A retrospective review of 146 active and passive fixation bradycardia lead implantations in 74 dogs undergoing pacemaker implantation in a research setting of short term duration.

BACKGROUND: Canine veterinary patients increasingly benefit from implantation of transvenous pacemakers for bradyarrhythmias. No published data exist examining procedural outcomes of pacemaker implantation performed in the preclinical laboratory. The purpose was to review short term complication, infection, dislodgement, penetration rates, plus overall morbidity following pacemaker implantation in the research setting. A retrospective review of 74 Class A purpose-bred mongrels implanted with active (n = 89) and passive fixation (n = 57) intracardiac leads for dual (n = 72) or single (n = 2) chamber pacing was performed. RESULTS: All leads were implanted successfully, meeting electrical implant criteria. Follow-ups typically occurred every 7 days (first month), then at 30 day intervals. Seroma formation was 1.4% and 10.8% at the venotomy and pulse generator site respectively. Overall infection rate was 1.4%. Overall dislodgement rate was 2.1%, (2 passive atrial leads, 1 passive ventricular lead). Overall fractures and insulation defects were zero. Two helix penetrations were noted incidentally post mortem, one at the right atrial appendage and one at the right ventricle (64 dogs, 128 leads evaluated), a 1.6% event rate. Major in-life adverse events were 5.4% (4 of 74 dogs), including 1 infection and 3 lead dislodgements. CONCLUSIONS: This review demonstrates a low complication rate with bradycardia lead implants in the short term (up to 180 days), in a high volume research setting. Lead type, implant technique, surgeon experience, healthy patient population, patient size and follow-up care play a role. This review also suggests active fixation leads in the right atrial appendage of dogs are safe and reliable.

Impact of bioresorbable versus permanent polymer on longterm vessel wall inflammation and healing: a comparative drug-eluting stent experimental study.

AIMS: Drug-eluting stents (DES) have evolved to using bioresorbable polymers as a method of drug delivery. The impact of bioresorbable polymer on long-term neointimal formation, inflammation, and healing has not been fully characterised. This study aimed to evaluate the biological effect of polymer resorption on vascular healing and inflammation. METHODS AND RESULTS: A comparative DES study was performed in the familial hypercholesterolaemic swine model of coronary stenosis. Permanent polymer DES (zotarolimus-eluting [ZES] or everolimus-eluting [EES]) were compared to bioresorbable polymer everolimus-eluting stents (BP-EES) and BMS. Post implantation in 29 swine, stents were explanted and analysed up to 180 days. Area stenosis was reduced in all DES compared to BMS at 30 days. At 180 days, BP-EES had significantly lower area stenosis than EES or ZES. Severe inflammatory activity persisted in permanent polymer DES at 180 days compared to BP-EES or BMS. Qualitative para-strut inflammation areas (graded as none to severe) were elevated but similar in all groups at 30 days, peaked at 90 days in DES compared to BMS (p<0.05) and, at 180 days, were similar between BMS and BP-EES but were significantly greater in DES. CONCLUSIONS: BP-EES resulted in a lower net long-term reduction in neointimal formation and inflammation compared to permanent polymer DES in an animal model. Further study of the long-term neointima formation deserves study in human clinical trials.

Fluorocopolymer-coated nitinol self-expanding paclitaxel-eluting stent: pharmacokinetics and vascular biology responses in a porcine iliofemoral model.

AIMS: Our aim was to evaluate arterial responses to paclitaxel and a novel fluorocopolymer-coated nitinol low-dose paclitaxel-eluting stent (FP-PES). METHODS AND RESULTS: Human smooth muscle cell (SMC) migration was assessed after exposure to paclitaxel in vitro. For pharmacokinetics and vascular response, FP-PES or bare metal stents (BMS) were implanted in porcine iliofemoral arteries. Paclitaxel significantly inhibited human coronary and femoral artery SMC migration at doses as low as 1 pM. Inhibition was significantly greater for femoral compared with coronary artery SMCs from 1 pM to 1 µM. Pharmacokinetics showed consistent paclitaxel release from FP-PES over the study duration. The peak arterial wall paclitaxel level was 3.7 ng/mg at 10 days, with levels decreasing to 50% of peak at 60 days and 10% at 180 days. Paclitaxel was not detected in blood or remote organs. Arteriogram and histomorphometry analyses showed FP-PES significantly inhibits neointimal proliferation versus BMS at 30 and 90 days. Re-endothelialisation scores were not different between groups. CONCLUSIONS: Paclitaxel affected femoral artery SMC migration at lower concentrations and to a greater degree than it did coronary artery SMCs. The novel FP-PES used in this preclinical study demonstrated a vascular healing response similar to BMS, while significantly inhibiting neointimal formation up to 90 days.

