CLINICAL RESEARCH: ENDOTHELIAL DYSFUNCTION
Endothelial Vasomotor Dysfunction in the Brachial Artery Is Associated With Late In-Stent Coronary Restenosis
Yoshinobu Kitta, MD,
Takamitsu Nakamura, MD,
Yasushi Kodama, MD,
Hajime Takano, MD, PhD,
Ken Umetani, MD, PhD,
Daisuke Fujioka, MD,
Yukio Saito, MD,
Ken-ichi Kawabata, MD, PhD,
Jyun-ei Obata, MD, PhD,
Yoshihide Ichigi, MD,
Akira Mende, MD and
Kiyotaka Kugiyama, MD, PhD*
Department of Internal Medicine II, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
Manuscript received January 23, 2005;
revised manuscript received April 19, 2005,
accepted April 25, 2005.
* Reprint requests and correspondence: Dr. Kiyotaka Kugiyama, Department of Internal Medicine II, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Nakakoma-gun, Yamanashi, 409-3898 Japan
(Email: kugiyama{at}yamanashi.ac.jp).
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Abstract
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OBJECTIVES: This study examined whether endothelial dysfunction in the brachial artery might be associated with late in-stent restenosis (ISR) after percutaneous coronary intervention (PCI).
BACKGROUND: Simple and noninvasive identification of late ISR might help to select patients who require further angiographic evaluation.
METHODS: Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was measured before (initial FMD) and at six months (follow-up FMD) after PCI in 141 consecutive patients who had elective and successful PCI with bare metal stents in de novo lesions of native coronary arteries for symptomatic coronary artery disease. Follow-up angiography was performed at six months after PCI in all patients.
RESULTS: With multivariate logistic regression analysis, the impairment ( 4.8% dilation from baseline diameter) of FMD at follow-up showed the strongest association with late ISR (defined as >50% diameter stenosis, n = 46) independently of other clinical and angiographic variables known to be associated with ISR (odds ratio 7.4, 95% confidence interval 2.8 to 19.2, p < 0.001), whereas the initial FMD did not have the association. The sensitivity of impaired FMD at follow-up (69%) in detecting ISR was higher than chest pain during the follow-up period (45%), with comparable specificity. The impaired FMD in combination with the chest pain increased the sensitivity to 90%.
CONCLUSIONS: The impairment of FMD in the brachial artery at the time of follow-up was independently and closely associated with late ISR in native coronary arteries. The noninvasive assessment of FMD at the time of follow-up might be useful for identification of late ISR.
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | ECG = electrocardiography | | FMD = flow-mediated dilation | | HDL-C = high-density lipoprotein cholesterol | | hsCRP = high-sensitivity C-reactive protein | | ISR = in-stent restenosis | | MLD = minimal lumen diameter | | PCI = percutaneous coronary intervention | | TLR = target lesions revascularization (defined as repeat percutaneous coronary intervention of the original stented target lesions) |
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In-stent restenosis (ISR), although less frequent than post-angioplasty restenosis, remains a clinical problem, because there is increasing use of coronary stents for the treatment of coronary artery disease (CAD). When chest pain develops during the follow-up period after stenting, patients might be recommended for angiographic evaluation to detect ISR or another coronary stenosis; however, several reports (1–3) have shown that approximately 50% of patients remain asymptomatic when restenosis occurs; thus, chest pain after percutaneous coronary intervention (PCI) is a poor indicator of restenosis. Therefore, a simple and noninvasive method for identifying late restenosis after PCI might help to select patients who require further angiographic evaluation.
The vascular endothelium suppresses intimal hyperplasia (4,5), an essential pathological feature of ISR (6,7). Furthermore, it has been shown that endothelial dysfunction in systemic arteries is a strong predictor of future coronary events (8,9). Thus, endothelial vasomotor dysfunction in systemic arteries in patients with coronary stenting might be associated with the development of ISR. In this study, we evaluated the usefulness of measuring endothelium-dependent dilation of the brachial artery for the identification of ISR.
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Methods
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Study patients.
