Author + information
- Received June 17, 2011
- Revision received September 7, 2011
- Accepted September 28, 2011
- Published online February 1, 2012.
- Mitsuyasu Terashima, MD⁎,⁎ (, )
- Hideaki Kaneda, MD†,
- Kenya Nasu, MD⁎,
- Hitoshi Matsuo, MD⁎,
- Maoto Habara, MD⁎,
- Tsuyoshi Ito, MD⁎,
- Nobuyoshi Tanaka, MD⁎,
- Sudhir Rathore, MD⁎,
- Yoshihisa Kinoshita, MD⁎,
- Masashi Kimura, MD⁎,
- Mariko Ehara, MD⁎,
- Yasuyoshi Suzuki, BS⁎ and
- Takahiko Suzuki, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Mitsuyasu Terashima, Department of Cardiology, Toyohashi Heart Center, 21-1 Gobudori, Oyama-cho, Toyohashi 441-8530, Japan
Objectives The aim of this prospective, randomized study was to evaluate the effects of telmisartan, compared with the calcium-channel blocker amlodipine, on endothelial function after coronary drug-eluting stent (DES) implantation in hypertensive patients.
Background DES implantation impairs local endothelial function, which may be associated with future cardiovascular events. Telmisartan, which has unique peroxisome proliferator-activated-receptor-gamma–mediated effects in addition to its renin-angiotensin system–inhibition effects, has favorable effects on endothelial function.
Methods Fifty-one hypertensive patients with coronary artery stenosis but without coronary artery spasm, treated with a sirolimus-eluting stent, were randomly assigned to either the telmisartan (25 cases) or amlodipine (26 cases) treatment groups. At baseline and at 3 months after DES implantation, endothelium-dependent and -independent vasomotion were evaluated by quantitative coronary angiography under the condition of medication withdrawal. The mean luminal diameter of a 20-mm coronary segment, beginning 5 mm distal to the stent, was measured before and after infusion of intracoronary acetylcholine (10−7, 10−6 mol/l) and then again after infusion of nitroglycerin.
Results Blood pressure was comparable between groups at baseline and after 3 months. Vasoconstriction after acetylcholine infusion at 3 months (impaired endothelial function) was less pronounced in the telmisartan group than in the amlodipine group (p < 0.0001), although there was no significant difference between the 2 groups before DES implantation. The response to nitroglycerin did not differ between groups before or at 3 months after DES implantation.
Conclusions Telmisartan, compared with amlodipine, significantly ameliorated endothelial dysfunction after DES implantation in terms of vasoconstriction induced by acetylcholine.
- angiotensin-II receptor blocker
- drug-eluting stent(s)
- endothelial function
Drug-eluting stents (DES) are widely used for the treatment of coronary artery disease to reduce both the rate of restenosis and the subsequent need for target lesion reintervention. Endothelial dysfunction after DES implantation is a concern (1–5), however, and might contribute to the development of severe adverse cardiac events. Therefore, amelioration of endothelial dysfunction after DES implantation might improve prognosis.
Angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers (ARB), which block the renin-angiotensin system, are widely used for their organoprotective actions, as well as for the treatment of hypertension (6). Among various organoprotective actions, renin-angiotensin system blockers favorably affect endothelial function (7–9). Telmisartan, an ARB, has unique peroxisome proliferator-activated receptor (PPAR)-gamma–mediated effects in addition to ARB class effects and is expected to improve endothelial function through several mechanisms, including angiotensin II inhibition with type-1 receptor blockade and induction of adiponectin via PPAR-gamma–mediated effects (10–12).
This prospective, randomized study compared the effects of telmisartan to a calcium-channel blocker, amlodipine, on endothelial function after DES implantation in hypertensive patients.
Patients between 20 and 80 years of age with clinically stable angina pectoris and hypertension scheduled for percutaneous coronary intervention (PCI) were enrolled. Inclusion criteria were: 1) hypertension defined based on the criteria put forth in the guidelines of the Japanese Society of Hypertension or use of an antihypertensive drug; 2) stable angina pectoris with a single de novo stenotic lesion (75% to 90% diameter stenosis) in the native coronary artery with a lesion length eligible for treatment with 1 or 2 sirolimus-eluting stents (SES) (Cypher, Cordis Corp., Miami Lakes, Florida) and with a reference vessel diameter of at least 2.5 mm and <4.0 mm. Exclusion criteria were: 1) vasospastic angina pectoris; 2) unstable angina pectoris or myocardial infarction within 4 weeks; 3) left main coronary artery disease; 4) totally or subtotally occluded lesion; 5) bifurcation lesion treated with bifurcation stenting; 6) bypass graft lesion; 7) previous PCI for the target vessel; 8) cardiogenic shock; 9) left ventricular ejection fraction <30%; 10) serum creatinine levels >1.5 mg/dl; and 11) judged by the investigator to be inappropriate for participation in this study. The study protocol was approved by the institutional review board, and all patients provided written informed consent.