Bipolar multi-electrode balloon catheter radiofrequency renal denervation with the Vessix system: preclinical safety evaluation.

AIMS: A bipolar multi-electrode 7 Fr-compatible balloon-catheter radiofrequency (RF) renal denervation system (Vessix™ Renal Denervation System; Boston Scientific, Marlborough, MA, USA) was evaluated for safety in domestic swine. METHODS AND RESULTS: Renal arteries of 27 swine received overlapping treatments proximally/single treatments distally to mimic balloon overlap clinically. Each histopathology cohort (30, 90, 180 days) had four RF-treated and three sham-treated (no RF energy delivered) animals, with the response of artery/surrounding nerves to bilateral treatment examined (42 arteries). Scanning electron microscopy of the renal artery flow surface for endothelialisation was performed in six additional pigs (three at each of 30 and 90 days: 12 arteries) following unilateral whole artery treatment with proximal overlap: RF one side, sham the other side. Power was ~1 watt, treatment duration 30 seconds, target temperature 68°C. Renal histology and assessment for off-target injury was performed in all 27 swine. Renal artery thermal injury was transmural and segmental involving <10% to >90% of the circumference (typically 30-60%) with segmental neointimal hyperplasia exceeding shams but haemodynamically trivial (maximum stenosis 17.7%). Healing of necrotic arterial media was by replacement fibrosis. Overlying nerves also became fibrotic. Endothelialisation was focally incomplete at 30 days but confluent at 90 days. No off-target injury occurred outside the renal arteries. CONCLUSIONS: Safety was demonstrated.

Experimental evaluation of efficacy and healing response of everolimus-eluting stents in the familial hypercholesterolemic swine model: a comparative study of bioabsorbable versus durable polymer stent platforms.

BACKGROUND: The utility of animal models for the prediction of drug-eluting stent (DES) efficacy in human clinical trials is still unclear. The familial hypercholesterolemic swine (FHS) model has been shown to induce a human-like neointimal response to bare metal stent (BMS) implantation. However, its utility to discriminate efficacy signals following DES implantation is unknown. In this study, we aimed to test the efficacy and healing response of several everolimus-eluting stent (EES) platforms in the coronary territory of the FHS. METHODS: A total of 19 EES platforms (SYNERGY=6, SYNERGY½-dose=7, and PROMUS Element=6) and an identical BMS control (Element=6) were implanted into the coronary arteries of nine FHS. All implants were performed under intravascular ultrasound guidance using a 1.2 : 1 overstretch ratio. At 30 days, the vascular response to the implant was evaluated by quantitative coronary angiography, optical coherence tomography, and histology. RESULTS: At 28 days, all EES platforms showed a significant decrease in angiographic late lumen loss (between 27 and 37%) compared with the BMS control group. This finding was confirmed both by optical coherence tomography (mean neointimal thickness=28-42% reduction) and by histology (mean neointimal thickness=44-55% reduction). All EES platforms showed similar degrees of neointimal inhibition. The presence of moderate to severe para-strut inflammation was observed in 83% of the stent sections in the BMS group compared with 28.6% in the SYNERGY½-dose group and 0% in the SYNERGY and PROMUS groups (P=0.0002). There was a 68-95% reduction in MMP9 expression in the media in all EES platforms compared with the BMS controls. The presence of mild to moderate para-strut fibrin deposits ranged from 66.7 to 83.4% in all EES platforms compared with 16.7% in the EBMS group. CONCLUSION: The FHS coronary injury model showed the efficacy of several EES platforms compared with an identical BMS control. Everolimus eluted from different polymeric platforms showed lower levels of inflammation and slightly higher fibrin deposits compared with BMS controls.

Impact of stent surface on thrombogenicity and vascular healing: a comparative analysis of metallic and polymeric surfaces.

