Genetic variants in haem oxygenase-1 and endothelial nitric oxide synthase influence the extent and evolution of coronary artery atherosclerosis.

The genetic basis for atherosclerosis development and progression is poorly characterized. We aimed to assess the relationship between endothelial nitric oxide synthase (ENOS) 894 G/T, haem oxygenase-1 (HO1) dinucleotide-length promoter polymorphisms and coronary artery atherosclerotic invol vement and its changes during statin therapy. Coronary angiography, intravascular ultrasound (IVUS), IVUS-derived virtual histology (VH) and genetic polymorphism analysis were performed at study entry. Patients were randomized 1:1 to standard or aggressive hypolipidaemic treatment, and a follow-up evaluation was performed after twelve months. Plaque magnitude was significantly higher in carriers of HO1 risk variants when compared with carriers of the protective variants (< 25 GT repeats). Similarly, the total coronary atherosclerotic burden was significantly greater in HO1 risk variant carriers than in HO1 protective variant carriers. Both parameters did not differ with respect to the ENOS genotype. A higher prevalence of thin-cap fibroatheroma (TCFA) in HO1 risk variant carriers was observed, compared with the HO1 protective variant carriers. The prevalence of TCFA was not influenced by the ENOS genotype. Baseline plaque composition did not differ significantly with respect to both polymorphisms. Significant interactions between plaque composition changes and ENOS and HO1 genotypes were observed during statin treatment. In conclusion, the protective HO1 promoter polymorphism correlates with a lower coronary artery plaque burden, whereas the protective ENOS 894 G/T polymorphism seems to favourably influence changes of coronary artery plaque composition during statin therapy, but has no significant correlation to the magnitude of coronary atherosclerosis.

Specific glycoprotein changes during development of the chick neural retina.

After separation of whole proteins of chick neural retina by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS), a number of glycoproteins can be detected by staining the gels with 125I-labeled wheat germ agglutinin (WGA) and other lectins. The glycoprotein patterns show both quantitative and qualitative changes between days 7 and 13 of development. Some of these glycoproteins can be separated by chromatography on columns of insolubilized lectins. These observations suggest that purification of some of these glycoproteins identified by staining with radioactive lectins would yield retinal antigens which may be specific for developmental stage and cell type.

Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often comorbid. Drinking tends to increase following trauma, which may exacerbate PTSD-related symptoms. Despite a clear relationship between excessive alcohol use and PTSD, how alcohol impacts the expression of traumatic fear remains unclear. This study aims to determine the neurobehavioral impact of chronic alcohol (ethanol; EtOH) on the expression of established fear memories in C57BL/6 N mice. We show that chronic EtOH selectively augments cued fear memory generalization and impairs fear extinction retrieval, leaving the expression of the original cued response intact. Immunohistochemistry for Arc/arg3.1 (Arc) revealed EtOH-induced decreases in Arc expression in the infralimbic cortex (IL) and basolateral amygdala complex (BLA) that were associated with cued fear memory overgeneralization. Chemogenetic stimulation of IL pyramidal neurons reversed EtOH-driven fear memory overgeneralization, identifying a role for the IL in cued fear memory precision. Considering the modulatory influence of the IL over conditioned fear expression, these data suggest a model whereby chronic EtOH-driven neuroadaptations in the IL promote fear memory overgeneralization. These findings provide new mechanistic insight into how excessive alcohol use, following exposure to a traumatic event, can exacerbate symptoms of traumatic fear.

Study comparing the double kissing (DK) crush with classical crush for the treatment of coronary bifurcation lesions: the DKCRUSH-1 Bifurcation Study with drug-eluting stents.

