Blood transfusion and ischaemic outcomes according to anemia and bleeding in patients with non-ST-segment elevation acute coronary syndromes: Insights from the TAO randomized clinical trial.

BACKGROUND: The benefits and risks of blood transfusion in patients with acute myocardial infarction who are anemic or who experience bleeding are debated. We sought to study the association between blood transfusion and ischemic outcomes according to haemoglobin nadir and bleeding status in patients with NST-elevation myocardial infarction (NSTEMI). METHODS: The TAO trial randomized patients with NSTEMI and coronary angiogram scheduled within 72h to heparin plus eptifibatide versus otamixaban. After exclusion of patients who underwent coronary artery bypass surgery, patients were categorized according to transfusion status considering transfusion as a time-varying covariate. The primary ischemic outcome was the composite of all-cause death or MI within 180 days of randomization. Subgroup analyses were performed according to pre-transfusion hemoglobin nadir and bleeding status. RESULTS: 12,547 patients were enrolled. Among these, blood transfusion was used in 489 (3.9%) patients. Patients who received transfusion had a higher rate of death or MI (29.9% vs. 8.1%, p<0.01). This excess risk persisted after adjustment on GRACE score and nadir of hemoglobin (HR 3.36 95%CI 2.63-4.29 p<0.01). Subgroup analyses showed that blood transfusion was associated with a higher risk in patients without overt bleeding (adjusted HR 6.25 vs. 2.85; p-interaction 0.001) as well as in those with hemoglobin nadir > 9.0 g/dl (HR 4.01; p-interaction<0.0001). CONCLUSION: In patients with NSTEMI, blood transfusion was associated with an overall increased risk of ischaemic events. However, this was mainly driven by patients without overt bleeding and those hemoglobin nadir > 9.0g/dl. This suggests possible harm of transfusion in those groups.

Two-year vascular hospitalisation rates and associated costs in patients at risk of atherothrombosis in France and Germany: highest burden for peripheral arterial disease.

OBJECTIVES: To obtain Western European perspectives on the economic burden of atherothrombosis in patients with multiple risk factors only (MRF), cerebrovascular disease (CVD), coronary artery disease (CAD), and in the under-evaluated group of patients with peripheral arterial disease (PAD), we examined vascular-related hospitalisation rates and associated costs in France and Germany. DESIGN: The prospective REACH Registry enrolled 4693 patients in France, and 5594 patients in Germany (from December 2003 until June 2004). METHODS: For each country, 2-year rates and costs associated with cardiovascular events and vascular-related hospitalisations were examined for patients with MRF, CVD, CAD, and PAD. RESULTS: Two-year hospitalisation costs were highest for patients with PAD (3182.1€ for France; 2724.4€ for Germany) and lowest for the MRF group (749.1€ for France; 503.3€ for Germany). Peripheral revascularizations and amputations were the greatest contributors to costs for all risk groups. Across all PAD subgroups, peripheral procedures constituted approximately half of the 2-year costs. CONCLUSION: Hospitalisation rates and costs associated with atherothrombotic disease in France and Germany are high, especially so for patients with PAD.

Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-controlled, STRATAGEM trial.

BACKGROUND: Patients receiving anti-platelet agents for secondary cardiovascular prevention frequently require non-cardiac surgery. A substantial proportion of these patients have their anti-platelet drug discontinued before operation; however, there is uncertainty about the impact of this practice. The aim of this study was to compare the effect of maintenance or interruption of aspirin before surgery, in terms of major thrombotic and bleeding events. METHODS: Patients treated with anti-platelet agents for secondary prevention and undergoing intermediate- or high-risk non-cardiac surgery were included in this multicentre, randomized, placebo-controlled, trial. We substituted non-aspirin anti-platelets with aspirin (75 mg daily) or placebo starting 10 days before surgery. The primary outcome was a composite score evaluating both major thrombotic and bleeding adverse events occurring within the first 30 postoperative days weighted by their severity (weights were established a priori using a Delphi consensus process). Analyses followed the intention-to-treat principle. RESULTS: We randomized 291 patients (n=145, aspirin group, and n=146, placebo group). The most frequent surgical procedures were orthopaedic surgery (52.2%), abdominal surgery (20.6%), and urologic surgery (15.5%). No significant difference was observed neither in the primary outcome score [mean values (SD)=0.67 (2.05) in the aspirin group vs 0.65 (2.04) in the placebo group, P=0.94] nor at day 30 in the number of major complications between groups. CONCLUSIONS: In these at-risk patients undergoing elective non-cardiac surgery, we did not find any difference in terms of occurrence of major thrombotic or bleeding events between preoperative maintenance or interruption of aspirin.

Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE).

OBJECTIVE: To determine whether revascularisation is more likely to be performed in higher-risk patients and whether the findings are influenced by hospitals adopting more or less aggressive revascularisation strategies. METHODS: GRACE (Global Registry of Acute Coronary Events) is a multinational, observational cohort study. This study involved 24,189 patients enrolled at 73 hospitals with on-site angiographic facilities. RESULTS: Overall, 32.5% of patients with a non-ST elevation acute coronary syndrome (ACS) underwent percutaneous coronary intervention (PCI; 53.7% in ST segment elevation myocardial infarction (STEMI)) and 7.2% underwent coronary artery bypass grafting (CABG; 4.0% in STEMI). The cumulative rate of in-hospital death rose correspondingly with the GRACE risk score (variables: age, Killip class, systolic blood pressure, ST segment deviation, cardiac arrest at admission, serum creatinine, raised cardiac markers, heart rate), from 1.2% in low-risk to 3.3% in medium-risk and 13.0% in high-risk patients (c statistic = 0.83). PCI procedures were more likely to be performed in low- (40% non-STEMI, 60% STEMI) than medium- (35%, 54%) or high-risk patients (25%, 41%). No such gradient was apparent for patients undergoing CABG. These findings were seen in STEMI and non-ST elevation ACS, in all geographical regions and irrespective of whether hospitals adopted low (4.2-33.7%, n = 7210 observations), medium (35.7-51.4%, n = 7913 observations) or high rates (52.6-77.0%, n = 8942 observations) of intervention. CONCLUSIONS: A risk-averse strategy to angiography appears to be widely adopted. Proceeding to PCI relates to referral practice and angiographic findings rather than the patient's risk status. Systematic and accurate risk stratification may allow higher-risk patients to be selected for revascularisation procedures, in contrast to current international practice.

Impact of chronic oral anticoagulation on management and outcomes of patients with acute myocardial infarction: data from the RICO survey.

OBJECTIVE: To determine the prevalence of chronic oral anticoagulant drug treatment (COA) among patients with acute myocardial infarction (AMI) and its impact on management and outcome. METHODS: All patients with ST segment elevation AMI on the RICO (a French regional survey for AMI) database were included in this analysis. COA was defined as continuous use >or= 48 hours before AMI. RESULTS: Among the 2112 patients with ST elevation myocardial infarction (STEMI), 93 (4%) patients were receiving COA. These patients were older and more likely to have a history of hypertension, diabetes and prior myocardial infarction than patients without COA. In addition, fewer patients who received COA underwent reperfusion therapy or received an antiplatelet agent (aspirin/thienopyridines). Moreover, patients receiving COA experienced a higher incidence of in-hospital major adverse events (death, recurrent myocardial infarction or major bleeding, p = 0.005). Multivariate analysis showed that only ejection fraction, current smoking and multiple vessel disease, but not COA, were independent predictive factors for major adverse events. In contrast, COA was an independent predictive factor for heart failure when adjusted for age, diabetes, creatinine clearance, reperfusion, heparin and glycoprotein IIb/IIIa inhibitors (odds ratio 2.06, CI 95% 1.23 to 3.43, p = 0.005). CONCLUSION: In this population based registry, patients with STEMI with prior use of COA constituted a fairly large group (4%) with an overall higher baseline risk profile than that of patients without COA. Fewer in the COA group received reperfusion therapy or aggressive antithrombotic treatment and they experienced more adverse in-hospital outcomes. Thus, further studies are warranted to develop specific management strategies for this high risk group.

