Minimal Lumen Diameter Loss Research Articles

Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis

BackgroundPlasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis.MethodsWe genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR).ResultsPlasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q ≤0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in CETP, APOA5, and APOC2 as well as with BMI, sex and age (all q values ≤0.03). The APOA5 variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD.ConclusionPutatively functional variants of APOA2, APOA5, APOC2, CETP, LPL, LIPC and SOAT2 are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in APOA5 is also an independent determinant of plasma apo A-I level, severity of coronary atherosclerosis and its progression.

Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the coronary AngioPlasty Amlodipine REStenosis Study (CAPARES)

OBJECTIVESOur intent was to investigate the effect of the dihydropyridine calcium channel blocker amlodipine on restenosis and clinical outcome in patients undergoing percutaneous transluminal coronary angioplasty (PTCA).BACKGROUNDAmlodipine has sustained vasodilatory effects and relieves coronary spasm, which may reduce luminal loss and clinical complications after PTCA.METHODSIn a prospective, double-blind design, 635 patients were randomized to 10 mg of amlodipine or placebo. Pretreatment with the study drug started two weeks before PTCA and continued until four months after PTCA. The primary angiographic end point was loss in minimal lumen diameter (MLD) from post-PTCA to follow-up, as assessed by quantitative coronary angiography (QCA). Clinical end points were death, myocardial infarction, coronary artery bypass graft surgery and repeat PTCA (major adverse clinical events).RESULTSAngioplasty was performed in 585 patients (92.1%); 91 patients (15.6%) had coronary stents implanted. Follow-up angiography suitable for QCA analysis was done in 236 patients in the amlodipine group and 215 patients in the placebo group (per-protocol group). The mean loss in MLD was 0.30 ± 0.45 mm in the amlodipine group versus 0.29 ± 0.49 mm in the placebo group (p = 0.84). The need for repeat PTCA was significantly lower in the amlodipine versus the placebo group (10 [3.1%] vs. 23 patients [7.3%], p = 0.02, relative risk ratio [RR]: 0.45, 95% confidence interval [CI]: 0.22 to 0.91), and the composite incidence of clinical events (30 [9.4%] vs. 46 patients (14.5%), p = 0.049, RR: 0.65, CI: 0.43 to 0.99) within the four months follow-up period (intention-to-treat analysis).CONCLUSIONSAmlodipine therapy starting two weeks before PTCA did not reduce luminal loss, but the incidence of repeat PTCA and the composite major adverse clinical events were significantly reduced during the four-month follow-up period after PTCA with amlodipine as compared with placebo.

Early plus delayed hirudin reduces restenosis in the atherosclerotic rabbit more than early administration alone: potential implications for dosing of antithrombin agents.

A 2-hour infusion of r-hirudin at the time of balloon angioplasty limits restenosis in atherosclerotic rabbits. Because thrombin activity in the vessel wall after angioplasty remains high for 48 to 72 hours, we hypothesized that a second infusion of hirudin at 24 hours would reduce restenosis more than early treatment alone. Femoral atherosclerosis was induced in 35 rabbits by air desiccation injury and a high-cholesterol diet. At the time of angioplasty, rabbits were randomly assigned to 1 of 4 groups: controls: heparin bolus, saline infusion at 24 hours; early hirudin: hirudin bolus+2 hours' infusion, saline infusion at 24 hours; delayed hirudin: heparin bolus, hirudin infusion+/-bolus at 24 hours; and early+delayed hirudin: hirudin bolus+2 hours' infusion, hirudin infusion+/-bolus at 24 hours. Rabbits were euthanized after 28 days. The early+delayed hirudin treatment group had less loss of minimal lumen diameter by angiography at 28 days. By histomorphometry, cross-sectional area narrowing by plaque was least in the early+delayed treatment group compared with controls (P=0.0001), early hirudin (P=0.01), or delayed hirudin (P=0.001). The early+delayed hirudin group also had a significant reduction in absolute plaque area and an improvement in lumen area compared with the other groups. No differences were observed between treatment groups with respect to the cross-sectional area encompassed by the internal or external elastic laminae. Combined early+delayed administration of hirudin significantly reduces angiographic restenosis and cross-sectional area narrowing by plaque compared with early or late treatment alone. These results suggest that restenosis after balloon angioplasty is markedly influenced by thrombin-mediated events not only occurring early but also extending beyond the first 24 hours in this model.

