Serial intravascular ultrasound and quantitative coronary angiography after self-expandable wallstent coronary artery implantation

Serial intracoronary ultrasound studies revealed significant postprocedural stent expansion accompanied by significant stent shortening during long-term follow-up. The disadvantageous lumen loss by neointimal formation could be balanced by late stent expansion.     

Stent design related neointimal tissue proliferation in human coronary arteries; an intravascular ultrasound study.

AIMS: Histological restenosis models in animals have indicated that stent design has a significant impact on vessel trauma during stent implantation and on the amount of subsequent neointimal tissue proliferation. The impact of different stent designs on intimal hyperplasia in human atherosclerotic coronary arteries has not been determined. METHODS AND RESULTS: Angiographic and intravascular ultrasound studies were performed at the 6 month follow-up in 131 consecutive native coronary lesions of 131 patients treated with 50 Multi-Link stents, 40 InFlow stents and 41 Palmaz-Schatz stents. Lumen and stent cross-sectional areas (CSA) were measured at 1 mm axial increments. Mean intimal hyperplasia cross-sectional area (stent CSA-lumen CSA) and mean intimal hyperplasia thickness were calculated. Intravascular ultrasound demonstrated different levels of intimal hyperplasia proliferation for the three stents. Mean intimal hyperplasia thickness was 0.16+/-0.08 mm for Multi-Link stents, 0.26+/-0.19 mm for Palmaz-Schatz stents and 0.39+/-0.14 mm for Inflow stents (P<0.001). Multivariate analysis proved that stent type was the only independent predictor of intimal hyperplasia thickness at follow-up (P<0.001). CONCLUSION: Coronary stent design has a significant impact on subsequent intimal hyperplasia after implantation into atherosclerotic human coronary arteries. The corrugated ring design of the Multi-Link stent proved to result in less tissue proliferation at 6-month follow-up than the tubular slotted design of Palmaz-Schatz and InFlow stents.     

First human experience with angiopeptin-eluting stent: a quantitative coronary angiography and three-dimensional intravascular ultrasound study.

Angiopeptin has been shown to reduce in-stent restenosis in various animal models. Meanwhile, BiodivYsio DD phosphorylcholine (PC)-coated stent provides a platform for local delivery of antiproliferative agents to the coronary artery. We studied the feasibility, safety, and impact on tissue growth of angiopeptin-eluting BiodivYsio DD PC-coated stents in human native de novo coronary lesions. We enrolled 14 patients (16 lesions) who underwent intravascular ultrasound (IVUS)-guided angiopeptin-eluting stent implantation in native coronary arteries between 3.0 and 4.0 mm in diameter with lesion length相似文献   

Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study

OBJECTIVES: The aim of the present study was to determine whether troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus (NIDDM). BACKGROUND: Increased in-stent restenosis in patients with diabetes mellitus is due to accelerated neointimal tissue proliferation after coronary stent implantation. Troglitazone inhibits intimal hyperplasia in experimental animal models. METHODS: We studied 62 stented lesions in 52 patients with plasma glucose levels (PG) > or = 11.1 mmol/liter at 2 h after 75 g oral glucose load. The study patients were randomized into two groups: the troglitazone group of 25 patients with 29 stents, who were treated with 400 mg of troglitazone, and the control group of 27 patients with 33 stents. All patients underwent oral glucose tolerance tests before and after their six-month treatment period. The sum of PG (sum of PG) and the sum of insulin levels (sum of IRI) were measured. Serial (postintervention and at six-month follow-up) intravascular ultrasound studies were performed. Cross-sectional images within stents were taken at every 1 mm, using an automatic pullback. Stent areas (SA), lumen areas (LA), and intimal areas (IA = SA - LA) were measured and averaged over a number of selected image slices. The intimal index was calculated as intimal index = averaged IA/averaged SA x 100%. RESULTS: There were no differences between the two groups before treatment in sum of PG (31.35 +/- 3.07 mmol/liter vs. 32.89 +/- 4.87 mmol/liter, respectively, p = 0.2998) and sum of IRI (219.6 +/- 106.2 mU/liter vs. 209.2 +/- 91.6 mU/liter, respectively, p = 0.8934). However, reductions in sum of PG at the six-month follow-up in the troglitazone group were significantly greater than those in the control group (-21.4 +/- 8.8% vs. -4.5 +/- 7.4%, respectively, p < 0.0001). Likewise, decreases in sum of IRI were greater in the troglitazone-treated group (-31.4 +/- 17.9% vs. -1.9 +/- 15.1%, respectively, p < 0.0001). Although, there were no differences between the two groups in SA at postintervention (7.4 +/- 2.2 mm2 vs. 7.3 +/- 1.7 mm2, respectively, p = 0.9482) and at follow-up (7.3 +/- 2.3 mm2 vs. 7.3 +/- 1.8 mm2, respectively, p = 0.2307), the LA at follow-up in the troglitazone group was significantly greater than that in the control group (5.3 +/- 1.7 mm2 vs. 3.7 +/- 1.7 mm2, respectively, p = 0.0002). The IA at follow-up in the troglitazone group was significantly smaller than that in the control group (2.0 +/- 0.9 mm2 vs. 3.5 +/- 1.8 mm2, respectively, p < 0.0001). This was also true for intimal index (27.1 +/- 11.5% vs. 49.0 +/- 14.4%, respectively, p < 0.0001). CONCLUSIONS: Serial intravascular ultrasound assessment shows that administration of troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with NIDDM.     

Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study

Background

It has been reported that pioglitazone reduces neointimal hyperplasia after balloon-induced vascular injury in an experimental model.

Methods

To determine whether pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus, we studied 44 stented lesions in 44 patients with diabetes mellitus who underwent successful coronary stent implantation. Study patients were randomized into 2 groups: the pioglitazone group (23 patients with 23 lesions) and the control group (21 patients with 21 lesions). All patients underwent serial quantitative coronary angiography and serial intravascular ultrasound scanning studies. With a motorized pullback system, multiple image slices within the stent were obtained at every 1 mm. The stent area and lumen area were measured, and the neointimal area was calculated. Measurements were averaged over the number of selected image slices. The neointimal index was calculated as the averaged neointimal area divided by the averaged stent area multiplied by 100 (%).

Results

After 6 months of treatment, angiographic in-stent restenosis (17% vs 43%, respectively, P = .0994) and target lesion revascularization (13% vs 38%, respectively, P = .0835) were less frequent in the pioglitazone group than the control group; however, these differences did not reach significance. The intravascular ultrasound scanning study demonstrated that the neointimal index in the pioglitazone group was significantly smaller than that in the control group (28% ± 9% vs 48% ± 15%, respectively, P <.0001).

Conclusion

A serial intravascular ultrasound scanning assessment demonstrated that pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus.     

Effect of cilostazol on in-stent neointimal hyperplasia after coronary artery stenting: a quantative coronary angiography and volumetric intravascular ultrasound study.

BACKGROUND: This study was designed to investigate the efficacy of cilostazol on the prevention of in-stent neointimal hyperplasia as measured by both quantitative coronary angiography (CAG) and volumetric intravascular ultrasound (IVUS). METHODS AND RESULTS: Fifty-nine patients (39 men, age 62 years) undergoing elective coronary stenting were randomly assigned to receive aspirin plus clopidogrel or ticlopidine (Group I, n=28, 30 lesions) or aspirin plus clopidogrel or ticlopidine plus cilostazol (Group II, n=31, 35 lesions). CAG and IVUS were performed and repeated at 6 months to assess the primary endpoints of minimal luminal diameter (MLD) and in-stent neointimal hyperplasia volume. Follow-up CAG was performed on all patients and follow-up IVUS study was available for 50 lesions in 48 patients (24 lesions in Group I, 26 in Group II). There were no significant differences in the baseline angiographic data between the 2 groups. At 6 months follow-up, in-stent MLD was 1.90+/-0.76 mm in Group I and 2.41+/-0.85 mm in Group II (p=0.006). Volumetric IVUS at 6 months demonstrated that in-stent intimal hyperplasia volume per stent length was 2.2+/-1.4 mm3/mm in Group I and 1.0+/-0.5 mm3/mm in Group II (p=0.001). CONCLUSIONS: Triple antiplatelet therapy including cilostazol seems to be more effective at preventing in-stent neointimal hyperplasia than a dual antiplatelet regimen.     