This study included 141 consecutive patients who had elective and successful PCI of de novo lesions with bare metal stents in native coronary arteries for symptomatic CAD and follow-up coronary angiography at six months after the PCI at Yamanashi University Hospital. Patients who had acute coronary syndrome, stroke, or other serious diseases occurring during the six-month follow-up periods were excluded. Patients with congestive heart failure, left main trunk disease, and other serious systemic diseases were also excluded. This study also included 48 control subjects with angiographically normal coronary arteries and normal ventriculography. These control subjects were selected to match the age and gender of the patients with PCI, and they were studied to compare endothelial vasomotor function with that of the PCI patients. The characteristics of the patients and control subjects are shown in Table 1. All patients were informed that the follow-up angiography would be required, regardless of ischemia/anginal symptoms, according to the study protocol. Written informed consent was obtained from all patients and control subjects before the study. This study was in agreement with the guidelines approved by the ethics committee at our institution.
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Table 1. Comparisons of Clinical, Lesion, and Procedural Variables at Baseline Between Patients With and Without ISR
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Study protocol.
Measurement of flow-mediated dilation (FMD) in the brachial artery was performed in the morning after an overnight fast in the same manner in all study patients, within three days before the PCI and within three days before the follow-up coronary angiography, at the end of the six-month follow-up period. An exercise treadmill electrocardiographic (ECG) test was performed in the morning after overnight fasting a day before the follow-up FMD. Vasodilators, including calcium blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers were withdrawn 48 h before the FMD measurement and the exercise stress test. Beta-blockers were discontinued more than 12 h before the FMD measurement and the exercise stress test. Sublingual nitroglycerin was allowed to be used when ischemia/anginal symptoms were developed. All of the examinations were performed during hospital stay at Yamanashi University Hospital. The ECG was continuously and carefully monitored during the hospital stay to ensure the safety of the patients. All patients were routinely questioned for the presence or absence of chest pain during the six-month follow-up period according to Canadian Cardiovascular Society angina classification class (10) by investigators (Drs. Saito and Fujioka) without knowledge of the follow-up angiographic results. In addition, physical activity (average min/day), especially leisure-time activity, was assessed with a questionnaire at the end of the follow-up period. All of the patients received standard medical therapy during the follow-up period. Venous blood was obtained from all patients immediately before FMD measurement. High-sensitivity C-reactive protein (hsCRP) levels in the serum were assayed by rate nephelometry (Dade Behring, Marburg, Germany).
Pci.
Coronary angioplasty was performed with the Judkins technique without intracoronary ultrasound scanning guidance under systemic heparinization and oral administration of aspirin and ticlopidine. The stent type and inflation pressure were chosen at the discretion of the physicians (Drs. Takano, Umetani, and Obata), who were blinded to the study protocol and the data regarding FMD. Rotablator and directional atherectomy were not performed in the stented coronary lesions in any study patients. Procedural success was defined as a residual lumen narrowing <20%. After PCI, patients received aspirin (100 mg/day) indefinitely and ticlopidine (200 mg/day) at least for four weeks. Original stented target lesions revascularization (TLR) was defined as repeated PCI or surgical bypass of the original stented lesions and was performed in the presence of ISR and any symptoms or objective signs of myocardial ischemia. Even if the symptoms or the objective signs were absent, TLR was performed in the presence of  75% diameter stenosis in the stented lesions.
Quantitative coronary angiography.
All patients had coronary angiography before and immediately after PCI and at the planned six-month follow-up in multiple projections after intracoronary injection of 1 mg of isosobide dinitrate. Quantitative coronary angiography was conducted with the projection that revealed the highest degree of stenosis. Measurements were performed with CARDIO500 (Kontron Instruments Inc., Everett, Massachusetts) by operators (Drs. Ichigi and Mende) who were blinded to the FMD data. Lesion length, reference lumen diameter, minimal lumen diameter (MLD), stented segment length, and diameter stenosis were measured with an automated edge-detection system. Late lumen loss was defined as the difference between the post-PCI MLD and the MLD at the six-month follow-up. When a lesion was totally occluded, the lesion length was measured after opening the occlusion. In-stent restenosis was defined as >50% diameter stenosis at the stented site on the follow-up angiogram. Patients that required stents in multilesions were classified as positive for ISR, if it occurred in at least one lesion. The lesion with the greatest lumen loss was analyzed in patients with multi-lesions intervention.
