Christophe Bauters

Restenosis rates in diabetic patients: a comparison of coronary stenting and balloon angioplasty in native coronary vessels.

BACKGROUND Diabetes is a major risk factor for restenosis after coronary balloon angioplasty. Recent studies have shown that coronary stenting significantly reduces restenosis compared with balloon angioplasty alone. However, limited information is available on the effect of coronary stenting in diabetic patients. METHODS AND RESULTS We designed this study to analyze the effect of diabetes on restenosis in patients treated with either balloon angioplasty or coronary stenting who were enrolled in a 6-month angiographic follow-up program. Three hundred consecutive patients, 19% of whom were diabetics, who underwent coronary stent implantation during a single-vessel procedure on native coronary vessels and who had 6-month angiographic follow-up constituted the study group (stent group). Three hundred consecutive patients who underwent 6-month angiographic follow-up after single-vessel conventional balloon angioplasty served as control patients (balloon group). Preprocedural, postprocedural, and follow-up angiograms were analyzed with quantitative angiography. In the balloon group, the restenosis rate was almost twofold higher in diabetic than in nondiabetic patients (63% versus 36%; P=.0002) owing to both a greater late loss (0.79+/-0.70 versus 0.41+/-0.61 mm, respectively; P<.0001) and a higher rate of late vessel occlusion (14% versus 3%, respectively; P<.001). In the stent group, restenosis rates were similar in diabetics and nondiabetics (25% versus 27%, respectively). Furthermore, in the stent group, late loss (0.77+/-0.65 versus 0.79+/-0.57 mm, respectively) and the rate of late vessel occlusion (2% versus 1%, respectively) did not differ significantly between diabetic and nondiabetic patients. CONCLUSIONS Although diabetics have increased rates of restenosis and late vessel occlusion after simple balloon angioplasty, they have the same improved outcome with coronary stenting that has been documented in nondiabetic patients.

Predictors of Restenosis After Coronary Stent Implantation

OBJECTIVES We sought to determine predictors of restenosis after coronary stenting (CS) in a consecutive series of patients. BACKGROUND Although stenting in highly selected patient groups reduces restenosis, the results of stenting in a heterogeneous patient group and the effects of clinical and procedural factors on stent restenosis are currently unclear. METHODS We analyzed the 6-month angiographic outcome of 500 lesions in 463 consecutive patients undergoing successful CS. Clinical, qualitative and quantitative angiographic variables were correlated with restenosis assessed as both a binary and a continuous variable. RESULTS Restenosis, defined as the presence of >50% diameter stenosis in the dilated segment, was present in 105 (26%) of the 405 lesions with angiographic follow-up. The mean late lumen loss during the follow-up period was 0.79+/-0.64 mm. Implantation of multiple stents (p < 0.0001) and a high acute gain (p < 0.0002) were independently associated with a higher late lumen loss. In contrast, the use of high inflation pressure (p < 0.02) and Palmaz-Schatz stents (p < 0.005) was independently associated with a lower late lumen loss. When restenosis was defined as a qualitative variable, implantation of multiple stents (p < 0.001), stenosis length (p < 0.01), small reference diameter (p < 0.02) and stent type other than Palmaz-Schatz (p < 0.01) were independent predictors of restenosis. None of the clinical variables tested was associated with restenosis. CONCLUSIONS Coronary stenting in an unselected patient group is associated with an acceptable restenosis rate. Although some risk factors were identified, the risk of restenosis was not related to most of the variables tested. This suggests that the superiority of CS over balloon angioplasty, in terms of restenosis, might also apply to subgroups of patients that were not included in the recent randomized studies.

Site-specific therapeutic angiogenesis after systemic administration of vascular endothelial growth factor