In-vivo validation of spatially correct three-dimensional reconstruction of human coronary arteries by integrating intravascular ultrasound and biplane angiography

OBJECTIVES: The in-vivo validation of geometrically correct three-dimensional reconstruction of human coronary arteries by integrating intravascular ultrasound and biplane coronary angiography has not been adequately investigated. The purpose of this study was to describe the reconstruction method and investigate its in-vivo feasibility and accuracy. METHODS: In 17 coronary arteries (mean length, 85.7+/-17.1 mm) from nine patients, an intravascular ultrasound procedure along with a biplane coronary angiography was performed. From each angiographic projection, a single end-diastolic frame was selected in order to reconstruct the intravascular ultrasound catheter trajectory in space. In each end-diastolic intravascular ultrasound image, the lumen and media-adventitia contours were detected semi-automatically by an active contour algorithm. Each pair of contours was located on the catheter trajectory appropriately and interpolated with the adjacent pairs creating a three-dimensional volume of the arterial lumen and wall. The reconstructed lumen was back-projected onto both angiographic planes and the agreement between the back-projected and the angiographic luminal outlines was calculated. RESULTS: The angiogram-derived catheter length showed very high correlation (y=0.97 x + 1.8, P<0.001) and agreement with the corresponding pullback-derived values. Accordingly, the semi-automated segmentation of intravascular ultrasound images was also in significant correlation (r> or =0.96, P<0.001) and agreement with the reference manual tracing. The back-projected luminal borders showed good overall association with the corresponding angiographic ones (r=0.78, P<0.001) as well as remarkable agreement. CONCLUSIONS: Spatially correct three-dimensional reconstruction of human coronary arteries constitutes an imaging method with considerably high in-vivo feasibility and accuracy.     

Serial intravascular ultrasonographic measurements after implantation of biodegradable polymer-coated stents in porcine coronary arteries

BACKGROUND: Biodegradable stent coatings provide a potential for local drug delivery at the time of vascular injury, while possible tissue toxicity is avoided through constant degradation, leaving behind a bare metal stent. DESIGN: Serial three-dimensional (3D) intravascular ultrasonographic results on bare Megaflex stents and biodegradable polymer-coated Megaflex stents (Hyper stents) (Eurocor, Bonn, Germany) were compared 1 and 4 weeks after intracoronary implantation in pigs. METHODS: Under general anaesthesia, the left anterior descending and circumflex coronary arteries of domestic pigs were stented with Megaflex and Hyper stents, using right femoral artery access. Control coronary angiography and intravascular ultrasonography (IVUS) were performed 1 and 4 weeks after stent implantation using left femoral artery access and right carotid artery access. After recording of angiographic and IVUS data, the pigs were allowed to recover. RESULTS: The 1- and 4-week IVUS follow-ups revealed less neointima formation with Hyper stents than with Megaflex stents: 1-week intimal volume, 11.8+/-0.93 compared with 15.02+/-4.18 mm3, P=0.065; intimal area, 0.81+/-0.06 compared with 1.1+/-0.16 mm2, P =0.003; maximal intimal thickness, 0.12+/-0.01 compared with 0.14+/-0.02 mm, P =0.049; 4-week intimal volume, 12.4+/-1.77 compared with 27.32+/-12.79 mm3, P =0.016; intimal area, 0.82+/-0.12 compared with 1.95+/-0.65 mm2, P=0.003; and maximal intimal thickness, 0.13+/-0.04 compared with 0.30+/-0.10 mm, P=0.003. CONCLUSIONS: Implantation of biodegradable polymer-coated (Hyper) stents results in significantly less neointima formation 1 and 4 weeks after intracoronary implantation than with bare Megaflex stents. Taking advantage of the good collateralization of femoral and carotid arteries of pigs, the use of different arterial accesses allows serial angiographic and 3D IVUS measurements on neointimal development without sacrificing the animals.     

