Mechanisms and prevention of restenosis: from experimental models to clinical practice.
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Angioplasty, Balloon, Coronary↗
Biomedical subjects
J M Lablanche
Publications and source records attributed to J M Lablanche.
[Relation between progression of atherosclerosis and the phenomenon of restenosis after coronary angioplasty].
The authors undertook a retrospective study of medium-term coronary angiographic controls of a group (Gr) of patients (pts) who had undergone coronary angioplasty for rapidly progressive lesions, to determine whether the rate of progression of a coronary stenosis before angioplasty affected the risk of restenosis. 89 pts underwent primary angioplasty with absence of restenosis at 6 months, but required another angioplasty for another lesion. Angiographic follow-up after the 2nd procedure was performed in 86 pts (96%). The coronary lesion dilated at the 2nd angioplasty procedure was analysed quantitatively with four measurements: one immediately before angioplasty, one after, one at the 6 months control, and finally, one measurement 6 months before the angioplasty during the procedure on the 1st site. Multivariate statistical analysis showed that the only predictive factor of post-angioplasty loss in the general population was the immediate gain (F = 11.82; p < 0.005). On the other hand, no correlation was found between progression of the lesion before angioplasty and loss. The rapidly progressive nature of the lesion was defined with a threshold of 0.4 mm, corresponding to the variability of the quantitative angiographic system. Analysis of the procedure parameters showed a lower inflation pressure in the Gr with rapidly progressive lesions (6.58 +/- 21 atm vs 7.63 +/- 1.96 atm; p < 0.05). The immediate gain was significantly greater in the rapidly progressive lesion Gr (0.82 +/- 0.34 vs 0.67 +/- 0.29 mm; p = 0.05). The loss at the 6 months control was identical in the two Gr (0.31 +/- 0.50 vs 0.31 +/- 0.42 mm; p < 0.05). The loss/gain ratio was also comparable (0.37 +/- 0.76 vs 0.45 +/- 0.52; p > 0.05). These results show that rapidly progressive atherosclerosis does not increase the risk of post-angioplasty restenosis.
Aged↗
Relation of coronary angioscopic findings at coronary angioplasty to angiographic restenosis.
BACKGROUND: Discordant results have been reported regarding morphological predictors of restenosis after percutaneous transluminal coronary angioplasty (PTCA). These discrepancies may be related to the limitations of angiography in the study of plaque morphology. METHODS AND RESULTS: We studied 117 consecutive patients who underwent successful PTCA and who underwent coronary angioscopy before and immediately after the procedure. Angiographic follow-up was performed in 99 (85%) patients. We analyzed the relationship between angioscopic variables at the time of PTCA and the occurrence of restenosis assessed by quantitative coronary angiography. Plaque shape and color had no effect on late loss in luminal diameter (late loss: smooth lesions, 0.55 +/- 0.68 mm; complex lesions, 0.76 +/- 0.60 mm; white plaques, 0.51 +/- 0.56 mm; yellow plaques, 0.65 +/- 0.72 mm; P = NS). An angioscopic protruding thrombus at the PTCA site was associated with significantly greater loss in luminal diameter (late loss: no thrombus, 0.47 +/- 0.54 mm; lining thrombus, 0.59 +/- 0.67 mm; protruding thrombus, 1.07 +/- 0.77 mm; P < .05). Dissection assessed by angioscopy immediately after PTCA had no effect on late loss in luminal diameter (late loss: no dissection, 0.60 +/- 0.60 mm; simple dissection, 0.82 +/- 0.75 mm; complex dissection, 0.57 +/- 0.80 mm; P = NS). CONCLUSIONS: These results show that coronary angioscopy may be helpful in predicting the risk of restenosis after PTCA. The high rate of angiographic recurrence observed when PTCA is performed at thrombus-containing lesions supports a role for thrombus in the process of luminal renarrowing after PTCA.
Aged↗
Relation between the deletion polymorphism of the angiotensin-converting enzyme gene and late luminal narrowing after coronary angioplasty.
