Clinical studies on coronary revascularization in patients with type 2 diabetes
Koon-Hou Maka,* and
David P. Faxonb
a Department of Cardiology, National Heart Centre, Singapore, Singapore
b Section of Cardiology, University of Chicago, 5841 S. Maryland Ave., Mail Code 6080, Rm. B608, Chicago, IL 60637-1643, USA
* Corresponding author: Koon-Hou Mak, MBBS, FESC, Department of Cardiology, National Heart Centre, 17 Third Hospital Avenue, Singapore 168752. Tel.: +65-6436-7545; fax: +65-6227-3562
E-mail address: mak_koon_hou{at}nhc.com.sg
Received 10 October 2002;
revised 27 November 2002;
accepted 6 December 2002
 |
Abstract
|
---|
With the increasing prevalence, diabetes is rapidly growing into a global public health problem. Cardiovascular disease is a major consequence of this chronic condition, and a critical issue facing physicians worldwide today is choice of coronary revascularization procedures in treating these patients. Since the Bypass Angioplasty Revascularization Investigation (BARI) alert in 1995, there have been several reports on subgroup analysis of clinical trials and registries concerning revascularization among patients with diabetes. Although randomized control studies comparing percutaneous and surgical revascularization procedures in this high-risk group of patients are lacking, this article provides the background for the excess risk and reviews the findings of these investigations. Current strategies to improve outcomes in patients with diabetes undergoing coronary revascularization procedures are discussed.
Key Words: Angioplasty Bypass GP IIb/IIIa inhibitor Stent
 |
1. Introduction
|
---|
Diabetes is a chronic disease with high cardiovascular morbidity and mortality.1 Approximately 150 million worldwide are suffering from this condition and the number is expected to rise to 300 million by 2025. In 1997, 22 million people in Europe suffer from diabetes and the number is projected to increase to 32.9 million in 2010.2 While only 17 million Americans suffer from diabetes in 1997,3 the total cost burden for this condition was estimated to be $98 billion, with more than half of the expenditure attributed to indirect cost such as temporary or permanent disability, and premature death.4 Of the $44 billion used for direct medical costs, almost a fifth was employed for management of cardiovascular complications. With a million new patients diagnosed with diabetes each year in the United States, the strain on financial and medical resources will continue to increase. Undoubtedly, diabetes has evolved into a major public health issue and is of great concern to both healthcare providers and administrators.
Although there has been considerable improvement in managing patients with coronary artery disease, unfavourable events remained heightened among patients with diabetes.5 For example, mortality was greater among diabetics with acute myocardial infarction, even when they were treated with contemporary fibrinolytic regimen6 or direct angioplasty.7 With the prevalence of diabetes rising, the number of patients with diabetes undergoing revascularization procedures is expected to increase. Unfortunately, the occurrence of adverse outcomes following percutaneous coronary intervention8,9 and coronary artery bypass grafting10,11 is still higher among patients with diabetes. In 1996, the Bypass Angioplasty Revascularization Investigation (BARI)12 revealed the wide gap in cardiovascular outcomes among patients with diabetes and multi-vessel disease randomly assigned to balloon angioplasty or coronary artery bypass grafting. Currently,
20% of patients referred for revascularization procedures are diabetics. With a large heterogenous body of information emerging, the triaging process to medical therapy, percutaneous coronary intervention or coronary artery bypass grafting has become increasing complex. Thisarticle reviews the findings of clinical studies on revascularization procedures comparing between patients with and without type 2 diabetes, and various therapeutic options in improving outcomes among this high-risk group of patients undergoing percutaneous coronary intervention.
 |
2. Biological and metabolic abnormalities
|
---|
Several biological and metabolic abnormalities exist in patients with diabetes rendering them particularly vulnerable to vascular complications. Indeed, even among non-diabetic with acute myocardial infarction, hyperglycaemia portends poor prognosis.13,14 Beyond elevation of blood sugar level, the aberrations of diabetes involve a complex interplay of a variety of processes, including a prothrombotic state, endothelial dysfunction, exuberance of growth factors and matrix formation, which has not been fully understood. Nonetheless, these factors provide a basis to explain the poor outcomes of patients with diabetesundergoing coronary revascularization.
2.1. Haemostatic abnormalities
Clearly, patients with diabetes have an enhanced thrombotic state with impaired fibrinolysis. Platelets are larger with greater number of glycoprotein (GP) Ib and IIb/IIIa receptors,15 and tend to aggregate more easily in an ex-vivo model.16 These aberrations may be related to activation of protein kinase C, reduced nitric oxide, increased active oxygen radicals and abnormal calcium metabolism.17,18 Furthermore, plasma concentrations of fibrinogen,19 coagulation factor VII20 and von Willebrand factor21 are elevated in diabetics, and thrombin activity is increased.22
The imbalance of the fibrinolytic system may also contribute to the problem of restenosis in patients with diabetes. Using samples derived from directional atherectomy, diabetics were found to have considerably higher levels of plasminogen activator inhibitor type I and lower levels of urokinase-type plasminogen activator.23 Taken together, these factors are likely to produce a prothrombotic state in patients with diabetes, and may account for a less favourable outcome.
2.2. Endothelial dysfunction
The important role of a normal functioning endothelium is increasingly recognized in vascular biology. Besides being a barrier between blood and tissue, it is highly metabolically active and regulates blood flow, delivery of numerous substances and cells across this single-layer.24 Notably, impairment of nitric oxide-mediated endothelial relaxation has been described in diabetics prior todevelopment of overt atherosclerosis,25 with production of prostacyclin reduced26 and endothelin-1 increased.27 High sugar level inhibits nitric oxide synthetase activation and increases oxidative stress by generating free radicals.28 Furthermore, acute hyperglycaemia29 and advanced glycation end-products30 have been also shown to impair endothelial relaxation. These factors result in lowered production of nitric oxide and diminished endothelial regenerative capacity.31
2.3. Exaggerated cellular and matrix proliferation
The roles of insulin-mediated mitogens, such as insulin-like growth factor-I (IGF-I), and hyperglycaemia in promoting cellular and matrix proliferation are complicated. Nonetheless, they are pivotal in the enhancing the process of restenosis in diabetics. Together with platelet-derived growth factors, insulin-like growth factor-I is known to stimulate smooth muscle migration andproliferation.32 Hyperglycaemia increases growth factors such as basic fibroblastic growth factor and transforming growth factor-
,33 and synthesis of matrix elements such as collagen type IV, fibronectin, and laminin.34 Correspondingly, lipid abnormalities in patients with diabetes, such as elevated very low-density lipoprotein, enhance the expression of endothelial nuclear factor-
B, adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumour necrosis factor-
35 promoting the development of atherosclerosis. Hyperglycaemia also transforms low-density lipoprotein particles to smaller and more atherogenic oxidized or glycated particles which stimulate smooth muscle cell migration and induce apoptosis.36 Furthermore, advanced glycation end products may lead to chronic cell activation, and probably proliferation.37 As neointimal formation following balloon angioplasty is greater among patients with diabetes,38 therapeutic strategies in preventing smooth muscle migration and proliferation are likely to reduce restenosis rates in this high-risk group of patients.
2.4. Insulin resistance
The clinical significance of insulin resistance is gaining prominence, and has been associated with several medical conditions such as polycystic ovarian syndrome and syndrome X. While insulin resistance may precede the onset of type 2 diabetes, its presence portends a heightened risk of occurrence of myocardial infarction39 and stroke.40 Indeed, the United Kingdom Prospective Diabetes Study (UKPDS) showed a reduction in macrovascular events by improving insulin resistance with metformin in obese patients with type 2 diabetes.41 Although the precise mechanisms for the deleterious effects of insulin resistance remain uncertain, excessive free fatty acids are likely to be a major contributor. They reduce production of the nitric oxide and other vasodilatory substances mediated through reactive oxygen radicals.42
Recently, this condition has been shown to be associated with increased neointimal hyperplasia, and restenosis following balloon angioplasty is higher among patients with elevated insulin levels after a glucose load43 Likewise, among patients with hyperinsulinaemia undergoing coronary stenting, there was increased neointimal proliferation in a serial intravascular ultrasound study.44 Interestingly, the exaggerated response to injury was observed only in insulin-resistant and not non-insulin resistant rats.45 The rate of 6-month target revascularization in a large clinical trial on coronary stenting was considerably higher amongpatients with clinical characteristics of insulin resistance (diabetes, hypertension and obesity) compared with those without (16.7% vs 7.5%; p<0.001). This difference persisted after adjusting for baseline characteristics.46
2.5. Burden of coronary atherosclerosis
Although an early angiographic study suggested that coronary atherosclerosis among patients with diabetes was not more diffuse than non-diabetics,47 subsequent investigation showed that they are associated with more extensive and diffuse coronary atherosclerosis.48 In addition, the prevalence of multivessel disease was higher among diabetics with myocardial infarction (65.4% vs 52.2%; p<0.001).6 Conversely, others reported that the extent49 and severity50 of symptomatic coronary atherosclerosis were comparable between patients with and without diabetes. But the incidence of left main disease remained higher in diabetics (13 vs 6%; p<0.01).49 Recently, a more robust autopsy study51 reported that those with diabetes were more likely to have any high-grade (75% vs 55%; p<0.0001) and multivessel high-grade coronary atherosclerosis (58% vs 41%; p<0.001). Lesion morphological characteristics also differed between unstable angina patients with and without diabetes.52 Plaque ulceration and intracoronary thrombus were observed more frequently among diabetics. Taken together, these features mayexplain partly the higher occurrence of ischaemic events and poorer outcomes of patients withdiabetes.