Evaluation of endothelial function
Coronary angiography (CAG) to evaluate endothelial function was performed both at the pre-intervention state and at the 3-month follow-up. Medications with potential effects on vasomotor responses were withheld for at least 48 h before CAG, except for sublingual nitroglycerin (NTG) as needed. CAG was performed after injection of 2,000 U of heparin, and all drugs were infused through the catheter selectively engaged in the target vessel. To evaluate endothelial function, endothelium-dependent and -independent vasomotor responses to intracoronary infusion of increasing doses of acetylcholine (ACh) or nitrates were assessed. As baseline, physiological saline was infused for 2 min at an infusion rate of 2 ml/min, followed by baseline CAG. Thereafter, the endothelium-dependent vasomotor response was evaluated over a 2-min infusion of ACh in increasing doses (1.4 and 14 μg/min; estimated 10−7 and 10−6 mol/l) into the target vessel with 5-min interval between doses. A temporary pacemaker was inserted if clinically needed. Subsequently, an intracoronary bolus injection of NTG (200 μg) was administered to assess the endothelium-independent vasomotor response. CAG was repeated after each dose of ACh and within 2 min of NTG administration. Patient's symptoms, blood pressure, heart rate, and 12-lead electrocardiogram were continuously monitored during the study.
Assessment of coronary artery diameter in response to ACh or NTG infusion
During the evaluation of endothelial function, projection of the CAG was fixed at the most suitable position with little foreshortening and without overlapping of side branches. At the follow-up study, care was taken to replicate angiographic views, tube height, and catheter positions used in the baseline study. Thus, the same conditions for assessment of the coronary artery were prepared for both the pre-intervention and follow-up studies. Offline quantitative CAG was performed using the subsegmental analysis method with an automated edge detection program (Cardiovascular Measurement System Medical Imaging System, Leiden, the Netherlands). The mean luminal diameter of a 20-mm coronary segment, beginning 5 mm distal to the stent and ending 25 mm distal to the stent (Fig. 1), was measured at baseline, after intracoronary infusion of ACh, and after intracoronary infusion of NTG. To evaluate vasomotor responses at the pre-intervention state, the mean luminal diameter of the corresponding 20-mm segment, identified in reference to specific anatomic landmarks on CAG before and after SES implantation, was measured in the same manner. Changes in coronary diameter in response to intracoronary infusion of ACh and NTG were expressed as percentage changes versus control angiograms (angiograms after saline infusion). Measurements were performed by 2 independent reviewers blinded to the patients' information.
Interobserver and intraobserver variability for quantitative CAG measurements were assessed in 10 randomly selected patients after intracoronary infusion of saline, 10−7 mol/l ACh, 10−6 mol/l ACh, and NTG.
Treatment and follow-up
After evaluation of endothelial function at the pre-intervention state, all patients underwent SES implantation using standard techniques. Stents were implanted after a pre-dilation procedure, and the pre-dilation site and atherosclerotic lesions were fully covered with 1 or 2 SES. All patients received oral aspirin (100 mg/day) and clopidogrel 75 mg for at least 2 days before PCI and continued during the follow-up period.
As described previously, before PCI, all medications with potential effects on vasomotor responses, including any antihypertensive drugs, were withheld for at least 48 h before CAG, and then patients were randomly assigned to the telmisartan treatment group or the amlodipine treatment group. Each drug was administered after SES implantation and titrated to the maximally tolerated dose (telmisartan: 40 to 80 mg, amlodipine: 5 to 10 mg) during the follow-up periods. If the blood pressure–reducing effect was not adequate, despite a maximum dose, patients were treated with a combination of diuretics, alpha-blockers, and/or beta-blockers per physician's guidance. In addition, fluvastatin 30 mg was administered in all patients, regardless of the serum low-density lipoprotein (LDL) level, and thiazolidinedione was not administered to any patients after SES implantation.