PURPOSE Recent experimental studies have established the feasibility of therapeutic angiogenesis; in all cases, this has been achieved with local administration of angiogenic growth factors. This study was designed to investigate the hypothesis that systemic administration of an angiogenic growth factor specifically mitogenic for endothelial cells--vascular endothelial growth factor (VEGF)--could augment collateral vessel development in a rabbit ischemic hindlimb model. METHODS Ten days after the ligation of the external iliac artery and excision of the common and superficial femoral arteries in one limb of New Zealand white rabbits, heparin (800 IU, n = 13), VEGF (1 mg, n = 3; 5 mg, n = 5), heparin (800 IU) + VEGF (1 mg, n = 5; 5 mg, n = 7), or saline solution (n = 8) was injected as a single bolus in a marginal ear vein. Collateral vessel formation and limb perfusion were assessed 10 and 30 days after treatment. RESULTS Animals in both VEGF-treated groups had a significantly higher (p < 0.01) increase in calf blood pressure ratio at day 10 (control, 0.44 +/- 0.02; heparin, 0.47 +/- 0.02; VEGF, 0.60 +/- 0.01; heparin+VEGF, 0.61 +/- 0.02) and day 30 (control, 0.49 +/- 0.05; heparin, 0.48 +/- 0.02; VEGF, 0.70 +/- 0.03; heparin+VEGF, 0.73 +/- 0.03). Both VEGF-treated groups had a significantly higher (p < 0.05) angiographic score at day 30 (control, 0.28 +/- 0.01; heparin, 0.28 +/- 0.01; VEGF, 0.37 +/- 0.01; heparin+VEGF, 0.38 +/- 0.02). Maximum flow reserve at day 30 in the ischemic limb was higher (p < 0.05) in VEGF-treated rabbits (control, 1.87 +/- 0.07; heparin, 1.92 +/- 0.08; VEGF, 2.42 +/- 0.16; heparin+VEGF, 2.33 +/- 0.12). Capillary density was higher (p < 0.01) in the ischemic muscles of VEGF-treated rabbits (control, 156 +/- 10/mm2; heparin, 178 +/- 8/mm2; VEGF, 230 +/- 10/mm2; heparin+VEGF, 233 +/- 8/mm2). CONCLUSIONS This series of in vivo experiments demonstrates that intravenous administration of VEGF, with or without heparin, results in both anatomic and physiologic evidence of enhanced collateral vessel formation in the rabbit ischemic hindlimb. Single-bolus systemic administration of VEGF may be a feasible therapeutic strategy in patients with lower-extremity ischemia.

Evidence for time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina.

BACKGROUND Platelet activation plays a pivotal role in the pathogenesis of acute coronary disease. Monocytes are involved in the progression of atherosclerosis and are potent activators of blood coagulation through their ability to synthesize tissue factor (TF). The aim of this study was to compare markers of monocyte and coagulation activation in the systemic blood of patients with unstable angina, acute myocardial infarction, or stable angina. METHODS AND RESULTS We studied 26 patients with unstable angina (10 +/- 5 hours after the onset of the last episode of pain), 18 patients with acute myocardial infarction (5 +/- 4 hours after the onset of pain), and 34 patients with stable angina. We measured levels of TF expression in peripheral blood mononuclear cells (isolated by gradient centrifugation and incubated for 16 hours, with or without endotoxin stimulation), levels of plasma prothrombin fragment 1 + 2 (F1 + 2), and levels of fibrinogen in peripheral blood. In patients with unstable angina, both stimulated and unstimulated cells exhibited higher levels of TF expression than in patients with stable angina (P = .0001). In patients with acute myocardial infarction, monocyte TF activity did not differ from that in patients with stable angina. Mean levels of F1 + 2 and of fibrinogen did not differ significantly between groups. Only in the unstable angina group, a modest correlation was found between fibrinogen (r = .72, P = .005) and F1 + 2 levels (r = .54, P = .001) levels and the degree of monocyte TF expression. In patients with unstable angina, monocyte TF expression (both stimulated and unstimulated, assessed by biological activity and by antigen techniques) and fibrinogen levels were correlated with the time elapsed from the beginning of the most recent episode of pain (.61 < r < .72, .02 < P < .0001). By contrast, there was no correlation between these variables and the time from onset of pain in patients with acute myocardial infarction. CONCLUSIONS A time-dependent activation of systemic monocytes and a time-dependent increase in fibrinogen levels occurs in unstable angina but not in myocardial infarction. These findings provide further evidence that a specific inflammatory process occurs in unstable angina. Further studies are required to determine whether monocyte activation is a cause or a consequence of plaque instability in patients with unstable angina and to clarify the interrelations between platelet and monocyte activation in these circumstances.

Long-term oral administration of L-arginine reduces intimal thickening and enhances neoendothelium-dependent acetylcholine-induced relaxation after arterial injury

BackgroundNitric oxide (NO), in addition to its potent vasorelaxant properties, may participate in growth regulation of cultured smooth muscle cells. It was recently demonstrated that in vivo endothelial injury induces the production of NO from L-arginine in the arterial wall. Methods and ResultsWe studied the effects of long-term administration of L-arginine, the precursor of NO, on neointimal thickening and on neoendothelium-dependent vasorelaxation 4 weeks after balloon denudation of normocholesterolemic rabbit iliac arteries. Rabbits were fed with either a standard diet or a diet supplemented with L-arginine (2.25%) in their drinking water 3 days before and during 4 weeks after balloon denudation. The effectiveness of L-arginine supplementation was confirmed by measurement of plasma arginine levels. L-Arginine had no effect on hemodynamic parameters. All animals were killed 4 weeks after balloon denudation, and a digital histomorphometric analysis of three serial nonconsecutive histological cross sections per iliac artery was performed. Intimal thickening was reduced (P<.05) from 0.43±0.08 (SE) mm2 in controls (n=8) to 0.24±0.02 mm2 in treated animals (n=8). Ten animals (n=5 in each group) were used for in vitro vasoreactivity assessment 4 weeks after balloon denudation. Neoendotheliumdependent acetylcholine-induced relaxation (10−8 mol/L to 3.10−5 mol/L) in treated animals (Emax=−24.1±5.5%) was significantly greater than in controls (Emax=−8.9±2.2%). Endothelium- independent relaxation did not differ between groups (Emax= −58.1±6.5% in L-argimine-supplemented animals versus −52.9±6.8% in controls). ConclusionsOur results demonstrate that L-arginine, a precursor of NO, reduces neointimal thickening after balloon denudation and improves neoendothelial-dependent acetylcholine- induced relaxation.

