CLINICAL STUDIES
Tissue characteristics of restenosis after percutaneous transluminal coronary angioplasty in diabetic patients
Pedro R. Moreno, MD, FACCa,
John T. Fallon, MD, PhD*  ,
Alvaro M. Murcia, MD ,
Miltiadis N. Leon, MD,
Hector Simosa, MD,
Valentín Fuster, MD, PhD, FACCa and
Igor F. Palacios, MD, FACC
a Gill Heart Institute, University of Kentucky, Lexington, Kentucky, USA
* The Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA
Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Manuscript received May 29, 1998;
revised manuscript received March 29, 1999,
accepted June 23, 1999.
Reprint requests and correspondence: Dr. Pedro R. Moreno, 111B-CDD, Veterans Affairs Medical Center, 2250 Leestown Road, Lexington, Kentucky 40511-1093
pmoreno{at}pop.uky.edu
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Abstract
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OBJECTIVES
The purposes of this study were to analyze coronary specimens from patients with diabetes mellitus (DM) and to compare them with specimens from patients without DM.
BACKGROUND
Diabetes mellitus is associated with an increased incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Increased hypercellular smooth muscle cell proliferation with exaggerated intimal hyperplasia formation may be responsible for this predisposition.
METHODS
Eighteen coronary atherectomy specimens with restenosis after PTCA from patients with DM were compared with 18 coronary atherectomy specimens with restenosis after PTCA from patients without DM. Total and segmental areas were quantified on trichrome-stained tissue of hypercellular tissue, collagen-rich sclerotic tissue, atheroma and thrombus. Demographic and angiographic data were similar in both groups.
RESULTS
The percentage of total plaque area composed of hypercellular tissue was lower in restenotic specimens from patients with DM than in restenotic specimens from patients without DM (19 ± 6% vs. 44 ± 5%; p = 0.003). The percentage of collagen-rich sclerotic tissue area was larger in restenotic specimens from patients with DM than in restenotic specimens from patients without DM (77 ± 9% vs. 53 ± 4%; p = 0.004). The percentages of atheroma and thrombus were similar in both groups.
CONCLUSIONS
Intimal hypercellular tissue content is reduced in restenotic tissue from patients with DM. Collagen-rich sclerotic content is increased in restenotic lesions from patients with DM. These results suggest an accelerated fibrotic rather than a proliferative response in diabetic lesions from patients with restenosis after PTCA.
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Abbreviations and Acronyms
| | DCA | = directional coronary atherectomy | | DM | = diabetes mellitus | | LAD | = left anterior descending coronary artery | | LCx | = left circumflex coronary artery | | PTCA | = percutaneous transluminal coronary angioplasty | | RCA | = right coronary artery |
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Coronary artery disease causes 75% of all deaths in patients with either insulin-dependent or non–insulin-dependent diabetes mellitus (DM) (1). Percutaneous transluminal coronary angioplasty (PTCA) has an increased morbidity and mortality in patients with DM (2). Furthermore, diabetes is an independent risk factor for restenosis after PTCA (2). In addition, five-year survival is significantly lower among diabetic patients undergoing multiple vessel PTCA than among diabetic patients undergoing surgical revascularization (3). Diabetes has been associated with increased expression and activity of growth factors that may lead to an exaggerated intimal hyperplastic response (4). Intravascular ultrasound at the time of intervention suggests that the predominant mechanism of restenosis is intimal thickening, supporting an increased hypercellular response in patients with DM (5). Despite these observations, histologic analysis of restenotic coronary lesions from patients with DM has not been reported. This study was designed to test the hypothesis that hypercellular tissue content was increased in coronary restenotic plaque tissue from patients with DM in comparison with patients without DM.
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Methods
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Patient group.
From October 1990 to October 1995, 80 consecutive directional coronary atherectomy (DCA) procedures were performed for symptomatic coronary restenosis after PTCA in the Cardiac Catheterization Laboratory of the Massachusetts General Hospital. Of these 80 procedures, 20 were performed in patients with DM and 60 in patients without DM. Restenosis was defined as percent diameter stenosis >50% by coronary angiography at the time of restudy. Eighteen consecutive DCA specimens from the diabetic group were analyzed and comprise the study group. Diabetes was defined as a fasting blood glucose level >140 mg/dl. All diabetic patients were known diabetics (mean duration 8 ± 4 years) at the time of the intervention. Three patients were taking insulin, five were taking sulfonylurea medication, one patient was taking a combination of sulfonylurea and glucophage and 11 patients were on a diet. Eighteen DCA specimens from nondiabetic patients matched by the time of restenosis were analyzed and were in the control group. Specimens from saphenous vein grafts were excluded.
