CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Coronary Collateral Function Long After Drug-Eluting Stent Implantation
Pascal Meier, MD,
Rainer Zbinden, MD,
Mario Togni, MD,
Peter Wenaweser, MD,
Stephan Windecker, MD,
Bernhard Meier, MD, FACC, FESC and
Christian Seiler, MD, FACC, FESC*
Department of Cardiology, University Hospital, Bern, Switzerland.
Manuscript received June 13, 2006;
revised manuscript received August 17, 2006,
accepted August 21, 2006.
* Reprint requests and correspondence: Dr. Christian Seiler, Professor and Co-Chairman of Cardiology, University Hospital, CH-3010 Bern, Switzerland. (Email: christian.seiler{at}insel.ch).
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Abstract
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OBJECTIVES: This study was designed to compare coronary collateral function in patients after bare-metal stent (BMS) or drug-eluting stent (DES) implantation.
BACKGROUND: Drug-eluting stents have an inhibitory effect on the production of cytokines, chemotactic proteins, and growth factors, and may therefore negatively affect coronary collateral growth.
METHODS: A total of 120 patients with long-term stable coronary artery disease (CAD) after stent implantation were included. Both the BMS group and the DES group comprised 60 patients matched for in-stent stenosis severity of the vessel undergoing collateral flow index (CFI) measurement at follow-up and for the duration of follow-up. The primary end point of the investigation was invasively determined coronary collateral function 6 months after stent implantation. Collateral function was assessed by simultaneous aortic, coronary wedge, and central venous pressure measurements (yielding CFI) and by intracoronary electrocardiogram during balloon occlusion.
RESULTS: There were no differences between the groups regarding age, gender, body mass index, frequency of cardiovascular risk factors, use of cardiovascular drugs, severity of CAD, or site of coronary artery stenoses. Despite equal in-stent stenosis severity (46 ± 34% and 45 ± 36%) and equal follow-up duration (6.2 ± 10 months and 6.5 ± 5.4 months), CFI was diminished in the DES versus BMS group (0.154 ± 0.097 vs. 0.224 ± 0.142; p = 0.0049), and the rate of collaterals insufficient to prevent ischemia during occlusion (intracoronary electrocardiographic ST-segment elevation  0.1 mV) was higher with 50 of 60 patients in the DES group and 33 of 60 patients in the BMS group (p = 0.001).
CONCLUSIONS: Collateral function long after coronary stenting is impaired with DES (sirolimus and paclitaxel) when compared with BMS. Considering the protective nature of collateral vessels, this could lead to more serious cardiac events in the presence of an abrupt coronary occlusion.
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Abbreviations and Acronyms
| | BMS = bare-metal stents | | CAD = coronary artery disease | | CFI = collateral flow index | | CVP = central venous pressure | | DES = drug-eluting stents | | ECG = electrocardiographic | | FFR = fractional flow reserve | | PCI = percutaneous coronary intervention |
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Drug-eluting coronary stents (DES) have been demonstrated to decrease restenosis rates compared to bare-metal stents (BMS) (1–3). The beneficial effects of DES have been shown to extend out to 2 years after implantation, driven by diminished re-intervention rates (4,5). Pathophysiologically, stent implantation causes endothelial denudation; medial dissection; and exposure of the subintima with subsequent platelet activation and production of cytokines, mitogens, chemotactic proteins, and activation of vascular smooth muscle cells (6). The anti-platelet agents prescribed after stenting, as well as the anti-proliferative drugs released from DES, have the purpose of mitigating the effects of the mechanical vascular injury, thus reducing the incidence of stent thrombosis and in-stent restenosis. However, the salutary effect of DES on restenosis may be bought at the price of toxic vascular injury, that is, delayed healing of the traumatized vessel wall (7), thereby heightening the risk of late stent thrombosis and impairing endothelial-dependent vasomotion. So far, there has been no evidence that early or mid-term stent thrombosis after DES implantation is more frequent than in BMS-treated patients (8,9). Conversely, endothelium-dependent coronary vasomotion adjacent to DES has been demonstrated to be impaired in practically all cases investigated so far (10,11). An additional, but thus far hypothetical, issue of concern has not been investigated yet: the inhibiting effect of the drugs eluted by DES on the production of cytokines, chemotactic proteins, and growth factors may negatively affect coronary collateral growth. Therefore, the goal of the present study was to quantitatively compare coronary collateral flow in patients 6 months after BMS or DES implantation.
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Methods
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Patients.
