Long-term performance and biocompatibility of a novel bioresorbable scaffold for peripheral arteries: A three-year pilot study in Yucatan miniswine.

AIMS: Peripheral arteries are constantly exposed to deformation (elongation, twisting, shortening, compression) making bioresorbable scaffolds (BRS) a potentially attractive therapeutic alternative to metallic stents. We conducted a long-term pilot preclinical study of a novel sirolimus-eluting BRS in peripheral arteries. METHODS AND RESULTS: Fourteen BRS were deployed in iliofemoral arteries of seven healthy Yucatan miniswine and examined with imaging, pharmacokinetic, histopathologic, and polymer degradation techniques at 0, 30, 90, 180 days, 1, 2, and 3.3 years. Angiographic late luminal loss remained unchanged at 30 and 180 days but significantly decreased from 1 to 3.3 years. optical coherence tomography (OCT) showed late increase in lumen area (1 year: 14.70 ± 3.58 mm2 , 2 years 22.04 ± 3.81 mm2 , and 3.3 years 23.45 ± 7.07 mm2 ; p < .05) primarily due to scaffold area enlargement between 1 and 3.3 years, while there was no difference in the percent area stenosis at all time points. Histologic evidence of scaffold degradation was observed starting at 2 years, with minimal inflammatory reaction. At 3.3 years, BRS struts were rarely discernible by OCT, confirmed by a nearly complete polymer degradation by molecular weight analysis. CONCLUSIONS: In this pilot study, novel sirolimus-eluting BRS showed promising acute and chronic performance in the iliofemoral arteries of Yucatan miniswine.

Novel ultrahigh molecular weight amorphous PLLA bioresorbable coronary scaffold upsized up to 0.8 mm beyond nominal diameter: An OCT and histopathology study in porcine coronary artery model.

OBJECTIVES: The aim of the study was to evaluate the biomechanical properties and healing pattern of novel sirolimus-eluting, ultrahigh molecular weight amorphous poly-L-lactic acid bioresorbable scaffolds (S-BRS) that have been postdilated by 0.55 and 0.8 mm beyond the nominal diameters within the pressure-diameter compliance chart range. BACKGROUND: Due to the inherent limitations of bioabsorbable polymeric materials, overexpansion/upsizing may be very limited for some BRS such as the benchmark Absorb BVS. The unique biomechanical properties of the novel S-BRS may allow it to be safely upsized. METHODS AND RESULTS: 12 coronary arteries of 4 healthy Yucatan mini-swine underwent implantation of a novel S-BRS. Upsizing by postdilation was performed up to 0.55mm (PLUS 0.55, n = 6) or 0.8 mm (PLUS 0.8, n = 6) in a manner maintaining consistent 1:1.1 stent-to-artery, thus ensuring not only the overexpansion of the scaffold but consistent level of arterial injury. Optical coherence tomography (OCT) follow-up was performed at 28 and 90-days follow-up. There was no statistical difference between the tested groups in terms of acute recoil. OCT analysis after 28 days showed numerically lower levels of neointimal formation in PLUS 0.8 compared to PLUS 0.55 group. These results were sustained at 90-days follow-up. There was no difference in late recoil between studied groups. No scaffold discontinuation, deformation or overlapping of the struts were observed. CONCLUSIONS: Overexpansion up to 0.8 mm of novel, high strength S-BRS is not associated with worse angiographic outcomes, neointimal formation or biomechanical issues such as scaffold discontinuation, deformation or overlapping of the struts, neither acutely nor chronically. © 2017 Wiley Periodicals, Inc.

Chronic myocardial and coronary arterial effects of intracoronary supersaturated oxygen therapy in swine with normal and ischemic-reperfused myocardium.

The study assessed chronic myocardial, coronary and systemic effects of intracoronary supersaturated oxygen (SSO2) therapy. Left anterior descending coronary arteries of 40 swine were stented and randomized to 90-min selective intracoronary infusion of SSO2 (pO2 760-1000 mmHg) or normoxemic saline. In 20 out of 40 animals, SSO2 delivery followed a 60-min balloon occlusion to induce myocardial infarction (MI). In both normal and MI models, intracoronary treatment with hyperoxemic SSO2 therapy showed no evidence of coronary thrombosis. There were no biologically relevant differences between treatments at either time point in regard to coronary intervention site healing and neointimal growth. No signs of any myocardial or systemic toxicity were observed after 7 or 30 days. A trend was observed toward reduced incidence of microscopic MI scars and reduced infarct size in histopathology, as well as toward better recovery of echocardiographically evaluated global and regional contractility at 30 days. No treatment related infarcts or thromboemboli were observed in the downstream organs.

