Campbell Rogers

Prediction of the Localization of High-Risk Coronary Atherosclerotic Plaques on the Basis of Low Endothelial Shear Stress An Intravascular Ultrasound and Histopathology Natural History Study

Background— Low endothelial shear stress (ESS) promotes the development of atherosclerosis; however, its role in the progression of atherosclerotic plaques and evolution to inflamed high-risk plaques has not been studied. Our hypothesis was that the lowest values of ESS are responsible for the development of high-risk coronary atherosclerotic plaques associated with excessive expansive remodeling. Methods and Results— Twenty-four swine, treated with streptozotocin to induce diabetes and fed a high-fat diet, were allocated into early (n=12) and late (n=12) atherosclerosis groups. Intima-media thickness was assessed by intravascular ultrasound in the coronary arteries at weeks 4 and 8 in the early group and weeks 23 and 30 in the late group. Plaques started to develop after week 8, leading to marked heterogeneity in plaque severity at week 30. ESS was calculated in plaque-free subsegments of interest (n=142) in the late group at week 23. Coronary arteries (n=31) of this group were harvested at week 30, and the subsegments of interest were identified and analyzed histopathologically. Low ESS was an independent predictor of the development of high-risk plaques, characterized by intense lipid accumulation, inflammation, thin fibrous cap, severe internal elastic lamina degradation, and excessive expansive remodeling. The severity of high-risk plaque characteristics at week 30 was significantly correlated with the magnitude of low ESS at week 23. Conclusions— The magnitude of low ESS determines the complexity and heterogeneity of atherosclerotic lesions and predicts the development of high-risk plaque.

Balloon-Artery Interactions During Stent Placement: A Finite Element Analysis Approach to Pressure, Compliance, and Stent Design as Contributors to Vascular Injury

Endovascular stents expand the arterial lumen more than balloon angioplasty and reduce rates of restenosis after coronary angioplasty in selected patients. Understanding the factors involved in vascular injury imposed during stent deployment may allow optimization of stent design and stent-placement protocols so as to limit vascular injury and perhaps reduce restenosis. Addressing the hypothesis that a previously undescribed mechanism of vascular injury during stent deployment is balloon-artery interaction, we have used finite element analysis to model how balloon-artery contact stress and area depend on stent-strut geometry, balloon compliance, and inflation pressure. We also examined superficial injury during deployment of stents of varied design in vivo and in a phantom model ex vivo to show that balloon-induced damage can be modulated by altering stent design. Our results show that higher inflation pressures, wider stent-strut openings, and more compliant balloon materials cause markedly larger surface-contact areas and contact stresses between stent struts. Appreciating that the contact stress and contact area are functions of placement pressure, stent geometry, and balloon compliance may help direct development of novel stent designs and stent-deployment protocols so as to minimize vascular injury during stenting and perhaps to optimize long-term outcomes.

Inhibition of experimental neointimal hyperplasia and thrombosis depends on the type of vascular injury and the site of drug administration.

BACKGROUND Heparin inhibits vascular smooth muscle cell proliferation in tissue culture and limits neointimal hyperplasia after experimental arterial injury but has been ineffective in reducing clinical restenosis. We examined how this discrepancy might reflect suboptimal drug-tissue interactions and/or differences in the vascular response to injury. METHODS AND RESULTS Intravenous infusion was compared with local administration of heparin to injured rabbit iliac arteries either from drug-impregnated polymeric controlled release matrices in the perivascular space or from drug-releasing endovascular stents. Occlusive thrombosis, seen in 42% of control stent-bearing arteries, and partial thrombosis were virtually eliminated by heparin delivery from any route. Intimal area 14 days after balloon withdrawal denudation alone was reduced to an equal extent by continuous systemic heparin or by perivascular heparin for the first 3 days. In contrast, endovascular stents produced more exuberant neointimal hyperplasia, the inhibition of which required continuous rather than only early heparin administration. Neither perivascular delivery limited to the first 3 days nor stent-based delivery reduced neointimal hyperplasia as effectively. CONCLUSIONS The antiproliferative and antithrombotic effects of heparin differ markedly, depending on the type of arterial injury and the mode of drug administration. Different forms of injury may require different therapies, and complications of arterial intervention such as excessive neointimal hyperplasia and thrombosis may demand alternate therapeutic regimens. Duration, dose, and site of delivery rather than frank resistance to therapy may explain why experimentally effective antiproliferative and antithrombotic agents fail clinically.