A total of 120 patients (age 60 ± 10 years, 101 men, 19 women) with 1- to 3-vessel long-term stable coronary artery disease (CAD) were included in the study. Initially, all had undergone percutaneous coronary intervention (PCI) with stenting of 1 stenotic lesion because of symptoms related to CAD. The present study focused on invasive measurements of collateral flow index (CFI) late after either BMS or DES implantation. Sixty patients were included in the BMS group, and 60 patients were matched for the following parameters in the DES group: 1) stenosis severity of the vessel undergoing CFI measurement at follow-up, and 2) duration of follow-up. Patients underwent follow-up coronary angiography because of recurrent chest pain. The BMS group being matched to the prospectively and consecutively recruited DES group was selected from our database of CFI measurements, including >1,000 CFI measurements. Among them, 99 patients underwent coronary angiography 1 to 58 months following stent implantation with a CFI measurement and with or without the finding of in-stent restenosis. Sixty of the 99 patients with BMS could be matched to 60 DES patients according to these criteria. Additional criteria for inclusion in the study were as follows: 1) no previous Q-wave infarction, 2) no baseline electrocardiographic (ECG) ST-segment abnormalities, and 3) stable CAD. The present investigation was approved by our institutional ethics committee, and the patients gave informed consent to participate in the study.
Cardiac catheterization and coronary angiography.
Patients underwent left heart catheterization for diagnostic purposes from the right femoral artery approach. Biplane left ventriculography was performed followed by coronary angiography. Central venous pressure (CVP) was measured via the femoral vein. Coronary artery in-stent restenosis and, if present, stenoses in other vascular areas were estimated quantitatively as percent diameter reduction using the guiding catheter for calibration.
Coronary hemodynamic and collateral assessment.
Additionally, the hemodynamic severity of (absent or present) in-stent restenosis was measured using distal coronary pressure-derived assessment of fractional flow reserve (FFR) in response to intracoronary adenosine (a bolus of 12 µg for the right and 18 µg for the left coronary artery).
In all patients, recruitable coronary collateral flow during vascular balloon occlusion relative to normal antegrade flow through the non-occluded coronary artery (CFI, no units) was determined using coronary pressure measurements. A 0.014-inch fiber-optic pressure monitoring wire (RadiWire, Radi, Upsala, Sweden) was set at zero, calibrated, advanced through the guiding catheter, and positioned distal to the site of CFI assessment. Collateral flow index was determined by simultaneous measurements of mean aortic pressure (Pao, mm Hg, via the angioplasty guiding catheter), distal coronary occlusive pressure (Poccl, mm Hg) and CVP: CFI = (Poccl – CVP)/(Pao – CVP) (Fig. 1). Sensor-derived CFI measurements have been previously validated (12,13).
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Figure 1 Collateral Function Determination
Determination of collateral function in a patient with a bare-metal stent (BMS) (left) and a patient with a drug-eluting stent (DES) (right). The intracoronary (i.c.) electrocardiogram (ECG) lead recording (apart from surface lead recordings) is shown in the upper part of the figure. During coronary balloon occlusion, the i.c. ECG leads of both patients show signs of myocardial ischemia, although those in the BMS group are much less pronounced than those in the DES group. Collateral flow index (CFI) is calculated by dividing mean distal coronary occlusive pressure (Poccl, mm Hg; scale 0 to 200 mm Hg) minus central venous pressure (CVP, mm Hg; scale 0 to 50 mm Hg) by mean aortic pressure (Pao, mm Hg; scale 0 to 150 mm Hg) minus CVP.
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As an additional dichotomic method for collateral assessment, a unipolar intracoronary ECG was obtained in all patients from the angioplasty guidewire (Fig. 1) aside from 3 surface leads. For that purpose, a cross-clamp was attached close to the end of the wire and connected to ECG lead V1 (14).
Study protocol.
Following diagnostic coronary angiography, an interval of at least 10 min was allowed for dissipation of the effect of the contrast medium on coronary vasomotion. Before coronary hemodynamic and CFI measurement, 5,000 U of heparin were given. Two puffs of oral nitroglycerin spray were applied shortly before coronary pressure measurements. The pressure guidewire was positioned distal to the site of the angioplasty balloon occlusion and fractional flow reserve was obtained. During the entire protocol, the intracoronary ECG obtained from the pressure guidewire and the surface lead ECG was recorded. Simultaneous recording of Pao via the 6-F guiding catheter, Poccl, CVP, and the ECG was started before and continued throughout the 60-s balloon occlusion. Coronary occlusion was performed within the stent using an appropriately sized angioplasty balloon. If indicated, PCI for in-stent restenosis was performed following CFI measurement.