Patency of Percutaneous Transluminal Coronary Angioplasty Sites at 6-Month Angiographic Follow-Up A Key Determinant of Survival in Diabetics After Coronary Balloon Angioplasty

Background — Several reports have demonstrated a high mortality rate in diabetic patients treated by standard coronary balloon angioplasty. No clear explanation has been provided for this finding. Methods and Results — Consecutive diabetic patients successfully treated by standard coronary balloon angioplasty (n=604) were enrolled in a follow-up program including repeated angiography at 6 months and long-term clinical follow-up. Clinical follow-up was available in 603 patients (99.8%). Twelve patients died, 2 underwent bypass surgery before scheduled repeated angiography, and 76 declined angiography. Determinants of long-term mortality were analyzed in the 513 patients with angiography at 6 months and long-term clinical follow-up (mean follow-up, 6.5±2.4 years). On the basis of the results of repeated angiography, 3 groups of patients were defined: group 1, 162 patients without restenosis (32%); group 2, 257 patients with nonocclusive restenosis (50%); and group 3, 94 patients with coronary occlusion (18%). Overall actuarial 10-year mortality rate was 36%. Actuarial 10-year mortality was 24% in group 1, 35% in group 2, and 59% in group 3 (P <0.0001). Multivariate analysis demonstrated that coronary occlusion was a strong and independent correlate of long-term total mortality (hazard ratio, 2.16; 95% CI, 1.43 to 3.26;P =0.0003) and cardiac mortality (hazard ratio, 2.38; 95% CI, 1.48 to 3.85;P =0.0004). Conclusions — This study demonstrates that restenosis, especially in its occlusive form, is a major determinant of long-term mortality in diabetic patients after coronary balloon angioplasty.

Effects of coronary stenting on vessel patency and long-term clinical outcome after percutaneous coronary revascularization in diabetic patients.

OBJECTIVES We sought to compare coronary stent implantation with balloon angioplasty (BA), in a diabetic population, in terms of the six-month angiographic outcome and four-year clinical events. BACKGROUND Diabetic patients have a poor angiographic and clinical outcome after standard coronary BA. To date, it is still unclear whether stent implantation may improve this outcome. METHODS We investigated this issue by individual matching of 314 diabetic patients treated with either coronary stenting or standard BA. These two groups were derived from a population of consecutive diabetic patients (1993 to 1996). Matching criteria were gender, anti-diabetic regimen, stenosis location, reference diameter, and minimal luminal diameter (+/-0.4 mm). One lesion per patient was considered for matching. RESULTS Baseline characteristics were similar between the two groups of 157 patients. At six months, the rates of restenosis (27% vs. 62%; p < 0.0001) and occlusion (4% vs. 13%; p < 0.005) were lower in the stent group than in the BA group. This was associated with a significant decrease in ejection fraction at six months in the BA group (p = 0.02) while, during the same period, no change was observed in the stent group (p = NS). Subgroup analysis demonstrated that angiographic benefit was consistent among the subgroups. At four years, the combined clinical end point of cardiac death and non-fatal myocardial infarction was lower in the stent group (14.8% vs. 26.0%; p = 0.02), as was the need for repeat revascularization (35.4% vs. 52.1%; p = 0.001). CONCLUSIONS In a population of diabetic patients, coronary stent implantation was associated with a highly beneficial effect on the six-month angiographic outcome and four-year clinical events compared with standard BA.

Restenosis, late vessel occlusion and left ventricular function six months after balloon angioplasty in diabetic patients