Two-year longitudinal evaluation of a second-generation thin-strut sirolimus-eluting bioresorbable coronary scaffold with hybrid cell design in porcine coronary arteries.

BACKGROUND: The first commercially available bioresorbable scaffold (BRS) had a strut thickness of 156 microns. As such, it had the potential for delivery challenges and higher thrombogenicity. The aim herein, is to evaluate biomechanical performance, pharmacokinetics and vascular healing of a novel thin strut (100 µm) sirolimus eluting BRS (MeRes-100, Meril Life Sciences, Gujarat, India) against the once clinically used BRS (Absorb BVS, Abbott, Santa Clara, CA) in porcine coronary arteries. METHODS: Following device implantation, angiographic and optical coherence tomography (OCT) evaluation were performed at 45, 90, 180 days, 1 year and 2 years. Histological evaluation was per-formed at 30, 90 and 180 days. RESULTS: At 2 years, both lumen (MeRes-100 7.07 ± 1.82 mm² vs. Absorb BVS 7.57 ± 1.39 mm2, p = NS) and scaffold areas (MeRes-100 9.73 ± 1.80 mm² vs. Absorb BVS 9.67 ± 1.25 mm², p = NS) were comparable between tested and control scaffolds. Also, the late lumen area gain at 2 years was similar in both groups tested (MeRes-100 1.03 ± 1.98 mm² vs. Absorb BVS 0.85 ± 1.56 mm², p = NS). Histologic examination up to 6 months showed comparable healing and inflammation profiles for both devices. CONCLUSIONS: The novel sirolimus-eluting BRS with thinner struts and hybrid cell design showed similar biomechanical durability and equivalent inhibition of neointimal proliferation when compared to the first-ever Absorb BVS up to 2 years in normal porcine coronary arteries.

Impact of Coronary Atherosclerosis on Bioresorbable Vascular Scaffold Resorption and Vessel Wall Integration.

The integration of the Absorb bioresorbable vascular scaffold (BVS) into the arterial wall has never been tested in an in vivo model of atherosclerosis. This study aimed to compare the long-term (up to 4 years) vascular healing responses of BVS to an everolimus-eluting metallic stent in the familial hypercholesterolemic swine model of atherosclerosis. The multimodality imaging and histology approaches indicate that the resorption and vascular integration profile of BVS is not affected by the presence of atherosclerosis. BVS demonstrated comparable long-term vascular healing and anti-restenotic efficacy to everolimus-eluting metallic stent but resulted in lower late lumen loss at 4 years.

In vitro mechanical behavior and in vivo healing response of a novel thin-strut ultrahigh molecular weight poly-l-lactic acid sirolimus-eluting bioresorbable coronary scaffold in normal swine.

BACKGROUND: New generation bioresorbable scaffolds (BRS) promise to improve the outcomes of current generation BRS technologies by decreasing wall thickness while maintaining structural strength. This study aimed to compare the biomechanical behavior and vascular healing profile of a novel thin-walled (98 µm) sirolimus-eluting ultrahigh molecular weight BRS (Magnitude, Amaranth Medical) to the Absorb everolimus-eluting bioresorbable vascular scaffold (Abbott Vascular). METHODS AND RESULTS: In vitro biomechanical testing showed lower number of fractures on accelerated cycle testing over time (at 21K cycles = 20.0 [19.0-21.0] in Absorb versus 0.0 [0.0-1.0] in Magnitude-BRS). Either Magnitude (n = 43) or Absorb (n = 22) was implanted in 65 coronary segments of 22 swine. Scaffold strut's coverage was evaluated using serial optical coherence tomography (OCT) analysis. At 14 days, Magnitude-BRS demonstrated a higher percentage of embedded struts (97.7% [95.3, 100.0] compared to Absorb (57.2% [48.0, 76.0], p = 0.003) and lower percentage of uncovered struts (0.0% [0.0, 0.0] versus Absorb 5.5% [2.6, 7.7], p = 0.02). Also, it showed a lower percent late recoil (-1.02% [-4.11, 3.21] versus 4.42% [-1.10, 8.74], p = 0.04) at 28 days. Histopathology revealed comparable neointimal proliferation and vascular healing responses between two devices up to 180 days. CONCLUSION: A new generation thin walled (98-µm) Magnitude-BRS displayed a promising biomechanical behavior and strut healing profile compared to Absorb at the experimental level. This new generation BRS platform has the potential to improve the clinical outcomes shown by the current generation BRS.