 |
3. Coronary angioplasty
|
---|
3.1. Balloon angioplasty
Although not widely recognized initially, the unfavourable influence of diabetes among patients undergoing conventional balloon angioplasty has been well-documented. Despite being older, more likely to be female, having a greater extent of coronary atherosclerosis and co-morbid conditions, procedural success rates were comparable between patients with and without diabetes.8,9 However, in-hospital adverse outcomes (Table 1), long-term mortality and need for repeat revascularization procedures were higher among diabetics. When the data from two early studies were put together,8,9 the odds ratio (OR) for a patient with diabetes suffering from death or myocardial infarction following balloon angioplasty was 1.7 times greater than that of a non-diabetic during the hospitalization period. Long-term survival was also considerably lower among patients with diabetes (Fig. 1, Panel A). The probabilities of 9-year survival for patients with and without diabetes were 68.0% (95% confidence interval [CI], 62.9% to 73.2%) and 83.5% (95% CI, 82.0% to 85.0%), respectively (p<0.0001). Furthermore, the proportion of patients who suffered from subsequent myocardial infarction was lower among those without diabetes (p<0.0001) (Fig. 1, Panel B). Similarly, long-term survival was poorer among patients with diabetes undergoing balloon angioplasty in a Dutch centre.53 After 15 years, the cumulative survival rates were 52% (95% CI, 42% to 62%) and 68% (95% CI, 64% to 72%) for patients with and without diabetes, respectively (p<0.0001). Indeed, the presence of treateddiabetes was a predictor for long-term mortality (relative risk, 1.82, 95% CI, 1.16 to 2.86).

View larger version (16K):
[in this window]
[in a new window]
|
Fig. 1 Estimates showing the probability of survival (Panel A, left) and freedom from myocardial infarction (Panel B, right) between patients with (broken line) and without (solid line) diabetes undergoing balloon angioplasty. Data are derived from life tables obtained from the Emory8 and National Heart, Lung, and Blood Percutaneous Transluminal Coronary Angioplatsy9 Registries. Mth=month; FF=freedom from.
|
|
Notably, differences in outcomes have beenobserved within the first 6 months after the index procedure. Indeed, angiographic restenosis rate following balloon angioplasty has been reported to be 62% (95% CI, 58% to 66%) in 476 lesions from 377 patients with diabetes,54 which is considerably higher than contemporary balloon angioplasty restenosis rates of 30%. Importantly, total occlusion occurred in 12.6% of the patients, of whom 36% remained asymptomatic. Those with total occlusion were associated with a 6.2% reduction in left ventricular ejection fraction, and may partly account for the poorer outcomes for diabetics following balloon angioplasty. Other independent predictor for restenosis in this study54 included treatment of saphenous vein grafts (OR, 16.6; 95% CI, 2.1 to 131.7), abnormal pre-procedural antegrade flow (OR, 3.2; 95% CI, 1.7 to 6.0), bifurcation (OR, 1.8; 95% CI, 1.0 to 3.2), organ damage (OR, 1.7; 95% CI, 1.1 to 2.7), and post-procedural residual stenosis (OR, 1.03; 1.01 to 1.05).
With greater restenosis rates, the need for coronary artery bypass grafting (p<0.0001) and repeat coronary angioplasty (p<0.0001) procedures were not unexpectedly higher among diabetics (Fig. 2). Between patients with and without diabetes, the estimates for subsequent coronary artery bypass grafting began to diverge after the first 2 years, while the difference for the need for repeatpercutaneous coronary intervention was observed much earlier.

View larger version (16K):
[in this window]
[in a new window]
|
Fig. 2 Estimates showing the probability of freedom from coronary artery bypass surgery (Panel A, left) and repeat coronary angioplasty (Panel B, right) between patients with (broken line) and without (solid line) diabetes undergoing balloon angioplasty. Data are derived from life tables obtained from the Emory8 and National Heart, Lung, and Blood Percutaneous Transluminal Coronary Angioplatsy9 Registries. Mth=month; FF=freedom from.
|
|
Several hypotheses have been put forward to explain the poor outcomes of patients with diabetes mellitus undergoing balloon angioplasty. These patients have smaller caliber vessels and probably from negative remodeling, particularly among those treated with insulin.55 In addition, another reason may be the high occlusive restenosis rates54 which is associated with higher mortality among 513 diabetic patients,56 After a meanperiod of 6.5 years, compared with patientswithout restenosis, the adjusted hazards ratio (HR) for total mortality among those with nonocclusive restenosis was 1.6 (95% CI, 1.1 to 2.6; p=0.03), and those with occlusive restenosis was 3.1 (95% CI, 1.9 to 5.1; p=0.0001). Although restenosis was not significantly higher in diabetics, new narrowings were more frequently encountered, particularly in the vessel which has been treated percutaneously.57 Pair cineangiograms of the 248 patients undergoing balloon angioplasty and repeat coronary angiography at a mean period of 250 days later were examined independently for the development of new disease in the coronary arterial tree. New lesions appeared more commonly (OR, 1.7; 95% CI, 1.1 to 2.6) among patients with diabetes (14.8% vs 8.5%; p=0.01). New stenoses appeared most frequently in treated diabetic vessels (16.9%) followed by non-treated diabetic vessels (13.2%), treated non-diabetic vessels (12.7%) and non-treated non-diabetic vessels (7.3%; p=0.009). The OR of new narrowings among treated diabetic vessels was 2.5 (95% CI, 1.3 to 4.7) higher than non-treated non-diabetic vessels. These findings suggested that disease progression was considerably faster among patients with diabetes, particularly when the vessel has been instrumented by angioplasty devices, and likely to also explain the greater occurrence of adverse events following coronary angioplasty for diabetics.
Although the rapid disease progression in diabetes was not shown in the Emory Angioplasty Surgery Trial (EAST),58 the BARI Investigators observed more lesion progression (23.2% vs 17.4%) and development of new lesions (3.5% vs 2.0%) at 5 years among diabetics undergoing balloon angioplasty. Another factor believed to contribute to the poorer outcomes for patients with diabetes undergoing balloon angioplasty was small caliber vessels.8 However, a recent study59 reported that the diabetic status rather than vessel diameter has been reported to be an independent determinant for adverse long-term cardiac outcomes. In addition, event-free survival for diabetic patients with glycosylated haemoglobin <6% was comparable to non-diabetics upto the first 5 years after the index procedure.
3.2. Atherectomy devices
The experience with directional atherectomy has been similar to balloon angioplasty. Of 512 patients treated with directional atherectomy in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I), there were 95 (18.6%) with diabetes.60 Acute results were comparable between patients with and without diabetes. The 6-month angiographic restenosis rates (59.7% vs 47.4%; p=0.068) and need for subsequent revascularization procedures at 6 months (31.6% vs 24.5%; p=0.19) were marginally higher among those with diabetes. Likewise, the angiographic restenosis rate was higher in diabetics when high-speed rotational atherectomy was used to treat diffuse (
25mm long) coronary artery disease (72.2% vs 45.5%; p<0.05).61 Importantly, the length of restenosis was considerably longer among patients with diabetes (18.1 vs 11.5mm; p<0.05).
 |
4. Balloon angioplasty and bypass surgery in multivessel disease
|
---|
Since its introduction, coronary angioplasty has progressed significantly, from treating single proximal lesions to complex multi-lesion, multi-vessel disease, challenging coronary artery bypass grafting as the principal mode of revascularization therapy. In addition to relieving symptoms, coronary artery bypass grafting has been shown to improve survival in certain subsets of patients.62 Although both technologies have been evolving rapidly, investigators were keen to evaluate the outcomes of different revascularization strategies. As such, several registries and clinical trials were established in the late 1980s and early 1990s to compare the efficacy of percutaneous coronary intervention with coronary artery bypass grafting among patients with multi-vessel disease. While most reports demonstrated similar survivalbetween percutaneous coronary intervention and coronary artery bypass grafting, patients with diabetes undergoing balloon angioplasty were consistently showed to suffer from higher mortality. However, there is no prospective randomized trial designed to directly compare these two techniques of coronary revascularization in patients with diabetes.