Statistical analysis.
All patients were individually matched between the BMS and the DES groups according to the quantitatively measured percent diameter narrowing of the stenosis of interest (primary variable) and according to the duration of follow-up after stent implantation. Between-group comparisons (including the subgroup analysis of BMS versus sirolimus- and paclitaxel-eluting stents) of continuous demographic, angiographic, hemodynamic, and collateral flow data were performed by a 2-sided paired Student t test. The McNemar test was used for comparison of categorical variables among the study groups. A p value <0.05 was considered statistically significant.
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Results
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Patient characteristics and clinical data.
There were no statistically significant differences between the 2 groups regarding age, gender, duration of chest pain, positive treadmill exercise ECG shortly before study inclusion, body mass index, and frequency of cardiovascular risk factors as well as the use of cardiovascular drugs (Table 1).
Coronary angiographic data.
The coronary arteries initially undergoing PCI with stenting were similarly distributed among the groups (Table 2). There was no difference between the groups in the number of coronary arteries diseased. Among patients with >1-vessel CAD, coronary arteries other than the target vessel had hemodynamically irrelevant stenotic lesions (i.e., <50% diameter stenosis). The vascular location where CFI measurement and/or PCI was performed was similar between the groups. Stenosis severity before stent implantation did not differ significantly between the groups. In the DES group, 37 patients had received sirolimus-eluting stents, and 23 patients had been treated with paclitaxel-eluting stents. Follow-up duration since stent implantation (median 4.15 months in the BMS group and 4.95 months in the DES group) and percent diameter stenosis of the target vessel at follow-up was equal between the groups (Table 2). The frequency of PCI as compared to balloon occlusion without PCI at follow-up was very similar between the groups (Table 2). There was no difference in the balloon inflation pressure, whereas in patients undergoing balloon occlusion without PCI the difference always amounted to 1 to 2 atm. Angioplasty balloon size was similar between the groups (Table 2).
Hemodynamic and collateral circulation data.
Heart rate, arterial blood pressure, left ventricular ejection fraction, left ventricular end-diastolic pressure, central venous pressure immediately before vascular occlusion, and FFR were similar between the groups (Table 3). The occurrence of angina pectoris during the 1-min coronary occlusion did not differ between the groups. However, ST-segment elevation >1 mm on intracoronary ECG (i.e., insufficient collateral flow) was seen significantly less often in the BMS group than in the DES group. Collateral flow index was significantly higher in the BMS group than in the DES group (Table 3, Fig. 2). This difference was less pronounced among patients with a sirolimus-eluting than with a paclitaxel-eluting stent.
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Discussion
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The novel result of this study is that coronary collateral function 6 months after implantation of a DES is 30% to 40% lower than that obtained equally long after BMS implantation. Considering the salvaging effect of well-grown collaterals, a potential clinical impact of this finding is that in the presence of stent thrombosis myocardial infarct size and, thus, mortality may be larger in DES- than in BMS-treated patients.
Determinants of coronary collateral function aside from the drugs eluted by DES.
The overlap of CFI values among the study groups (Fig. 2) indicates that the association between DES and impaired collateral function is not entirely clear cut, that is, other, perhaps unevenly distributed factors could be responsible for the CFI difference. Numerous clinical factors have been reported to influence the human coronary collateral circulation: age, gender, hypercholesterolemia, arterial hypertension, presence of diabetes mellitus, statins, and other cardiovascular drugs (15). However, very few pathogenetic factors have been consistently described to be related to well-developed coronary collaterals (i.e., the duration of myocardial ischemic symptoms and the severity of arterial stenotic lesions) (16,17). In the present study, none of the putative and unconfirmed factors differed between the groups (Tables 1 and 2). The indisputable co-determinants of collaterals were accounted for by matching the cases of both groups one by one for stenosis severity at the time of CFI measurement and for the duration following BMS or DES implantation. Considering that individuals without coronary stenoses have variably preformed anastomoses between vascular territories (18), there must be other factors influencing the collateral circulation, such as genetic predisposition for well or poorly grown collateral arteries. We did not correct for these factors in the present investigation, and by chance, they may have been unevenly distributed among the groups. However, the likelihood that CFI in patients after DES was worse than after BMS implantation for reasons entirely different from DES can be regarded as very low.
DES as determinants of coronary collateral function.