[Acute coronary syndromes and pheochromocytoma]. / Syndromes coronariens aigus et phéochromocytome.

Pheochromocytoma can induce a adrenergic cardiomyopathy. This one occurs sometimes clinical, biological or and electrocardiographic signs of an acute coronary syndrome. We report two cases of rudimentary necrosis due to a pheochromocytoma: the first one after tumorectomy, the second one has revealed the disease in a patient who was suffering from high blood pressure for many years. The coronarography was in each case normal.

[Measurement of coronary reserve by high-frequency transthoracic Doppler ultrasonography: indications and results]. / Mesure de la réserve coronaire par Doppler transthoracique haute fréquence: indications et résultats.

Coronary flow reserve is the ability of coronary flow to increase above its basal value when the coronary vascular bed is maximally dilated. It is a global parameter of coronary flow, which is early altered in the presence of epicardial coronary artery stenosis or a coronary microcirculation disorder. Until now, clinical use of coronary flow reserve has been hampered by the lack of an easy, reliable and non-invasive method. Recently developed high-frequency transthoracic Doppler echocardiography now allows non-invasive assessment of coronary flow reserve. After an initial learning curve, it is possible to study coronary flow, essentially in the left anterior descending artery. Coronary flow reserve is expressed as the ratio of maximal hyperaemic to basal mean coronary velocity. Maximal hyperaemic flow is obtained with adenosine. Clinical applications of coronary flow reserve are numerous. Coronary flow reserve enables the assessment of hemodynamic relevance of a moderate coronary stenosis. Detection of coronary restenosis is also possible by repeated non-invasive measurement of coronary flow reserve. Moreover, evaluation of the microcirculation is of crucial importance in order to appreciate myocardial reperfusion following successful recanalisation on the infarct-related artery. Transthoracic Doppler echocardiography could allow identification of "no-reflow" by analysis of coronary flow pattern and coronary flow reserve. Furthermore, transthoracic Doppler echocardiography constitutes one of the only available and simple means to evaluate microcirculatory disorders (hypertension, diabetes,...). Finally, the possibility of non-invasive follow-up of arterial bypasses constitutes a major advantage of this technique.

[Myocardial revascularization at the acute phase of myocardial infarction in the octogenarian]. / Revascularisation myocardique à la phase aiguë de l'infarctus du myocarde chez les octogénaires.

Elderly patients are at high risk of complications in acute myocardial infarction (AMI). In this population, myocardial reperfusion at the acute phase improves the prognostic. The mortality rate is above 50% in the absence of reperfusion strategy, and decreases at less than 20% in case of such treatment. The thrombolytic use is limited in those patients, coronary angioplasty is taking an important place in this reperfusion therapy, but is not well evaluated in patients older than 80 years. Prospective registry of patients older than 80 years admitted in Hôpital Bichat for acute myocardial infarction within the first 6 hours (n = 92), between 1990 january to 1999 december. Eight patients (10%) received a thrombolytic therapy. Coronary angiogram was achieved in eighty patients (87%). In 58 (63%) patients a coronary angioplasty was performed. The success rate of the coronary angioplasty was 86%. In-hospital mortality rate was 26% (death in 24 patients), 20% in the absence of cardiogenic shock and 62% when this complication was noted. Two patients (2%) were treated by emergent coronary artery bypass surgery. The results comparison between the periods of 1990 to 95 and 1955 to 99 showed, a real trend of decrease mortality rate (28 to 13% in the absence of cardiogenic shock, p = 0.10), an increase of the proportion of patients treated by angioplasty. These results are more and more encouraging. Coronary reperfusion by primary angioplasty in possible in patients older than 80 years with a low rate of complications. Technical progress such as stents and GpIIb/IIIa inhibitors must be evaluated in this population.