Relation between estrogen replacement therapy and restenosis after percutaneous coronary interventions

We attempted to determine the relation between estrogen replacement therapy and the rate of restenosis after coronary angioplasty and atherectomy. Although estrogen replacement therapy in women has been associated with a reduction in cardiovascular events and improvement in endothelial function, no study has examined whether estrogen reduces restenosis rates after percutaneous coronary interventions. A total of 204 women enrolled in the Coronary Angioplasty Versus Excisional Atherectomy Trial with angiographic follow-up were contacted, and their menopausal and estrogen replacement status was determined. Late loss in minimal lumen diameter, late loss index, minimal lumen diameter, rate of restenosis > 50% and actual percent of stenosis were compared in estrogen users and nonusers by quantitative coronary angiography at 6-month follow-up. Late loss in minimal lumen diameter was significantly less in women using estrogen than in nonusers (-0.13 vs. -0.46 mm, p = 0.01). A regression analysis of the determinants of late loss in minimal lumen diameter revealed that estrogen use was the single most important predictor of subsequent late loss (F = 13.38, p = 0.0006). Formal testing revealed a highly significant interaction between the use of estrogen and intervention (angioplasty or atherectomy). Women undergoing atherectomy who received estrogen had a significantly lower late loss index (0.06 vs. -0.63, p = 0.002), less late loss (0.06 vs. -0.61 mm, p = 0.0006), larger minimal lumen diameter (p = 0.044) and lower restenosis rates (p = 0.038 for > 50% stenosis) than those not using estrogen. In contrast, estrogen had minimal effects on restenosis end points after angioplasty. This study demonstrates the potential for estrogen replacement therapy to reduce angiographic measures of restenosis in postmenopausal women after coronary intervention, particularly in those undergoing atherectomy.

Low molecular weight heparin (reviparin) in percutaneous transluminal coronary angioplasty results of a randomized, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial)

Objectives. The specific objective of the REDUCE trial was to evaluate the effect of low molecular weight heparin on the incidence and occurrence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA).Background. Unfractionated heparin and its low molecular weight fragments possess antiproliferative effects and have been shown to reduce neointimal smooth muscle cell migration and proliferation in response to vascular injury in experimental studies.Methods. The REDUCE trial is an international prospective, randomized, double-blind, multicenter study. Twenty-six centers in Europe and Canada enrolled 625 patients with single-lesion coronary artery obstructions suitable for PTCA. Three hundred six patients received reviparin as a 7,000-U bolus before PTCA, followed by 10,500 U as an infusion over 24 h and then twice-daily 3,500-U subcutaneous application for 28 days. The 306 patients in the control group received a bolus of 10,000 U of unfractionated heparin followed by an infusion of 24,000 U over 24 h. These patients then underwent 28 days of subcutaneous placebo injections. The primary end points were efficacy (defined as a reduction in the incidence of major adverse events [i.e., death, myocardial infaction, need for reintervention or bypass surgery]), absolute loss of minimal lumen diameter and incidence of restenosis during the observation period of 30 weeks after PTCA.Results. Using the intention to treat analysis for all patients, 102 (33.3%) in the reviparin group and 98 (32%) in the control group have reached a primary clinical end point (relative risk [RR] 1.04, 95% confidence interval [CI] 0.83 to 1.31, p = 0.707). Likewise, no difference in late loss of minimal lumen diameter was evident for both groups. Acute events within 24 h occurred in 12 patients (3.9%) in the reviparin group and 25 (8.2%) in the control group (RR 0.49, 95% Cl 0.26 to 0.92, p = 0.027) during or immediately after the initial procedure. In the control group, eight major bleeding complications occurred, and in the reviparin group, seven were observed within 35 days after PTCA.Conclusions. Reviparin use during and after coronary angioplasty did not reduce the occurrence of major clinical events or the incidence of angiographic restenosis over 30 weeks.

Restenosis After Delayed Coronary Angioplasty of the Culprit Vessel in Patients With a Recent Myocardial Infarction Treated by Thrombolysis

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. 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%). 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.