BACKGROUND: Emerging drug-eluting stent technologies are evolving toward the elimination of polymeric component used as the method for modulating drug delivery. Although this technological approach seems to be biologically appealing, the impact of durable polymers and metallic stent surfaces on vascular healing remains unclear. In the present study, we aimed to compare the independent effect of a durable polymer and a metallic stent surface on thrombogenicity and endothelial cell coverage using different in vitro and in vivo experimental models. METHODS AND RESULTS: Platinum chromium (PtCr) and polyvinylidene fluoride-co-hexafluoropropene (PVDF-HFP)-coated surfaces were evaluated in this study. Thrombogenicity was assessed by exposing all surfaces to human blood under shear flow conditions. The inflammatory potential of the material was evaluated by measuring cytokine release from THP-1 cells exposed to all surfaces for 24 hours. Endothelial cell coverage was evaluated by detection of CD31 after the stents were exposed to human coronary artery endothelial cells for ≤ 14 days. Platelet adhesion (P<0.01) and activation (P=0.03) on PVDF-HFP were greater than on PtCr. In vivo, PVDF-HFP revealed more neointimal area (P<0.01) and residual parastrut fibrin (P=0.01) at 30 days compared with PtCr. PtCr displayed higher endothelialization rates and higher vascular endothelial-cadherin expression at 7 and 14 days (P=0.02) compared with PVDF-HFP. CONCLUSIONS: Thrombogenicity and vascular healing differ among metallic and polymeric stent surfaces. PVDF-HFP exhibits higher degrees of platelet activation-adhesion and thrombus accumulation in vivo compared with PtCr. PtCr displayed higher degrees of endothelial surface coverage compared with PVDF-HFP surfaces.

Comparison of the SYNERGY with the PROMUS (XIENCE V) and bare metal and polymer-only Element control stents in porcine coronary arteries.

AIMS: This study evaluated vascular compatibility of the novel platinum chromium alloy Element stent platform delivering abluminal everolimus from a poly-lactide-co-glycolide bioabsorbable polymer (SYNERGY stent), currently undergoing clinical trial, compared with the PROMUS (XIENCE V) and bare metal and polymer-only Element stents. METHODS AND RESULTS: Stents (n=161) were implanted one per coronary artery in 72 swine at a stent-to-artery ratio of 1.1:1. Similar numbers of each device group were explanted at each of 30, 90, 180, and 360 days (except no PROMUS (XIENCE V) stent at 360 days) for pathological analysis. There was no stent thrombosis, myocardial infarction, or strut fractures in any group. Vascular response was similar between the SYNERGY and PROMUS (XIENCE V) stents, with no thrombi and complete endothelialisation on both scanning electron microscopy and histology at 30, 90 and 180 days. There were no significant differences for the morphologic parameters of luminal thrombus, endothelial cell coverage, strut tissue coverage, inflammation, internal elastic lamina (IEL) disruption, external elastic lamina (EEL) disruption and medial smooth muscle cell loss across device groups or between time points, but there was mild but greater (p<0.0001) para-strut fibrin at 30 days for both drug-eluting stents (DES) compared with the bare and polymer-only controls; this difference completely dissipated by 90 days. Inflammation was predominantly minimal to mild for all device types. No morphometric parameters, including intimal thickness, stent profile-based area stenosis, and EEL area were significantly different when comparing the SYNERGY stent with the bare metal Element and polymer-only Element control stents at 90, 180 and 360 days. CONCLUSIONS: In this non-injured porcine coronary artery model, the bioabsorbable polymer SYNERGY stent demonstrated vascular compatibility equivalent to the PROMUS (XIENCE V) stent and to the bare metal and polymer-only Element stents.

Vascular responses to drug-eluting and bare metal stents in diabetic/hypercholesterolemic and nonatherosclerotic porcine coronary arteries.

BACKGROUND: Animal models used to gain insight into the vascular response to drug-eluting stents are generally juvenile and nonatherosclerotic, whereas stents are placed in patients with complex atherosclerosis and comorbidities. Hence, models reflecting these complexities are needed to help elucidate the vascular effects of drug-eluting stents. We compared the vascular responses with bare metal stent (BMS) and paclitaxel-eluting stent (PES) implantation in a diabetic/hypercholesterolemic (DM/HC) porcine model of advanced coronary atherosclerosis with the standard juvenile porcine model. METHODS AND RESULTS: Two studies using similar stent procedural protocols were performed in either DM/HC (n=20) or domestic swine (non-DM/HC, n=20). Animals pretreated with dual-antiplatelet therapy, underwent BMS or PES implantation (1/artery, 2 stents per animal) and were euthanized 30 or 90 days later. DM/HC resulted in a 24% increase in platelet aggregation (P=0.05 versus baseline), whereas dual-antiplatelet therapy reduced platelet aggregation in both groups (P<0.0001). DM/HC pigs developed substantially greater neointimal area versus non-DM/HC pigs, regardless of stent type, (P=0.004 for BMS at 30 days and P=0.002 at 90 days, P=0.005 for PES at 30 days, P=0.002 at 90 days). Compared with non-DM/HC pigs, reendothelialization was delayed in DM/HC pigs, more so after PES implantation. Increased para-strut leukocytes were observed for PES compared with BMS in the DM/HC pigs at both 30 days (P=0.023) and 90 days (P=0.04). As well, increased T-lymphocyte infiltration was seen in the DM/HC pigs. CONCLUSIONS: Stent implantation in a DM/HC swine model provides a metabolic environment closer to human disease, including hyperglycemia, hypercholesterolemia, and increased platelet aggregation. This model augmented differences in the vascular response between PES and BMS that are not as clearly evident in the non-DM/HC swine, including increased neointimal area, delayed reendothelialization, and greater, persistent vascular inflammation.