4.1. Mortality comparison among randomized trials
Among five randomized trials of patients with multivessel disease comparing between coronary angioplasty and coronary artery bypass grafting, there were 627 patients with diabetes.6366Between a follow-up period of 1 and 8 years, mortality was consistently lower among diabetics undergoing coronary artery bypass grafting (Fig. 3), although the association was less evident when follow-up duration was short. Taken together, mortality was 33.7% (95% CI, 28.3 to 39.1%) among those undergoing coronary angioplasty and 18.9% (95% CI, 14.5 to 23.3%) among those undergoing coronary artery bypass grafting.

View larger version (16K):
[in this window]
[in a new window]
|
Fig. 3 Bar chart showing mortality rates, obtained from randomized trials, of patients with diabetes undergoing coronary artery bypass grafting (CABG) and coronary angioplasty. The number at the bottom of each pair of bars indicates length of follow-up in years (yr). EAST=Emory Angioplasty Versus Surgery Trial; BARI=Bypass Angioplasty Revascularization Investigation; CABRI=Coronary Angioplasty versus Bypass Revascularization Investigation; ERACI=Argentine Randomized Study: Coronary Angioplasty versus Coronary Bypass Surgery in Multivessel Disease.
|
|
The BARI Investigators offered some insightinto the higher mortality among diabetic patients undergoing balloon angioplasty.67 Notably, the survival benefit afforded by coronary artery bypass grafting was provided by the use of the internal mammary artery graft, resulting in a striking reduction of cardiac mortality.68 This conduit was believed to be less susceptible to disease progression, and was more likely to be available for myocardial perfusion during episodes of coronary occlusion, even from a remote area, as evident by the protection offered to patients undergoing coronary artery bypass grafting who subsequentlysustained a Q-wave myocardial infarction.69Furthermore, distal dispersion of vasoactive substances may retard progression of native vessel disease. However, the type of revascularization procedure did not influence the occurrence of myocardial infarction, and the rate was comparable to earlier studies.70,71 But diabetic patients with Q-wave myocardial infarction after coronary artery bypass grafting were less likely to die, with an adjusted relative risk of only 0.09 (95% CI, 0.03 to 0.29; p<0.001) compared with those who underwent balloon angioplasty.69 Although the likelihood of death was also lowered for those treated with surgery but did not suffer from a Q-wave myocardial infarction, the estimate was smaller (adjusted RR, 0.65; 95% CI, 0.45 to 0.94; p=0.02). These differences were observed soon after onset of myocardial infarction, and this relationship was stronger among those receiving the left internal mammary artery conduits.
Another reason for the poorer outcome among patients with diabetes treated with balloon angioplasty compared with coronary artery bypass grafting may be related to progression of disease. In BARI, 369 of 914 coronary artery bypass grafting patients and 528 of 915 balloon angioplasty patients who were successfully revascularized and underwent
1 follow-up angiography were evaluated for the amount of myocardium at risk after the initial procedure.72 Diabetes was present in 58 and 97 patients treated with coronary artery bypass grafting and balloon angioplasty, respectively. Among patients undergoing coronary artery bypass grafting, there was no increase in the percentage of jeopardized myocardium between those with and without diabetes. Conversely, among patients undergoing balloon angioplasty, those with diabetes had a substantial increase in the proportion of jeopardized myocardium at 1-year (protocol-directed) (42% vs 24%; p=0.05) and 30-month (clinically driven) angiography (63% vs 26%; p=0.01), but not at 5-year (protocol directed) angiography (34% vs 26%; p=0.33).
4.2. Mortality comparison among registries
In contrast to the findings from subgroup analysis from randomized trials, the difference in mortality among diabetic patients undergoing percutaneous coronary intervention or coronary artery bypass grafting was less evident. From a broad period of study extending >20 years, survival data of 8818 patients derived from seven registries (Fig. 4), with follow-up periods ranging from 5 to 12 years, were reviewed.68,7378 Of these, only two showed increased mortality among diabetic patients undergoing balloon angioplasty.76,77 The overall probability of long-term mortality of 27.8% for the percutaneous strategy compared with 26.3% for surgery. The reason for the discrepancy between subgroup analysis of clinical trials and observational data is unclear. However, coronary artery bypass grafting patients in registries were much sicker than those undergoing percutaneous coronary intervention. In the BARI study,79 1829 patients consented and randomized, and 2010 others with multivessel disease were followed-up in a registry. Among those in the Registry, educational level and quality of life was higher, and they were more physically active and were less likely to smoke cigarettes than randomized patients. Of those receiving revascularization in the BARI registry, almost two-thirds were treated with percutaneous coronary intervention. There was little difference in 7-year mortality between these two therapeutic modalities, including diabetics. Likely patient selection remains as a critical determining factor, and practicing clinicians are able to choose the appropriate revascularization strategy forindividuals with diabetes.

View larger version (19K):
[in this window]
[in a new window]
|
Fig. 4 Bar chart showing mortality rates, obtained from non-randomized studies, of patients with diabetes undergoing coronary artery bypass grafting (CABG) and coronary angioplasty. Duration of follow-up was expressed in years. EMORY=Emory University Hospitals Database;73 LDCMC=Lady Davis Carmel Medical Center Registry;74 DUKE=Duke University Medical Center Database;75 MAHI=Mid America Heart Institute;76BARI-R=Bypass Angioplasty Revascularization InvestigationRegistry;68 NNE=Northern New England Cardiovascular Disease Study Group;77 APPROACH=Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease.78
|
|
Despite coronary artery bypass grafting provided a more favourable outcome than balloon angioplasty for patients with diabetes, the risk of diabetics undergoing surgery remained higher than those without diabetes.11,80 However, others81 found comparable short-term survival. Recently, a report of 146 786 patients undergoing coronary artery bypass grafting, of whom 28.4% suffered from diabetes,82 showed that 30-day mortality was higher in those with diabetes (3.7% vs 2.7%), with an adjusted OR of 1.23 (95% CI, 1.15 to 1.32). Not surprisingly, stroke, renal failure and infections occurred more frequently among patients with diabetes. By reducing these peri-operative morbidities, outcomes of patients with diabetes undergoing coronary artery bypass grafting can be further improved.
4.3. Need for repeat revascularization procedures
In the BARI trial,64 revascularization procedures were performed more frequently among patients randomized to percutaneous coronary intervention regardless of diabetic status (Fig. 5). Notably, there was little difference in repeat procedures among patients with and without diabetes in the coronary artery bypass grafting group. In contrast, the rate of repeat revascularization procedureswas significantly greater among diabetics undergoing percutaneous coronary intervention than non-diabetics, with the excess accounted by higher coronary artery bypass grafting rates. Among patients undergoing percutaneous coronary intervention, the odds for a patient with diabetes requiring subsequent coronary artery bypass grafting in next 7 years was 1.9 (95% CI, 1.3 to 2.6) higher.

View larger version (23K):
[in this window]
[in a new window]
|
Fig. 5 Need for subsequent revascularization at 7 years after the index procedures for patients with and without diabetes in the Bypass Angioplasty Revascularization Investigation.64
|
|
 |
5. Coronary stenting
|
---|
5.1. Balloon angioplasty vs coronary stenting in patients with diabetes
While the occurrence of restenosis has been shown to be lower among selected patients undergoing coronary stenting compared with balloon angioplasty,83,84 its benefit among diabetics was less certain. From a total of 555 patients in four reports8588 (Fig. 6), the angiographic restenosis rate was considerably higher among those treated with balloon angioplasty compared with coronary stenting (59% vs. 29%; p<0.001). The rate of occlusion at 6-month follow-up was also higher for patients treated with balloon angioplasty (4% vs 13%; p<0.005).88 Patients with occlusion were associated with a substantial reduction in left ventricular ejection fraction (9.9±11.2%; p=0.001) which was not observed among those without restenosis or with non-occlusive restenosis. Due to the higher occurrence of occlusive restenosis among those treated with balloon angioplasty, there was a significant fall in left ventricular ejection fraction (2.4±10.9%; p=0.02), while there was little change in this measurement in the stented group. Among those treated with stents, the rates of death or nonfatal myocardial infarction (14.8% vs 26.0%; p=0.02) and repeat revascularization procedures (35.4% vs 52.1%; p=0.001) were lower at 4 years. These benefits translated to a higher event-free survival rates for patients with diabetes treated with stents (58.8% vs 36.9%; p<0.0001). Furthermore, among patients with chronic total occlusion, there was a trend towards higher patency rates for those with diabetes treated with coronary stents compared with balloon angioplasty (96.3% vs 81.6%; p=0.076) at follow-up.89 Although the results are promising, but whether coronary stenting provides similar benefit to diabetic and non-diabetic patients remains uncertain.