Is there evidence from experimental studies to support and mechanistically explain the relevance of DES as determinants of coronary collateral function? There is, but exclusively for sirolimus/rapamycin as the drug eluted by the stent. Guba et al. (19) documented that rapamycin inhibited metastatic tumor growth in in vivo mouse models when compared to conventional immunosuppression with cyclosporine. The finding appeared to be related to rapamycin possessing anti-angiogenic properties linked both to a decrease in the production of vascular endothelial growth factor and to an inhibited response of vascular endothelial cells to stimulation by vascular endothelial growth factor. Recently, Fukuda et al. (20) found that peripheral blood mononuclear cells from healthy human volunteers were inhibited by sirolimus to outgrow to smooth muscle-like cells (the principle component of neointimal hyperplasia) and to endothelial cell-like cells. Thus, although the clinical efficacy of sirolimus-eluting stents against restenosis is very likely achieved by their inhibitory effect on smooth muscle progenitors, re-endothelialization following vascular injury may promote stent thrombosis (21), and the decrease in both these cellular elements may impede collateral growth. In a human organ culture model (renal artery segments), rapamycin has even been documented to have an effect on transcriptional programs governing neointima formation (22). In the study by Nührenberg et al. (22), many of the genes differentially regulated in response to rapamycin were related to recruitment of blood cells and inflammatory reactions of the vessel wall. Thus, to account for genetic variability in the present study would have likely detected a drug effect and not an accidental maldistribution in the genetic background between the groups.
Anti-arteriogenic effect of DES and its potential clinical impact.
Is there, aside from the present study’s findings, evidence from clinical investigations consistent with the above described pathophysiologic mechanisms elicited by DES? Togni et al. (10) and Hofma et al. (11) respectively described flow-induced (physical exercise) acetylcholine-induced endothelial dysfunction in 3 of 16 patients following BMS implantation but in the vast majority of patients (18 of 21) after DES implantation. Considering that endothelial dysfunction can be regarded as the earliest stage of atherosclerosis, and its presence foretells adverse cardiovascular events (23), an unfavorable clinical impact related to DES can be imagined. Such an interpretation is propagated by data from the literature indicating that a decrease in circulating endothelial progenitor cells is associated with an increased frequency of cardiovascular disease (24). However, the adverse effect of DES on endothelial structural repair and function has so far been shown exclusively for sirolimus-eluting stents. In this regard, the present study contributes two new findings aside from the principal one of the anti-arteriogenic effect of DES: first, both sirolimus and paclitaxel elicit a negative effect on collateral function, and second, the effect of sirolimus appears to be less pronounced than that of paclitaxel (Table 3). Clinically, the fact of a significantly higher CFI in the BMS than the DES group translates into a reduced frequency of about 1 of 2 patients with ECG signs of ischemia during coronary occlusion versus 5 of 6 in the DES group. Having said that, it becomes also evident that the effect of different stents on collateral function was assessed by two independent methods that have been extensively validated (13).
Our study’s new finding of a DES-induced anti-arteriogenic effect creates a further clinical risk aside from that of more frequent cardiovascular events due to endothelial dysfunction and deficit of endothelial progenitor cells. In the event of stent thrombosis, impaired collateral function in patients with DES could render the thrombosis more dangerous (i.e., could worsen the consequences of abrupt coronary occlusion by increasing mortality). In support of this notion, 6-month mortality after BMS stent thrombosis has been found to amount to 11% (10 of 95 stent thromboses in 6,058 patients) (8) to 21% (11 of 53 stent thromboses in 6,219 patients) (25), whereas that after DES-stent thrombosis has been 29% (2 of 7 stent thromboses in 2,006 patients) (9) to 45% (13 of 29 stent thromboses in 2,229 patients) (26).
Study limitations.
Aside from the previously cited limitations, the present investigation is a cross-sectional rather than a longitudinal observation of collateral function in BMS- and DES-treated patients. The ideal study design would have a randomized group allocation with baseline and follow-up CFI measurement allowing intra- and inter-group comparisons. Because nowadays the vast majority of our patients routinely receive DES, such a design would be ethically questionable.
The quality of matching was not absolute, that is, not 1:1 for both percentage points of diameter stenosis and days of follow-up. However, the quality of matching was so high that, statistically, an influence of stenosis severity and/or follow-up duration on the study’s main outcome can be ruled out.
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Footnotes
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Supported by a grant from the Swiss National Science Foundation, #3200BO-100065/1.
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References
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Abstract
Methods