Measurements of FMD in the brachial artery.
Vasodilator responses in the brachial arteries were measured with B-mode ultrasound images with a 7.5-MHz linear array transducer (HP-5500, Phillips Corp., Tokyo, Japan), as validated in our previous studies (11,12). Measurements were performed by two observers (Drs. Nakamura and Kitta) who were blinded to the coronary angiography data. The brachial artery was scanned in the antecubital fossa in a longitudinal fashion. Optimal brachial artery images were obtained between 1 and 5 cm above the antecubital crease. This location was marked, and all subsequent images were obtained at the same location. The exact distance of the measured point of the skin surface from the antecubital crease was recorded in each subject to ensure that the same segment of the brachial artery was measured at each time point during follow-up. The gain setting was optimized at the beginning of the study and was kept constant throughout the recording period. After baseline measurements of the diameter and flow velocity in the brachial artery, a blood pressure cuff was placed around the forearm and inflated to a pressure of 250 to 300 mm Hg for 5 min and then released. Diameter measurements during reactive hyperemia were taken 45 to 90 s after cuff deflation. Then, sublingual nitroglycerin (0.3 mg) was administered, and three min later, the measurements were repeated. Images were recorded on a super-VHS videocassette recorder (model BR-S601M, Victor Corp., Tokyo, Japan), and brachial arterial diameters were measured from the tape with ultrasonic calipers as described previously (11,12). The response of the vessel diameter to reactive hyperemia and nitroglycerin were expressed as a percentage increase in diameter from the baseline value. The diameter responses were assessed at three points along a 10-mm length of the artery, and the diameter responses were averaged. Blood flow was calculated by multiplying the velocity-time integral of the Doppler flow signal by heart rate and the vessel cross-sectional area. The increase in brachial blood flow was calculated as the maximum flow recorded in the first 15 s after cuff deflation and was expressed as a percentage increase in flow from the baseline value.
Exercise stress test.
Symptom-limited treadmill exercise testing was performed with the Bruce protocol while recording a 12-lead ECG in 116 (82%) patients in the morning after overnight fasting at the end of the six-month follow-up period. The remaining 25 (18%) patients could not have the exercise stress test because of disability. A cuff blood pressure was recorded every min before and during exercise. Vasodilators and beta-blockers were discontinued more than 12 h before the exercise test. The exercise stress test was considered positive if >0.1 mV ST-segment depression occurred with or without chest pain.
Statistical analysis.
Data are expressed as mean ± SD unless otherwise indicated. The mean value and frequency between two groups were compared with the Student unpaired t test and chi-square analysis, respectively. The mean values among three groups were compared with one-way analysis of variance, followed by a Scheffe test for post-hoc comparisons between groups. Chi-square test followed by Tukey test was used for comparing frequencies among three groups. Comparisons of FMD in patients with coronary stenting were performed with two-way analysis of variance for repeated measures, followed by post-hoc testing with a Scheffe test. The correlation of FMD with risk factor profiles was examined by linear regression analysis. The assessment of independent association of late ISR and TLR with the impairment of the follow-up FMD was performed with multivariate logistic regression analysis that included the following factors as categorical variables: impairment of the follow-up FMD (4.8%, obtained from receiver-operator characteristic analysis of FMD in the study patients), chest pain, positive exercise ECG test, infarct-related artery, lesion length (10 mm, arbitrarily defined as the 50th percentile of the distribution of the length in the study patients), multiple lesions with stenting, stented segment length (18 mm, arbitrarily defined as the 50th percentile of the distribution of the length in the study patients). All these variables had a significant relationship with late ISR in the Student unpaired t test or chi-square analysis. Statistical significance was defined as p < 0.05. Analyses were assessed, in part, with StatView 5.0 for Windows (Tokyo, Japan).