BACKGROUND: Classical crush has a lower rate of final kissing balloon inflation (FKBI) immediately after percutaneous coronary intervention (PCI). The double kissing (DK) crush technique has the potential to increase the FKBI rate, and no prospective studies on the comparison of classical with DK crush techniques have been reported. MATERIALS AND METHODS: Three hundred and eleven patients with true bifurcation lesions were randomly divided into classical (n = 156) and DK crush (n = 155) groups. Clinical and angiographic details at follow-up at 8 months were indexed. The primary end point was major adverse cardiac events (MACE) including myocardial infarction, cardiac death and target lesion revascularization (TLR) at 8 months. RESULTS: FKBI was 76% in the classical crush group and 100% in the DK group (P < 0.001). The incidence of stent thrombosis was 3.2% in the classical crush group (5.1% in without- and 1.7% in with-FKBI) and 1.3% in the DK crush group. Cumulative 8 month MACE was 24.4% in the classical crush group and 11.4% in the DK crush group (P = 0.02). The TLR-free survival rate was 75.4% in the classical crush group and 89.5% in the DK crush group (P = 0.002). CONCLUSIONS: DK crush technique has the potential of increasing FKBI rate and reducing stent thrombosis, with a further reduction of TLR and cumulative MACE rate at 8 months.

Intravascular ultrasound assessment of coronary artery involvement in Fabry disease.

AIM: We used intravascular ultrasound (IVUS) to characterize coronary artery involvement in patients with Fabry disease (FD). METHODS: Nine FD patients (5 women) were matched to 10 control patients (5 women) chosen from our IVUS database. Standard volumetric IVUS analyses were performed along with assessment of plaque echodensity. RESULTS: Plaques in FD patients were diffuse and hypoechogenic compared with more focal and more echogenic lesions in control patients. Echogenicity of plaques was significantly lower in FD patients (median 30.7 +/- 12.9 vs 55.9 +/- 15.7, p = 0.0052, mean 37.2 +/- 15.6 vs 66.2 +/- 13.3, p = 0.0014). Diffusiveness was assessed as differences between mean and median plaque burden versus the plaque burden in each of the analysed cross-sections. These differences were lower in FD vs controls (5.8 +/- 4.8 vs 8.7 +/- 6.6, p < 0.001 for mean, and 5.8 +/- 4.9 vs 8.8 +/- 7.3, p < 0.001 for median) indicating a more diffuse involvement. The occurrence of lipid cores was significantly higher in FD patients than in controls (2.4 +/- 1.5 vs 1.0 +/- 0.94, p = 0.02). CONCLUSION: IVUS showed diffuse hypoechogenic plaques in patients with FD. The explanation may be higher lipid content in plaques and accumulation of glycosphingolipid in smooth-muscle and endothelial cells.

Mechanism of lumen enlargement during intracoronary stent implantation: an intravascular ultrasound study.

BACKGROUND: Intravascular ultrasound analysis has assessed mechanisms of lumen enlargement after nonstent interventions, but not after stenting. METHODS AND RESULTS: Preintervention and postintervention intravascular ultrasound was used to study 25 de novo native coronary lesions treated with single MultiLink stents without preatheroablation. External elastic membrane, lumen, and plaque and media (P&M) areas were measured every 1 mm to include the lesion and reference segments that were 5 mm proximal and distal to it. Lesion mean lumen area increased from 4.0+/-1.0 mm(2) before the intervention to 8.8+/-2.0 mm(2) after the intervention (P<0.0001) as a result of an increase in mean external elastic membrane area (14. 2+/-2.7 to 16.1+/-3.0 mm(2), P<0.0001) and a decrease in mean P&M area (10.2+/-2.2 to 7.2+/-1.8 mm(2), P<0.0001). The decrease in lesion P&M was accompanied by an increase in both proximal reference mean P&M (7.0+/-1.9 to 8.4+/-2.0 mm(2), P<0.0001) and distal reference mean P&M (5.8+/-2.1 to 7.2+/-2.1 mm(2), P<0.0001). Volumetric analysis showed an axial redistribution of plaque away from the center of the lesion toward the reference segments to increase the plaque burden in both the proximal and distal reference segments. Total (lesion plus reference) mean P&M decreased from 8. 6+/-2.1 to 7.5+/-1.8 mm(2) (P<0.0001). CONCLUSIONS: The mechanisms of lumen enlargement after stenting involved (1) significant axial redistribution of plaque from the lesion into the reference segments, (2) vessel expansion, and (3) either plaque embolization or compression.

Safety of intracoronary gamma-radiation on uninjured reference segments during the first 6 months after treatment of in-stent restenosis: a serial intravascular ultrasound study.