Impact of Fluoropolymer-Based Paclitaxel Delivery on Neointimal Proliferation and Vascular Healing: A Comparative Peripheral Drug-Eluting Stent Study in the Familial Hypercholesterolemic Swine Model of Femoral Restenosis.

BACKGROUND: A polymer-free peripheral paclitaxel-eluting stent (PES, Zilver PTX, Cook, IN) has shown to improve vessel patency after superficial femoral angioplasty. A new-generation fluoropolymer-based PES (FP-PES; Eluvia, Boston Scientific, MA) displaying more controlled and sustained paclitaxel delivery promise to improve the clinical outcomes of first-generation PES. We sought to compare the biological effect of paclitaxel delivered by 2 different stent-coating technologies (fluoropolymer-based versus polymer-free) on neointimal proliferation and healing response in the familial hypercholesterolemic swine model of femoral restenosis. METHODS AND RESULTS: The biological efficacy of clinically available FP-PES (n=12) and PES (n=12) was compared against a bare metal stent control (n=12; Innova, Boston Scientific, MA) after implantation in the femoral arteries of 18 familial hypercholesterolemic swine. Longitudinal quantitative vascular angiography and optical coherence tomography were performed at baseline and at 30 and 90 days. Histological evaluation was performed at 90 days. Ninety-day quantitative vascular angiography results showed a lower percent diameter stenosis for FP-PES (38.78% [31.27-47.66]) compared with PES (54.16% [42.60-61.97]) and bare metal stent (74.52% [47.23-100.00]; P<0.001). Ninety-day optical coherence tomography results demonstrated significantly lower neointimal area in FP-PES (8.01 mm2 [7.65-9.21]) compared with PES (10.95 mm2 [9.64-12.46]) and bare metal stent (13.83 mm2 [11.53-17.03]; P<0.001). Histological evaluation showed larger lumen areas and evidence of higher biological activity (smooth muscle cell loss and fibrin deposition) in the FP-PES compared with PES and bare metal stent. CONCLUSIONS: In the familial hypercholesterolemic swine model of femoral restenosis, the implantation of an FP-PES resulted in lower levels of neointimal proliferation and sustained biological effect ≤90 days compared with a polymer-free stent-based approach.

Comparative Biomechanical Behavior and Healing Profile of a Novel Thinned Wall Ultrahigh Molecular Weight Amorphous Poly-l-Lactic Acid Sirolimus-Eluting Bioresorbable Coronary Scaffold.

BACKGROUND: Mechanical strength of bioresorbable scaffolds (BRS) is highly dependent on strut dimensions and polymer features. To date, the successful development of thin-walled BRS has been challenging. We compared the biomechanical behavior and vascular healing profile of a novel thin-walled (115 µm) sirolimus-eluting ultrahigh molecular weight amorphous poly-l-lactic acid-based BRS (APTITUDE, Amaranth Medical [AMA]) to Absorb (bioresorbable vascular scaffold [BVS]) using different experimental models. METHODS AND RESULTS: In vitro biomechanical testing showed no fractures in the AMA-BRS when overexpanded 1.3 mm above nominal dilatation values (≈48%) and lower number of fractures on accelerated cycle testing over time (at 21 K cycles=20.0 [19.5-20.5] in BVS versus 4.0 [3.0-4.3] in AMA-BRS). In the healing response study, 35 AMA-BRS and 23 BVS were implanted in 58 coronary arteries of 23 swine and followed-up to 180 days. Scaffold strut healing was evaluated in vivo using weekly optical coherence tomography analysis. At 14 days, the AMA-BRS demonstrated a higher percentage of embedded struts (71.0% [47.6, 89.1] compared with BVS 40.3% [20.5, 63.2]; P=0.01). At 21 days, uncovered struts were still present in the BVS group (3.8% [2.1, 10.2]). Histopathology revealed lower area stenosis (AMA-BRS, 21.0±6.1% versus BVS 31.0±4.5%; P=0.002) in the AMA-BRS at 28 days. Neointimal thickness and inflammatory scores were comparable between both devices at 180 days. CONCLUSIONS: A new generation thinned wall BRS displayed a more favorable biomechanical behavior and strut healing profile compared with BVS in normal porcine coronary arteries. This novel BRS concept has the potential to improve the clinical outcomes of current generation BRS.