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Results
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Comparisons of clinical characteristics between patients with and without ISR.
In-stent restenosis was found in 46 (33%) patients at the follow-up coronary angiography. Patients with and without ISR had comparable clinical characteristics, including coronary risk factors and frequencies of each of the cardiac medications before PCI and during the six-month follow-up (Tables 1, 2, and 3). Also, frequencies of newly started or increased cardiac medications immediately after PCI were not significantly different between patients with and without ISR (Table 2). Levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), glycosylated hemoglobin (HbA1c), high-sensitivity C-reactive protein (hsCRP), systolic blood pressure, and body mass index at follow-up were improved compared with baseline in both groups of patients, and there was a reduction in the number of smokers and an increase in leisure-time physical activity, mainly by walking (30 min/day increase from baseline activity for >1 month) during the treatment periods in both groups (Table 3). These favorable changes, however, were not significantly different between patients with and without ISR (Table 3). During the six-month follow-up period, chest pain occurred in 21 (46%) of 46 patients with ISR and in 12 (13%) of the 95 patients without ISR (p < 0.01), as shown in Table 3. Although all of the study patients had the follow-up angiography and the discontinuation of the vasodilators before the measurements, according to the study protocol, there was neither an adverse complication nor refractory myocardial ischemia associated with the examinations in any patients.
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Table 2. Comparisons of Frequency in Use of Medications Before PCI, Newly Added or
Increased Immediately After PCI, and Medications During the Follow-Up Period
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Quantitative coronary angiography.
Patients with ISR had a higher prevalence of infarct-related artery and multiple lesions with stenting, longer stented segment length, and longer lesion length at the time of the stenting than those without ISR (Table 1). Target lesions revascularization at the six-month follow-up angiography was performed with PCI in 36 (78%) patients with ISR. Percutaneous coronary intervention for coronary segments other than the stented segments was performed at the six-month follow-up angiography in 5 (11%) patients with ISR and 8 (8%) patients without ISR (p = NS).
Exercise treadmill ECG test.
The exercise ECG test was performed in 41 (89%) patients with ISR and 75 (79%) patients without ISR (p = NS). Among patients who had the exercise stress test, the test was positive in 22 (54%) patients with ISR and 17 (23%) patients without ISR (p < 0.01). Chest pain during the exercise test occurred in 15 (37%) patients with ISR and 5 (7%) patients without ISR (p < 0.01).
FMD.
The initial FMD within three days before the coronary stenting was comparable between patients with and without ISR, and the initial FMD was lower in patients with or without ISR than in the age- and gender-matched control subjects (Fig. 1). In patients without ISR, the FMD at the end of the six-month follow-up period improved to levels comparable to the control subjects, whereas the follow-up FMD in patients with ISR did not significantly change compared with the initial FMD (Fig. 1). As a result, the follow-up FMD was lower in patients with ISR than without ISR. Dilator responses to nitroglycerin, brachial arterial diameter at baseline, and brachial blood flow at baseline, and increase in the blood flow at reactive hyperemia were not significantly different among control subjects and patients with or without ISR at either the initial time or the end of the follow-up period (Table 4). The extent of the improvement of the follow-up FMD from the initial FMD in patients without ISR significantly correlated with the percentage changes in levels of total cholesterol (r = –0.36, p < 0.01), HDL-C (r = 0.34, p < 0.05), HbA1c (r = –0.37, p < 0.05), and hsCRP (r = –0.32, p < 0.05) from baseline to follow-up, whereas there was no significant correlation in patients with ISR (data not shown).
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Figure 1 Comparison of flow-mediated dilation (FMD) of the brachial artery at coronary stenting (Initial) and at the six-month follow-up (Follow-up) between patients with (n = 46) and without (n = 95) in-stent restenosis (ISR). The control subjects (n = 48) with normal coronary angiograms were selected to match age and gender of the patients with stenting and served as comparison of FMD with the patients. Data are expressed as mean ± SE. *p < 0.01 versus initial FMD in patients without ISR;  p < 0.01 versus control subjects.
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Association of the angiographic findings and FMD.