Effect of high dose angiotensin-converting enzyme inhibition on restenosis: Final results of the MARCATOR study, a multicenter, double-blind, placebo-controlled trial of cilazapril

Objectives. We conducted a randomized, double-blind, placebo-controlled trial to assess the effect of low and high dose angiotensin-converting enzyme inhibition with cilazapril on angiographic restenosis prevention after percutaneous transluminal coronary angioplasty.Background. Angiotensin-converting enzyme inhibitors possess antiproliferative effects in animal models of vascular injury. However, a recent clinical trial using low dose cilazapril, a long-acting angiotensin-converting enzyme inhibitor, failed to prevent restenosis.Methods. Patients received either cilazapril (1 or 2.5 mg in the evening after successful coronary angioplasty, then 1, 5 or 10 mg twice daily for 6 months) or matched placebo. All patients received aspirin for 6 months. Coronary angiograms before and after angioplasty and at 6-month follow-up were quantitatively analyzed. In addition, the clinical, procedural and angiographic factors associated with restenosis were determined with the use of stepwise logistic analysis.Results. A total of 1,436 patients with a successful coronary angioplasty were recruited. As assessed by an intention-to-treat analysis, the mean difference in minimal coronary lumen diameter (mean ± 1 SD) between the postangioplasty and follow-up angiogram at 6 months (primary end point) was −0.35 ± 0.51 for the placebo group and −0.37 ± 0.52, −0.45 ± 0.52 and −0.412 ± 0.53, respectively, for the 1-, 5- and 10-mg twice daily cilazapril groups (p = NS). Clinical events during follow-up did not differ among the four study groups. Multivariate analysis revealed only six variables as independent predictors of the loss of minimal lumen diameter: duration of angina <6 months, history of myocardial infarction, minimal lumen diameter before and after angioplasty as well as a proximal lesion location and reference diameters. Traditional risk factors for atherosclerosis did not relate to restenosis.Conclusions. Long-term angiotensin-converting enzyme inhibition with cilazapril in high as well as low dosages does not prevent restenosis and does not favorably influence the overall clinical and angiographic outcome after coronary angioplasty. Few factors are predictive of restenosis.

Mechanisms of restenosis and redilation within coronary stents—Quantitative angiographic assessment

Objectives. This study was designed to assess the relative contributions of intimal hyperplasia and stent compression to the lumen narrowing seen after intracoronary stenting and to determine whether the lumes enlargement produced by angioplasty of in-stent restenosis results primarily from compression or extrusion of intimal hyperplasia through the stent or from additional stent expansion.Background. Palmaz-Schatz stent placement outwardly displaces plaque and eliminates elastic vessel recoil to provide a large and smooth lumen. Some degree of late lumen narrowing occurs within each stent and causes significant restenosis (≥50% stenosis) in 25% to 30% of treated lesions. It has not been clear, however, whether this narrowing results from stent compression (crush) or from in-stent intimal hyperplasia. Because the Palmaz-Schatz stent has a distinct radiographic shadow, it is possible to determine the late diameter of both the stent and the enclosed vessel lumen to assess the relative contributions of these two processes.Methods. From cineangiograms, initial (after stenting) and late (follow-up) lumen and stent diameters were examined in 55 patients (59 stents, group I) who had both immediate and 6-month (192 ± 117 days) angiography. Lumen and stent diameter were also examined before and after dilation in 30 patients (30 stents, group II) who underwent angioplasty of severe in-stent restenosis.Results. Late loss in minimal lumen diameter was 0.99 ± 0.87 mm for group I despite only a slight (0.03 ± 0.23-mm) reduction in the corresponding stent diameter. After redilation for in-stent restenosis, the acute gain in minimal lumen diameter was 1.51 ± 0.82 mm for group II, again without appreciable increase (0.06 ± 0.20 mm) in stent diameter.Conclusions. Restenosis after intracoronary Palmaz-Schatz stenting appears to be due predominantly to lumen encroachment by intimal hyperplasia within the stent, with minimal contribution of stent compression. Lumen enlargement after coronary angioplasty of in-stent restenosis appears to be due primarily to compression or extrusion of intimal hyperplasia the ough the stent, or both, rather than to further stent expansion.