Biological effect on restenosis and vascular healing of encapsulated paclitaxel nanocrystals delivered via coated balloon technology in the familial hypercholesterolaemic swine model of in-stent restenosis.

AIMS: The aim of this study was to evaluate the biological efficacy of a novel lower-dose (2.5 µg/mm2) encapsulated paclitaxel nanocrystal-coated balloon (Nano-PCB) in the familial hypercholesterolaemic swine (FHS) model of iliofemoral in-stent restenosis. METHODS AND RESULTS: Nano-PCB pharmacokinetics were assessed in 20 femoral arteries (domestic swine). Biological efficacy was evaluated in ten FHS: 14 days following bare metal stent implantation each stent segment was randomised to a clinically available PCB (IN.PACT, n=14), the Nano-PCB (n=14) or an uncoated balloon (n=12). Angiographic, optical coherence tomography and histological evaluation was performed at 28 days after treatment. Arterial paclitaxel concentration was 120.7 ng/mg at one hour and 7.65 ng/mg of tissue at 28 days with the Nano-PCB. Compared to the control uncoated group, both PCBs significantly reduced percent area stenosis (Nano-PCB: 36.0±14.2%, IN.PACT: 29.3±9.2% vs control: 67.9±15.1%, p<0.001). Neointimal distribution in the entire stent length was more homogenous in the Nano-PCB. Histological evaluation showed comparable degrees of neointimal proliferation in both PCBs; however, the Nano-PCB showed slightly higher levels of neointimal maturity and endothelialisation. CONCLUSIONS: Lower-dose encapsulated paclitaxel nanocrystals delivered via a coated balloon displayed comparable biological efficacy with superior healing features compared to a clinically validated PCB technology.

Comparative Characterization of Biomechanical Behavior and Healing Profile of a Novel Ultra-High-Molecular-Weight Amorphous Poly-l-Lactic Acid Sirolimus-Eluting Bioresorbable Coronary Scaffold.

BACKGROUND: Clinically available bioresorbable scaffolds (BRS) rely on polymer crystallinity to achieve mechanical strength resulting in limited overexpansion capabilities and structural integrity when exposed to high-loading conditions. We aimed to evaluate the biomechanical behavior and vascular healing profile of a novel, sirolimus-eluting, high-molecular-weight, amorphous poly-l-lactic acid-based BRS (Amaranth BRS). METHODS AND RESULTS: In vitro biomechanical testing was performed under static and cyclic conditions. A total of 99 devices (65 Amaranth BRS versus 34 Absorb bioresorbable vascular scaffold [BVS]) were implanted in 99 coronary arteries of 37 swine for pharmacokinetics and healing evaluation at various time points. In the Absorb BVS, the number of fractures per scaffold seen on light microscopy was 6.0 (5.0-10.5) when overexpanded 1.0 mm above nominal values (≈34%). No fractures were observed in the Amaranth BRS group at 1.3 mm above nominal values (≈48% overexpansion). The number of fractures was higher in the Absorb BVS on accelerated cycle testing over time (at 24K cycles=5.0 [5.0-9.0] Absorb BVS versus 0.0 [0.0-0.5] Amaranth BRS). Approximately 90% of sirolimus was found to be eluted by 90 days. Optical coherence tomography analysis demonstrated lower percentages of late scaffold recoil in the Amaranth BRS at 3 months (Amaranth BRS=-10±16.1% versus Absorb BVS=10.7±13.2%; P=0.004). Histopathology analysis revealed comparable levels of vascular healing and inflammatory responses between both BRSs up to 6 months. CONCLUSIONS: New-generation high-molecular-weight amorphous poly-l-lactic acid scaffolds have the potential to improve the clinical performance of BRS and provide the ideal platform for the future miniaturization of the technology.