Angiographic and three-dimensional intravascular ultrasound analysis of combined intracoronary beta radiation and self-expanding stent implantation in human coronary arteries

This study tested the combination of vascular brachytherapy (VBT) and self-expanding Wallstent implantation in coronary lesions of patients at high risk for restenosis as assessed angiographically by quantitative coronary analysis and by 3-dimensional intravascular ultrasound analysis. Twenty-nine "de novo" lesions were managed with a self-expanding stent alone (n = 19) or with a self-expanding stent after beta-VBT (n = 10) in 27 patients who had been identified by high levels of plasma angiotensin-converting enzyme as being prone to myointimal growth after stent implantation. At 6 months, the increase in stent strut diameter was similar in the 2 groups by quantitative coronary analysis and 3-dimensional intravascular ultrasound (Delta mean stent strut diameter -0.33 +/- 0.3 vs -0.40 +/- 0.3 mm, p = 0.5; Delta stent area -11.8 +/- 6.1 vs -12.0 +/- 6.1 mm(2), p = 0.9; Delta stent volume -96.9 +/- 112 vs -83.5 +/- 73 mm(3), p = 0.7; for groups treated with VBT and self-expanding stents and only self-expanding stents, respectively). In-stent neointimal proliferation was decreased in the group treated with VBT and self-expanding stents (minimal luminal diameter 2.5 +/- 0.8 vs 1.88 +/- 0.8 mm, p = 0.04) by quantitative coronary analysis (minimal luminal area 6.7 +/- 2.5 vs 4.1 +/- 1.9 mm(2), p = 0.01), by intravascular ultrasound, and proliferation volume (84.6 +/- 66.4 vs 159.2 +/- 103.5 mm(3), p = 0.05) by 3-dimensional intravascular ultrasound. Positive vessel and luminal remodelings were observed in 50% of the group treated with VBT and self-expanding stents and in 11% of the group treated only with self-expanding stents (p = 0.02). The combined use of VBT and self-expanding stents is a novel approach that enlarges vascular lumen by preventing vessel constriction and neointimal proliferation. The feasibility and good results of this experimental approach suggest that the simultaneous use of these 2 technologies may be an interesting alternative for difficult vascular districts with high restenosis rates, such as peripheral circulation in the lower limbs.     

L-arginine supplementation does not inhibit neointimal formation after coronary stenting in human beings: an intravascular ultrasound study

Background

In-stent restenosis results from neointimal tissue proliferation. L-arginine supplementation improves endothelial function and reduces neointimal formation after arterial injury in animals. The aim of the study was to assess the influence of L-arginine administration on neointimal proliferation after coronary stenting in human beings.

Methods

We performed a prospective, randomized, double-blinded, placebo-controlled study in 60 men without diabetes. L-arginine/placebo was administered intravenously 12 hours before percutaneous coronary intervention (200 mg/kg for 240 minutes), during the procedure (200 mg/kg for 240 minutes), and intracoronarily immediately before stent implantation (500 mg for 10 minutes), and it was followed by oral treatment for next 2 weeks (6.0 g/d). By quantitative coronary angiography, late lumen loss, and intravascular ultrasound, neointimal volume and percent neointimal volume were calculated after 7 months of follow-up to assess neointimal formation.

Results

There were no differences in baseline clinical or angiographic characteristics between the two groups. Intravenous infusion of L-arginine increased plasma L-arginine concentrations 6-fold compared with placebo (661 ± 264 vs 107 ± 71 mmol/L, P < .001). During the 2-week period of oral treatment with L-arginine there was a sustained, significant increase of plasma L-arginine level (150 ± 50 vs 100 ± 17, P < .001, 135 ± 42 vs 89 ± 27, P < .001, respectively, on days 7 and 14 in the L-arginine group vs placebo). However, at 7-month follow-up, there was no difference in neointimal formation measured both by quantitative coronary angiography and intravascular ultrasound between the study groups.

Conclusions

Chronic systemic L-arginine administration has no effect on neointimal formation after coronary stenting in human beings.     

Effect of plaque debulking before stent implantation on in-stent neointimal proliferation: a serial 3-dimensional intravascular ultrasound study

Background

Recent intravascular ultrasound (IVUS) studies have suggested that plaque burden has a role in promoting intimal hyperplasia after stenting. We report on volumetric assessments of in-stent neointimal formation with 3-dimensional IVUS analysis, comparing directional coronary atherectomy (DCA) plus stenting (DCA/stenting) to stenting without DCA.

