressure are listed in Table 3 . No significant difference was found in the IVUS measurements between the 2 groups ( Table 4 ).
| Variable | Pioglitazone (n = 25) | Control (n = 25) |
|---|---|---|
| Age (years) | 66.4 ± 7.9 | 66.8 ± 9.6 |
| Men | 22 (88%) | 23 (92%) |
| Body mass index (kg/m 2 ) | 23.0 ± 1.8 | 23.9 ± 3.9 |
| Hypertension ⁎ | 18 (72%) | 20 (80%) |
| Hypercholesterolemia † | 20 (80%) | 22 (88%) |
| Current smoker | 5 (20%) | 3 (12%) |
| Previous myocardial infarction | 4 (16%) | 2 (8%) |
| Previous percutaneous coronary intervention | 12 (48%) | 11 (44%) |
| Clinical presentation at procedure | ||
| Unstable angina pectoris | 6 (24%) | 5 (20%) |
| Stable angina pectoris | 19 (76%) | 20 (80%) |
| Left ventricular ejection fraction (%) | 61.1 ± 6.5 | 59.7 ± 7.8 |
| Medication | ||
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⁎ Defined as any patient receiving antihypertensive drugs or with systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg.
† Defined as any patient receiving antihypercholesterelemic therapy or with untreated total cholesterol ≥220 mg/dl.
| Variable | Pioglitazone (n = 25) | Control (n = 25) |
|---|---|---|
| Coronary artery | ||
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| Bifurcation | 3 (12%) | 7 (28%) |
| Moderate calcium | 3 (12%) | 4 (16%) |
| Chronic total occlusion | 0 (0%) | 2 (8%) |
| American Heart Association/American College of Cardiology type B2 or C | 15 (60%) | 18 (72%) |
| Stents/lesion | 1.3 ± 0.5 | 1.4 ± 0.5 |
| Stent diameter (mm) | 3.0 ± 0.4 | 3.1 ± 0.4 |
| Stent length (mm) | 29.2 ± 11.9 | 33.4 ± 15.5 |
| Maximum balloon diameter (mm) | 3.1 ± 0.5 | 3.2 ± 0.4 |
| Maximum balloon inflation (atm) | 17.7 ± 3.1 | 17.5 ± 3.6 |
| Variable | Pioglitazone (n = 25) | Control (n = 25) | p Value |
|---|---|---|---|
| Fasting plasma glucose (mg/dl) | |||
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| Hemoglobin A1c (%) | |||
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| Triglycerides (mg/dl) | |||
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| High-density lipoprotein cholesterol (mg/dl) | |||
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| Low-density lipoprotein cholesterol (mg/dl) | |||
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| Malondialdehyde low-density lipoprotein (U/L) | |||
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| High-sensitivity C-reactive protein (mg/L) | |||
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| High-molecular-weight adiponectin (μg/ml) | |||
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| Brain natriuretic peptide (pg/ml) | |||
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| Systolic blood pressure (mm Hg) | |||
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| Diastolic blood pressure (mm Hg) | |||
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| Pioglitazone (n = 25) | Control (n = 25) | p Value | |
|---|---|---|---|
| Proximal to sirolimus-eluting stent | |||
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| Distal to sirolimus-eluting stent | |||
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