Strut tissue coverage and endothelial cell coverage: a comparison between bare metal stent platforms and platinum chromium stents with and without everolimus-eluting coating.

AIMS: In a rabbit denudation model, assess impact of strut thickness on arterial healing by comparing endothelial cell coverage and strut tissue coverage after implantation of bare metal stents of varying thickness; evaluate the effect of an everolimus-eluting stent. METHODS AND RESULTS: Strut tissue coverage and endothelialisation were assessed 14 and 21 days after implantation with scanning electron microscopy quantitation methods and immunostaining against the endothelial cell marker PECAM-1 (CD-31). At 14 days, strut tissue coverage was higher with the stainless steel Liberté stent (88%, 97 µm) versus Express (77%, 132 µm). The platinum chromium Element stent with the thinnest strut (81 µm) had the highest level (95%). By 21 days endothelialisation was complete for all. The everolimus-eluting Element stent had a 1-week delay in luminal endothelialisation but was >89% by 21 days; strut endothelial coverage was >79% in 80% (4/5) of animals, with total strut tissue coverage >95%. CONCLUSIONS: This study demonstrated that strut thickness affects strut tissue coverage post stent implantation and the addition of an everolimus-eluting polymer introduces a short delay in endothelialisation. The results highlight the need to control for aspects of stent design such as strut thickness when comparing across drug-eluting stent platforms.

Vascular response to a third generation everolimus-eluting stent.

AIMS: In a non-injured porcine coronary artery model, the aim was to evaluate vascular compatibility of the novel platinum chromium everolimus-eluting PROMUS Element stent as compared to the following control stents: everolimus-eluting PROMUS (XIENCE V), bare metal Element, and polymer-only Element. METHODS AND RESULTS: Stent pairs (n=228) evenly distributed among the four stent types were implanted in overlap configuration in 79 pigs at a targeted stent-to-artery ratio of 1.1:1. Similar numbers were explanted at each of 7, 30, 90, 180, and 270 days for pathological analysis. No stent-related mortality or morbidity was observed. There were no stent occlusions or strut fractures. The PROMUS Element was more radiopaque than PROMUS (relative densities 9.9 and 9.1, respectively) and demonstrated at all time points vascular compatibility similar to that of the control stents for endothelial cell coverage, inflammatory response, and neointima formation. At 30 days, parastrut fibrin was mild but greater (P<0.0001) for the drug-eluting stents than either for the bare metal or the polymer-only Element; however, by 90 days the fibrin had dissipated. CONCLUSIONS: In the non-injured porcine coronary artery model, the PROMUS Element demonstrated vascular compatibility equivalent to PROMUS and the bare metal and polymer-only stents.

New stent design for use in small coronary arteries during percutaneous coronary intervention.