View larger version (17K):
[in this window]
[in a new window]
|
Fig. 6 6-month angiographic restenosis rates among patients with diabetes undergoing balloon angioplasty and coronary stenting. Data were derived from van Belle et al.,85 STRESS=Stent Restenosis Studies I and II,86 ISAR-SMART=Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries,87 van Belle et al.88
|
|
5.2. Coronary stenting in patients with and without diabetes
An early observational study,90 using the Palmaz-Schatz stent, reported that restenosis occurred substantially higher among patients with diabetes (55% vs 20%; p=0.001). Despite similar acute results, late loss was significantly greater among patients with diabetes (1.66 vs 1.23mm; p=0.04), and the authors attributed this finding to increased intimal hyperplasia, which was subsequently validated by intravascular ultrasound examination.38
While there are no randomized trials, several observational and case-control studies provided some insight on the impact of coronary stenting among patients with and without diabetes. From five studies,95,9093 with >4800 patients, angiographic restenosis rate was consistently higher among diabetic patients undergoing coronary stenting (Fig. 7, Panel A). Despite using different stents over a broad range of patients, the overall 5 to 6-month angiographic restenosis rates were 36.8% and 26.3% for patients with and without diabetes, respectively (p<0.001), translating to an increased OR of 1.6 (95% CI, 1.4 to 1.9). In fact, the presence of diabetes was an independent predictor for the occurrence of death, myocardial infarction or stroke at 9 years in patients with single-vessel disease.94

View larger version (15K):
[in this window]
[in a new window]
|
Fig. 7 Angiographic restenosis (Panel A, left) and clinical restenosis (Panel B, right) among patients with and without diabetes treated by coronary stenting. Data derived from Carozza et al.,90 Lau et al.,91 van Belle et al.,85 Elezi et al.,92 and Schofer et al.,93 for Panel A; and Elezi et al.,92 Abizaid et al.,97 Marso et al.,98 and Carrozza et al.,99 for Panel B.
|
|
Similar to balloon angioplasty, diabetic patients had a greater propensity (OR, 2.1; 95% CI, 1.5 to 3.0) to suffer from total occlusion (6.4% vs 3.1%) after coronary stenting.85,92,93 Furthermore, the interaction between heightened mortality andocclusive restenosis following balloon angioplasty may be operative, accounting for the pooreroutcomes.56
Unlike balloon angioplasty, vessel recoil is almost eliminated by coronary stenting, the underlying mechanism of renarrowing is largely attributed exaggerated neointimal hyperplasia. Therefore, the reference diameter may be an important predictor and smaller vessel were more likely to develop restenosis in multivariate analysis.92 After coronary stenting, restenosis rates were higher than non-diabetic patients only in vessels <3mm in diameter (44% vs 23%; p=0.002) and not vessels
3mm (18% vs 15%).95
Other investigators96 have observed a dissociation between luminal diameter stenosis and clinical outcomes. Angiographic restenosis, generallydefined as luminal diameter stenosis
50%, may have little clinical impact, and rates of adverse events may be more relevant. Based on a pool of
11,000 patients obtained from 4 reports92,9799 (Fig. 7, Panel B), the composite unfavourable event rate, consisting of the occurrence of any of the following at 6 months or 1 year: death, myocardial infarction or repeat revascularization, was substantially higher among patients with diabetes (21.1% vs 15.3%; p<0.001), with an OR of 1.5 (95% CI, 1.3 to 1.7). Notwithstanding the differences in patient groups and use of intravascular ultrasound for stent deployment, the rates of individual component of the composite endpoint remained higher for diabetics. Importantly, at 1 year, patients with diabetes were 2.0 (95% CI, 1.5 to 2.8) and 1.7 (95%CI, 1.3 to 2.2) times more likely to die (6.4% vs 3.2%; p<0.001) or suffer from myocardial infarction (7.2% vs 4.5%; p<0.001), respectively.92,97 Although repeat revascularization procedures were performed more frequently among diabetics, notably there was little difference between the rates of non-target lesion revascularization (8.3% vs 7.2%; p=0.28).92,97 Conversely, in another report on balloon angioplasty,57 the rate of disease progression in treated and non-treated vessels were substantially higher among diabetics.
Better glycaemic control reduces blood thrombogenicity100 and its significance was explored in 151 diabetic patients undergoing coronary stenting.101 Glycosylated haemoglobin level was significantly higher among those with restenosis (7.5% vs 6.8%; p=0.012). Indeed, OR for the occurrence of restenosis was 0.4 (95% CI, 0.2 to 0.8) when glycaemic control was good (<6.5%) compared to those who were poor (>7.5%). Other factors, including cholesterol levels, type of diabetic treatment, lipoprotein (a) and body mass index were not predictors for restenosis. However, glycaemic control hadlittle impact on long-term adverse clinical outcomes in another study.102 But the definition of control less stringent (good, <8.0%; poor, >10%), and may have accounted for the lack of significant association.
 |
6. Coronary stenting and bypass surgery in multivessel disease
|
---|
Both coronary stents and coronary artery bypass grafting, with the use of arterial conduits, have improved outcomes in patients with coronary artery disease. Although there are randomized studies comparing between these 2 revascularization strategies, their findings have been conflicting.103105 The Arterial Revascularization Therapies Study (ARTS) demonstrated comparable mortality between patients undergoing coronary stenting (2.5%) and bypass surgery (2.8%) at 1 year.103 Conversely, the second Argentine Randomized Study: Coronary Angioplasty versus Coronary Bypass Surgery in Multivessel Disease (ERACI II)104 reported a higher likelihood of death among those undergoing coronary artery bypass grafting (7.6% and 5.4%; p=0.017) after a mean follow-up period of 18.5 months. On the other hand, the Stent or Surgery Study (SoS) found that mortality was significantly higher among those treated with percutaneous coronary intervention (4.5%) than coronary artery bypass grafting (1.6%) (HR, 2.91, 95% CI, 1.29 to 6.53; p=0.01) after a median follow-up period of 2 years.105 The wide discrepancies in relative and absolute mortality among these three studies may be a reflection on patient selection and procedural expertise. Not surprisingly, patients receiving stents were more likely to require repeat revascularization procedures (16.6% vs 7.3%; p<0.001).103,104
In the ERACI II study,104 diabetes was not a significant predictor for 30-day adverse cardiovascular outcomes in a multivariable model. However, this may be attributed to the small number of patients with diabetes. The influence of diabetes on long-term outcome was not presented. In contrast, the diabetic cohort was described in the ARTS trial.106 Among those treated with stents, mortality was considerably higher among patients with diabetes (6.3% vs 1.6%; p=0.013) (Fig. 8). Regardless of diabetic status, the rate of repeat revascularization was higher in the stented than coronary artery bypass grafting patients (16.6% vs 7.3%; p<0.001).103,104 While these procedures were performed more frequently among diabetic patients receiving stents by 1 year, the difference was not statistically significant. However, using a multivariable model, the patients with diabetes was more than twice as likely to experience any adverse cardiovascular events at 1 year.
Adjunctive medical therapies differed between the ERACI II and ARTS trial. Notably, the proportions of stented patients treated with abciximab in these two trials were 28% and 3%, respectively. This important difference may account, at least partly, for the variation in outcome. Others107,108 have attributed the excess in adverse events amongdiabetic patients with multivessel disease undergoing percutaneous coronary intervention, at least in part, to incomplete revascularization. Whether this explanation applies to the comparison between coronary stenting and coronary artery bypass grafting remains controversial. A similar analysis for the SoS study is planned.
Novel techniques in preventing myocardialinjuries during coronary revascularization procedures may further improve outcomes. The use of beating heart surgery109 may enhance the safety and efficacy of coronary artery bypass grafting. Reports focussing on cellular protective agents have been encouraging. The sodium-hydrogenexchanger110 is activated during ischaemia leading to intracellular accumulation of hydrogen ions, and subsequent injury and necrosis. Cariporide (HOE642A), a potent inhibitor of the exchanger, was extensively studied in the GUARDIAN (GUARd During Ischemia Against Necrosis) trial.111 There were 3439 and 2918 patients undergoing high-risk percutaneous coronary intervention and coronary artery bypass grafting, respectively. Diabetes was present in 33% and 47% of the percutaneous coronary intervention and coronary artery bypass grafting groups, respectively. Patients were randomly assigned to 3 dosing regimens and infusion of cariporide commenced prior to the procedure, and treatment discontinued after 2 to 7 days. There was a trend towards lower adverse cardiovascular events in the low-dose percutaneous coronary intervention group, but a 25% relative reduction in death or myocardial infarction at 36 days in the coronary artery bypass grafting group. There was no information on patients with diabetes.
 |
7. Glycoprotein IIb/IIIa blockade
|
---|
7.1. Balloon angioplasty
The complementary interaction between abciximab and coronary angioplasty was explored in the Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) study.112 Of 2792 patients, 638 (23%) had diabetes. Compared with placebo, bolus and infusion of abciximab reduced the occurrence of death or myocardial infarction at 6 months (HR, 0.36, 95% CI, 0.21 to 0.61). Surprisingly, the amount of benefit afforded by abciximab was marginally higher than patients without diabetes (HR, 0.60, 95% CI, 0.44 to 0.82). Interestingly, the investigators observed a relationship between heparin dose and outcome. Among patients with diabetes, the rate of death, myocardial infarction or urgent repeat re-intervention was slightly lower among thosereceiving standard-dose (100U/kg) than low-dose heparin (70U/kg) (23.1% vs 31.4%; p=0.074). This finding may reflect upon the need for greater anticoagulation for patients with diabetes undergoing balloon angioplasty, even in the setting of potent antiplatelet inhibition.