BACKGROUND: The effects of endovascular irradiation on uninjured reference segments during the treatment of in-stent restenosis are unknown. METHODS AND RESULTS: In the Washington Radiation for In-Stent restenosis Trial (WRIST), patients with in-stent restenosis were first treated with conventional catheter-based techniques and then randomized (blinded) to receive either gamma-irradiation ((192)Ir) or a placebo (dummy seeds). We identified all patients in whom the active (n=19) or dummy seeds (n=19) extended >10 mm proximal and distal to the in-stent restenosis lesion. Serial (postirradiation and follow-up) external elastic membrane (EEM), lumen, and plaque and media (EEM-lumen) areas were measured (using intravascular ultrasound) every 1 mm over 5-mm-long reference segments that were 6 to 10 mm proximal and distal to the in-stent restenosis lesion. During follow-up, a similar small increase occurred in the plaque and media area in the proximal and distal reference segments in both (192)Ir and placebo patients. However, in the (192)Ir patients, an increase in both proximal and distal EEM area occurred; as a result, no change in lumen area occurred. Conversely, in the placebo patients, the proximal reference EEM area decreased, and no change occurred in the distal reference EEM area; this contributed to a decrease in lumen area. CONCLUSIONS: There was no evidence of a deleterious effect of gamma-irradiation on angiographically normal uninjured reference segments in the first 6 months after the treatment of in-stent restenosis.

Atherosclerotic plaque burden and CK-MB enzyme elevation after coronary interventions : intravascular ultrasound study of 2256 patients.

BACKGROUND: Elevation of serum creatine kinase MB fraction (CK-MB) after percutaneous coronary interventions has been associated with early and late mortality; however, the pathogenesis of CK-MB elevation is still unknown. We hypothesized that CK-MB elevation was related to atherosclerotic plaque burden as assessed by preintervention intravascular ultrasound (IVUS). METHODS AND RESULTS: We studied 2256 consecutive patients who underwent intervention of 2780 native coronary lesions and had complete high-quality preintervention IVUS imaging in the era before routine use of platelet glycoprotein IIb/IIIa inhibitors. Patients were divided into 3 groups: CK-MB within normal range (1675 patients; 2061 lesions); CK-MB elevation 1 to 5 times upper limit of normal (292 patients; 355 lesions); and CK-MB elevation > or = 5 times upper limit of normal (289 patients; 364 lesions). Qualitative angiographic lesion morphology and quantitative analysis were similar among the 3 groups. On preintervention IVUS, progressively more reference segment and lesion site plaque burden and lesion site calcium occurred in the groups with CK-MB elevation. Positive remodeling was more common in lesions with CK-MB elevation. As levels of CK-MB increased, cross-sectional narrowing (percentage plaque burden) increased, both at the reference site (mean cross-sectional narrowing values were 45.1%, <49.3%, and <52.2% for normal CK-MB, 1 to 5 times upper limit of normal, and > or =5 times upper limit of normal groups, respectively; P=0.03) and at the lesion site (81.9%, <85.4%, and <87.1%, respectively; P=0.04). Multivariate analysis indicated that de novo lesions, atheroablative technique, plaque burden at the lesion and reference segments, and final minimal lumen diameter were independent predictors of CK-MB elevation. CONCLUSIONS: CK-MB elevation correlates with a greater atherosclerotic plaque burden. CK-MB elevation after intervention may be a marker of diffuse atherosclerotic disease or a consequence of catheter-based intervention in more diseased arteries or both.

Preintervention arterial remodeling as an independent predictor of target-lesion revascularization after nonstent coronary intervention: an analysis of 777 lesions with intravascular ultrasound imaging.