BACKGROUND: The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been implicated in the pathogenesis of coronary artery disease. The deletion allele is strongly associated with the level of circulating ACE and is a potent risk factor for myocardial infarction. Recently, the deletion allele was also associated with the occurrence of visually diagnosed restenosis after percutaneous transluminal coronary angioplasty (PTCA) in a selected population of patients with acute myocardial infarction. METHODS AND RESULTS: We investigated the influence of the ACE I/D polymorphism on the occurrence of restenosis after PTCA with the use of quantitative coronary angiography. ACE I/D genotypes were characterized in 118 consecutive patients who had one-vessel disease and were undergoing systematic angiographic follow-up. Coronary angiograms were analyzed before and after PTCA and at follow-up (7.4 +/- 3.0 months). Before PTCA, there were no clinical or angiographic differences among the three groups of genotypes (DD, n = 39; ID, n = 62; II, n = 17). After PTCA, the mean differences in minimal luminal diameter between post-PTCA and pre-PTCA angiograms (acute gain) were identical in the three groups, as was the mean percent residual stenosis. At follow-up angiography, the mean difference in minimal coronary luminal diameter between post-PTCA and follow-up angiograms (late loss) was not significantly different in the three groups of genotypes. The percentage of patients with restenosis defined as a > 50% stenosis was identical in the three groups. CONCLUSIONS: In this quantitative study, the I/D polymorphism of the ACE gene had no influence on the occurrence of restenosis after coronary angioplasty.
Adult↗
Restenosis after delayed coronary angioplasty of the culprit vessel in patients with a recent myocardial infarction treated by thrombolysis.
BACKGROUND: Clinical follow-up after percutaneous transluminal coronary angioplasty (PTCA) of an infarct-related lesion has demonstrated a low incidence of recurrent symptoms and repeated revascularization. In the absence of systematic angiographic follow-up, this low rate of clinical restenosis may reflect either a truly lower incidence of anatomic restenosis or the lack of recurrent symptoms in patients with extensive infarction in the territory of the restenotic vessel. METHODS AND RESULTS: We studied 300 consecutive patients who, after a thrombolysis for myocardial infarction, underwent delayed (10.5 +/- 6 days after the myocardial infarction) PTCA of the infarct-related lesion. Procedural success was obtained in 253 patients (84%), and angiographic follow-up was performed in 205 of this group (81%) at a mean of 7.3 +/- 1.9 months. Restenosis (defined as the recurrence of > 50% stenosis) was present in 105 patients (51%). Only 34 of the 105 patients (32%) with angiographic restenosis were symptomatic; the other 68% had clinically silent restenosis. Of these 105 patients, 27 (13% of the total population undergoing follow-up angiography) had reocclusion at the dilated site at follow-up. The severity of the stenosis at follow-up and the late loss in minimal lumen diameter followed a nearly Gaussian distribution if the lesions that were totally occluded at follow-up were excluded. By multivariate analysis, two independent predictors of reocclusion were identified: a small reference diameter (P < .0005) and the presence of collateral vessels before the procedure (P < .01). Only one factor was associated with restenosis in the 178 patients who did not have reocclusion at follow-up; a Thrombolysis in Myocardial Infarction grade < or = 2 before the procedure (P < .0001). At follow-up, there was a significantly (P < .01) higher ejection fraction in patients without restenosis (56.1 +/- 13.4%) and in patients with restenosis without total occlusion (56.0 +/- 13.8%) than in patients with reocclusion (46.4 +/- 13.0%). CONCLUSIONS: Despite a satisfactory clinical outcome, delayed PTCA of an infarct-related lesion is associated with a high rate of angiographic recurrence. Two distinct mechanisms account for recurrent stenosis: progressive luminal renarrowing as documented after angioplasty of stable lesions and reocclusion of the infarct-related lesion. Only reocclusion is associated with a deterioration in left ventricular function at follow-up.
Angioplasty, Balloon, Coronary↗
Local lesion-related factors and restenosis after coronary angioplasty. Evidence from a quantitative angiographic study in patients with unstable angina undergoing double-vessel angioplasty.