7.2. Coronary stenting
With the favourable results from coronary stenting and GP IIb/IIIa blockade, the synergistic combination will potentially provide far better outcomes. In the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT), there were 491 (20.5%) patients with diabetes, a pre-specified subgroup.113 The 6-month occurrence of death, myocardial infarction or target vessel revascularization was lowest among those treated with stent plus abciximab (13.0%) compared with balloon angioplasty plus abciximab (23.4%) or stent only (25.2%) (p=0.005). Compared with diabetic patients treated with stent alone, those receiving stent plus abciximab have lower incidence of death or myocardial infarction (6.2% vs 12.7%; p=0.041). Indeed, by pooling the results of three large clinical trials114 comparing abciximab with placebo among patients with diabetes undergoing percutaneous coronary intervention using a variety of devices, 1-year mortality was substantially lower among those receiving GP IIb/IIIa blockade (2.5% vs 4.5%; p=0.031).
In the EPISTENT study113 , target vessel revascularization was reduced among diabetic patients treated with stent plus abciximab (8.1% vs 16.6%; p=0.021), to a rate comparable to non-diabetics treated with stent plus abciximab (8.8%). Of 149 patients (30.3%) who underwent 6-month angiography, net gain was considerably greater among those treated with stent plus abciximab compared with stent alone (0.88 vs 0.55mm; p=0.011), with a marginally lower loss index (0.40 vs 0.60; p=0.061). Although abciximab has not been shown to prevent angiographic restenosis,115 its effect on patients with diabetes is less certain. Currently, there is an on-going randomized placebo-control trial,Abciximab in Stenting Inhibits restenosis Among Diabetics (ASIAD), evaluating the role of coronary stent plus abciximab in preventing angiographic restenosis in 260 patients with diabetes. The effect of abciximab on late adverse events in 570 patients with diabetes undergoing non-acute myocardial infarction percutaneous coronary intervention was also reviewed based on the Mayo Clinic Registry.116 While the rates of 30-day mortality (0.6% vs 3.0%; p=0.03) and repeat percutaneous coronary intervention (0% vs 1.1%; p=0.03) were lower among those treated with abciximab, there was littledifference in individual or composite unfavourable cardiovascular events at 1-year, even after adjusting for baseline characteristics.
The Do Tirofiban and ReoPro Give SimilarEfficacy Trial (TARGET)117 compared the efficacy of tirofiban and abciximab to prevent ischaemic complications among patients undergoing coronary stenting. Overall, at 30 days, the composite event of death, myocardial infarction or urgent target vessel revascularization occurred more frequently among those randomized to tirofiban (7.6% vs 6.0%; p=0.038). Of 4809 patients enrolled, there were 1117 (23.2%) who had diabetes. In this subgroup of patients, there was little difference in the incidence of the composite endpoint (tirofiban, 15.7%, abciximab, 16.9%; p=0.61), with a comparable rate of target vessel revascularization at 6 months (tirofiban, 9.5%, abciximab, 11.1%; p=0.366).118 Mortality at 1-year was also similar (tirofiban, 2.1%, abciximab, 2.9%; p=0.436). In contrast, administration of eptifibatide was not shown to be superior to placebo among diabetic patients undergoing coronary stenting.119 The lack of benefit for eptifibatide may be related to an unexpectedly low risk group of patients with diabetes in the study.
 |
8. Current strategy and future directions
|
---|
The modality of coronary revascularization for patients with diabetes and multivessel disease remains controversial. Several issues were not addressed by contemporary clinical studies, such as the type of treatment, adequacy of glycaemic control, aggressive management of other atherosclerotic risk factors, adjunctive therapy with statins and angiotensin converting enzyme inhibitors, and status of distal vessel bed. With rapidly evolving technologies in the arena of interventional cardiology and cardiac surgery, most techniques employed by the investigators were outmoded by the time the results became widely available. Notwithstanding these limitations, coronary artery bypass grafting was shown to provide better outcomes. However, the synergism of coronary stenting and GP IIb/IIIa blockade may afford similar results between patients with and without diabetes. Currently, lesion morphological characteristics are likely to play an important role in determining the type of revascularization procedure. Patients with discrete lesions in large caliber vessels may be suitable for percutaneous coronary intervention, particularly when theproximal left anterior descending artery is not significantly diseased. Furthermore, percutaneous coronary intervention may be the procedure of choice when the left internal mammary artery is not available as a conduit or when the patient has several other co-morbid medical conditions. However, the use of other arterial conduits may provide comparable outcomes.120,121 Conversely, patients with diffuse narrowings in small caliber vessels and poor left ventricular function should undergo coronary artery bypass grafting. Among patients whereby concomitant cardiac procedures are required, such as valve surgery, coronary artery bypass grafting is more appropriate.
With the number of patients with diabetes increasing worldwide, there are several on-going studies evaluating numerous strategies in their optimizing outcomes. The advent of drug-eluting coronary stents has changed the entire landscape of interventional cardiology with the promise of no restenosis122 The encouraging results of the sirolimus-eluting stent was amplified in the much larger RAVEL (Randomized Double-Blind Study with the Sirolimus-Eluting Bx Velocity (Cordis, Warren, NJ) Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Lesions) Study, consisting of 238 patients.123 At 6 months, the angiographic restenosis rates for the stents with and without drugs were 0% and 26%, respectively (p<0.0001), with a 1-year event-free survival of 94.2% and 71.2% (p<0.0001), respectively.124 Of 44 patients with diabetes, 19 were treated with the sirolimus-eluting stent and 25 with uncoated stents. The restenosis rates were 0% and 42% (p<0.0001), respectively. The late loss for patients with diabetes was comparable to non-diabetics (0.08 vs 0.01mm, respectively). In the larger SIRIUS trial (Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with De Novo Coronary Artery Lesions), the overall results on 1053 patients showed an in-segment restenosis rates of 8.9% and 36.3% (p<0.0001) for stents with and without sirolimus.125 There were 279 patients (26.5%) with diabetes, and thein-segment restenosis rate was also lower among those treated with sirolimus-eluting stent (17.6% vs 50.5%; p<0.001). Despite using sirolimus-eluting stents, patients with diabetes continued to have higher restenosis rate than those without. It remains unclear if this finding was dose-related. However, the relative reduction of restenosis was comparable to non-diabetic patients. The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) study, a prospective multicenter international randomized trial comparing the drug-eluting stent with bypass surgery among 1500 patients with diabetes, is being planned. An European registry, ARTS-2, will compare the outcomes of patients with multivessel disease treated with sirolimus-eluting stents and coronary artery bypass grafting.
With the favourable results from the use ofmetformin in preventing myocardial infarction in the UKPDS,41 other investigators focussed on improving insulin sensitivity as a key interventional strategy for patients with type 2 diabetes undergoing coronary revascularization. A novel receptor, peroxisome proliferator-activator receptor-
(PPAR-
), which regulates gene expression, appears to be a promising approach to improve outcomes of patients with type 2 diabetes undergoing coronary revascularization.126 Agonists such as thiazolidinediones bind to peroxisome proliferator-activator receptor-
and promote insulin-mediated glucose transport into adipose and skeletal muscles, lowering hyperglycaemia and improving insulin resistance. Recently, this group of pharmacological agents has been shown to reduce smooth muscle cell proliferation,127 and rosiglitazone (Avandia®, GlaxoSmithKline, Philadelphia, PA) was shown to reduce neointimal hyperplasia in patients with type 2 diabetes undergoing coronary stenting.128 Currently, the PPAR (peroxisome proliferator-activator receptor-
agonist for the prevention of lateadverse events following percutaneous revascularization) is being conducted to evaluate the efficacy of rosiglitazone, compared with placebo, in preventing 1-year adverse cardiac events in 200 obese patients with type 2 diabetes or hypertension. As advanced glycation end products alter the compliance of vessel walls, and responses toinjury,37 delinking sugars and amino groups is an attractive approach to restore normal vascular characteristics. A thiazolium derivative, ALT-711 (3-phenyl acyl-4,5-dimethylthiazolium bromide) breaks down these cross-linkages129 and reduce wall stiffness.130 The use of this novel agent may provide a rational alternative to improve outcomes of patients with diabetes undergoing coronary revascularization. Finally, the BARI-2D trial aims to enroll 2600 patients with type II diabetes evaluating the role of revascularization and glycaemic control in a 2X2 matrix design. Patients are to be randomized to medical therapy or revascularization, employing either percutaneous coronary intervention or coronary artery bypass grafting at the investigator's discretion. As for type of glycaemic control, patients are randomly allocated to insulin-sensistizing agents, such as thiazolidinedione or biguanide, or insulin-providing drugs, such as sulphonylurea. Physicians worldwide are eagerly awaiting the desperately needed results of these new studies to provide more data and better manage this extremely high-risk group of patients.
 |
References
|
---|
- Stamler J, Vaccaro O, Neaton JD et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434444.[Abstract]
- Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabetic Medicine. 1997;17:S7S85.
- Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2000. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2002..
- American Diabetes Association. Economic consequences of diabetes mellitus in the U.S. in 1997. Diabetes Care. 1998;21:296309.[Abstract]
- Haffner SM, Lehto S, Rönnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;330:229234.
- Mak KH, Moliterno DJ, Granger CB et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. J Am Coll Cardiol. 1997;30:171179.[CrossRef][Medline]
- Hasdai D, Granger CB, Srivatsa S et al. Diabetes mellitus and outcome after primary coronary angioplasty for acute myocardial infarction: lessons from the GUSTO-IIb angioplasty substudy. J Am Coll Cardiol. 2000;35:15021512.[CrossRef][Medline]
- Stein B, Weintraub WS, Gebhart SSP et al. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation. 1995;91:979989.[Abstract/Free Full Text]
- Kip KE, Faxon DP, Detre KM et al. Coronary angioplasty in diabetic patients. The National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation. 1996;94:18181825.[Abstract/Free Full Text]
- Alderman EL, Corley SD, Fisher LD et al. Five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study (CASS). CASS Participating Investigators and Staff. J Am Coll Cardiol. 1993;22:11411154.[Medline]
- Thourani VH, Weintraub WS, Stein B et al. Influence of diabetes mellitus on early and late outcome after coronary artery bypass grafting. Ann Thorac Surg. 1999;67:10451052.[Abstract/Free Full Text]
- The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med. 1996;335:217225.[Abstract/Free Full Text]
- Mak KH, Mah PK, Tey BH et al. Fasting blood sugar level: a prognostic indicator for myocardial infarction. Ann Acad Med Singapore. 1993;22:291295.[Medline]
- Norhammar A, Tenerz
, Nilsson G et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2002;359:21402144.[CrossRef][Medline]
- Tschoepe D, Roesen P, Kaufmann L et al. Evidence for abnormal platelet glycoprotein expression in diabetes mellitus. Eur J Clin Invest. 1990;20:166170.[Medline]
- Knobler H, Savion N, Shenkman B et al. Shear-induced platelet adhesion and aggregation on subendothelium are increased in diabetic patients. Thromb Res. 1998;90:181190.[CrossRef][Medline]
- Assert R, Scherk G, Bumbure A et al. Regulation of protein kinase C by short term hyperglycaemia in human platelets in vivo and in vitro. Diabetologia. 2001;44:188195.[CrossRef][Medline]
- Vinik AI, Erbas T, Park TS et al. Platelet dysfunction in type 2 diabetes. Diabetes Care. 2001;24:14761485.[Abstract/Free Full Text]
- Missov RM, Stolk RP, van der Bom JG et al. Plasma fibrinogen in NIDDM: the Rotterdam study. Diabetes Care. 1996;19:157159.[Abstract]
- Heywood DM, Mansfield MW, Grant PJ. Factor VII gene polymorphisms, factor VII: C levels and features of insulin resistance in non-insulin-dependent diabetes mellitus. Haemost Thromb. 1996;75:401406.
- Heywood DM, Mansfield MW, Grant PJ. Levels of von Willebrand factor, insulin resistance syndrome, and a common vWF gene polymorphism in non-insulin-dependent (type 2) diabetes mellitus. Diabet Med. 1996;13:720725.[CrossRef][Medline]
- Jones RL. Fibrinopeptide-A in diabetes mellitus. Relation to levels of blood glucose, fibrinogen disappearance, and hemodynamic changes. Diabetes. 1985;34:836843.[Abstract]
- Sobel BE, Woodcock-Mitchell J, Schneider DJ et al. Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence. Circulation. 1998;97:22132221.[Abstract/Free Full Text]
- Cines DB, Pollak ES, Buck CA et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998;91:35273561.[Free Full Text]
- Williams SB, Cusco JA, Roddy MA et al. Impaired nitric oxide-mediated vasodilation in non-insulin-dependent diabetes. J Am Coll Cardiol. 1996;27:567574.[CrossRef][Medline]
- Umeda F, Inoguchi T, Nawata H. Reduced stimulatory activity on prostacyclin production by cultured endothelial cells in serum from aged and diabetic patients. Atherosclerosis. 1989;75:6166.[Medline]
- Takahashi K, Ghatei MA, Lam HC et al. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia. 1990;33:306310.[Medline]
- Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol. 1992;263(2 Pt 2):H321H326.[Medline]
- Williams SB, Goldfine AB, Timimi FK et al. Acute hyperglycaemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation. 1998;97:16951701.[Abstract/Free Full Text]
- Bucala R, Tracey KJ, Cerami A. Advanced glycosylated products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991;97:432438.
- Lorenzi M, Cagliero E, Toledo S. Glucose toxicity for human endothelial cells in culture. Delayed replication, disturbed cell cycle, and accelerated death. Diabetes. 1985;34:621627.[Abstract]
- Bornfeldt KE, Raines EW, Nakano T et al. Insulin-like growth factor-I and platelet-derived growth factor-BB inducedirected migration of human arterial smooth muscle cell via signaling pathways that are distinct from those of proliferation. J Clin Invest. 1994;93:12661274.[Medline]
- McClain DA, Paterson AJ, Roos MD et al. Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells. Proc Natl Acad Sci USA. 1992;89:81508154.[Abstract]
- Roy S, Sala R, Cagliero E et al. Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci USA. 1990;87:404408.[Abstract]
- Dichtl W, Nilsson L, Goncalves I et al. Very low-density lipoprotein activates nuclear factor-KB in endothelial cells. Circ Res. 1999;84:10851094.[Abstract/Free Full Text]
- Taguchi S, Oinuma T, Yamada T. A comparative study of cultured smooth muscle cell proliferation and injury, utilizing glycated low density lipoproteins with slight oxidation, auto-oxidation, or extensive oxidation. J Atheroscler Thromb. 2000;7:132137.[Medline]
- Schmidt AM, Yan SD, Wautier JL et al. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res. 1999;84:489497.[Abstract/Free Full Text]
- Kornowski R, Mintz GS, Kent KM et al. Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia. A serial intravascularultrasound study. Circulation. 1997;95:13661369.[Abstract/Free Full Text]
- Bavenholm P, Proudler A, Tornvall P et al. Insulin, intact and split proinsulin, and coronary artery disease in young men. Circulation. 1995;92:14221429.[Abstract/Free Full Text]
- Folsom AR, Rasmussen ML, Chambless LE et al. Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Diabetes Care. 1999;22:10771083.[Abstract]
- United Kingdom Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854865.[CrossRef][Medline]
- Inoguchi T, Li P, Umeda F et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000;49:19391945.[Abstract]
- Nishimoto Y, Miyazaki Y, Toki Y et al. Enhanced secretion of insulin plays a role in the development of atherosclerosis and restenosis of coronary arteries: elective percutaneous transluminal coronary angioplasty in patients with effort angina. J Am Coll Cardiol. 1998;32:16241629.[CrossRef][Medline]
- Takagi T, Yoshida K, Akasaka T et al. Hyperinsulinemia during oral glucose tolerance test is associated with increased neointimal tissue proliferation after coronary stent implantation in nondiabetic patients: a serial intravascular ultrasound study. J Am Coll Cardiol. 2000;36:731738.[CrossRef][Medline]
- Park SH, Marso SP, Zhou Z et al. Neointimal hyperplasia after arterial injury is increased in a rat model of non-insulin-dependent diabetes mellitus. Circulation. 2001;104:815819.[Abstract/Free Full Text]
- Marso SP, Mak K-H, Topol EJ. Diabetes mellitus: biological determinants of atherosclerosis and restenosis. Semin Intervent Cardiol. 1999;4:129143.[Medline]
- Dortimer AC, Shenoy PN, Shiroff RA et al. Diffuse coronary artery disease in diabetic patients: fact or fiction? Circulation. 1978;57:133136.[Abstract]
- Vlietstra RE, Kronmal RA, Frye RL et al. Factors affecting the extent and severity of coronary artery disease in patients enrolled in the Coronary Artery Surgery Study. Atherosclerosis. 1982;2:208215.