BACKGROUND: Pathological and intravascular ultrasound (IVUS) studies have documented arterial remodeling during atherogenesis. However, the impact of this remodeling process on the long-term outcome after percutaneous intervention is unknown. METHODS AND RESULTS: We used preintervention IVUS to define positive and negative/intermediate remodeling in a total of 777 lesions in 715 patients treated with nonstent techniques. Positive remodeling (lesion external elastic membrane area greater than average reference) was present in 313 lesions; intermediate/negative remodeling (lesion external elastic membrane area less than or equal to reference) was present in the other 464. Baseline clinical and angiographic characteristics were similar, except for a slightly higher percentage of insulin-dependent diabetic patients (10.2% versus 6.1%; P=0.054) in the negative/intermediate-remodeling group. Angiographic success and in-hospital and short-term complications were comparable in the 2 groups. There was no significant correlation between remodeling (as a continuous variable) and final lumen area (r=0.06) or final lesion plaque burden (r=0.17). At 18+/-13 months of clinical follow-up, both groups had similar rates of death and Q-wave myocardial infarction: 3.4% and 2.5% for the negative/intermediate-remodeling group versus 2.7% and 2.7% for the positive-remodeling group. However, the target-lesion revascularization (TLR) rate was 20.2% for the negative/intermediate-remodeling group versus 31.2% for the positive-remodeling group (P=0.007), and remodeling, as a continuous variable, was strongly correlated with probability of TLR (P=0.0001). By multivariable logistic regression analysis, diabetes (OR=2.3), left anterior descending artery location (OR=1.8), and remodeling (OR=5.9) were independent predictors of TLR. CONCLUSIONS: Positive lesion-site remodeling is associated with a higher long-term TLR after a nonstent interventional procedure. Thus, long-term clinical outcome appears to be determined in part by preintervention lesion characteristics.

Serial intravascular ultrasound assessment of the efficacy of intracoronary gamma-radiation therapy for preventing recurrence in very long, diffuse, in-stent restenosis lesions.

BACKGROUND: The efficacy of coronary gamma-irradiation in preventing recurrent in-stent restenosis (ISR) is well established. However, brachytherapy may be less effective in very long, diffuse ISR lesions. METHODS AND RESULTS: We used serial intravascular ultrasound (IVUS) to study patients with long, diffuse ISR lesions (length, 36 to 80 mm) who were enrolled in (1) Long WRIST (Washington Radiation In-Stent Restenosis Trial), a double-blind, placebo-controlled trial of intracoronary gamma-irradiation (15 Gy at 2 mm from the source) and (2) high-dose (HD) Long WRIST, a registry that used a dose prescription of 18 Gy at 2 mm from the source. IVUS was performed using automated pullback (0.5 mm/s). Stent, lumen, and intimal hyperplasia were measured at 2-mm intervals. Complete postintervention and follow-up IVUS imaging was available in 30 irradiated and 34 placebo patients from Long WRIST and in 25 patients from HD Long WRIST. Stent length was longer in HD Long WRIST than in placebo or treated patients in Long WRIST (P=0.0064 and P=0.0125, respectively). Otherwise, baseline measurements were similar. At follow-up, the minimum lumen area was largest in the HD Long WRIST patients (4.0+/-1.4 mm(2)); areas were 2.9+/-1.0 mm(2) in irradiated patients in Long WRIST and 1.9+/-1.1 mm(2) in placebo patients in Long WRIST (P<0.005 for all comparisons). CONCLUSIONS: - Serial IVUS analysis shows that gamma-irradiation reduces recurrent in-stent neointimal hyperplasia in long, diffuse ISR lesions; however, it is even more effective when given at a higher dose.

Treatment of in-stent restenosis with excimer laser coronary angioplasty versus rotational atherectomy: comparative mechanisms and results.

