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J Am Coll Cardiol, 1999; 34:1675-1679
© 1999 by the American College of Cardiology Foundation
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CLINICAL STUDIES

Long-term endothelial dysfunction after coronary artery stenting

Paulo R. A. Caramori, MD, FACCa,b, Valter C. Lima, MDa,b, Peter H. Seidelin, MDa,b, Gary E. Newton, MDa,b, John D. Parker, MD, FACCa and Allan G. Adelman, MD, FACCa,b

a Bayer Inc., Cardiovascular Clinical Research Laboratory, Toronto, Canada
b Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada

Manuscript received January 15, 1999; revised manuscript received June 14, 1999, accepted August 5, 1999.

Reprint requests and correspondence: Dr. Paulo Caramori, Servicio de Cardiologia, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, Sala 2050 Porto Alegre, RS 90035.003 Brazil


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

We assessed the endothelial-dependent vasomotor function in nonrestenotic coronary arteries more than six months following stent implantation, balloon angioplasty (BA), and directional atherectomy (DCA).

BACKGROUND

Catheter-based coronary interventions are associated with extensive arterial injury. Endothelial function has been shown to remain chronically abnormal after vascular injury. The long-term effects of different percutaneous coronary interventions on endothelial function are not known.

METHODS

Thirty-nine patients treated at least six months earlier with a coronary intervention for isolated proximal left anterior descending (LAD) stenosis, with no evidence of restenosis, were studied. Twelve patients had been stented, 15 had been treated with BA, and 12 had undergone DCA. Changes in diameter of the intervened LAD, and the unintervened circumflex coronary artery (Cx), in response to intracoronary acetylcholine infusions were assessed by quantitative angiography.

RESULTS

The groups had similar angiographic characteristics and risk factors for endothelial dysfunction. The LAD constricted significantly more (p = 0.02) in previously stented patients (–21.8 ± 4.3%), as compared to patients previously treated with BA (–9.5 ± 2.8%) or with DCA (–9.1 ± 3.6%). In contrast, acetylcholine infusion resulted in mild constriction in the Cx, which was similar in the three groups (p = 0.47). By multiple regression analysis, previous implant of a stent was the only significant predictor of LAD constriction (p = 0.008).

CONCLUSIONS

More severe endothelial dysfunction was observed long term after stenting as compared to BA or DCA. These findings may have implications with respect to the progression of atherosclerosis in coronary arteries subjected to percutaneous interventions.

Abbreviations and Acronyms
  BA = balloon angioplasty
  Cx = circumflex coronary artery
  DCA = directional atherectomy
  LAD = left anterior descending coronary artery

Catheter-based coronary interventions are associated with extensive arterial wall injury (1). Although the endothelium appears to regenerate after experimental vascular injury, endothelium-dependent vasodilation remains impaired long after endothelial regrowth (2,3). Consistent with this phenomenon, studies in humans have demonstrated abnormal endothelium-dependent vasomotion of the intervened artery several months after a coronary balloon angioplasty (BA) (4–6).

The long-term effects of different percutaneous coronary interventions on endothelial function are not known. The severity of endothelial dysfunction after a coronary intervention may depend both on the severity of injury and the specific type of percutaneous intervention. Coronary stenting appears to cause a more severe arterial injury (7,8) and a more intense inflammatory response within the vessel wall than other modalities of percutaneous interventions (9,10). Stenting may also be associated with incomplete endothelial regrowth (11). Recent experimental evidence in porcine coronary arteries indicates that stenting might be associated with a more pronounced and prolonged endothelial dysfunction (12). In this study, the endothelial-dependent vasomotor response was assessed long term following either a successful coronary stent implantation, BA, or directional atherectomy (DCA).


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Study population.   Patients who had undergone a successful percutaneous coronary intervention for a single proximal left anterior descending (LAD) lesion at least six months earlier were invited to participate in this study. Thirty-nine patients with no clinical or angiographic evidence of restenosis who had undergone BA, DCA, or stent implantation were enrolled. Balloon angioplasty had been performed by standard techniques. Directional atherectomy had been performed using a standard atherectomy catheter (Devices for Vascular Intervention, Redwood City, California). All stented patients had received a single Palmaz-Schatz 15- or 18-mm stent (Johnson & Johnson, Warren, New Jersey), deployed at high pressures (17.8 ± 0.6 atm).