BACKGROUND: Restenosis rates are high when coronary angioplasty is performed in patients with unstable angina. The relative contributions of local and systemic factors to this excess risk of restenosis are unclear. To assess these, we compared changes in minimal lumen diameter and the incidence of restenosis, determined by quantitative coronary angiography, after coronary angioplasty at culprit and nonculprit lesions dilated in the course of a single procedure in patients with unstable angina. METHODS AND RESULTS: We identified 67 consecutive patients with unstable angina in whom two lesions, in different vessels, were dilated during the same procedure. Lesions were designated as culprit or nonculprit on the basis of the location of ECG changes during chest pain combined with assessment of the angiographic characteristics of the lesions. With these criteria, 43 patients had identifiable culprit lesions. Stenosis severity before and immediately after angioplasty and at follow-up was assessed with quantitative angiography. Angiographic follow-up was performed in 91% (39 patients) of this subgroup. Culprit lesions were more severe (P < .02) than nonculprit lesions. The late loss at culprit lesions (0.87 +/- 0.75 mm) was significantly (P < .01) greater than the equivalent value for nonculprit lesions (0.33 +/- 0.69 mm). With a categorical definition (> 50% stenosis at follow-up), restenosis occurred at 67% of culprit lesions and at 32% of nonculprit lesions (P < .01). CONCLUSIONS: The greater loss in minimal lumen diameter and the consequent higher rate of restenosis at culprit compared with nonculprit lesions suggest that local "lesion-related" factors are an important determinant of the high rate of restenosis when coronary angioplasty is performed in patients with unstable angina.
Angina, Unstable↗
Restenosis after coronary angioplasty.
The major disadvantage of using percutaneous transluminal coronary angioplasty to treat patients with atherosclerotic coronary disease is the frequent occurrence of restenosis after an initially successful procedure. Studies in animals and histological observations in man have demonstrated that restenosis is characterized by neointimal hyperplasia due to smooth muscle cell proliferation and to the synthesis of extracellular matrix. Improvements in technology or pharmacological interventions have had no significant impact on the rate of restenosis. In spite of our increased understanding of the molecular mechanisms of restenosis. no effective treatment is available at the present time. Gene therapy, which has produced encouraging initial results in experimental models, may provide a solution in the medium term.
Angioplasty, Balloon, Coronary↗
Two-pronged antiplatelet therapy with aspirin and ticlopidine without systemic anticoagulation: an alternative therapeutic strategy after bailout stent implantation.
BACKGROUND: Intracoronary stent implantation for failed angioplasty is associated with a relatively high incidence of coronary and peripheral complications. On the basis of previous clinical and experimental data, we investigated a protocol of intensive antiplatelet therapy, with aspirin (200 mg) and ticlopidine (500 mg), without oral anticoagulation, and with only periprocedural heparin, after stent implantation. METHODS: Between November 1993 and May 1994, 650 patients underwent balloon angioplasty in our institution. Stent implantation was attempted in 45 patients because of acute (58%) or threatened acute (22%) closure, or because the result of the primary angioplasty was inadequate (9%). RESULTS: Stents were successfully implanted in 42 (93%) patients. Two patients were not enrolled in the protocol (referring physician preference in one, metallic heart valve prosthesis in the other). In the remaining 40 patients, two sustained Q-wave infarctions and three sustained non Q-wave infarctions, which were already established at the time of stent implantation. No further clinical events occurred during hospitalization. During follow-up (mean 3.2 months) none of the patients died and none developed unstable angina or myocardial infarction. Ticlopidine-related rash occurred in two patients who were consequently put on warfarin therapy instead. CONCLUSIONS: Antiplatelet therapy with ticlopidine and aspirin, without systemic anticoagulation, appears to be a promising alternative to the classical approach with heparin and warfarin therapy, which requires intensive biological monitoring. This approach considerably simplifies patient management, and it could reduce the need for prolonged hospitalization.
Aged↗
[Reflections of an expert committee of the French Society of Cardiology on the use of methylergometrine maleate (Methergin) for the detection of abnormal coronary vasomotricity].
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Contraindications↗
Angiotensin converting enzyme inhibition prevents proto-oncogene expression in the vascular wall after injury.