BACKGROUND: Atheroablation yields improved clinical results for balloon angioplasty (percutaneous transluminal coronary angioplasty, PTCA) in the treatment of diffuse in-stent restenosis (ISR). METHODS AND RESULTS: We compared the mechanisms and clinical results of excimer laser coronary angioplasty (ELCA) versus rotational atherectomy (RA), both followed by adjunct PTCA; 119 patients (158 ISR lesions) were treated with ELCA+PTCA and 130 patients (161 ISR lesions) were treated with RA+PTCA. Quantitative coronary angiographic and planar intravascular ultrasound (IVUS) measurements were performed routinely. In addition, volumetric IVUS analysis to compare the mechanisms of lumen enlargement was performed in 28 patients with 30 lesions (16 ELCA+PTCA, 14 RA+PTCA). There were no significant between-group differences in preintervention or final postintervention quantitative coronary angiographic or planar IVUS measurements of luminal dimensions. Angiographic success and major in-hospital complications with the 2 techniques were also similar. Volumetric IVUS analysis showed significantly greater reduction in intimal hyperplasia volume after RA than after ELCA (43+/-14 versus 19+/-10 mm(3), P<0.001) because of a significantly higher ablation efficiency (90+/-10% versus 76+/-12%, P = 0.004). However, both interventional strategies had similar long-term clinical outcome; 1-year target lesion revascularization rate was 26% with ELCA+PTCA versus 28% with RA+PTCA (P = NS). CONCLUSIONS: Despite certain differences in the mechanisms of lumen enlargement, both ELCA+PTCA and RA+PTCA can be used to treat diffuse ISR with similar clinical results.

Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis.

BACKGROUND: Intracoronary gamma-radiation therapy reduces recurrent in-stent restenosis (ISR). This study, BETA WRIST (Washington Radiation for In-Stent restenosis Trial) was designed to examine the efficacy and safety of the beta-emitter 90-yttrium for the prevention of recurrent ISR. METHODS AND RESULTS: A total of 50 consecutive patients with ISR in native coronaries underwent percutaneous transluminal coronary angioplasty, laser angioplasty, rotational atherectomy, and/or stent implantation. Afterward, a segmented balloon catheter was positioned and automatically loaded with a 90-yttrium, 0.014-inch source wire that was 29 mm in length to deliver a dose of 20.6 Gy at 1.0 mm from the balloon surface. In 17 patients, manual stepping of the radiation catheter was necessary for lesions >25 mm in length. The radiation was delivered successfully to all patients, with a mean dwell time of 3.0+/-0.4 minutes. Fractionation of the dose due to ischemia was required in 11 patients. At 6 months, the binary angiographic restenosis rate was 22%, the target lesion revascularization rate was 26%, and the target vessel revascularization rate was 34%; all rates were significantly lower than those of the placebo group of gamma-WRIST. CONCLUSIONS: beta-Radiation with a 90-yttrium source used as adjunct therapy for patients with ISR results in a lower-than-expected rate of angiographic and clinical restenosis.

Long-term follow-up after percutaneous transluminal coronary angioplasty was not performed based on intravascular ultrasound findings: importance of lumen dimensions.

BACKGROUND: Angiography is limited in determining the anatomic severity of coronary artery stenoses. Clinical decision-making in patients with symptoms and intermediate lesions remains challenging. METHODS AND RESULTS: The current analysis included 300 patients (357 intermediate native artery lesions) in whom intervention was deferred based on intravascular ultrasound (IVUS) findings. Standard clinical, angiographic, and IVUS parameters were collected. Patients were followed for >1 year. Events occurred in 24 patients (8%). They included 2 cardiac deaths, 4 myocardial infarctions, and 18 target-lesion revascularizations (TLR; 12 percutaneous transluminal coronary angiographies and 6 coronary artery bypass grafts; only 3 TLRs occurred within 6 months after the IVUS study). All significant univariate clinical, angiographic, and IVUS parameters (P<0.05) were tested in multivariate models. These included diabetes mellitus, IVUS lesion lumen area, maximum lumen diameter, minimum lumen diameter, plaque area, plaque burden, and area stenosis (AS). No angiographic measurement was significant at P<0.05. The only independent predictors of an event (death, myocardial infarction, or TLR) were IVUS minimum lumen area and AS. The only independent predictors of TLR were diabetes mellitus, IVUS minimum lumen area, and AS. In 248 lesions with a minimum lumen area >/=4.0 mm(2), the event rate was only 4.4% and the TLR rate 2.8%. CONCLUSIONS: Long-term follow-up after IVUS-guided deferred interventions in patients with de novo intermediate native artery lesions showed a low event rate. In patients with a minimum lumen area >/=4.0 mm(2), the event rate was especially low. IVUS imaging is an acceptable alternative to physiological assessment in these patients.

Creatine kinase-MB enzyme elevation following successful saphenous vein graft intervention is associated with late mortality.