OBJECTIVES We studied angiographic outcome and its predictors after traditional coronary balloon angioplasty in diabetics. We further examined whether changes in ejection fraction were influenced by the status of the dilated site(s) at follow-up. BACKGROUND Recent studies have suggested that diabetics have a particularly poor outcome after balloon angioplasty. The reasons for this observation are not known. METHODS We investigated procedural and six-month angiographic outcome, analyzed by quantitative coronary angiography, and left ventricular function in 485 consecutive diabetics (627 lesions) treated by balloon angioplasty without stent implantation. RESULTS The procedure was successful in 455 (94%) patients; angiographic follow-up was available in 377 patients (83%). At follow-up, the rates of restenosis and total occlusion were 62% and 13%, respectively. Five independent predictors of restenosis were identified: the presence of organ damage, a saphenous vein graft (SVG) angioplasty, a bifurcation lesion, a Thrombolysis in Myocardial Infarction (TIMI) flow <3 preprocedure and the degree of residual stenosis. Four independent predictors of vessel occlusion were identified: treatment with insulin, a SVG angioplasty, a TIMI flow <3 preprocedure and the degree of residual stenosis after angioplasty. Late vessel occlusion at angioplasty site(s) was observed in 15% of patients, ranging from 11% for a one-site procedure to 37% for a three-site procedure. This complication was associated with a decrease in ejection fraction at follow-up (-6.2 +/- 9.9%, p = 0.0001), whereas no significant change was observed in patients without occlusion. CONCLUSIONS This study shows that late vessel occlusion is a frequent mode of restenosis in diabetic patients and is associated with a significant decrease in ejection fraction. This could partly explain the poor long-term clinical outcome reported in such patients after traditional balloon angioplasty.

Phenylephrine, vasopressin and angiotensin II as determinants of proto-oncogene and heat-shock protein gene expression in adult rat heart and aorta.

The expression of two oncogenes (conc) c-myc and c-fos, coding for nuclear proteins which play a regulatory role in growth and differentiation, and of two genes coding for two heat shock proteins (HSP) 68 (molecular weight 68,000) and 70 (molecular weight 70,000), which have a protective function during stress, have been investigated by Northern blot analysis of the total RNA, extracted from adult rat ventricle and aorta. (1) The two onc transcripts are absent from these tissues but their expression can be enhanced by a pretreatment with cycloheximide. (2) The HSP70 is, in part, constitutive, while HSP68 is not; both are thermo-inducible in an isolated coronary perfused rat heart. (3) The four messenger RNA (mRNA) are expressed in both ventricles and aorta, 1 or 2 hours after i.p. injection of 6 mg/kg phenylephrine or 12 IU/kg of vasopressin. (4) They are also induced by a continuous or discontinuous injection of angiotensin II (7.5 micrograms/kg per min) for 1-2 h, but only in the aorta. The lack of ventricular response to angiotensin II in rat ventricles has been attributed to the lack of angiotensin II receptors in this tissue. This indicates that, in addition to mechanical factors, circulating hormones which have in common the use of the phosphoinositol pathway, may activate the expression of genes coding for regulatory proteins. This may play a role in the genesis of both ventricular and aortic hypertrophy.

Endothelial regrowth after arterial injury: from vascular repair to therapeutics

Time for primary review 32 days. Interventional strategies for patients with coronary artery disease such as percutaneous transluminal coronary angioplasty or coronary stent implantation invariably result in a marked degree of vascular injury (deendothelialization, mechanical damage to the medial and adventitial layers) [1–3]. The loss of the endothelial monolayer is associated with a variety of deleterious consequences such as thrombus formation, neointimal thickening, and abnormal responses to endothelium-dependent agonists [3–5]. These effects may contribute to each of the known limitations of these techniques (vessel occlusion, restenosis, coronary spasm). The objective of the present review will be to present applied reendothelialization as a possible treatment for patients with coronary artery disease undergoing mechanical revascularization. Our aim will be twofold: first, to summarize current knowledge on the beneficial effect of endothelial regrowth after arterial injury; second, to discuss the potential role of growth factors or other compounds to accelerate reendothelialization. Occupying a strategically important location between circulating blood and tissues and having the ability to respond to changes in its physical, chemical, and humoral environment by the production of bioactive substances, the normal endothelium controls the tone and the proliferative state of the underlying vascular smooth muscle cells (VSMCs) and maintains a non-adhesive luminal surface. Modulation of VSMC tone is mediated by the synthesis and release of endothelium-derived relaxing and contracting factors. The proliferative state of VSMCs is controlled through these endothelium-derived factors and through the secretion of matrix proteins. Anticoagulant, fibrinolytic, and antithrombotic properties of the endothelium contribute to the maintenance of the fluidity of the blood. ### 1.1 Endothelium-dependent vasomotion #### 1.1.1 Relaxing factors Prostacyclin (PGI2), a potent vasorelaxant and platelet-inhibitory metabolite of arachidonic acid was the first endothelium-derived vasoactive factor discovered [6]. After the seminal observation of Furchgott and Zawadski in 1980 [7]that an intact endothelial layer was required for acetylcholine-induced vasorelaxation, … * Corresponding author. Service de Cardiologie B, Hopital Cardiologique, Boulevard du Professeur J. Leclercq, 59037 Lille Cedex, France. Tel. (+33-3) 2044 5302; Fax (+33-3) 2053 5874; E-mail: cbauters@chru-lille.fr