OBJECTIVES: Angiotensin converting enzyme (ACE) inhibitors reduce neointimal hyperplasia after balloon denudation, but the mechanisms are not completely understood. It has been demonstrated that nuclear oncogenes are induced in the vascular wall in the hours immediately after injury, and that the same genes are induced by angiotensin II in vascular smooth muscle cells. It has therefore been suggested that the effects of ACE inhibitors on the response of the vessel wall could be mediated by an inhibition of proto-oncogene expression. METHODS AND RESULTS: Sixteen New Zealand White rabbits were randomly assigned for histologic analysis to receive placebo (n = 9) or 1 mg/kg per day perindopril (n = 7). After treatment for 7 days balloon aortic injury was performed. The treatment was continued and the rabbits were killed 28 days after injury. In the perindopril group the neointimal cross-sectional area was significantly smaller than in the control group. Six untreated rabbits were used to assess the time course of proto-oncogene expression in the aortic wall after injury in the present model. After extraction, total aortic RNA was hybridized with myc, fos and jun probes. Based on the results, the effects of ACE inhibition on proto-oncogene expression were tested 1 h after balloon denudation. Accordingly, 24 rabbits were randomly assigned to pretreatment for 7 days with placebo or with 1 or 10 mg/kg per day perindopril (n = 8, for each group) and were killed 1 h after injury. Expression of c-myc was not altered by pretreatment. However, 1 mg/kg per day perindopril induced significant reductions of 50% in c-jun and 45% in c-fos expression compared with control. No additional effect was obtained with the higher dose. CONCLUSION: The effect of ACE inhibition on intimal hyperplasia is associated with a reduction in early cellular events such as c-fos and c-jun expression. These results suggest that potent ACE inhibition at the time of vascular injury may be required to limit the hyperplastic response of the vessel wall.
Animals↗
Neointimal thickening after balloon denudation is enhanced by aldosterone and inhibited by spironolactone, and aldosterone antagonist.
OBJECTIVE: The aim was to examine the effects of aldosterone and of an aldosterone antagonist, spironolactone, on neointimal thickening in a rabbit model of balloon injury. METHODS: Eighteen rabbits underwent aortic and iliac balloon injury and were randomised to subcutaneous infusion of aldosterone (70 micrograms.kg-1.d-1) or vehicle solution for 28 d. Eighteen other rabbits were randomised to receive daily subcutaneous injections of spironolactone (50 mg.kg-1.d-1) or of vehicle for 7 d before injury and for 28 d after the procedure. All animals were then killed just after measurement of plasma renin activity and of arterial pressure. Vessels were fixed and five cross sections were analysed per rabbit (three aortic; two from iliac artery). Mean values of neointimal area and of the neointimal area/medial area ratio were calculated. RESULTS: Aldosterone treatment was associated with a decrease in renin activity and a non-significant increase in mean arterial pressure. Aldosterone significantly augmented the neointimal thickening in the iliac artery [0.42(SEM 0.07) v 0.24(0.03) mm2, P < 0.05] but not in the aorta [0.63(0.08) v 0.59(0.12) mm2, NS]. Spironolactone significantly inhibited intimal thickening, both in the iliac artery [0.09(0.02) v 0.29(0.01) mm2, P < 0.001] and in the aorta [0.31(0.03) v 0.59(0.06) mm2, P < 0.001]. Spironolactone administration was associated with an increase in renin activity and a decrease in mean arterial blood pressure. CONCLUSIONS: Aldosterone administration enhances neointimal thickening after injury and spironolactone, an aldosterone antagonist, is a potent inhibitor of neointimal thickening in the same model. This suggests a role for aldosterone in the pathophysiology of neointimal proliferation after balloon injury and for aldosterone antagonists in its prevention.
Aldosterone↗
[Comparative study of verapamil LI 120 mg 3 times a day and verapamil LP 120 mg twice a day in stable exertion-induced angina. A multicenter study].
A multicentre, open, crossover study in 27 patients with exertional angina compared the efficacy of verapamil LP 120 mg twice a day (VP LP 120) with that of verapamil LI 120 mg 3 times a day (VP LI 120) by means of stress tests. The study procedure was as follows: 7-day selection period during which the patient received placebo, and two 21-day treatment periods by VP LI 120 or VP LP 120 according to the crossover principle. At the end of each treatment phase, a stress test was performed at the trough serum concentration for each substance. VP LP 120 mg and VP LI 120 mg both improved exercise capacity compared to placebo. Comparison of VP LP 120 and VP LI 120 did not reveal any significant difference for stress test parameters (total duration of effort: 12 +/- 3.2 min with placebo, 13.3 +/- 3.7 min for the VP LI phase, 13.9 +/- 3.2 min for the VP LP phase; % FMT reached: 87.2% +/- 7.2 for VP LI, 89% +/- 7.3 for VP LP; time to onset of significant ST depression: 10 min +/- 2.9 for VP LI, 11 min 3.6 for VP LP). The efficacy of VP LP 120 in exertional angina is therefore identical to that of VP LI 120, despite a reduction of the total dose and serum levels.