Laboratory tests, including lipid profiles (total, LDL, and high-density lipoprotein cholesterol and triglyceride), diabetic parameters (fasting blood sugar and hemoglobin A1c), high-sensitivity C-reactive protein, and adiponectin were performed at the pre-intervention state and at the 3-month follow-up.
We determined sample size based on a previous randomized study comparing telmisartan and amlodipine based on peripheral vascular endothelial function (flow-mediated dilation) in patients with essential hypertension (13).
Statistical analysis was performed with StatView version 5.0 (SAS Institute, Cary, North Carolina). For continuous variables, differences between groups were evaluated using the unpaired t test or Mann-Whitney rank-sum test, and those within groups were evaluated using paired t test or Wilcoxon signed rank test. Change in coronary lumen diameters in response to infusion of 10−7 and 10−6 mol/l ACh were compared between groups and between the values before intervention and 3 months after SES implantation using a repeated measured analysis of variance. For discrete variables, differences were expressed as counts and percentages and analyzed with a chi-square (or Fisher exact) test between groups and with a McNemar test or Fisher exact test within groups, as appropriate. A 2-tailed p value of <0.05 was considered statistically significant. Data are expressed as mean ± SD. When the variable was significantly skewed, the median (25th to 75th percentiles) was reported.
Between July 2008 and June 2009, 51 patients, who were eligible based on the inclusion criteria, were enrolled in this study, and 25 patients were assigned to the telmisartan treatment group and 26 were assigned to the amlodipine treatment group (Fig. 2). At the before-intervention evaluation of endothelial function, 4 patients in the telmisartan group and 5 patients in the amlodipine group were excluded because they demonstrated a coronary spasm with total or subtotal occlusion (>90% stenosis) at the target lesion for SES implantation or had more than 50% coronary vasoconstriction at other sites in response to ACh infusion. SES were successfully implanted in all patients under intravascular ultrasound guidance. Twenty-one patients in each group underwent a 3-month follow-up CAG. None of them demonstrated angiographic restenosis, and endothelial function was evaluated.
Patient characteristics and serial changes in blood pressure and in laboratory data
Patient characteristics at baseline are summarized in Table 1. There were no significant differences in baseline patient characteristics between groups. At the time of enrollment, 17 (81.0%) and 19 (90.5%) patients were being treated with antihypertensive agents, including angiotensin-converting enzyme inhibitors, ARB, calcium channel blockers, and beta-blockers, which did not differ significantly between groups. At baseline, 10 patients (47.6%) in the telmisartan treatment group and 7 (33.3%) in the amlodipine treatment group were receiving statins (p = 0.34), which were replaced with fluvastatin 30 mg. Oral glycemic agents for diabetes mellitus were being taken by 6 patients (28.6%) in the telmisartan treatment group and 3 (14.3%) in the amlodipine group (p = 0.26), and none of the patients required insulin treatment. Pioglitazone was administered to 1 patient in each group and was withheld for 48 h before PCI and discontinued during the follow-up period. Angiographic and procedural characteristics of PCI were not significantly different between groups (Table 1).
The applied doses of telmisartan or amlodipine and adjuvant remedies during follow-up periods are presented in Table 2. None of the patients quit taking telmisartan or amlodipine. Systolic, diastolic, and mean blood pressure at baseline, after 3 months, and changes during the 3 months was comparable between groups, although blood pressure significantly improved in both groups (Table 3).
Serial changes in laboratory tests are presented in Table 4. There were no significant differences between groups in the baseline values of the lipid profiles, diabetic parameters (fasting blood sugar and hemoglobin A1c) and high-sensitivity C-reactive protein and those at the 3-month follow-up, or in the changes in these parameters from the baseline state to the 3-month follow-up, except for LDL cholesterol and adiponectin. After 3 months, LDL cholesterol significantly decreased in the telmisartan group (p = 0.021), but not in the amlodipine group. From baseline to the 3-month follow-up, there was a nonsignificant trend toward a reduction in adiponectin levels in the amlodipine group (p = 0.067), and the change from the baseline value to follow-up was significantly different between treatment groups.