Methods

Twenty-four patients (24 lesions) treated with DCA before stenting were matched to 24 patients (24 lesions) receiving stenting without DCA. All stents were a single Multilink stent. In both groups, serial IVUS was performed before and after intervention and during the 6-month follow-up period. The arterial segments that were analyzed with a computer-based contour detection program were the same as the stented segments analyzed on serial studies. These measurements were obtained: (1) lumen volume (LV), (2) stent volume (SV), (3) vessel volume (VV), (4) in-stent neointimal volume (ISV) calculated as SV-LV, and (5) percent in-stent neointimal volume (%ISV) calculated as ([SV-LV]/SV) × 100.

Results

Baseline characteristics of the 2 groups were similar. After intervention, both groups achieved similar LV (140.0 mm³ DCA/stenting vs 135.2 mm³ stenting alone). However, the follow-up ISV and %ISV were significantly smaller in the DCA/stenting group (19.6 ± 12.2 mm³ DCA/stenting vs 44.6 ± 29.5 mm³ stenting alone; P = .00040; 15.3% ± 10.6% DCA/stenting vs 31.5% ± 17.7% stenting alone; P = .00040). Consequently, the DCA/stenting group showed a significantly greater follow-up LV (121.0 ± 51.5 mm³ DCA/stenting vs 91.5 ± 26.7 mm³ stenting alone; P = .016).

Conclusions

Plaque removal with DCA before stenting inhibits in-stent neointimal hyperplasia.     

Evaluation of coronary remodeling after sirolimus-eluting stent implantation by serial three-dimensional intravascular ultrasound

This study evaluates the response of the coronary vessel wall to implantation of the sirolimus-eluting stent (SES), Bx-VELOCITY, by using serial intravascular ultrasound. SESs have a major impact on the inhibition of in-stent neointimal hyperplasia. However, changes in the vessel wall and behind stent struts in animal models and humans have not been evaluated after SES implantation. Thirty-four patients who received a SES (n = 24) or a Bx-VELOCITY bare stent (BS) (n = 10) for single de novo coronary lesions and had serial motorized pullback 3-dimensional intravascular ultrasound were included. Stent, lumen, and vessel volumes were similar in the 2 groups at baseline. At follow-up, significantly larger lumen and lower neointimal hyperplasia volumes (0.7 vs 33 mm(3), p = 0.001) were seen in the SES group compared with the BS group. There was no significant difference between SES and BS in either the vessel volume (+2.4% vs +0.7%, p = NS) or the plaque behind stent volume change (+3.4% vs +2.5%, p = NS) from after the procedure to late follow-up. The stent edges also showed no significant difference between postprocedural and follow-up measurements, either in patients receiving SESs or BSs. No stented or edge segment required redilatation in the SES group, whereas 2 patients underwent repeat percutaneous coronary angioplasty in the BS group. In the SES group, 1 patient (4%) showed late acquired incomplete stent apposition. Thus, the SES is effective in inhibiting neointimal hyperplasia without affecting vessel volume and plaque behind the stent.     