- Waller BF, Palumbo PJ, Lie JT et al. Status of the coronary arteries at necropsy in diabetes mellitus with onset after age 30 years. Analysis of 229 diabetic patients with and without clinical evidence of coronary heart disease and comparison to 183 control subjects. Am J Med. 1980;69:498506.[Medline]
- Pajunen P, Nieminen MS, Taskinen M-R et al. Quantitative comparison of angiographic characteristics of coronary artery disease in patients with noninsulin-dependent diabetes mellitus compared with matched nondiabetic control subjects. Am J Cardiol. 1997;80:550556.[CrossRef][Medline]
- Goraya TY, Leibson CL, Palumbo PJ et al. Coronary atherosclerosis in diabetes mellitus. A population-based autopsy study. J Am Coll Cardiol. 2002;40:946953.[CrossRef][Medline]
- Silva JA, Escobar A, Collins TJ et al. Unstable angina. A comparison of angioscopic findings between diabetic and nondiabetic patients. Circulation. 1995;92:17311736.[Abstract/Free Full Text]
- van Domburg RT, Foley DP, de Feyter PJ et al. Long-term clinical outcome after coroary balloon angioplasty. Eur Heart J. 2001;22:934941.[Abstract/Free Full Text]
- Van Belle E, Abolmaali K, Bauters C et al. Restenosis, late vessel occlusion and left ventricular function six months after balloon angioplasty in diabetic patients. J Am Coll Cardiol. 1999;34:476485.[CrossRef][Medline]
- Kornowski R, Mintz GS, Lansky AJ et al. Paradoxic decreases in atherosclerotic plaque mass in insulin-treated diabetic patients. Am J Cardiol. 1998;98:12981304.[CrossRef]
- Van Belle E, Ketelers R, Bauters C et al. Patency of percutaneous transluminal coronary angioplasty sites at 6-month angiographic follow-up. A key determinant of survival in diabetics after coronary balloon angioplasty. Circulation. 2001;103:12181224.[Abstract/Free Full Text]
- Rozenman Y, Sapoznikov D, Mosseri M et al. Long-term angiographic follow-up of coronary balloon angioplasty in patients with diabetes mellitus. A clue to the explanation of the results of the BARI study. J Am Coll Cardiol. 1997;30:14201425.[CrossRef][Medline]
- King IIISB, Lembo NJ, Weintraub WS et al. Emory Angioplasty Versus Surgery Trial (EAST): a randomized trial comparing coronary angioplasty with coronary bypass surgery. N Engl J Med. 1994;331:10441050.[Abstract/Free Full Text]
- Otsuka Y, Myazaki S, Okumura H et al. Abnormal glucose tolerance, not small vessel diameter, is a determinantof long-term prognosis in patients treated with balloon coronary angioplasty. Eur Heart J. 2000;21:17901796.[Abstract/Free Full Text]
- Levine GN, Jacobs AK, Keeler GP et al. Impact of diabetes mellitus on percutaneous revascularization (CAVEAT-I). Am J Cardiol. 1997;79:748755.[CrossRef][Medline]
- Kishi K, Hiasa Y, Ogata T et al. Comparison of results of rotational atherectomy for diffuse coronary artery disease in diabetics versus nondiabetics. Am J Cardiol. 2001;87:894896.[CrossRef][Medline]
- Yusuf S, Zucker D, Peduzzi P et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Trialists Collaboration. Lancet. 1994;344:563570.[Medline]
- King IIISB, Kosinski AS, Guyton RA et al, for the Emory Angioplasty Versus Surgery Trial (EAST) Investigators. Eight-year mortality in the Emory Angioplasty Versus Surgery Trial (EAST). J Am Coll Cardiol. 2000;35:11161121.[CrossRef][Medline]
- The BARI Investigators. Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol. 2000;35:11221129.[CrossRef][Medline]
- Kurbaan AS, Bowker TJ, Ilsley CD et al, on behalf of the CABRI Investigators. Difference in mortality of the CABRI diabetic and nondiabetic populations and its relation to coronary artery disease and the revascularization mode. Am J Cardiol. 2001;87:947950.[CrossRef][Medline]
- Pereira CF, Bernardi V, Martinez J et al. Diabetic patients with multivessel disease treated with percutanous coronary revascularization had similar outcome than those treated with surgery: one year follow up results from two Argentine randomized studies (ERACI-ERACI II) (abstract). J Am Coll Cardiol. 2000;35:3A.
- The BARI Investigators. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96:17611769.[Abstract/Free Full Text]
- Detre KM, Guo P, Holubkov R et al. Coronary revascularization in diabetic patients: a comparison of the randomized and observational components of teh Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1999;99:633640.[Abstract/Free Full Text]
- Detre KM, Lombardero MS, Brooks MM et al. The effect of previous coronary-artery bypass surgery on the prognosis of patients with diabetes who have acute myocardial infarction. N Engl J Med. 2000;342:989997.[Abstract/Free Full Text]
- Peduzzi P, Detre K, Murphy ML et al. Ten-year incidence of myocardial infarction and prognosis after infarction. Department of Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery. Circulation. 1991;83:747755.[Abstract]
- Davis KB, Alderman EL, Kosinski AS et al. Early mortality of acute myocardial infarction in patients with and without prior coronary revascularization surgery. A Coronary Artery Surgery Study Registry Study. Circulation. 1992;85:21002109.[Abstract]
- Kip KE, Alderman EL, Bourassa MG et al. Differential influence of diabetes mellitus on increased jeopardized myocardium after initial angioplasty or bypass surgery. Bypass Angioplasty Revascularization Investigation. Circulation. 2002;105:19141920.[Abstract/Free Full Text]
- Weintraub WS, Stein B, Kosinski A et al. Outcome of coronary bypass surgery versus coronary angioplasty in diabetic patients with multivessel coronary artery disease. J Am Coll Cardiol. 1998;31:1019.[CrossRef][Medline]
- Halon DA, Flugelman MY, Merdler A et al. Similar late revascularization rates 10 to 12 years after angioplasty or bypass surgery for multivessel coronary artery disease: a report from the Lady Davis Carmel Medical Center (LDCMC) Registry. Am J Cardiol. 2000;86:11311134.[CrossRef][Medline]
- Barsness GW, Peterson ED, Ohman EM et al. Relationship between diabetes mellitus and long-term survival after coronary bypass and angioplasty. Circulation. 1997;96:25512556.[Abstract/Free Full Text]
- Gum PA, O'Keefe JH Jr, Borkon AM et al. Bypass surgery versus coronary angioplasty for revascularization of treated diabetic patients. Circulation. 1997;96:II-7II-10.
- Niles NW, McGrath PD, Malenka D et al. Survival of patients with diabetes and multivessel coronary artery disease after surgical or percutaneous coronary revascularization: results from a large regional prospective study. J Am Coll Cardiol. 2001;37:10081015.[CrossRef][Medline]
- Dzavik V, Ghali WA, Norris C et al. Long-term survival in 11,661 patients with multivessel coronary artery disease in the era of stenting: a report from the Alberta Provincial Project for Outcome Assessment in Coronary HeartDisease (APPROACH) Investigators. Am Heart J. 2001;142:119126.[CrossRef][Medline]
- Feit F, Brooks MM, Sopko G et al. Long-Term Clinical Outcome in the Bypass Angioplasty Revascularization Investigation Registry. Circulation. 2000;101:27952802.[Abstract/Free Full Text]
- Herlitz J, Wognsen GB, Emanuelsson H et al. Mortality and morbidity in diabetic and nondiabetic patients during a 2-year period after coronary artery bypass grafting. Diabetes Care. 1996;19:698703.[Abstract]
- Lawrie G, Morris G, Gleser D. Influence of diabetes mellitus on results of coronary artery bypass surgery. JAMA. 1986;256:29672971.[Abstract]
- Carson JL, Scholz PM, Chen AY et al. Diabetes mellitus increases short-term mortality and morbidity in patients undergoing coronary artery bypass graft surgery. J Am Coll Cardiol. 2002;40:418423.[CrossRef][Medline]
- Serruys PW, de Jaegere P, Kiemeneij F et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994;331:489495.[Abstract/Free Full Text]
- Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994;331:496501.[Abstract/Free Full Text]
- Van Belle E, Bauters C, Hubert E et al. Restenosis rates in diabetic patients. A comparison of coronary stenting and balloon angioplasty in native coronary vessels. Circulation. 1997;96:14541460.[Abstract/Free Full Text]
- Savage MP, Fischman DL, Slota P et al. Coronary intervention in the diabetic patient: improved outcome following stent implantation versus balloon angioplasty [abstract]. J Am Coll Cardiol. 1997;29:188A.