Four-year polymer biocompatibility and vascular healing profile of a novel ultrahigh molecular weight amorphous PLLA bioresorbable vascular scaffold: an OCT study in healthy porcine coronary arteries.

AIMS: The vascular healing profile of polymers used in bioresorbable vascular scaffolds (BRS) has not been fully characterised in the absence of antiproliferative drugs. In this study, we aimed to compare the polymer biocompatibility profile and vascular healing response of a novel ultrahigh molecular weight amorphous PLLA BRS (FORTITUDE®; Amaranth Medical, Mountain View, CA, USA) against bare metal stent (BMS) controls in porcine coronary arteries. METHODS AND RESULTS: Following device implantation, optical coherence tomography (OCT) evaluation was performed at 0 and 28 days, and at one, two, three and four years. A second group of animals underwent histomorphometric evaluation at 28 and 90 days. At four years, both lumen (BRS 13.19±1.50 mm2 vs. BMS 7.69±2.41 mm2) and scaffold areas (BRS 15.62±1.95 mm2 vs. BMS 8.65±2.37 mm2) were significantly greater for BRS than BMS controls. The degree of neointimal proliferation was comparable between groups. Histology up to 90 days showed comparable healing and inflammation profiles for both devices. CONCLUSIONS: At four years, the novel PLLA BRS elicited a vascular healing response comparable to BMS in healthy pigs. Expansive vascular remodelling was evident only in the BRS group, a biological phenomenon that appears to be independent of the presence of antiproliferative drugs.

Impact of Paclitaxel Dose on Tissue Pharmacokinetics and Vascular Healing: A Comparative Drug-Coated Balloon Study in the Familial Hypercholesterolemic Swine Model of Superficial Femoral In-Stent Restenosis.

OBJECTIVES: This study sought to compare the effect of paclitaxel-coated balloon (PCB) concentration on tissue levels and vascular healing using 3 different PCB technologies (In.Pact Pacific = 3 µg/mm(2), Lutonix = 2 µg/mm(2) and Ranger = 2 µg/mm(2)) in the experimental setting. BACKGROUND: The optimal therapeutic dose for PCB use has not been determined yet. METHODS: Paclitaxel tissue levels were measured up to 60 days following PCB inflation (Ranger and In.Pact Pacific) in the superficial femoral artery of healthy swine (18 swine, 36 vessels). The familial hypercholesterolemic swine model of superficial femoral artery in-stent restenosis (6 swine, 24 vessels) was used in the efficacy study. Two weeks following bare-metal stent implantation, each in-stent restenosis site was randomly treated with a PCB or an uncoated control balloon (Sterling). Quantitative vascular analysis and histology evaluation was performed 28 days following PCB treatment. RESULTS: All PCB technologies displayed comparable paclitaxel tissue levels 4 h following balloon inflation. At 28 days, all PCB had achieved therapeutic tissue levels; however, the In.Pact PCB resulted in higher tissue concentrations than did the other PCB groups at all time points. Neointimal inhibition by histology was decreased in all PCB groups compared with the control group, with a greater decrease in the In.Pact group. However, the neointima was more mature and contained less peri-strut fibrin deposits in both 2-µg/mm(2) PCB groups. CONCLUSIONS: Compared with the clinically established PCB dose, lower-dose PCB technologies achieve lower long-term tissue levels but comparable degrees of neointimal inhibition and fewer fibrin deposits. The impact of these findings in restenosis reduction and clinical outcomes needs to be further investigated.

Optimizing flushing parameters in intracoronary optical coherence tomography: an in vivo swine study.