Clinical exclusion criteria were any coronary revascularization since the initial coronary intervention; history of coronary spasm; symptomatic congestive heart failure or severe left ventricular dysfunction; insulin-dependent diabetes mellitus; and clinically significant renal or hepatic disease. Patients with a diameter stenosis >50% in the left coronary system were also excluded. The study protocol was approved by the Committee on Human Subjects Experimentation of the University of Toronto, and written informed consent was obtained from all patients.

Study protocol.   Patients had their cardiac medications withdrawn 48 h before the study. Patients were allowed to use sublingual nitroglycerin for angina, but no study was performed within six hours of nitroglycerin use. Vitamin supplements were discontinued for seven days.

Risk factors for endothelial dysfunction were assessed for each patient at the time of the study. These factors included age >45 years, male gender, previous diagnosis of hypertension, non–insulin-dependent diabetes mellitus, current cigarette smoking, family history of premature coronary atherosclerosis, and total cholesterol >5.3 mmol/liter. Serum lipids were evaluated in the fasting state at the time of the study angiogram.

The research studies were performed at approximately 9:00 AM. Left coronary angiograms were performed by power injection of 9 to 12 ml (3 to 4 ml/s) of nonionic contrast medium in the control state and after serial acetylcholine infusions. Solutions were infused at 1.25 ml/min for 3 min into the left coronary artery via a diagnostic catheter in the following sequence: 1) control (5% dextrose in water); 2) three incremental acetylcholine infusions: concentrations of 10–6, 10–5, and 10–4 molar; and 3) recontrol. Angiography was repeated immediately after each infusion. A 3-min time period was allowed to elapse between each angiogram and the following infusion, to compensate for contrast medium-induced changes in coronary tone. Constant angiographic technique was maintained throughout the study. Heart rate, femoral arterial pressure, and electrocardiographic leads I, II, and V5 were continuously monitored.

Quantitative angiography was performed by a blinded technician, using an automated edge detection system (CMS, Neunen, The Netherlands) as previously reported (13). In our laboratory, coronary artery diameter measurements performed with this system have interobserver variability of 0.09 mm, and intraobserver variability of 0.01 mm on repeated analysis of the same frame.

A long, clearly visualized segment of the LAD distal to the intervention site, and a segment of the nonintervened circumflex coronary artery (Cx) were selected from the control angiogram. Proximal and distal boundaries of the selected segments were referenced to anatomical landmarks to ensure replication of the analysis. The mean luminal diameter of the entire segment was recorded from each of the study angiograms. The average length of these segments was 25.3 ± 2.0 mm (LAD) and 19.2 ± 1.8 mm (Cx).

Statistical analysis.   Baseline characteristics were compared using one-way analysis of variance (ANOVA) followed by the Student-Newman-Keuls test for multiple comparisons for continuous variables, or Kruskal-Wallis ANOVA on ranks followed by the Dunn test for categorical variables. Binary variables were analyzed by the Fisher exact test. Changes in mean luminal diameter from control values to maximal acetylcholine dose were compared using unbalanced ANOVA with post hoc (Student-Newman-Keuls) tests for pairwise comparison whenever the general test was significant. Multiple regression analysis was used to assess predictors of the change in luminal diameter in response to maximal acetylcholine infusion (SAS release 6.12, SAS Institute, Cary, North Carolina). A two-sided p value <0.05 was considered significant. Results are expressed as mean ± SE.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Baseline characteristics.   Thirty-nine patients were studied: 15 patients previously treated with BA, 12 with DCA, and 12 with coronary stenting (Table 1). The average time from the index intervention to this study was 19 ± 2 months. The study groups were well matched for baseline characteristics. Current smoking was more prevalent among DCA patients (p = 0.05). Antioxidant vitamins were taken more often by stented patients (p = 0.05). Overall, no significant difference existed in the total number of risk factors for endothelial dysfunction among groups.