Quantitative measurement of coronary stenosis.
Angiography was performed before and immediately after DCA using the same single-view projections and angulation as shown in Table 2. Reference diameter, percent diameter stenosis and minimal lumen diameter were determined by quantitative coronary analysis after intracoronary administration of 100 µg of nitroglycerin, using a computer-assisted automated edge detection algorithm (Computer Measurements Systems, MEDIS, Nuenen, The Netherlands) (6).
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Table 2 Angiographic and Procedural Data of Patients With Diabetes Mellitus Versus Patients Without Diabetes Mellitus With Restenosis After Successful Coronary Atherectomy
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Atherectomy specimen.
Multiple pieces of tissue were obtained from each lesion and immediately immersion-fixed in 10% buffered formalin. Tissue was processed for paraffin embedding. Sections were cut at 5 µm and stained by the combined Masson elastic method.
Morphometry.
The combined Masson elastic stain was used to identify and quantify coronary tissue components, as previously reported (7). Briefly, hypercellular tissue is composed of loose connective tissue matrix containing numerous stellate cells; collagen-rich sclerotic tissue is composed of tissue with scant cells and densely stained collagen; atheromatous gruel is composed of acellular debris with cholesterol clefts; and thrombus is composed of red blood cells and fibrin. Each specimen’s areas were outlined at low magnification (x40) and quantified by manual planimetry.
Statistical analysis.
Results are expressed as the mean value ± SEM. P values <0.05 are considered statistically significant. For comparison of discrete variables the Fisher exact test was used. For comparison of two gaussian samples, the two-tailed Student t test was used.
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Results
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Clinical, demographic and angiographic data.
There were no significant differences between the two groups with regard to age, gender, hypercholesterolemia, hypertension, cigarette smoking and family history of coronary artery disease (Table 1). The artery containing the culprit lesion was similar in both groups. In the diabetic group, the culprit lesion was located in the left anterior descending coronary artery (LAD) in nine patients, in the right coronary artery (RCA) in five patients and in the left circumflex coronary artery (LCx) in four patients. In the nondiabetic group, the culprit lesion was located in the LAD in eight patients, in the RCA in five patients and in the LCx in five patients (p = NS for all comparisons). The incidence of first restenosis was 89% in the diabetic group and 78% in the nondiabetic group (p = NS). The reference diameter, percent diameter stenosis and minimal lumen diameter at the time of DCA were similar for both groups (Table 2). The number of vessels with stenosis >50%, the number of pieces of tissue and the number of cuts performed with the DCA catheter were also similar in both groups (Table 2).
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Table 1 Clinical and Demographic Data of Patients With Diabetes Mellitus Versus Patients Without Diabetes Mellitus With Restenosis After Successful Coronary Atherectomy
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Morphometry data.
The total area and the areas of each of the plaque components are given in Table 3. The percent total area occupied by hypercellular tissue was significantly lower in samples from patients with DM than in samples from patients without DM (p = 0.003). The area occupied by collagen-rich sclerotic tissue was significantly larger in samples from patients with DM than in samples from patients without DM (p = 0.004). Areas of atheromatous tissue and thrombus were similar both groups. Atheromatous core was present in 4 of the 18 samples from patients with DM and in 1 of the 18 samples from patients without DM (p = NS). Thrombus was present in 6 of the 18 samples from patients with DM and in 7 of the 18 samples from patients without DM (p = NS).
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Table 3 Total and Segmental Areas of Coronary Restenotic Tissue From Patients With Diabetes Mellitus Versus Patients Without Diabetes Mellitus
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To identify possible differences in coronary plaque composition among diabetic patients with or without pharmacologic therapy, a subgroup analysis was performed (Table 4). There were no significant differences in total area, hypercellular tissue, collagen-rich sclerotic tissue, atheromatous tissue or thrombus between diabetic patients treated with insulin or oral hypoglycemic medication and diabetic patients treated with diet alone.