[Revision of the "Smoker's Paradox": smoking is not a good prognostic factor immediately after myocardial infarction]. / Révision du "paradoxe du fumeur": le tabac n'est pas un facteur de bon pronostic au décours immédiat de l'infarctus du myocarde.

In order to determine the reasons for the low mortality after myocardial infarction in smokers compared with non-smokers (the smoker's paradox), the authors analysed the initial clinical data, the therapeutic interventions and hospital mortality in 790 consecutive patients (555 smokers, 235 non-smokers) admitted to hospital within 6 hours of the first symptoms of acute myocardial infarction and treated by intravenous thrombolytic agents and/or coronary angioplasty. Multivariate analysis with linear regression was used to identify the predictive factors of hospital mortality. The main differences between smokers and non-smokers were age (56 vs 67 years, p < 0.0001), gender (male, 90 vs 60%, p < 0.01), cardiogenic shock on admission (3 vs 8%, p < 0.01). TIMI 3 flow was obtained in the culprit artery in 84% of smokers and 79% of non-smokers (NS). Hospital mortality was 5% in the smoking population and 16% in non-smokers (p < 0.0001). In multivariate analysis, the variables of cardiogenic shock, age, gender and hypertension provided most of the prognostic information and tobacco consumption did not appear to have a protective effect. In patients admitted to hospital with acute myocardial infarction, identical incidences of early reperfusion are obtained in smokers and in non-smokers. However, mortality is higher in the non-smoking group due to more severe clinical characteristics on admission. Tobacco consumption is not a protective factor in the immediate period after acute myocardial infarction.

Comparison of direct coronary stenting with and without balloon predilatation in patients with stable angina pectoris. BET (Benefit Evaluation of Direct Coronary Stenting) Study Group.

The purpose of this study was to compare the effects of stent placement with and without balloon predilatation on duration of the procedure, reduction of procedure-related costs, and clinical outcomes. Although preliminary trials of direct coronary stenting have demonstrated promising results, the lack of randomized studies with long-term follow-up has limited the critical evaluation of the role of direct stenting in the treatment of obstructive coronary artery disease. Between January and September 1999, 338 patients were randomly assigned to either direct stent implantation (DS+; 173 patients) or standard stent implantation with balloon predilatation (DS-; 165 patients). Baseline clinical and angiographic characteristics were similar in the 2 groups. Procedural success was achieved in 98.3% of patients assigned to DS+ and 97.5% of patients assigned to DS- (p = NS), with a crossover rate of 13.9%. Compared with DS-, DS+ conferred a dramatic reduction in procedure-related cost ($956.4 +/- $352.2 vs $1,164.6 +/- $383.9, p <0.0001) and duration of the procedure (424.2 +/- 412.1 vs 634.5 +/- 390.1 seconds, p < 0.0001). At 6-month follow-up, the incidence of major adverse cardiac events including death, angina pectoris, myocardial infarction, congestive heart failure, repeat angioplasty, or coronary artery bypass graft surgery was 5.3% in DS+ and 11.4% in DS- (p = NS). Multivariate analysis demonstrated that major adverse cardiac events rates were related to stent length of 10 mm (relative risk [RR] 3.25, 95% confidence intervals [CI] 1.36 to 7.78; p = 0.008), stent diameter of 3 mm (RR 2.69, 95% CI 1.03 to 7.06; p = 0.043), and complex lesion type C (RR 2.83, 95% CI 1.02 to 7.85; p = 0.045). Thus, in selected patients, this prospective randomized study shows the feasibility of DS+ with reduction in procedural cost and length, and without an increase in in-hospital clinical events and major adverse cardiac events at 6-month follow-up.

Effect of percutaneous adenovirus-mediated Gax gene delivery to the arterial wall in double-injured atheromatous stented rabbit iliac arteries.