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  		Table 1 Demographic, Clinical and Laboratory Characteristics of the Study Group

 
Angiographic characteristics.   Quantitative angiography of the proximal LAD before the remote intervention was similar in the three groups (Table 2). Immediately after the coronary intervention, the stent group had a significantly smaller residual stenosis (p < 0.001) and a greater lumen gain (p = 0.02). At the time of the follow-up, the proximal LAD in the three groups had similar angiographic characteristics. As per protocol, no patient had significant LAD stenosis. The average percent diameter stenosis of the proximal LAD was approximately 20% for all groups (p = NS). Single-vessel coronary artery disease in the right coronary artery was present in two previously stented patients, one with previous BA, and four with previous DCA.


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  		Table 2 Quantitative Angiographic Data of the Proximal LAD, Pre- and Postintervention, and at the Time of Study

 
Coronary responses to acetylcholine.   All but three patients tolerated the intracoronary acetylcholine 10–4 molar. In two patients in the stent group and one in the BA group, acetylcholine 10–5 molar was the highest concentration infused, as it caused severe coronary constriction associated with chest pain. No further acetylcholine was administered to these patients. The change in mean luminal diameter from control values to maximal acetylcholine dose of the LAD distal to the intervention site was significantly greater (p = 0.02) in patients who had previously undergone stenting (–21.8 ± 4.3%) than in patient with previous BA (–9.5 ± 2.8%), or DCA (–9.1 ± 3.6%) (Fig. 1 and 2) . All patients who had previously undergone stenting presented some degree of constriction of the LAD, whereas the response of patients with previous BA and DCA was mixed (Fig. 3). In contrast, the response of the unintervened Cx to acetylcholine was mild constriction, similar in all groups (p = 0.47).



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  		Figure 1 Percent change in mean luminal diameter of the left anterior descending coronary artery (A) and circumflex artery (B) from baseline, in response to intracoronary acetylcholine infusion. *p = 0.02 versus balloon angioplasty and directional atherectomy groups. Open triangle = Stent group. Closed circle = Balloon angioplasty group. Open square = Directional atherectomy group.

 


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  		Figure 2 Representative coronary angiograms from patients previously treated with coronary stenting (A), balloon angioplasty (B), and directional atherectomy (C) in the control state (Control) and after acetylcholine 10–4 molar infusion (Ach 10–4). Arrows indicate the intervened left anterior descending artery.

 


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  		Figure 3 Mean luminal diameter of the left anterior descending coronary artery at baseline (C) and in response to maximal intracoronary acetylcholine infusion (Ach) for all the study patients. BA = balloon angioplasty group; DCA = directional coronary atherectomy group; Stent = stent group. *p = 0.02 versus balloon angioplasty and directional atherectomy groups.

 
By multiple regression analysis, stenting was the only factor associated with LAD response to acetylcholine (p = 0.008) (Table 3). No relationship was found between the LAD responses and remote procedure luminal gain, time of follow-up, total number of risk factors, and circumflex artery response to acetylcholine.


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  		Table 3 Multivariable Analysis of Change in Luminal Diameter in Response to Maximal Acetylcholine Infusion

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study examined the endothelium-dependent vasomotor function of patients who had undergone a successful percutaneous coronary intervention of the proximal LAD. Several months after the intervention, we found persistent endothelial dysfunction in the intervened coronary artery. More severe endothelium-dependent vasoconstriction was observed in the LAD of stented patients than in the LAD of patients who had undergone either BA or DCA. In experimental studies, endothelial dysfunction after arterial injury persists in the chronic regenerated state (2,3). Both the degree and the duration of the endothelial dysfunction appear to be proportional to the severity of the injury (14). In humans, abnormal endothelium-dependent vasomotion of the intervened coronary artery long after BA has been previously reported (4–6).

Potential mechanisms of increased coronary constriction to acetylcholine after stenting.   We observed more severe endothelial dysfunction in previously stented coronary arteries. Similar findings have recently been reported in porcine coronary arteries, where stenting was associated with decreased endothelial integrity as compared to balloon angioplasty for a period of 12 weeks (12). There are several possible explanations for this finding. Stenting is associated with larger luminal gain and more intense proliferative response as compared to other coronary interventions (7,8). Therefore, stenting probably causes more severe arterial injury that might partially explain more severe endothelial dysfunction. In addition, restoration of endothelial-dependent vasomotion after injury is closely related to endothelial regrowth (15). Although complete endothelial regrowth has been observed after BA (14,16) this may not be the case after stenting (11,12). Finally, there is growing evidence that stenting is associated with increased inflammatory cell infiltration within the arterial wall (9,10,12). Because inflammatory activation is associated with endothelial dysfunction after vascular injury (16,17), an increased inflammatory response to stenting might also explain the more severe endothelial dysfunction observed.