BACKGROUND: Although the risk for development of creatine kinase (CK-MB) elevation after saphenous vein graft (SVG) intervention is high, its prognostic significance remains unknown. This study evaluated the impact of periprocedural CK-MB elevation on late clinical events following successful SVG angioplasty. METHODS AND RESULTS: We studied 1056 consecutive patients with successful (defined by angiographic success and absence of major complications) intervention of 1693 SVG lesions. These patients were grouped as normal CK-MB (n=556), minor CK-MB rise (CK-MB 1 to 5 times normal, n=339), and major CK-MB rise (CK-MB >5 times normal, n=161). There were no differences in major clinical events at 30-day follow-up among the 3 groups. However, 1-year mortality was 4.8%, 6.5%, and 11. 7%, respectively, P<0.05 (ANOVA). Even within a population without any intraprocedure or in-hospital complications (n=727, 69% of the overall cohort), 1-year mortality remained significantly higher with CK-MB elevation: 2.4%, 5.5%, and 10.7%, respectively, P<0.05 (ANOVA). Multivariate analysis revealed major CK-MB elevation as the strongest independent predictor of late mortality (odds ratio 3.3, with 95% CI 1.7 to 6.2), followed by diabetes mellitus (odds ratio 2. 6, with 95% CI 1.5 to 4.5). CONCLUSIONS: Major CK-MB elevation occurs after 15% of otherwise successful SVG interventions and is associated with increased late mortality.

Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome.

BACKGROUND: The angiographic presentation of in-stent restenosis (ISR) may convey prognostic information on subsequent target vessel revascularizations (TLR). METHODS AND RESULTS: We developed an angiographic classification of ISR according to the geographic distribution of intimal hyperplasia in reference to the implanted stent. Pattern I includes focal (< or =10 mm in length) lesions, pattern II is ISR>10 mm within the stent, pattern III includes ISR>10 mm extending outside the stent, and pattern IV is totally occluded ISR. We classified a total of 288 ISR lesions in 245 patients and verified the angiographic accuracy of the classification by intravascular ultrasound. Pattern I was found in 42% of patients, pattern II in 21%, pattern III in 30%, and pattern IV in 7%. Previously recurrent ISR was more frequent with increasing grades of classification (9%, 20%, 34%, and 50% for classes I to IV, respectively; P=0.0001), as was diabetes (28%, 32%, 39%, and 48% in classes I to IV, respectively; P<0.01). Angioplasty and stenting were used predominantly in classes I and II, whereas classes III and IV were treated with atheroablation. Final diameter stenosis ranged between 21% and 28% (P=NS among ISR patterns). TLR increased with increasing ISR class; it was 19%, 35%, 50%, and 83% in classes I to IV, respectively (P<0.001). Multivariate analysis showed that diabetes (odds ratio, 2.8), previously recurrent ISR (odds ratio, 2. 7), and ISR class (odds ratio, 1.7) were independent predictors of TLR. CONCLUSIONS: The introduced angiographic classification is prognostically important, and it may be used for appropriate and early patient triage for clinical and investigational purposes.

Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS).

BACKGROUND: Intracoronary gamma-radiation reduces recurrent in-stent restenosis. Late thrombosis (>30 days after radiation therapy) is identified as a serious complication. The Washington Radiation for In-Stent Restenosis Trial (WRIST) PLUS, which involved 6 months of treatment with clopidogrel and aspirin, was designed to examine the efficacy and safety of prolonged antiplatelet therapy for the prevention of late thrombosis. METHODS AND RESULTS: A total of 120 consecutive patients with diffuse in-stent restenosis in native coronary arteries and vein grafts with lesions <80 mm underwent percutaneous coronary transluminal angioplasty, laser ablation, and/or rotational atherectomy. Additional stents were placed in 34 patients (28.3%). After the intervention, a closed-end lumen catheter was introduced into the artery, a ribbon with different trains of radioactive (192)Ir seeds was positioned to cover the treated site, and a dose of 14 Gy to 2 mm was prescribed. Patients were discharged with clopidogrel and aspirin for 6 months and followed angiographically and clinically. All patients but one tolerated the clopidogrel. The late occlusion and thrombosis rates were compared with the gamma-radiation-treated (n=125) and the placebo patients (n=126) from the WRIST and LONG WRIST studies (which involved only 1 month of antiplatelet therapy). At 6 months, the group receiving prolonged antiplatelet therapy had total occlusion and late thrombosis rates of 5.8% and 2.5%, respectively; these rates were lower than those in the active gamma-radiation group and similar to those in the placebo historical control group. CONCLUSIONS: Six months of clopidogrel and aspirin and a reduction in re-stenting for patients with in-stent restenosis treated with gamma-radiation is well tolerated and associated with a reduction in the late thrombosis rate compared with a similar cohort treated with only 1 month of clopidogrel and aspirin.