国产西罗莫司洗脱支架与紫杉醇洗脱支架抑制血管内膜增生的血管内超声比较研究

目的利用血管内超声（IVUS）方法比较国产西罗莫司洗脱支架（Firebird^TM）与紫杉醇洗脱支架（Taxus^TM）对冠心病患者新生内膜增生的抑制作用。方法自2003年5月至2007年6月,203例冠心病患者（283处病变）行药物洗脱支架术并在术后1年行冠状动脉造影和血管内超声（IVUS）检查。其中136例患者（185处病变）置入Firebird^TM支架（Firebird组）,67例患者（98处病变）置入TaxusTM支架（Taxus组）。结果203例患者（283处病变）中168例患者（236处病变）接受了一年随访造影和血管内超声检查,其中Firebird组108例患者（147处病变）,Taxus组60例患者（89处病变）。两组患者基础临床情况及造影特征相似。Firebird组支架内晚期管腔丢失（0.17±0.29mm比0.43±0.51mm,P〈0.0001）和节段内晚期管腔丢失（0.18±0.36mm比0.38±0.33mm,P=0.003）明显小于Taxus组,而两组近端参考血管晚期管腔丢失（0.11±0.27mm比0.15±0.32mm,P=0.321）和远端参考血管晚期管腔丢失（0.08±0.10mm比0.09±0.16mm,P=0.483）差异并无统计学意义。IVUS分析显示,两组间平均支架面积、平均管腔面积、最小支架面积、平均支架体积、平均管腔体积比较,差异均无统计学意义。但Firebird组平均内膜增生面积（0.35±0.58mm^2比1.29±1.26mm^2,P〈0.0001）、平均内膜增生面积百分数（5.45%±9.26%比17.38%±13.75%,P〈0.0001）、内膜增生最大面积百分数（9.41%±14.15%比31.56%±20.99%,P〈0.0001）、平均内膜增生容积（2.09±5.46mm^3比13.43±18.59mm^3,P〈0.0001）和平均内膜增生容积百分数（1.68%±5.84%比8.62%±9.90%,P〈0.0001）较Taxus组均明显减少。结论国产西罗莫司洗脱支架（Firebird^TM）置入术后再狭窄发生率较低,与TaxusTM支架相比,抑制内膜增生作用更显著。     

血管内超声与定量冠脉造影应用于冠脉临界病变诊治的比较

目的 研究血管内超声（intravascular ultrasound,IVUS）在优化民航飞行员冠脉临界病变诊断和治疗中的应用。 方法 通过定量冠脉造影（quantitative coronary angiography,QCA）和IVUS对120例飞行员患者165处冠脉临界病的最小管腔直径（minimal lumen diameter,MLD）、直径狭窄率（diamter stenosis,DS）与最小管腔面积（minimal lumen area,MLA）、面积狭窄率（area stenosis,AS）等参数进行对比分析;对IVUS提示管腔MLA<4 mm2飞行员患者的冠脉临界病变行支架植入术。 结果 ①同一临界病变处QCA显示的MLD,DS及MLA,AS值均小于IVUS相应的测量值,且差异有统计学意义（P<0.01）,表明IVUS对冠脉病变狭窄定量测量方面准确性更高;②IVUS提高血栓病变（15.0% vs. 2.5%,P<0.05）和心肌桥（42.5% vs. 2.5%,P<0.01）的诊断率;③与QCA相比,IVUS直接显示介入治疗中支架的贴壁情况,指导支架扩张完全。 结论 IVUS较QCA能更准确地检测冠脉临界病变范围,更灵敏地诊断血栓和心肌桥,利于全面优化临界病变的诊疗。     

Effects of gold coating of coronary stents on neointimal proliferation following stent implantation

Experimental studies suggest a reduced neointimal tissue proliferation in vascular stainless steel stents coated with gold. This prospective multicenter trial evaluated the impact of gold coating on neointimal tissue proliferation in patients undergoing elective stent implantation. The primary end point was the in-stent tissue proliferation measured by intravascular ultrasound at 6 months comparing stents of identical design with or without gold coating (Inflow). Two hundred four patients were randomized to receive uncoated (group A, n = 101) or coated (group B, n = 103) stents. Baseline parameters did not differ between the groups. Stent length and balloon size were comparable, whereas inflation pressure was slightly higher in group A (14 +/- 3 vs 13 +/- 3 atm, p = 0.013). Procedural success was similar (A, 97%; B, 96%). The acute angiographic result was better for group B (remaining stenosis 4 +/- 12% vs 10 +/- 11%, p = 0.002). Six-month examinations revealed more neointimal proliferation in group B. By ultrasound, the neointimal volume within the stent was 47 +/- 25 versus 41 +/- 23 mm(3) (p = 0.04), with a ratio of neointimal volume-to-stent volume of 0.45 +/- 0.12 versus 0.40 +/- 0.12 (p = 0.003). The angiographic minimal luminal diameter was smaller in group B (1.47 +/- 0.57 vs 1.69 +/- 0.70 mm, p = 0.04), with a higher late luminal loss of 1.17 +/- 0.51 versus 0.82 +/- 0.56 mm (p = 0.001). Thus, gold coating of the tested stent type resulted in more neointimal tissue proliferation.