Study limitations.   There are limitations to this study. Although the groups were well balanced in relation to baseline characteristics, patients were not randomized to receive the various forms of coronary intervention. Thus, it is conceivable that these results are consequence of differences in baseline endothelial function among the groups. All stented patients received a Palmaz-Schatz stent. It is unknown whether these findings can be generalized to other stents.

Conclusions.   The long-term effects of stent implantation into stenotic human coronary arteries are not well known. Clinical and experimental evidence suggest that endothelial dysfunction is implicated both in early atherogenesis and later in the disease process. Our findings may, therefore, have implications with respect to the progression of atherosclerosis in coronary arteries subjected to percutaneous intervention, especially stent deployment. The observation that implantation of foreign bodies in coronary arteries may be associated with adverse consequences other than restenosis warrants further studies.


   Acknowledgments
 
We are indebted to the staff of the Bayer Cardiovascular Clinical Research Laboratory for their assistance in carrying out these experiments.


   Footnotes
 
Dr. Caramori was funded by the Brazilian Council of Scientific and Technologic Development (CNPq). This study was supported in part with a grant from Bayer Inc.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Waller BF. Pathology of transluminal balloon angioplasty used in the treatment of coronary heart disease. Hum Pathol. 1987;18:476–484[Medline]
  2. Shimokawa H, Flavahan NA, Shepherd JT, Vanhoutte PM. Endothelium-dependent inhibition of ergonovine-induced contraction is impaired in porcine coronary arteries with regenerated endothelium. Circulation. 1989;80:643–650[Abstract/Free Full Text]
  3. Cox RH, Haas KS, Moisey DM, Tulenko TN. Effects of endothelium regeneration on canine coronary artery function. Am J Physiol. 1989;257(5 Pt 2):H1681–H1692
  4. Suter TM, Buechi M, Hess OM, Haemmerli-Saner C, Gaglione A, Krayenbuehl HP. Normalization of coronary vasomotion after percutaneous transluminal coronary angioplasty? Circulation. 1992;85:86–92[Abstract/Free Full Text]
  5. McFadden EP, Bauters C, Lablanche JM, Quandalle P, Leroy F, Bertrand ME. Response of human coronary arteries to serotonin after injury by coronary angioplasty. Circulation. 1993;88:2076–2085[Abstract/Free Full Text]
  6. Vassanelli C, Menegatti G, Zanolla L, Molinari J, Zanotto G, Zardini P. Coronary vasoconstriction in response to acetylcholine after balloon angioplasty: possible role of endothelial dysfunction. Coron Artery Dis. 1994;5:979–986[Medline]
  7. Hanke H, Kamenz J, Hassenstein S, et al. Prolonged proliferative response of smooth muscle cells after experimental intravascular stenting. Eur Heart J. 1995;6:785–793
  8. Hoffmann R, Mintz GS, Dussaillant GR, et al. Chronic arterial response to stent implantation: a serial intravascular ultrasound analysis of Palmaz-Schatz stents in native coronary arteries. J Am Coll Cardiol. 1996;28:1134–1139[Abstract]
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  10. Hofma SH, Whelan DM, van Beusekom HM, Verdouw PD, van der Giessen WJ. Increasing arterial wall injury after long-term implantation of two types of stent in a porcine coronary model. Eur Heart J. 1998;19:601–609[Abstract/Free Full Text]
  11. Grewe PH, Deneke T, Machraoui A, Barmeyer J, Muller KM. Pathogenesis of neointima-generation after coronary stent-implantation. Morphological findings in 18 stents. (abstr)Circulation. 1997;96:I–403
  12. van Beusekom HMM, Whelan DM, Hofma SH, et al. Long-term endothelial dysfunction is more pronounced after stenting than after balloon angioplasty in porcine coronary arteries. J Am Coll Cardiol. 1998;32:1109–1117[Abstract/Free Full Text]
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