Though the efficacy of intravascular gene transfer has been demonstrated in native vessels following acute injury, this methodology has not been validated in complex models of vascular injury that more closely mimic clinical angioplasty procedures. Previous studies have shown that Gax gene overexpression modulates the injury-induced remodeling of the vessel in rat carotid and normal rabbit iliac arteries. Here, we evaluated the effect of the Gax gene delivery in atheromatous stented vessels. Rabbits were fed 120 g daily of 1% cholesterol diet for 3 weeks. At 1 week they underwent initial injury on the external iliac artery, then balloon angioplasty was performed at 3 weeks at the same site with a 2.5 mm diameter channel balloon catheter (three times 1 min at 6 atm). Either saline (n = 4) or the control viral construct Ad-CMVluc (5 x 109 p.f.u.) (n = 5) or Ad-CMVGax (5 x 10(9) p.f.u.) (n = 4) was delivered with a poloxamer mixture via a channel balloon (6 atm, 30 min), and a 15 mm long Palmaz-Schatz stent (PS154) was then deployed at the site (1 min, 8 atm). Arteries were analyzed 1 month later. At 1 month, the Ad-CMVGax treated arteries exhibited a lower maximal intimal area (1. 15+/-0.1 mm2) than saline (1.87+/-0.15 mm2, P = 0.007) or Ad-CMVluc-treated vessels (1.98+/-0.31 mm2, P = 0.04). Likewise Ad-CMVGax-treated vessels displayed a lower maximal percentage cross-sectional area narrowing (35.1+/-3.5%) than saline (65.3+/-9.4%, P = 0.01) or Ad-CMVluc-treated vessels (62.7+/-6.7%, P = 0.02). Angiographic analysis revealed larger minimal lumen diameter in Ad-CMVGax treated arteries (2.0+/-0.1 mm) than saline (1.14+/-0.36 mm, P = 0.06) or Ad-CMVluc-treated vessels (1.23+/-0.25 mm, P = 0.02). Overexpression of the Gax gene inhibits neointimal hyperplasia and lumen loss in atheromatous stented rabbit iliac arteries.

Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes.

BACKGROUND: Apoptotic microparticles are responsible for almost all tissue factor activity of the plaque lipid core. We hypothesized that elevated levels of procoagulant microparticles could also circulate in the peripheral blood of patients with recent clinical signs of plaque disruption and thrombosis. METHODS AND RESULTS: We studied 39 patients with coronary heart disease, including 12 patients with stable angina and 27 patients with acute coronary syndromes (ACS), and 12 patients with noncoronary heart disease. We isolated the circulating microparticles by capture with annexin V and determined their procoagulant potential with a prothrombinase assay. The cell origins of microparticles were determined in an additional 22 patients by antigenic capture with specific antibodies. The level of procoagulant microparticles did not differ between stable angina patients and noncoronary patients (10.1+/-1.6 nmol/L phosphatidylserine [PS] equivalent versus 9.9+/-1.6 nmol/L PS equivalent, respectively). However, procoagulant microparticles were significantly elevated in patients with ACS (22.2+/-2.7 nmol/L PS equivalent) compared with other coronary (P<0.01) or noncoronary (P<0.01) patients. Microparticles of endothelial origin were significantly elevated in patients with ACS (P<0.01), which suggests an important role for endothelial injury in inducing the procoagulant potential. CONCLUSIONS: High levels of procoagulant endothelial microparticles are present in the circulating blood of patients with ACS and may contribute to the generation and perpetuation of intracoronary thrombi.

Differential expression of rat frizzled-related frzb-1 and frizzled receptor fz1 and fz2 genes in the rat aorta after balloon injury.