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Table 4 Total and Segmental Areas of Coronary Restenotic Tissue From Patients With Diabetes Mellitus Treated With Insulin or Hypoglycemic Medication Versus Patients With Diabetes Mellitus Treated With Diet
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Discussion
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The major findings of this study reveal that hypercellular tissue is reduced in coronary restenotic specimens from patients with DM compared with coronary restenotic specimens from patients without DM. Furthermore, areas composed of collagen-rich sclerotic tissue are increased in restenotic tissue from patients with DM. Diabetic patients with or without pharmacologic therapy have a higher incidence of myocardial infarction and a greater need for additional revascularization procedures than patients without DM (8). This study included patients with either insulin, oral hyploglycemic medication or diet. In an effort to establish differences in coronary tissue composition between patients with or without pharmacologic therapy, a subgroup analysis was performed. There were no significant differences in coronary tissue composition between diabetics taking either insulin or oral hypoglycemic therapy and diabetics on diet alone.
Experimental and clinical studies have demonstrated that the contribution of smooth muscle cell proliferation to restenosis after PTCA is limited, and lumen renarrowing is predominately related to vessel remodeling (9,10). In contrast, in-stent restenotic tissue analysis reveals abundant smooth muscle cell proliferation (11). Diabetes is an independent predictor for restenosis after PTCA, so balloon angioplasty in diabetic patients with multivessel coronary artery disease has been seriously questioned (12). However, there are conflicting reports regarding restenosis after coronary stents in diabetic patients. Carrozza et al. (13) demonstrated an enhanced late loss and a higher rate of restenosis in diabetic patients. More recently, Elezi et al. (14) followed diabetic patients with or without pharmacologic therapy after coronary stenting and compared them with nondiabetic patients. In-stent restenosis was found to be significantly higher in diabetic patients. In contrast, two studies failed to identify diabetes as an independent risk factor for restenosis after coronary stenting (15,16). Furthermore, Van Belle et al. (17) provided evidence that diabetic patients do not have an increased rate of restenosis after coronary stenting in comparison with nondiabetic patients. The results of this study support the findings of a predominant collagen-mediated sclerotic reaction instead of an exaggerated hyperplastic response as the main mechanism of restenosis after PTCA in patients with DM. Elastic recoil may play a role in restenosis after PTCA in diabetic patients. Using quantified planimetry on coronary atherectomy specimens from patients with early loss after PTCA, we have recently shown that lesions undergoing elastic recoil are predominately composed of collagen-rich sclerotic tissue (18). Arterial wall collagen in diabetic patients has a fourfold greater content of advanced glycosylation end products than in nondiabetic patients (19). Specific receptors for proteins modified by advanced glycosylation end products have been identified in both monocytes/macrophages and endothelial cells (20). Our laboratory has recently identified an increased content of macrophages in coronary tissue from patients with DM (21). Considering that macrophage content is an independent predictor of restenosis after percutaneous intervention (22), this interaction may play a role in the pathophysiology of restenosis after PTCA in diabetic patients. Finally, an accelerated transformation of hypercellular tissue into mature collagen in restenotic tissue from diabetics should be considered. We matched the control group by the time of restenosis. However, with a more rapid response, diabetics may have similar cellular changes as nondiabetics, but just earlier. Further studies should be performed to resolve this question.
Study limitations.
Smooth muscle cell proliferation should be evaluated by specific proliferation assays and not by quantified planimetry. However, this is not a study of smooth muscle cell proliferation. In contrast, comparison of intimal hyperplastic areas (mm2) are properly evaluated by quantified planimetry. Directional coronary atherectomy is able to extract only 33% of the plaque in primary lesions, so histologic analysis may not reflect total plaque composition (23). However, it is a unique technique to obtain human coronary tissue in vivo. To diminish the possibility of a selection bias, we compared clinical, angiographic, procedural and histologic variables in both groups. There were no significant differences in any of these variables between the two groups, diminishing the risk of a selection bias. Finally, the subgroup analysis does not have enough power to identify tissue differences in diabetics treated with medications, insulin or diet alone. More information is required to completely elucidate this issue.
Conclusions.
Intimal hypercellular tissue content is reduced in restenotic tissue from patients with DM. Collagen-rich sclerotic content is increased in restenotic lesions from patients with DM. These results suggest an accelerated fibrotic rather than a proliferative response in diabetic lesions from patients with restenosis after PTCA.
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Acknowledgments
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We thank Ms. Veronica Gulle for her technical assistance and Dr. Vivian M. Abascal for her critical review of the manuscript.
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Footnotes
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This study was supported in part by a research grant to Dr. Moreno from the Mario Santo Domingo Foundation, Barranquilla, Colombia, and by funds from the Cardiovascular Institute at Mount Sinai Medical Center, New York, New York.
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References
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Abstract
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