The late luminal loss significantly and inversely correlated with the follow-up FMD, whereas it did not correlate with the initial FMD (Fig. 2). Furthermore, the late luminal loss inversely correlated with changes in the follow-up FMD from the initial FMD (Fig. 2). In multivariate logistic statistical analysis, ISR at the six-month follow-up period was most strongly associated with the impairment of the follow-up FMD (Table 5). This association was independent of the infarct-related artery, longer lesion length, multiple lesions with stenting, longer stented segment length, chest pain during the follow-up period, and a positive exercise stress test at the end of the six-month follow-up period (Table 5). Also, TLR was significantly associated with the impairment of the follow-up FMD independently of the same co-variables (odds ratio 4.95; 95% confidence interval 1.95 to 12.5, p = 0.005).
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Figure 2 Correlations of late luminal loss with flow-mediated dilation (FMD) at coronary stenting (Initial FMD, upper panel), at the six-month follow-up (Follow-up FMD, middle panel), and with changes in FMD from the initial FMD to the follow-up FMD (lower panel).
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Table 5. Multivariate Logistic Regression Analysis; Association of ISR With FMD, Clinical, Lesion, and Procedural Variables
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Sensitivity and specificity for identification of late ISR and TLR.
The sensitivity of the impairment of the follow-up FMD (69%) for the identification of late ISR was significantly higher than chest pain during the follow-up period (46%), and it was also nearly higher than a positive exercise stress test at the end of the six-month follow-up period (54%) (Table 6). The specificity among these three assessments was not statistically different. The assessment of the follow-up FMD in combination with chest pain during the follow-up period had an incremental effect on the sensitivity for the identification of late ISR, and the impaired FMD at follow-up in combination with chest pain during the follow-up increased the sensitivity to 90% (Table 6, Fig. 3). In addition, the impaired FMD in combination with the positive exercise ECG test had an incremental effect on the sensitivity in detecting ISR (Fig. 3). The sensitivity and specificity of the follow-up FMD for TLR were 69% and 70%, respectively. The sensitivity for TLR of the combined assessment of the follow-up FMD and chest pain was 94%.
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Figure 3 Incremental effects on the relative risk for late in-stent restenosis of the combination of impairment of follow-up flow-mediated dilation (FMD) with chest-pain positive (upper panel) and positive exercise electrocardiographic test (lower panel).
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Discussion
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The present study showed that impairment of FMD during the follow-up period was associated with the late diameter loss and ISR after stenting in native coronary arteries. The association was independent of clinical and angiographic variables known to be related to ISR. Thus, endothelial vasomotor function in a systemic artery might be importantly linked with the pathobiological process of ISR. It was previously shown that endothelial-derived nitric oxide suppresses smooth muscle proliferation, leading to inhibition of intimal hyperplasia after vascular injury in animal models (4,5). Endothelial vasomotor function of the brachial artery has been shown to reflect nitric oxide-mediated dilation of the coronary arteries (13). These previous findings might explain the relationship between ISR and endothelial vasomotor dysfunction of the brachial artery in the present study, although the initial FMD did not predict ISR. Endothelial vasomotor function, a sensitive indicator of early development of atherosclerosis, is reversible and can be modified in parallel with changes in coronary risk status (14–16). All the study patients had well-established prophylactic treatments such as lipid-lowering medication and life style changes for cardiovascular disease after the first-time PCI. In fact, both patients with and without ISR had favorable changes with similar degrees in levels of lipids, HbA1c, and hsCRP, body mass index, smoking status, and physical activity during the six-month follow-up period. The favorable changes in some of these risk factors, such as total cholesterol levels, HDL-C levels, HbA1c, and hsCRP, were significantly related to the improvement of FMD at follow-up in patients without ISR. These treatment-related reductions in the atherogenic burden improved endothelial vasomotor dysfunction, leading to attenuation of the intimal thickening of coronary arteries after stenting in patients without ISR; the reduction in these risk factors, however, failed to improve FMD in patients with ISR in spite of the similar treatments and reductions in risk factors. The reversibility of endothelial dysfunction in response to reduction in atherogenic burden might vary among individuals (17). The mechanisms that might explain the different responses of the follow-up FMD to the similar anti-atherosclerotic treatments and atherosclerotic burden between patients with and without ISR remain unknown. Unknown or other risk factors, not examined in the present study, might importantly affect reversibility of endothelial dysfunction in response to reduction in atherosclerotic burden. The normalization of endothelial dysfunction could be related to suppression of the intimal growth within stent after PCI, leading to attenuation of ISR; however, persistent impairment of endothelial dysfunction might fail to suppress it.