Comparative efficacy of gamma-irradiation for treatment of in-stent restenosis in saphenous vein graft versus native coronary artery in-stent restenosis: An intravascular ultrasound study.

BACKGROUND: We used serial volumetric (post-irradiation and follow-up) intravascular ultrasound (IVUS) to compare the effectiveness of gamma-irradiation ((192)Ir) in saphenous vein graft (SVG) versus native coronary artery in-stent restenosis (ISR). METHODS AND RESULTS: The study population consisted of 47 patients with native coronary artery ISR from WRIST (Washington Radiation for In-Stent Restenosis Trial) and 31 patients with SVG ISR (12 from the WRIST and 19 from SVGWRIST). After irradiation and at 6-month follow-up, stent, lumen, and intimal hyperplasia (IH, stent minus lumen) areas were measured every 1 mm. ISR length was similar in the 2 groups (29+/-12 versus 29+/-14 mm, P=0.9). Post-intervention measurements of stent (280+/-154 versus 324+/-270 mm(3), P=0.4), lumen (184+/-91 versus 214+/-172 mm(3), P=0.3), and IH (96+/-77 versus 109+/-119 mm(3), P=0.5) volumes were similar in the 2 groups. The post-intervention minimum lumen cross sectional areas tended to be smaller in native artery ISR lesions (4.7+/-1.7 versus 5.4+/-1.6 mm(2), P=0.11). During follow-up, there was a slight increase in IH volume (9+/-38 mm(3)) in native artery ISR lesions and a slight decrease in IH volume in SVG ISR lesions (-9+/-32 mm(3), P=0.0463). There was also a slight decrease in minimum lumen area in the native artery ISR lesions versus a slight increase in minimum lumen area in the SVG ISR lesions (-0.8+/-1.7 versus 0.2+/-1.1, P=0.0087). As a result, the follow-up minimum lumen area in native artery lesions was smaller than in SVG ISR lesions (4.1+/-2.1 mm(2) versus 5.6+/-2.2 mm(2), P=0.0067). CONCLUSION: gamma-Irradiation with (192)Ir brachytherapy appears to be as effective in SVGs as it is in native artery ISR lesions.

Effect of intracoronary gamma-radiation therapy on in-stent restenosis: An intravascular ultrasound analysis from the gamma-1 study.

BACKGROUND: The aim of this study was to use serial volumetric intravascular ultrasound to evaluate the effect of gamma-radiation on recurrent in-stent restenosis. METHODS AND RESULTS: After successful reintervention, patients were randomized to receive either (192)Ir or placebo. Intravascular ultrasound studies with motorized pullback (0.5 mm/s) were performed immediately after irradiation and at 8-month follow-up in 70 patients. Paired volumetric analysis of the stented segment and of 5-mm proximal and distal reference segments was performed; this included measurements of the external elastic membrane, lumen, plaque and media (external elastic membrane minus lumen), stent, and intimal hyperplasia (stent minus lumen). Baseline proximal reference, stent, and distal reference measurements were similar in both groups. The changes in proximal and distal reference measurements of the external elastic membrane, plaque and media, and lumen areas were similar in both groups. However, the decrease in stented segment lumen volume was less in the (192)Ir patients than the placebo patients (-25+/-34 mm(3) versus -48+/-42 mm(3); P:=0.0225), and the increase in the volume of intimal hyperplasia in the stented segment was less in the (192)Ir patients than in the placebo patients (28+/-37 mm(3) versus 50+/-40 mm(3); P:=0.0352). When averaged over the length of the stented segment (32+/-13 mm versus 33+/-14 mm; P:=0.9), the increase in mean area of intimal hyperplasia was 0.8+/-1.0 mm(2) in the (192)Ir group and 1.6+/-1.2 mm(2) in the control group (P:=0.0065). Late stent-vessel wall malapposition was noted in one placebo patient and no (192)Ir patients. CONCLUSIONS: gamma-Radiation therapy can effectively prevent recurrent in-stent restenosis by inhibiting neointimal formation within the stent. At the stent edge, there were no significant differences between (192)Ir and placebo patients.

Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis.

BACKGROUND: Treatment of in-stent restenosis presents a critical limitation of intracoronary stent implantation. Ionizing radiation has been shown to decrease neointimal formation within stents in animal models and in initial clinical trials. We studied the effects of intracoronary gamma-radiation therapy versus placebo on the clinical and angiographic outcomes of patients with in-stent restenosis. METHODS AND RESULTS: One hundred thirty patients with in-stent restenosis underwent successful coronary intervention and were then blindly randomized to receive either intracoronary gamma-radiation with (192)Ir (15 Gy) or placebo. Four independent core laboratories blinded to the treatment protocol analyzed the angiographic and intravascular ultrasound end points of restenosis. Procedural success and in-hospital and 30-day complications were similar among the groups. At 6 months, patients assigned to radiation therapy required less target lesion revascularization and target vessel revascularization (9 [13.8%] and 17 [26.2%], respectively) compared with patients assigned to placebo (41 [63.1%, P=0.0001] and 44 [67.7%, P=0.0001], respectively). Binary angiographic restenosis was lower in the irradiated group (19% versus 58% for placebo, P=0.001). Freedom from major cardiac events was lower in the radiation group (29.2% versus 67.7% for placebo, P<0.001). CONCLUSIONS: Intracoronary gamma-radiation used as adjunct therapy for patients with in-stent restenosis significantly reduces both angiographic and clinical restenosis.

Normal and abnormal prosthetic valve function as assessed by Doppler echocardiography.

Doppler echocardiography was performed in 136 patients with a normally functioning prosthetic valve in the aortic (n = 59), mitral (n = 74) and tricuspid (n = 3) positions. These included patients with St. Jude (n = 82), Björk-Shiley (n = 18), Beall (n = 13), Starr-Edwards (n = 7) or tissue (n = 16) valves. Peak and mean pressure gradients across the prostheses were measured using the simplified Bernoulli equation. The prosthetic valve orifice (PVO, in square centimeters), only in the mitral position, was calculated by the equation: PVO = 220/pressure half-time. In the aortic position, the St. Jude valve had a lower peak velocity (2.3 +/- 0.6 m/s, range 1.0 to 3.9), peak gradient (22 +/- 12 mm Hg, range 4 to 61) and mean gradient (12 +/- 7 mm Hg, range 2 to 32) than the other valves (p less than 0.05) when compared with Starr-Edwards). In the mitral position, the St. Jude valve had the largest orifice (3.0 +/- 0.6 cm2, range 1.8 to 5.0) (p less than 0.0001 compared with all other valves). Insignificant regurgitation was commonly found by pulsed mode Doppler technique in patients with a St. Jude or Björk-Shiley valve in the aortic or mitral position and in patients with a Starr-Edwards or tissue valve in the aortic position. In 17 other patients with a malfunctioning prosthesis (four St. Jude, two Björk-Shiley, four Beall and seven tissue valves) proven by cardiac catheterization, surgery or autopsy, Doppler echocardiography correctly identified the complication (significant regurgitation or obstruction) in all but 2 patients who had a Beall valve. It is concluded that 1) the St. Jude valve appears to have the most optimal hemodynamics; mild regurgitation can be detected by the Doppler technique in normally functioning St. Jude and Björk-Shiley valves in the aortic or mitral position and in Starr-Edwards and tissue valves in the aortic position, and 2) Doppler echocardiography is a useful method for the detection of prosthetic valve malfunction, especially when the St. Jude, Björk-Shiley and tissue valves are assessed.