Frzb-1 is a secreted protein, presenting similarity with the Wnt-binding domain of the frizzled family of receptors, which acts as an antagonist of Wnt signaling. Using mRNA differential display in the rat aorta balloon injury model, we identified overexpression of Frzb-1 mRNA and determined its cDNA sequence. By quantitative reverse transcription-polymerase chain reaction and RNase protection assay, a biphasic upregulation of rFrzb-1 expression was observed, with significant peaks of a 1.7-fold increase at 4 days and a 1. 5-fold increase at 3 weeks after aortic injury in vivo. In contrast, expression of the rat frizzled receptor genes rfz1 and rfz2 were transiently downregulated at 1 and 4 hours after balloon injury. rFrzb-1 was expressed predominantly in rat aortic smooth muscle cells (RASMCs) and barely in aortic fibroblasts and endothelial cells (RAECs), whereas rfz1 and rfz2 were expressed in all of these cells when stimulated with serum. Transient downregulation of rfz1 and rfz2 expression was reproduced by stimulation of quiescent RASMCs with serum, platelet-derived growth factor-BB, or fibroblast growth factor-2. In contrast, rFrzb-1 expression diminished slowly, to reach a 2-fold decrease 24 hours after growth factor stimulation, implying that quiescent RASMCs expressed higher levels of rFrzb-1 mRNA than did proliferative ones. Overexpression of rFrzb-1 in the aorta seemed to coincide with the arrest of RASMC proliferation occurring in the media 4 days and in the neointima 3 weeks after balloon injury. Our results demonstrate that rfrzb-1, rfz1, and rfz2 are differentially regulated in response to arterial injury and that this modulation seems to follow the proliferative state of RASMCs, suggesting that these Wnt-signaling components may be involved in intimal vascular disease.

[The coronary atherosclerosis of the diabetic]. / L'athérosclérose coronaire du diabétique.

Diabetes mellitus is one of the main risk factors of coronary atherosclerosis. The relative risk of cardiovascular disease is 2 to 4 times higher in type II diabetes than in the general population. The number of cases, especially type II, is increasing, especially as the definition of diabetes has been changed recently by the specialist scientific societies (American Diabetic Association, World Health organisation and ALFEDIAM) to include all patients with fasting glucose levels > or = 7 mmol/L on two occasions. Therefore, in the next 25 years, the number of diabetic patients will probably double, not only because of this new definition but also because of the combined effects of an ageing population, dietary changes (with an increase in obesity) and a progressively more sedentary and urbanized life-style in the so-called "emerging" countries.

[Coronary revascularization in the diabetic]. / La revascularisation coronaire chez le diabétique.

Diabetes mellitus is associated with increased risk of short and long-term complications after balloon angioplasty. In patients with multivessel disease, there may be a substantial increase in long-term mortality when percutaneous transluminal coronary angioplasty (PTCA) is preferred over surgery in patients who are amenable to both techniques, which should lead to caution in selecting PTCA as a routine revascularization method for these patients. However, many diabetic patients will still require revascularization with PTCA, either for single-vessel disease or because they are poor surgical candidates. Finally, the impact of recent advances, such as stents and glycoprotein IIb/IIIa inhibitors, on the short and long-term results of percutaneous interventions is still not fully defined and deserves further study.

Elevated cardiac troponin I predicts a high-risk angiographic anatomy of the culprit lesion in unstable angina.

BACKGROUND: This study assessed the relation between the angiographic appearance of the culprit lesion and cardiac troponin I (cTnI) or C-reactive protein (CRP) elevations within the first 24 hours in unstable angina. Intracoronary thrombus or a complex morphology, is frequently observed on angiography in patients with unstable angina and is associated with a higher rate of spontaneous or coronary angioplasty-related complications. Biochemical parameters related to myocardial injury (eg, cTnI) or to systemic inflammation (eg, CRP) are known prognostic markers for clinical outcome and may help in angiographic risk stratification to provide new adjunctive therapy. METHODS AND RESULTS: We studied 100 patients admitted for unstable angina with angiographically proven coronary artery disease (with normal creatine kinase [CK] and CK-MB mass). Serum concentrations of cTnI (N < 0.4 ng/mL) and CRP (N < 3 mg/L) were measured at admission and 12 and 24 hours later. Multivariate analysis showed that elevated cTnI (>/=0.4 ng/mL) within 24 hours (35 patients) was an independent predictor of an angiographic appearance of the culprit lesion carrying a high risk of major cardiac events in the outcome and whether angioplasty is attempted (coronary thrombus, occlusion, or type C lesions; odds ratio 4.1, 1. 6 to 10.5). cTnI levels at admission and CRP at 0, 12, and 24 hours were not predictive of high-risk angiographic anatomy. CONCLUSIONS: In patients with unstable angina and angiographically proven coronary artery disease, increased cTnI within 24 hours of admission but not increased CRP is associated with an angiographic appearance of the culprit lesion carrying a high risk of complication, especially in the event of angioplasty.