Intracoronary optical frequency domain imaging (OFDI), requires the displacement of blood for clear visualization of the artery wall. Radiographic contrast agents are highly effective at displacing blood however, may increase the risk of contrast-induced nephropathy. Flushing media viscosity, flow rate, and flush duration influence the efficiency of blood displacement necessary for obtaining diagnostic quality OFDI images. The aim of this work was to determine the optimal flushing parameters necessary to reliably perform intracoronary OFDI while reducing the volume of administered radiographic contrast, and assess the influence of flushing media choice on vessel wall measurements. 144 OFDI pullbacks were acquired together with synchronized EKG and intracoronary pressure wire recordings in three swine. OFDI images were graded on diagnostic quality and quantitative comparisons of flushing efficiency and intracoronary cross-sectional area with and without precise refractive index calibration were performed. Flushing media with higher viscosities resulted in rapid and efficient blood displacement. Media with lower viscosities resulted in increased blood-media transition zones, reducing the pullback length of diagnostic quality images obtained. Flushing efficiency was found to increase with increases in flow rate and duration. Calculations of lumen area using different flushing media were significantly different, varying up to 23% (p < 0.0001). This error was eliminated with careful refractive index calibration. Flushing media viscosity, flow rate, and flush duration influence the efficiency of blood displacement necessary for obtaining diagnostic quality OFDI images. For patients with sensitivity to contrast, to reduce the risk of contrast induced nephrotoxicity we recommend that intracoronary OFDI be conducted with flushing solutions containing little or no radiographic contrast. In addition, our findings show that careful refractive index compensation should be performed, taking into account the specific contrast agent used, in order to obtain accurate intravascular OFDI measurements.

Early feasibility evaluation of thoracoscopically assisted transcatheter ventricular reconstruction in an experimental model of ischaemic heart failure with left anteroapical aneurysm.

AIMS: To test the feasibility of a thoracoscopically assisted, off-pump, transcatheter ventricular reconstruction (TCVR) approach in an ovine model of left ventricular (LV) anteroapical aneurysm. METHODS AND RESULTS: Myocardial infarction (MI) was induced by coil occlusion of the middle left anterior descending artery and diagonals. Two months after MI creation, TCVR was performed via a minimal thoracotomy in eight sheep. Under endoscopic and fluoroscopic guidance, trans-interventricular septal puncture was performed from the LV epicardial scar. A guidewire was externalised via a snare placed in the right ventricle from the external jugular vein. An internal anchor was inserted over the wire and positioned on the right ventricular septum and an external anchor was deployed on the LV anterior epicardium. Serial pairs of anchors were placed and plicated together to exclude the scar completely. Immediately after TCVR, echocardiography showed LV end-systolic volume decreased from pre-procedure 58.8±16.6 ml to 25.1±7.6 ml (p<0.01) and the ejection fraction increased from 32.0±7.3% to 52.0±7.5% (p<0.01). LV twist significantly improved (3.83±2.21 vs. pre-procedure -0.41±0.94, p=0.01) and the global peak-systolic longitudinal strain increased from -5.64% to -10.77% (p<0.05). CONCLUSIONS: TCVR using minimally invasive access techniques on the off-pump beating heart is feasible and resulted in significant improvement in LV performance.

Stent healing response following delivery of paclitaxel via durable polymeric matrix versus iopromide-based balloon coating in the familial hypercholesterolaemic swine model of coronary injury.

AIMS: The routine use of paclitaxel-coated balloons (PCB) in combination with bare metal stents (BMS) in de novo coronary lesions has been questioned. In this study, we aimed to compare the vascular response of BMS implanted using a second-generation PCB (BMS+PCB) with the TAXUS stent (PES) and a BMS control (BMS) in the familial hypercholesterolaemic swine (FHS) model of coronary injury. METHODS AND RESULTS: A total of 17 stents (PES=6, BMS+PCB=6, and BMS=5) were implanted in the coronary territory of 10 FHS using a 20% overstretch injury ratio. Imaging evaluation (QCA and IVUS) was conducted in all animals at baseline and 28 days following stent implantation. Following terminal imaging all animals were euthanised and stented coronary segments harvested for histological evaluation. At 28 days, the lowest degree of percentage diameter stenosis by QCA was achieved by the PES (2.9 ± 9%) followed by the BMS+PCB (9.5 ± 16.4%) and the BMS group (25.65 ± 18.7%, p<0.05). In histology, percentage area of stenosis (BMS+PCB=29.6 ± 6.4% vs. PES=21.5 ± 3.3% vs. BMS=55.2 ± 12.9%; p<0.01) and neointimal thickness (BMS+PCB=0.26 ± 0.1 mm vs. PES=0.21 ± 0.1 mm vs. BMS=0.59 ± 0.2 mm; p<0.01) were significantly reduced in both paclitaxel groups in comparison to BMS controls. Both BMS+PCB and BMS groups had higher endothelialisation scores (PES=1.50 ± 0.9 vs. BMS+PCB=2.73 ± 0.4 vs. BMS=3.00; p<0.05) and lower peri-strut inflammatory scores (PES=0.83 ± 0.4 vs. BMS+PCB=0.20 ± 0.2 vs. BMS=0.43 ± 0.6, p<0.05) when compared to PES. Neointima maturity (PCB+BMS: 2.00 [2-2.4] vs. PES: 1.00 [0.3-1] vs. BMS: 3.00, p<0.05) and fibrin deposition (PCB+BMS: 1.40 ± 0.3 vs. PES: 2.17 ± 0.7 vs. BMS: 0.27 ± 0.3, p<0.05) scores in PCB+BMS appeared to fall between the PES and the BMS ranges. CONCLUSIONS: In the FHS coronary injury model, BMS implantation using a PCB yields a degree of neointimal inhibition comparable to the PES. The BMS+PCB combination presented lower degrees of inflammation and fibrin deposition; however, signs of delayed healing were still present.