Patients with diabetes mellitus, of female gender, increased age, and/or with peripheral vascular disease often develop coronary stenoses in small caliber vessels. This review describes treatment of these lesions with the paclitaxel-eluting 2.25 mm TAXUS(®) Liberté(®) Atom™ stent. Given the same stent composition, polymer, antirestenotic drug (paclitaxel), and release kinetics as the first-generation 2.25 mm TAXUS(®) Express(®) Atom™ stent, the second-generation TAXUS Liberté Atom stent incorporates improved stent design characteristics, including thinner struts (0.0038 versus 0.0052 inches), intended to increase conformability and deliverability. In a porcine noninjured coronary artery model, TAXUS Liberté Atom stent implantation in small vessels demonstrated complete strut tissue coverage compared with the bare metal stent control, suggesting a similar degree of tissue healing between the groups at 30, 90, and 180 days. The prospective, single-armed TAXUS ATLAS Small Vessel trial demonstrated improved instent late loss (0.28 ± 0.45 versus 0.84 ± 0.57 mm, P < 0.001), instent binary restenosis (13.0% versus 38.1%, P < 0.001), and target lesion revascularization (5.8% versus 17.6%, P < 0.001) at nine months with the TAXUS Liberté Atom stent as compared with the bare metal Express stent control, with similar safety measures between the two groups. The TAXUS Liberté Atom also significantly reduced nine-month angiographic rates of both instent late loss (0.28 ± 0.45 versus 0.44 ± 0.61 mm, P = 0.03) and instent binary restenosis (13.0% versus 25.9%, P = 0.02) when compared with the 2.25 mm TAXUS Express Atom control. The observed reduction in target lesion revascularization with the TAXUS Liberté Atom compared with the TAXUS Express Atom at nine months (5.8% versus 13.7%, P = 0.02) was sustained through three years (10.0% versus 22.1%, P = 0.008) with similar, stable safety outcomes between the groups. In conclusion, these data confirm the safety and favorable performance of the TAXUS Liberté Atom stent in the treatment of small coronary vessels.

Early vascular response to overlapped paclitaxel-eluting stents in swine coronary arteries.

BACKGROUND: The early response to the TAXUS Express2 paclitaxel-eluting stent (PES) system was compared to the response to the Express2 bare metal stent (BMS) system in porcine arteries. METHODS: Swine coronary arteries were implanted with overlapping PES or BMS and examined at 1, 2, 4, 10, and 20 days postimplantation using scanning electron microscopy or light microscopy. RESULTS: Vascular healing in terms of strut coverage, reendothelialization, degree of inflammation, and absence of thrombus was equivalent in both groups from 1 to 20 days. Interstrut member spaces were unaffected by stent deployment and remained covered with endothelium from Day 1. In both groups at 2 days, small patches of endothelial cells covered approximately 5-10% of the stent surface. At 4 days, endothelial cell coverage progressed to nearly 50% in both groups. After 10 days, endothelial cell strut coverage was nearly complete (>90%), with regions of incomplete coverage located primarily in strut overlap regions in both groups. BMS exhibited a fibrocellular neointima and no parastrut fibrin, whereas PES exhibited a developing but immature fibrocellular neointima and prominent parastrut fibrin. By Day 20, an endothelialized neointima was present in both groups, with comparable coverage of proximal and distal stented regions. The neointima of PES was more fibrocellular and parastrut fibrin was still comparable to that at 10 days. CONCLUSION: Early vascular response was comparable for both PES and BMS, with similar rates of reendothelialization, limited inflammatory response, and absence of thrombus, but differed parastrut fibrin clearance and neointimal maturation rate.

Overlapping paclitaxel-eluting stents: long-term effects in a porcine coronary artery model.

OBJECTIVE: At 4-year follow-up, paclitaxel-eluting stents (PES, TAXUS) have demonstrated clinical effectiveness in reducing restenosis without increasing death or myocardial infarction. Concerns remain with all drug-eluting stents, however, regarding potential interference with long-term healing, particularly in zones with adjacent stent overlap due to theoretical doubling in both drug release and tissue contact with coating polymer. Therefore, we evaluated long-term healing of overlapped TAXUS stents in an accepted animal model. METHODS: Seventy-one non-injured swine underwent coronary artery placement of 138 overlapping stent-pairs (91 PES TAXUS Liberté 1 microg/mm(2) slow release formulation, 3.0 or 3.5 mm diameter pairs and 47 control bare metal Liberté pairs) deployed at a 1.1:1 to 1.2:1 target stent-to-artery diameter ratio. Pathological analysis was performed at 30 (9 bare, 10 paclitaxel), 90 (9 bare, 10 paclitaxel), 180 (10 bare, 16 paclitaxel), 360 (10 bare, 21 paclitaxel), and 580 (9 bare, 22 paclitaxel) days. RESULTS: At all time intervals overlapped TAXUS stents were consistently endothelialized and free of luminal thrombus or vascular dilatation. Full healing, however, was delayed compared to control, with macrophage processed para-strut fibrin and cellular debris still present, but reduced and sequestered from blood flow by an endothelialized neointima at 360 and 580 days. While neointimal thickness in TAXUS overlap zones was significantly less than control at 30 days, greater neointima formation was observed with TAXUS at > or =90 days, but was stable and did not progress further from 90 to 580 days. CONCLUSION: In this porcine model TAXUS stents demonstrated safety and acceptable healing with prolonged time to resolution of para-strut deposits, and did not produce the sustained neointimal suppression seen clinically.