Administration, Oral↗
Effect of balloon inflation in angiographically normal coronary segments during coronary angioscopy: a quantitative angiographic study.
Visualization of coronary stenoses by coronary angioscopy is facilitated by inflating an occlusive cuff located near the distal end of the device to temporarily interrupt blood flow. In animal models, this procedure induces substantial endothelial denudation. Experimental studies show that endothelial denudation may lead to neointimal hyperplasia at the denuded site. This study was designed to determine whether angioscopy was associated with significant changes in lumen diameter at the site of cuff inflation. We studied 52 consecutive patients undergoing coronary angioscopy. We measured with use of quantitative edge-detection angiography [computer-assisted evaluation of stenosis and restenosis (CAESAR) system] the mean and minimal lumen diameters at the site of cuff inflation localized by filming the inflated cuff during angioscopy and at control non-instrumented segments on angiograms performed before angioscopy, after angioscopy, and at 6 months follow-up. Follow-up angiograms were performed in 80% of eligible patients. At follow-up, the mean (3.22 +/- 0.54 mm) and minimal (2.76 +/- 0.58 mm) diameters of the segment exposed to the inflated cuff were not significantly different from the equivalent values (3.22 +/- 0.58 and 2.75 +/- 0.61 mm) before angioscopy. No significant changes occurred in the mean or minimal diameters of the control segments over the same period. The late change (follow-up minus pre-angioscopy) in mean lumen diameter at the cuff inflation site (-0.005 +/- 0.18 mm) was not significantly different from that at the control site (0.004 +/- 0.20 mm).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Silent ischemia].
Silent myocardial ischaemia is a very common phenomenon in patients with coronary artery disease. It may occur in patients with clinical manifestations of angina, be detected during the post-myocardial infarction period or in patients totally asymptomatic. Whatsoever, it is well demonstrated that silent myocardial ischaemia has a very potent prognostic value. Therapeutic implications are similar to those in symptomatic ischaemia. Indications for myocardial revascularization by mean of angioplasty or bypass grafting may be discussed and depend on ventricular function and extension of coronary lesions.
Angina Pectoris↗
The 'Ermenonville' classification of observations at coronary angioscopy--evaluation of intra- and inter-observer agreement. European Working Group on Coronary Angioscopy.
A European coronary angioscopy working group has been established to create and evaluate a classification system for angioscopic observation. The 'Ermenonville' classification features items, graded in 3-5 categories, such as lumen diameter, shape of narrowing, colours of surface, atheroma, dissection, thrombus, etc. Inter- and intra-observer agreement on the interpretation of angioscopic images, using this classification system, was studied within the working group. Kappa values for chance-corrected intra-observer agreement of the diagnostic items were 0.51-0.67. The mean kappa values for inter-observer agreement were very low at 0.13-0.29. The important items, such as red thrombus and dissection were studied after recoding as either present or absent. These items proved to have a good intra-observer agreement, and an acceptable inter-observer agreement after recoding. Other angioscopic diagnoses should be made with caution. Multicentre angioscopy studies should make use of an angioscopy core laboratory. A set of definitions for coronary angioscopy is proposed, and this working group will re-evaluate observer agreements using these definitions.
Angioscopy↗
Angiopeptin inhibits oncogene induction in rabbit aorta after balloon denudation.