Although risk factor status at the end of the six-month follow-up period in patients without ISR was similar or still somewhat high compared with control subjects, the follow-up FMD in patients without ISR was improved to levels comparable to the control subjects. This might be explained by the higher frequencies in use of statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, which have pleiotropic endothelial protective actions, in these patients than in control subjects (data not shown).
The present study also showed that the sensitivity of FMD impairment at follow-up in detecting late ISR was significantly higher or nearly higher than chest pain during the follow-up period and the positive exercise ECG test at the end of the follow-up period. The specificity among these three assessments was comparable. Furthermore, FMD impairment at follow-up in combination with chest pain during follow-up resulted in an incremental improvement in sensitivity (90% in patients with impaired FMD and chest-pain). Although the combined assessment did not significantly improve the specificity (83%) compared with each individual assessment, the sensitivity and specificity of the presence of impaired FMD at follow-up in combination with chest pain during follow-up appeared similar to the 70% to 95% sensitivity and 70% to 95% specificity that has been reported for detection of late ISR with stress myocardial perfusion scintigraphy (1,18). Also, results that are similar to ISR were obtained with TLR. The assessment of FMD is easily applied in clinical practice and requires only conventional equipment for vascular ultrasonography. Thus, the assessment of endothelial vasomotor dysfunction of the brachial artery during the follow-up period was useful for the identification of late ISR and TLR after stenting, especially when combined with the assessment of chest pain or the stress tests.
A previous report (19) showed an association between ISR and vasodilator dysfunction of forearm resistance vessels in a smaller number of patients. Unfortunately, this report failed to evaluate the influence of clinical, angiographic, and procedural factors on the association between ISR and vasodilator function with multivariate statistical analysis. In addition, there was no information reported with regard to the clinical usefulness of the association between ISR and vasodilator function. In another recent report (20) published during preparation of our present paper, an impairment of FMD at 30 days after PCI predicted ISR in patients with recurrent anginal symptoms or inducible myocardial ischemia at the six-month follow-up, although our study showed that an impairment of FMD before PCI did not predict ISR. It is possible that local coronary injury with PCI might affect their positive association of impaired FMD at 30 days after the procedure with ISR (21). Furthermore, this report (20) repeated the follow-up angiography only in patients with inducible ischemia (17% of the total patients), thereby the association between an impaired FMD and the angiographic ISR was not precisely determined in the study (20).
Although drug-eluting stents limit ISR, it remains to be determined whether endothelial dysfunction in systemic arteries might be also associated with ISR with drug-eluting stents, especially in high-risk patients with complex lesions.
In conclusion, the impairment of FMD at the follow-up time was independently and closely associated with late ISR after stenting in the native coronary arteries. The assessment of FMD at the time of follow-up might be useful for identification of late ISR after stenting.
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Footnotes
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This study was supported by grants-in-aid for (B)(2)-15390244, Priority Areas (C) "Medical Genome Science 15012222" from the Ministry of Education, Culture, Sports, Science, and Technology, Health and Labor Sciences Research Grants for Comprehensive Research on Aging and Health (H15-Choju-012), the Smoking Research Foundation, Tokyo, Japan.
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Y. Kitta, J.-e. Obata, T. Nakamura, M. Hirano, Y. Kodama, D. Fujioka, Y. Saito, K.-i. Kawabata, K. Sano, T. Kobayashi, et al.
Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease.
J. Am. Coll. Cardiol.,
January 27, 2009;
53(4):
323 - 330.
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Abstract
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