- Mehilli J, Kastrati A, Dirschinger J et al. Comparison of stenting with balloon angioplasty for lesions of small coronary vessels in patients with diabetes mellitus. Am J Med. 2002;112:1318.[Medline]
- Van Belle E, Périé M, Braune D et al. Effects of coronary stenting on vessel patency and long-term clinical outcome after percutaneous coronary revascularization in diabetic patients. J Am Coll Cardiol. 2002;40:410417.[CrossRef][Medline]
- Dzavik V, Yee KM, Anderson T et al. Outcome of PTCA and stenting in diabetic and nondiabetic patients: a report from the Total Occlusion Study of Canada (TOSCA) Investigators (abstract). J Am Coll Cardiol. 2002;39:28A.
- Carrozza Jr JP, Kuntz RE, Fishman RF et al. Restenosis after arterial injury caused by coronary stenting in patients with diabetes mellitus. Ann Intern Med. 1993;118:344349.[Abstract/Free Full Text]
- Lau KW, Ding ZP, Johan A et al. Midterm angiographic outcome of single-vessel intracoronary stent placement in diabetic versus nondiabetic patients: a matched comparative study. Am Heart J. 1998;136:150155.[Medline]
- Elezi S, Kastrati A, Pache J et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol. 1998;32:18661873.[CrossRef][Medline]
- Schofer J, Schlöter M, Rau T et al. Influence of treatment modality on angiographic outcome after coronary stenting in diabetic patients: a controlled study. J Am Coll Cardiol. 2000;35:15541559.[CrossRef][Medline]
- Karam C, Fajadet J, Beauchet A et al. Nine-year follow-up of balloon-expandable Palmaz-Schatz stent in patients with single-vessel disease. Cathet Cardiovasc Intervent. 2000;50:170174.[CrossRef][Medline]
- Süselbeck T, Latsch A, Siri H et al. Role of vessel size as a predictor for the occurrence of in-stent restenosis in patients with diabetes mellitus. Am J Cardiol. 2001;88:243247.[CrossRef][Medline]
- Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation. 1995;92:23332342.[Abstract/Free Full Text]
- Abizaid A, Kornowski R, Mintz GS et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol. 1998;32:584589.[CrossRef][Medline]
- Marso SP, Ellis SG, Bhatt DL et al. The stenting in diabetics debate: insight from the large GUSTO IIb experience with extended follow-up. Circulation. 1998;98:I-78.
- Carrozza JP, Ho KKL, Neimann D et al. Diabetes mellitus is associated with adverse 6-month angiographic and clinical outcome following coronary stenting. Circulation. 1998;98:I-79.
- Osende JI, Badimon JJ, Fuster V et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control. J Am Coll Cardiol. 2001;38:13071312.[CrossRef][Medline]
- Yumoto K, Kato K-I, Doi H et al. The influence of diabetic control on restenosis after coronary stenting (abstract). Circulation. 2000;102:II-730.
- Hasdai D, Rizza RA, Grill DE et al. Glycemic control and outcome of diabetic patients after successful percutaneous coronary revascularization. Am Heart J. 2001;141:117123.[CrossRef][Medline]
- Serruys PW, Unger F, Sousa JE et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med. 2001;344:11171124.[Abstract/Free Full Text]
- Rodriguez A, Bernardi V, Navia J et al. Argentine randomized study: coronary angioplasty with stenting versus coronary artery bypass surgery in patients with multi-vessel disease (ERACI II): 30-day and one-year follow-up results. J Am Coll Cardiol. 2001;37:5158.[CrossRef][Medline]
- The SoS Investigators. Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial. Lancet. 2002;360:965970.[CrossRef][Medline]
- Abizaid A, Costa MA, Centemero M et al. Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary disease patients. Insights from the Arterial Revascularization Therapy Study (ARTS) Trial. Circulation. 2001;104:533538.[Abstract/Free Full Text]
- Bourassa MG, Kip KE, Jacobs AK et al. Is a strategy of intended incomplete percutaneous transluminal coronary angioplasty revascularization acceptable in nondiabetic patients who are candidates for coronary artery bypass graft surgery? The Bypass Angioplasty Investigation (BARI). J Am Coll Cardiol. 1999;33:16271636.[CrossRef][Medline]
- Nikolsky E, Patil C, Rouguin A et al. Percutaneous coronary intervention in diabetic patients: the impact of complete revascularization on long-term prognosis (abstract). J Am Coll Cardiol. 2002;39:74A.
- Angelini GD, Taylor FC, Reeves BC et al. Early and midterm outcome after off-pump and on-pump surgery beating heart against cardioplegic arrest studies (BHACAS 1 and 2): a pooled analysis of two randomised control trials. Lancet. 2002;359:11941199.[CrossRef][Medline]
- Frölich O, Karmazyn M. The Na-H exchanger revisited: an update on Na-H exchange regulation and the role of the exchanger in hypertension and cardiac function in health and disease. Cardiovasc Res. 1997;36:138148.[CrossRef][Medline]
- Théroux P, Chaitman BR, Danchin N et al. Inhibition of the Sodium-Hydrogen Exchanger With Cariporide to Prevent Myocardial Infarction in High-Risk Ischemic Situations. Circulation. 2000;102:30323038.[Abstract/Free Full Text]
- Kleiman NS, Lincoff AM, Kereiakes DJ et al. Diabetes mellitus, glycoprotein IIb/IIIa blockade, and heparin. Evidence for a complex interaction in a multicenter trial. Circulation. 1998;97:19121920.[Abstract/Free Full Text]
- Marso SP, Lincoff AM, Ellis SG et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus. Results of the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial) Diabetic Substudy. Circulation. 1999;100:24772484.[Abstract/Free Full Text]
- Bhatt DL, Marso SP, Lincoff AM et al. Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol. 2000;35:922928.[CrossRef][Medline]
- The ERASER Investigators. Acute platelet inhibition with abciximab does not reduce in-stent restenosis (ERASER Study). Circulation. 1999;100:799806.[Abstract/Free Full Text]
- Velianou JL, Mathew V, Wilson SH et al. Effect of abciximab on late adverse events in patients with diabetes mellitus undergoing stent implantation. Am J Cardiol. 2000;86:10631068.[CrossRef][Medline]
- Topol EJ, Moliterno DJ, Herrmann HC et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med. 2001;344:18881894.[Abstract/Free Full Text]
- Roffi M, Moliterno DJ, Meier B et al. Impact of different platelet glycoprotein IIb/IIIa receptor inhibitors among diabetic patients undergoing percutaneous coronary intervention. Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) 1-year follow-up. Circulation. 2002;105:27302736.[Abstract/Free Full Text]
- Labinaz M, Madan M, McGuire DK et al. Effects of eptifibatide, a glycoprotein IIb/IIIa antagonist, among diabetic patients following coronary stenting: results from ESPRIT (abstract). Circulation. 2000;102:II-665.
- Shin H, Yozu R, Hashizume K et al. Free right internal thoracic artery as a second arterial conduit: modification of proximal anastomosis for improvement of graft patency. Ann Thorac Cardiovasc Surg. 2001;7:155158.[Medline]
- Hirose H, Amano A, Takanashi S et al. Coronary artery bypass grafting using the gastroepiploic artery in 1,000 patients. Ann Thorac Surg. 2002;73:13711379.[Abstract/Free Full Text]
- Sousa JE, Costa MA, Abizaid AC et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents one-year angiographic and intravascular ultrasound follow-up. Circulation. 2001;104:20072011.[Abstract/Free Full Text]
- Morice M-C, Serruys PW, Sousa JE et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:17731778.[Abstract/Free Full Text]
- Fajadet J, Perin M, Ban Hayashi E et al. 210-day follow-up of the RAVEL Study: a randomized study with the sirolimus-eluting Bx VelocityTM balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions (abstract). J Am Coll Cardiol. 2002;39:20A.
- Leon MB, Moses JW, Popma JJ et al., for the SIRIUS Investigators. SIRIUS: Prospective randomized evaluation of the sirolimus-eluting stent in patients with de novo coronary lesions. In: Transcatheter Therapeutics 2002; Washington, D.C..
- Spiegelman BM. PPAR
: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507514.[Abstract]
- Marx N, Schonbeck U, Lazar MA et al. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res. 1998;83:10971103.[Abstract/Free Full Text]
- Takagi T, Akasaka T, Yamamuro A et al. Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study. J Am Coll Cardiol. 2000;36:15291535.[CrossRef][Medline]
- Vasan S, Zhang X, Zhang X et al. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature. 1996;382:275278.[CrossRef][Medline]
- Kass DA, Shapiro EP, Kawaguchi M et al. Improve arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation. 2001;104:14641470.[Abstract/Free Full Text]