Barbara Huibregtse

Comparison of Inflammatory Response After Implantation of Sirolimus- and Paclitaxel-Eluting Stents in Porcine Coronary Arteries

Background— Although both sirolimus (CYPHER) and paclitaxel (TAXUS) drug-eluting stents have demonstrated efficacy and safety in clinical trials, human autopsy data have raised concerns about long-term healing and the potential for local inflammatory reactions. Methods and Results— Overlapping stents (CYPHER drug-eluting stents, Bx SONIC bare metal stents, TAXUS drug-eluting stents, and Liberté bare metal stents) were implanted in noninjured coronary arteries of 58 domestic swine. Histopathological evaluation of proximal, overlapped, and distal stented segments was determined with emphasis on inflammation at 30, 90, and 180 days. Circumferential granulomatous inflammation in all stented segments was defined as inflammation consisting of macrophages, multinucleated giant cells, lymphocytes, and granulocytes, including many eosinophils, adjacent to almost all struts. Circumferential granulomatous inflammation was more prevalent in CYPHER (9 of 23, 39%) compared with TAXUS (1 of 21, 5%; P=0.01) and control bare metal stents (0 of 44) in the combined 90- and 180-day cohorts. Only CYPHER specimens showed marked adventitial inflammation (P=0.0025) and fibrosis (P=0.0055) accompanied by extensive remodeling. Fibrin deposition within neointima and medial smooth muscle cell death were greater (both P<0.001) in TAXUS than CYPHER at 30 days, with more fibrin in TAXUS than CYPHER through 90 days (P<0.05). Conclusions— Although these data cannot be directly extrapolated to humans, the high prevalence in this porcine model of diffuse granulomatous inflammation seen with CYPHER stents, persisting at 180 days and associated with extensive remodeling of the artery, and persistent para-strut fibrin deposition with TAXUS stents emphasize the need for further investigation of biocompatibility with these and other novel combination drug/polymer drug-eluting stents.

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.

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.

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.

The SYNERGY biodegradable polymer everolimus eluting coronary stent: Porcine vascular compatibility and polymer safety study.

SYNERGY is a novel platinum chromium alloy stent that delivers abluminal everolimus from an ultrathin poly‐lactide‐co‐glycide (PLGA) biodegradable polymer. This study evaluated the in vivo degradation of the polymer coating, everolimus release time course, and vascular compatibility of the SYNERGY stent.

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.

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.

Time dependent vascular and myocardial responses of a second generation, small vessel, paclitaxel-eluting stent platform.

Objectives: The purpose of this study was to evaluate the time‐dependent vascular and myocardial responses to a second‐generation, small vessel (≤2.5 mm) paclitaxel‐eluting stent (PES) platform. Background: Small caliber coronary vessels present complex challenges for percutaneous coronary intervention (PCI) and are associated with lower technical success and inferior long‐term efficacy. A next‐generation, highly deliverable PES may improve clinical outcomes in small vessels. Methods: Sixty single stents were implanted in noninjured coronary arteries in 30 domestic swine (one TAXUS® Liberté™ small vessel PES (svPES) and one Liberté small vessel bare metal stent (svBMS) in each animal). Ten animals each were allocated to 30‐, 90‐, and 180‐day follow‐up groups; final quantitative angiography and necropsy were performed. Samples of myocardium, liver, and kidney were processed and evaluated for pathology. Radiography and either histopathology or scanning electron microscopy were performed on all the explanted stented vessels. Results: There were no stent‐related deaths or downstream myocardial pathology. Both the svPES stent and its svBMS control demonstrated complete strut tissue coverage and complete endothelialization at all timepoints, and there was no evidence of macro‐ or microscopic thrombus or stent fracture. Medial smooth muscle cell content was markedly reduced in all the svPES groups compared with that in the svBMS controls. Conclusions: The small diameter paclitaxel‐eluting TAXUS Liberté stent has a safe and predictable biologic vascular response in the noninjured swine model. This device warrants further investigation targeting the currently poorly met clinical need for small vessel PCI.

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.