Tissue uptake, distribution, and healing response after delivery of paclitaxel via second-generation iopromide-based balloon coating: a comparison with the first-generation technology in the iliofemoral porcine model.

OBJECTIVES: This study sought to evaluate vascular drug uptake, distribution and response of second-generation paclitaxel coated balloon (PCB) (Cotavance, MEDRAD Interventional, Indianola, Pennsylvania) and compare it with first-generation technology, containing identical excipient and drug concentration. BACKGROUND: Original PCB technologies displayed a heterogeneous deposition of crystalline paclitaxel-iopromide inside the balloon folds, whereas second-generation PCBs consisted of more homogeneous, circumferential coatings. METHODS: Paclitaxel tissue uptake was assessed in 20 iliofemoral arteries of a domestic swine. Vascular healing response was assessed in the familial hypercholesterolemic model of iliofemoral in-stent restenosis. Three weeks after bare-metal stent implantation, vascular segments were randomly revascularized with first-generation PCBs (n = 6), second-generation PCBs (n = 6), or plain balloon angioplasty (PBA) (n = 6). At 28 days, angiographic and histological evaluation was performed in all treated segments. RESULTS: One-hour paclitaxel tissue uptake was 42% higher in the second-generation PCBs (p = 0.03) and resulted in more homogeneous segment-to-segment distribution compared with first-generation PCBs. Both angiography (percentage of diameter stenosis: second-generation 11.5 ± 11% vs. first-generation 21.9 ± 11% vs. PBA 46.5 ± 10%; p < 0.01) and histology (percentage of area stenosis: second-generation 50.5 ± 7% vs. first-generation 54.8 ± 18% vs. PBA 78.2 ± 9%; p < 0.01) showed a decrease in neointimal proliferation in both PCB groups. Histological variance of the percentage of area stenosis was lower in second-generation compared with first-generation PCBs (51.7 vs. 328.3; p = 0.05). The presence of peristrut fibrin deposits (0.5 vs. 2.4; p < 0.01) and medial smooth muscle cell loss (0 vs. 1.7; p < 0.01) were lower in the second-generation compared with first-generation PCBs. CONCLUSIONS: In the experimental setting, second-generation PCB showed a comparable efficacy profile and more favorable vascular healing response when compared to first-generation PCB. The clinical implications of these findings require further investigation.

Catheter-based endomyocardial delivery of mesenchymal precursor cells using 3D echo guidance improves cardiac function in a chronic myocardial injury ovine model.

The administration of bone marrow-derived stem cells may provide a new treatment option for patients with heart failure. Transcatheter cell injection may require multi-imaging modalities to optimize delivery. This study sought to evaluate whether endomyocardial injection of mesenchymal precursor cells (MPCs) could be guided by real-time 3D echocardiography (RT3DE) in treating chronic, postinfarction (MI) left ventricular (LV) dysfunction in sheep. Four weeks after induction of an anterior wall myocardial infarction in 39 sheep, allogeneic MPCs in doses of either 25 × 10(6) (n = 10), 75 × 10(6) (n = 9), or 225 × 10(6) (n = 10) cells or nonconditioned control media (n = 10) were administered intramyocardially into infarct and border zone areas using a catheter designed for combined fluoroscopic and RT3DE-guided injections. LV function was assessed before and after injection. Infarct dimension and vascular density were evaluated histologically. RT3DE-guided injection procedures were safe. Compared to controls, the highest dose MPC treatment led to increments in ejection fraction (3 ventricula 3% in 225M MPCs vs. -5 ± 4% in the control group, p < 0.01) and wall thickening in both infarct (4 ± 4% in 225M MPCs vs. -3 ± 6% in the control group, p = 0.02) and border zones (4 ± 6% in 225M MPCs vs. -8 ± 9% in the control group, p = 0.01). Histology analysis demonstrated significantly higher arteriole density in the infarct and border zones in the highest dose MPC-treated animals compared to the lower dose or control groups. Endomyocardial implantation of MPCs under RT3DE guidance was safe and without observed logistical obstacles. Significant increases in LV performance (ejection fraction and wall thickening) and neovascularization resulted from this technique, and so this technique has important implications for treating patients with postischemic LV dysfunction.