Vasomotion in response to intracoronary infusion of ACh or NTG
Absolute values in the mean lumen diameters in response to intracoronary infusion of ACh and NTG are shown in Table 5. Before SES implantation, there was no significant difference between groups in terms of the mean lumen diameter in response to the infusion of saline (control), 10−7 mol/l ACh infusion, 10−6 mol/l ACh infusion, and NTG infusion. At the 3-month follow-up, there were no differences between groups in the lumen size in response to saline or NTG infusion; however, the mean lumen diameters in response to 10−7 mol/l ACh and 10−6 mol/l ACh infusion were significantly smaller in the amlodipine group than in the telmisartan group.
Percentage of change in the mean lumen diameter for the evaluation of vasomotion in response to intracoronary infusion of ACh and NTG is shown in Figure 3. Before SES implantation, mild but significant vasoconstriction was observed in response to ACh infusion in both groups (p < 0.0001), but there was no significant difference between groups in the vasoconstriction induced (p = 0.81). At the 3-month follow-up, however, vasoconstriction was significantly greater in the amlodipine group than in the telmisartan group (p < 0.0001). In an additional analysis of covariance analysis, including LDL reduction as covariate, the results were unchanged. Endothelial dysfunction was not correlated with drug dose or blood pressure change.
In the amlodipine group, the magnitude of vasoconstriction in response to infusion of 10−7 and 10−6 mol/l ACh was greater at the 3-month follow-up than in the pre-SES implantation state (−16.0 ± 21.2% and −35.5 ± 27.8% vs. −1.8 ± 1.5% and −5.7 ± 6.8%, p = 0.005 and p < 0.0001, respectively). In the telmisartan group, however, greater vasoconstriction was observed only after the infusion of 10−6 mol/l ACh at the 3-month follow-up compared with that before SES implantation (−8.7 ± 5.6% vs. −6.3 ± 3.6%, p = 0.048).
There was no significant difference between treatment groups in vasodilatation by NTG before SES implantation or at the 3-month follow-up.
Interobserver and intraobserver variability
Inter- and intraobserver variability for quantitative CAG measurements were 0.05 ± 0.03 mm and 0.01 ± 0.02 mm.
The findings of the present study demonstrated that, compared with a calcium-channel blocker, amlodipine, treatment, telmisartan treatment for hypertensive patients after SES implantation significantly ameliorated endothelial dysfunction in terms of vasoconstriction induced by infusion of ACh although there was no significant difference between groups in endothelium-independent vasodilation by NTG. Furthermore, telmisartan treatment reduced LDL cholesterol and preserved plasma adiponectin concentrations.
Endothelial dysfunction after DES implantation
In patients with coronary artery disease, DES dramatically reduces restenosis as a major problem after bare-metal stent implantation. Endothelial dysfunction after DES implantation has recently become a concern (1–3), and several case reports indicate that severe coronary spasm after DES implantation was probably associated with endothelial dysfunction, leading to serious cardiac events, such as myocardial infarction, fatal arrhythmia, or sudden cardiac death (4). Endothelial dysfunction after DES implantation may also contribute to late stent thrombosis, a life-threatening complication (5,14). Thus, coronary endothelial dysfunction might have a crucial role in the long-term cardiovascular prognosis for patients treated with DES, as in patients with established atherosclerosis or early disease (15).
Potential mechanisms of endothelial dysfunction specific to DES implantation include delayed endothelial repair by the original action of the DES drug (neointimal inhibition) and direct negative actions of the drug. Pathological data indicate delayed endothelial repair (16,17), and this physical delay would result in a functional delay, namely, insufficient nitric oxide (NO) production, which is thought to contribute to endothelial dysfunction caused by DES. Obata et al. (18) and Guba et al. (19) reported that sirolimus reduces the production of vascular endothelial growth factor and attenuates the response of the vascular endothelium to vascular endothelial growth factor, causing delayed endothelial repair after vascular injury.
DES drugs also have direct negative actions. In vitro, Jabs et al. (20) showed that sirolimus induces endothelial dysfunction via increased mitochondrial and reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase-dependent superoxide production and decreases vascular NO formation.
Endothelial dysfunction is associated with a worse clinical outcome in patients with established atherosclerosis or early disease (15). Interventions to reverse endothelial dysfunction improve clinical outcome (21). Although the exact mechanisms of endothelial dysfunction after DES implantation remain unknown, reversal of endothelial dysfunction might improve the long-term outcome in patients treated with DES.