Vascular closure devices and the risk of vascular complications after percutaneous coronary intervention in patients receiving glycoprotein IIb-IIIa inhibitors

Vascular closure devices offer advantages over traditional means of obtaining hemostasis after percutaneous coronary intervention (PCI) in terms of patient comfort and time to ambulation. We investigate whether such devices also reduce the risk of vascular complications in selected patient populations. We conducted a retrospective analysis of all patients who underwent PCI at our institution between January 1998 and December 1999. Of 3,151 consecutive patients, 3,027 were eligible to receive vascular closure devices. Of these, 1,485 received a closure device and 1,409 received glycoprotein IIb-IIIa antagonists. The overall vascular complication rate, as defined by the need for surgical repair or transfusion, or the development of arteriovenous fistula, pseudoaneurysm, or large hematoma, was 4.20%. By univariate analysis, the use of closure devices was associated with a lower vascular complication rate (3.03% vs 5.52%; p = 0.002) and a shorter length of hospital stay (2.77 vs 3.97 days, p <0.001). Multivariate analysis showed a significant reduction in vascular complications with closure devices (odds ratio 0.59, p = 0.007). For the subgroup of patients receiving glycoprotein IIb-IIIa antagonists, the use of closure devices was associated with an even more pronounced reduction in the risk of vascular complications (odds ratio 0.45, p <0.008). Thus, the use of closure devices in selected patients undergoing PCI is associated with a low rate of vascular complications and decreased length of stay. This benefit was most marked for patients receiving glycoprotein IIb-IIIa antagonists.

The porcine coronary model of in-stent restenosis: Current status in the era of drug-eluting stents

Drug‐eluting stents are revolutionizing interventional cardiology. Sirolimus‐eluting stents are in widespread clinical use, associated with well‐documented remarkably low restenosis rates, and a number of other agents appear promising in clinical trials. These human studies have been preceded by numerous animal studies, foremost among them the pig coronary model of in‐stent restenosis (ISR). The histologic response to porcine coronary stenting was described over a decade ago. Porcine stenting studies now provide examinations not only of histology, but also mechanisms of action, toxicity, and biocompatibility. This review therefore examines the current status of this porcine coronary model of ISR. Contemporary methods of pig coronary stenting are discussed. The morphometric, cellular, and molecular analyses of the responses to stent injury are then described. Finally, recent pig coronary drug‐eluting stent studies are examined, with a discussion of their advantages, limitations, and possible future modifications. Catheter Cardiovasc Interv 2003;60:515–523.

Six-Month Results of the NEVO RES-ELUTION I (NEVO RES-I) Trial A Randomized, Multicenter Comparison of the NEVO Sirolimus-Eluting Coronary Stent With the TAXUS Liberté Paclitaxel-Eluting Stent in De Novo Native Coronary Artery Lesions