BACKGROUND: Angiopeptin, a synthetic cyclic octapeptide analogue of somatostatin, reduces neointimal hyperplasia after balloon denudation of rabbit aorta if administered before injury. The aim of this study was to analyze the effect of angiopeptin pretreatment on the level of expression of the c-fos and c-jun protooncogenes, early markers of smooth muscle cell proliferation, after balloon denudation of rabbit aorta. METHODS AND RESULTS: For histological analysis of the effect of angiopeptin on neointimal thickening after aortic balloon denudation, rabbits were randomized into three groups: group 1 (controls), twice-daily injections of saline begun 24 hours before balloon denudation (n = 9); group 2, twice-daily injections of angiopeptin 10 micrograms/kg begun 24 hours before balloon denudation (n = 9); and group 3, twice-daily injections of angiopeptin 10 micrograms/kg begun 1 hour after balloon denudation (n = 7). The degree of neointimal thickening 28 days after balloon denudation was significantly less in group 2 than in group 1 (neointimal area: group 1, 0.59 +/- 0.11 mm2; group 2, 0.22 +/- 0.05 mm2; P < .05. Neointima/media: group 1, 0.85 +/- 0.17; group 2, 0.23 +/- 0.05; P < .05). When angiopeptin was started 1 hour after denudation (group 3), however, the neointimal area (0.52 +/- 0.09 mm2) and the neointima/media ratio (0.76 +/- 0.10) were not statistically different from the control group. For analysis of protooncogene induction, rabbits received twice-daily subcutaneous injections of saline (n = 7), angiopeptin 10 micrograms/kg (n = 8), or angiopeptin 100 micrograms/kg (n = 4) begun 24 hours before balloon denudation. The animals were killed 30 minutes after balloon denudation, and total aortic RNA was hybridized with fos and jun probes. Expression of c-fos and c-jun was detected 30 minutes after injury; angiopeptin pretreatment at 20 micrograms.kg-1.d-1 induced a 41% reduction in c-fos expression and a 42% reduction in c-jun expression compared with control animals. The inhibitory effect at the higher dose of angiopeptin was similar. CONCLUSIONS: Our results show that the inhibitory effect of angiopeptin on neointimal thickening is related to events that occur very early after injury and suggest that the inhibition of smooth muscle cell activation may be responsible, at least in part, for this effect.
Animals↗
Exercise-induced ST-segment depression in patients without restenosis after coronary angioplasty. Relation to preprocedural impaired left ventricular function.
BACKGROUND: ST-segment depression during exercise testing is frequently observed in the absence of restenosis after coronary angioplasty. METHODS AND RESULTS: We studied the determinants of this phenomenon in 70 consecutive patients with unstable angina related to a single left anterior descending coronary artery lesion who had successful angioplasty without restenosis (< 50% stenosis by quantitative angiography). We compared preangioplasty clinical, angiographic, and hemodynamic variables in the group with positive (ExT Pos, n = 35; ST depression, 2.3 +/- 0.9 mm) and negative (ExT Neg, n = 35; ST depression, 0.3 +/- 0.5 mm) results on exercise testing at follow-up angiography. At this time, minimal lumen diameter (1.7 +/- 0.4 mm) and mean residual stenosis (34 +/- 11%) in the ExT Pos group were not significantly different from the values (1.9 +/- 0.5 mm, 38 +/- 10%) in the ExT Neg group. Before angioplasty, the ExT Pos group had a lower ejection fraction (63 +/- 8% versus 68 +/- 9%, P < .05), more marked anterior hypokinesis estimated by the extent of anterior wall contraction on quantitative ventriculography (P < .05), and a greater end-systolic volume (30 +/- 11 versus 25 +/- 9 mL/m2, P < .05) than the ExT Neg group. At follow-up angiography, regional anterior wall motion was normal in 68 patients (97%). Anterior hypokinesis before angioplasty was strongly associated (P < .01) with a positive exercise test at control (71% compared with 31% in patients with normal wall motion before angioplasty). CONCLUSIONS: In the absence of significant epicardial stenosis after angioplasty, ST-segment depression is strongly associated with the presence of preprocedural regional ventricular dysfunction that has recovered at follow-up angiography.
Aged↗
Long-term oral administration of L-arginine reduces intimal thickening and enhances neoendothelium-dependent acetylcholine-induced relaxation after arterial injury.
BACKGROUND: Nitric 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 RESULTS: We 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. Neoendothelium-dependent 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-arginine-supplemented animals versus -52.9 +/- 6.8% in controls). CONCLUSIONS: Our results demonstrate that L-arginine, a precursor of NO, reduces neointimal thickening after balloon denudation and improves neoendothelial-dependent acetylcholine-induced relaxation.
Acetylcholine↗