[Gene therapy of restenosis]. / Thérapie génique de la resténose.

Although angioplasty has undergone considerable development, restenosis remains an unsolved problem. No drugs have been proved effective in the prevention of restenosis. Prophylactic stenting is the only treatment with some efficacy. The pathophysiology of restenosis involves both intimal hyperplasia with a major proliferative component at the dilated site and geometric constrictive remodeling of the artery. Stenting seems to prevent the remodeling but does not prevent and may even worsen the intimal hyperplasia. Gene therapy may be effective in preventing the proliferative component of the intimal hyperplasia: therapeutic genes can be delivered locally to the arterial wall cells at the dilated site during or immediately after angioplasty, using viral (e.g., adenoviruses) or nonviral vectors. The main candidate genes stimulate a variety of endogenous mechanisms whose effects consist in inhibition of smooth muscle cell proliferation (Rb gene); sensitization of proliferating cells to the effects of cytotoxic substances, thus allowing selective chemotherapy (HSV-tk gene); or stimulation of reendothelization (VEGF gene). Other genes have also yielded promising results (ecNOs, p21, Coxl, etc.). Clinical application of these techniques cannot be envisioned until studies are available proving that the delivery methods (transfer vectors or local delivery systems) are completely safe, and that the candidate genes are effective in "realistic" models. If these hurdles are cleared successfully, preventive gene therapy for gene restenosis may well become a clinical reality.

Arterial response to mild balloon injury in the normal rabbit: evidence for low proliferation rate in the adventitia.

BACKGROUND: The role of constrictive remodeling, spasm and proliferation (particularly in the adventitia) in the genesis of chronic lumen narrowing after balloon injury remains under debate. This study analyzed the time course of these components following mild injury in normal arteries. METHODS: Iliac injury was induced by balloon overstretch in 32 rabbits, sacrificed at timed intervals from day 3 to 28. Angiographic response to nitrates, morphometric, immunohistochemical and biochemical analysis were performed at each time point. RESULTS: Quantitative angiography showed a decrease in lumen diameter and no change in response to nitrates over time. On morphometric analysis, remodeling was usually constrictive, appeared as early as day 3 and was responsible for 69+/-14% of the histologic lumen area stenosis at day 28. Constrictive remodeling was correlated negatively to intimal hyperplasia (r= 0.51, P< 0.002) and positively to the lumen area stenosis (r= 0.92, P< 0.0001). Macrophages (labeled by anti-RAM 11 antibodies) were very rare at all time points. Immunohistochemistry identified a high rate of proliferating smooth muscle cells in the media (13+/-7%) and intima (49+/-8%) at day 7, which decreased rapidly. Proliferating cells in the adventitia were rare (3+/-2% at day 7). The number of proliferating cells was time-dependent (r= 0.82, P< 0.0001) and related to cyclin A mRNA measured by reverse transcription-polymerase chain reaction (r= 0.84, P< 0.0001). CONCLUSIONS: In this model, luminal loss was mainly caused by constrictive remodeling rather than intimal hyperplasia. Constrictive remodeling appeared early and was not time-dependent. Macrophages, spasm and adventitial proliferation did not contribute to this constrictive remodeling.