Benefits of standardizing the treatment of arrhythmias in the sheep (Ovis aries) model of chronic heart failure after myocardial infarction.

Large animal models of heart failure are essential in preclinical device testing. In sheep, catheter-based coil embolization of the left anterior descending and diagonal artery provides a minimally invasive and reproducible model of myocardial infarction (MI). Although widely used, this model has historically been plagued with a 30% mortality rate, both in the literature and in our own experience. Our study endeavored to decrease the mortality rate by targeting the most common cause of death, intractable arrhythmias, during creation of the ovine MI model. To this end, we evaluated 2 methods of managing perioperative antiarrhythmic therapy and cardiopulmonary resuscitation during model creation. The first group of sheep was managed at the discretion of the individual operator, whereas the second group was treated according to a standardized protocol that included mandatory pretreatment with amiodarone. Sheep experiencing life-threatening arrhythmias, most commonly ventricular fibrillation, were either resuscitated according to operator-driven instructions or the standardized protocol. By comparing these 2 treatment groups, we have shown that using a standardized protocol is advantageous in reducing mortality associated with the ovine MI model. Since implementing the standardized protocol, our laboratory has lowered the expected mortality rate to 10% during catheter-based induction of ovine MI and has greatly reduced the number of animals required for study needs. In addition, the standardized protocol has proven beneficial in training new staff members. By implementing this standardized method of model management, the outcomes of model creation have been optimized.

Evaluation of efficacy and dose response of different paclitaxel-coated balloon formulations in a novel swine model of iliofemoral in-stent restenosis.

OBJECTIVES: The authors aimed to validate a novel iliofemoral in-stent restenosis (ISR) model for the efficacy evaluation of paclitaxel-coated balloons (PCB) using the familial hypercholesterolemic swine (FHS). BACKGROUND: Most of the validation work regarding PCB technologies has been performed in the coronary territory of juvenile domestic swine. Although invaluable for safety evaluation, this model is not suited for the evaluation of the efficacy of peripheral PCB technologies. METHODS: Twenty-four iliofemoral segments in 12 FHS underwent balloon injury and self-expanding stent placement. After 21 days, the resulting ISR lesions were treated with either 1 µg/mm(2) dose (n = 8), or 3 µg/mm(2) dose (n = 8) PCB (Cotavance, Bayer Pharma AG/MEDRAD, Indianola, Pennsylvania), or with an identical uncoated control balloon (n = 8). RESULTS: At termination (28 days after treatment), the percent diameter stenosis by quantitative vascular analysis in the control group was higher (31.2 ± 13.7%) compared with the 1 µg/mm(2) (19.3 ± 14.0%, 38% reduction) and 3 µg/mm(2) (8.6 ± 10.7%, 72% reduction) PCB groups. Intravascular ultrasound analysis showed 36% (1 µg/mm(2) dose, p = 0.04) and 55% (3 µg/mm(2) dose, p < 0.01) reductions in neointimal volume stenosis. In the histological analysis, the control group showed the highest degree of percent area stenosis (65 ± 14.3%). The reductions in percent area stenosis was 13.2% (p = 0.5) and 26% (p = 0.04) in the 1 µg/mm(2) and 3 µg/mm(2) dose groups, respectively. CONCLUSIONS: The FHS model of iliofemoral ISR demonstrated a dose-dependent effect on the inhibition of neointimal proliferation of a clinically validated PCB technology. This model represents a positive step toward the efficacy evaluation of PCB in the peripheral vascular territory.