Effects of an ARB on endothelial dysfunction
The renin-angiotensin system contributes to endothelial injury by the following mechanisms. Angiotensin II increases NAD(P)H oxidase activity (22), leading to increased production of reactive oxygen species and NO inactivation. Furthermore, the balance between angiotensin II and NO is a major determinant of endothelial and vascular phenotype (23). Therefore, angiotensin-II inhibition by an angiotensin-II type-1 receptor blockade would reverse endothelial dysfunction (24). Several studies have demonstrated that inhibition of the vascular angiotensin-II type-1 receptors in patients with atherosclerosis improves coronary and peripheral vasomotion (7–9). Angiotensin receptor blockers also appear to reduce endothelial markers of inflammation and oxidative stress (25).
Pleiotropic effects of telmisartan
In addition to antagonizing angiotensin-II type-1 receptors, telmisartan has PPAR-gamma–activating effects (26). In a porcine model, the combination of candesartan and pioglitazone (a PPAR-gamma agonist) more effectively restored endothelial function after SES implantation than candesartan monotherapy did (27). Because PPAR-gamma activation inhibits the expression of inflammatory genes, the effect on endothelial function could potentially be mediated by an improvement in inflammation (28). Moreover, the inhibitory effects of sirolimus on circulating endothelial progenitor cells would be associated with delayed reendothelialization after SES implantation. The benefits of PPAR-gamma agonists on the endothelial progenitor cell endothelialization capacity would improve endothelial dysfunction (29).
Telmisartan induces adiponectin protein expression in adipocytes at a post-transcriptional level via its PPAR-gamma–activating effect, leading to an increase in adiponectin plasma levels (30). Adiponectin is an adipocyte-specific plasma protein with anti-inflammatory, antiatherogenic, and antidiabetic properties (31), and it improves vascular endothelial function via several mechanisms, including enhanced NO production by increased endothelial NO synthase activity and suppressed superoxide generation in endothelial cells through an NAD(P)H oxidase-linked mechanism (32,33). In the present study, serum adiponectin concentrations decreased in the amlodipine group, but not in the telmisartan group, during follow-up.
Further, serum LDL-cholesterol levels were significantly decreased in the telmisartan treatment group but not in the amlodipine treatment group. Telmisartan effectively reduces LDL-cholesterol levels by different mechanisms than statins (34). Telmisartan may accelerate reverse cholesterol transport from nonhepatic peripheral cells to the liver, thereby lowering LDL cholesterol. Furthermore, telmisartan might inhibit intestinal cholesterol absorption via its PPAR-gamma–activating effect.
Thus, PPAR-gamma–mediated effects of telmisartan might confer vascular protection through several mechanisms after SES implantation.
Comparison between telmisartan and amlodipine in amelioration of endothelial dysfunction after DES
Amlodipine improves endothelial function and has antioxidant properties (35). In the present study, however, telmisartan treatment induced significantly stronger amelioration of endothelial dysfunction after DES implantation than amlodipine treatment did. Consistent with our results, a recent randomized study demonstrated that, compared with the calcium-channel blocker amlodipine, telmisartan treatment improves endothelial function (flow-mediated dilation) in peripheral vessels in hypertensive patients (13).
The present study was a single-center study with a small sample size. The lesions involved in the study were limited to a single stenosis suitable for treatment with 1 or 2 SES. In addition, the present study focused on the first-generation DES (SES), although second-generation DES are commonly used in current practice. Further studies are needed to examine whether this study finding is applicable to other DES, especially second-generation DES.
Furthermore, the results of the present study are only preliminary; a larger number of subjects and a longer follow-up for clinical outcomes are crucial to confirm the efficacy of telmisartan treatment for hypertensive patients with DES implantation.
In this group of hypertensive patients, compared with treatment with a calcium-channel blocker, telmisartan treatment significantly ameliorated endothelial dysfunction in terms of ACh-induced vasoconstriction after DES implantation.
The authors thank Masahisa Tsuzuki of Toyohashi Heart Center (Toyohashi, Japan) and Satoru Hashimoto of TCROSS Co. Ltd. (Tokyo, Japan) for their kind help.
This study was supported by a grant from Japan Vascular Disease Research Foundation (Kyoto, Japan). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- angiotensin-II receptor blocker(s)
- coronary angiography
- drug-eluting stent(s)
- low-density lipoprotein
- reduced nicotinamide adenine dinucleotide phosphate
- nitric oxide
- percutaneous coronary intervention
- peroxisome proliferator-activated receptor
- sirolimus-eluting stent(s)
- Received June 17, 2011.
- Revision received September 7, 2011.
- Accepted September 28, 2011.
- American College of Cardiology Foundation
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