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.

Vasomotor function and re-endothelialisation after implantation of biodegradable abluminal polymer coated paclitaxel-eluting stents in rabbit iliac arteries: a time-course study.

AIMS: To evaluate the time-course of vasomotor function and re-endothelialisation after implantation of a novel platinum-chromium (PtCr) abluminal biodegradable polymer-coated paclitaxel-eluting stent (PES, Labcoat Element) in rabbit iliac arteries. METHODS AND RESULTS: Either PES (n=18) or an identical platform of bare metal stents (BMS, Element, n=18) were implanted in rabbit iliac arteries (six animals per time-point). At 14, 30, and 90 days, acetylcholine- and nitroglycerine-induced vasomotor reactivity at 5-10 mm distal to the stent was measured. Subsequently, the animals were terminated. The stented artery was bisected longitudinally for either SEM or en face CD31 immunochemistry examination. All arteries were patent with normal angiographic flow. Decreased endothelial-dependent vasomotion was found at both 14 and 30 days for PES compared to BMS (p<0.01, respectively); however, these differences resolved by 90 days. Endothelial-independent vasorelaxation was similar at all three time-points. Both SEM and en face staining demonstrated equivalent endothelial coverage on the surface of the stented segments above and between struts at all time-points. CONCLUSIONS: This novel bioabsorbable polymer abluminal-coated PES demonstrated vasomotor function comparable to BMS within three months post-deployment in the rabbit iliac model. Despite indistinguishable endothelial cell coverage on the stent surface between groups, earlier differences in vasomotion were detected: this finding suggests that the timing of restoration vasomotor function lags morphologic endothelial recovery.

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.

Coronary bare metal stent implantation in homozygous LDL receptor deficient swine induces a neointimal formation pattern similar to humans.

INTRODUCTION: To date, most of all new developments in stent technologies are tested in normal animals. Although invaluable in the evaluation of device safety, the juvenile domestic swine (DS) do not follow the biological healing response occurring in humans following coronary stent implantation. By using a novel swine breed afflicted with familial hypercholesterolemia (FHS), we aimed to analyse the vascular response occurring following bare metal stent (BMS) implantation by comparing in vivo endovascular imaging and histological data. METHODS: A total of 26 swine were included in this study (12 FHS and 14 DS). Sixty eight BMS (FHS=28 versus DS=40) were implanted using a 10% overstretch ratio. Imaging evaluation (IVUS and OCT) was conducted in all animals at 30 (n=14) or 90 (n=12) days following stent implantation. After imaging, the stented coronary segments were harvested for histological evaluation. RESULTS: At 30 days, the degree of neointimal formation analysed by OCT (%AS=DS 21.9 ± 10% versus FHS 25.4 ± 12%; p=0.18) and histology (DS 24.6 ± 10% versus FHS 23.58 ± 10%; p=0.8) was similar between both animal groups. At 90 days, the degree of neointimal formation in the DS group decreased in all analysed variables (-40% in IVUS neointimal volume, -57% in OCT %AS, and -30% in %AS by histology) compared to the progression of neointimal formation observed in the FHS group (+29% in IVUS neointimal volume, +27% in OCT %AS and +43% in %AS by histology). CONCLUSION: The pattern of neointimal formation following BMS implantation in the FHS follows a progressive course that does not occur in the DS. Therefore, by providing a progressive neointimal biological response to BMS implantation, the FHS could serve as an ideal efficacy model for the validation of drug eluting stent technologies.

Induction of immunological tolerance/hyporesponsiveness in baboons with a nondepleting CD4 antibody.

Tolerance induction with anti-CD4 Abs is well established in rodent transplant and autoimmune disease models, but has yet to be demonstrated in non-human primates or in clinical studies. In retrospect, failure of anti-CD4 Abs to induce tolerance in primates may be technical, a consequence of insufficient dosing and Ab properties influencing immunogenicity and cell depletion. To circumvent these possible limitations, we constructed a novel anti-CD4 mAb, TRX1, humanized to reduce immunogenicity and Fc-modified to prevent cell depletion. Using equine immune globulin (equine Ig) as a model Ag, we examined the tolerance-inducing capacity of TRX1 in baboons. During the induction phase, TRX1 inhibited the humoral response to equine Ig in a dose-dependent manner, with complete suppression of response at the highest dose tested (40 mg/kg). Upon challenge, anti-equine Ig responses were generated in baboons treated with 1 and 10 mg/kg doses of TRX1 and in control animals. In higher dosing cohorts (20 and 40 mg/kg), however, the immune response to equine Ig was modulated in seven of nine animals, including complete unresponsiveness to Ag challenges in two animals. Five of nine were hyporesponsive to equine Ig, generating titers 50- to 250-fold lower than control groups. Repeated challenge resulted in titers falling to baseline or near baseline, with two of five hyporesponsive animals becoming unresponsive to Ag. All animals responded to neoantigen immunization, indicating that the modified response to equine Ig was Ag specific. These studies demonstrate that anti-CD4 Ab-mediated, Ag-specific tolerance can be achieved in baboons without long term immune suppression.