Background—Drug-eluting stents reduce restenosis and reintervention rates but are complicated by stent thrombosis, which may be related to polymer coating. The NEVO sirolimus-eluting coronary stent (NEVO SES) is designed to improve long-term percutaneous coronary intervention safety by combining sirolimus release from reservoirs with bioabsorbable polymer to reduce spatial and temporal polymer exposure. Methods and Results—NEVO ResElution-I was a prospective randomized study in 394 patients with coronary artery disease comparing the NEVO SES with the TAXUS Liberté paclitaxel-eluting coronary stent (TAXUS Liberté PES) stent. The primary end point was in-stent angiographic late loss at 6 months. Six months after percutaneous coronary intervention (PCI), the primary end point favored NEVO SES (0.13±0.31 mm versus 0.36±0.48 mm, P<0.001 for noninferiority and superiority). The study was not powered for clinical end points and showed no significant difference for NEVO SES versus TAXUS Liberté PES: death: 0.5 versus 1.6%, P=0.36; myocardial infarction: 2.0 versus 2.6%, P=0.75; target lesion revascularization: 1.5 versus 3.2%, P=0.33; major adverse cardiac events: 4.0 versus 7.4%, P=0.19. No stent thrombosis was observed with NEVO SES, whereas 2 cases occurred in TAXUS Liberté PES. Intravascular ultrasound showed lower percent volume obstruction for NEVO SES (5.5±11% versus 11.5±9.7%, P=0.016). Conclusions—This trial proved the superiority of NEVO SES over TAXUS Liberté PES for the primary angiographic end point of in-stent late loss. No stent thrombosis occurred in the NEVO SES group. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00606333.Background— Drug-eluting stents reduce restenosis and reintervention rates but are complicated by stent thrombosis, which may be related to polymer coating. The NEVO sirolimus-eluting coronary stent (NEVO SES) is designed to improve long-term percutaneous coronary intervention safety by combining sirolimus release from reservoirs with bioabsorbable polymer to reduce spatial and temporal polymer exposure. Methods and Results— NEVO ResElution-I was a prospective randomized study in 394 patients with coronary artery disease comparing the NEVO SES with the TAXUS Liberte paclitaxel-eluting coronary stent (TAXUS Liberte PES) stent. The primary end point was in-stent angiographic late loss at 6 months. Six months after percutaneous coronary intervention (PCI), the primary end point favored NEVO SES (0.13±0.31 mm versus 0.36±0.48 mm, P <0.001 for noninferiority and superiority). The study was not powered for clinical end points and showed no significant difference for NEVO SES versus TAXUS Liberte PES: death: 0.5 versus 1.6%, P =0.36; myocardial infarction: 2.0 versus 2.6%, P =0.75; target lesion revascularization: 1.5 versus 3.2%, P =0.33; major adverse cardiac events: 4.0 versus 7.4%, P =0.19. No stent thrombosis was observed with NEVO SES, whereas 2 cases occurred in TAXUS Liberte PES. Intravascular ultrasound showed lower percent volume obstruction for NEVO SES (5.5±11% versus 11.5±9.7%, P =0.016). Conclusions— This trial proved the superiority of NEVO SES over TAXUS Liberte PES for the primary angiographic end point of in-stent late loss. No stent thrombosis occurred in the NEVO SES group. Clinical Trial Registration— URL: . Unique identifier: [NCT00606333][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00606333&atom=%2Fcirccvint%2F3%2F6%2F556.atom

Deep Myocardial Ablation Lesions Can Be Created with a Retractable Needle-Tipped Catheter

RF catheter ablation of ventricular tachycardia is sometimes limited by inadequate lesion depth. This study investigated the use of a retractable needle‐tipped catheter to create deep RF lesions in vivo in porcine myocardium. An 8 Fr electrode catheter with an extendable 27‐gauge needle at the tip was modified for RF ablation by embedding a thermocouple and attaching a pin connector. In three swine (32–58 kg) the left ventricle was entered via the femoral artery and endocardial contact was made. The needle was advanced 10 mm and 13 RF applications were made under a controlled temperature (90°C × 120 s). Nine control lesions were made using a standard 4‐mm tip catheter (60°C × 120 s). The lesions were fixed, serially sectioned from the endocardium, digitally imaged, and quantified. Needle ablation lesions were deeper (10.15 ± 0.77 vs 5.67 ± 0.37 mm, P < 0.001) and more likely to be transmural (77 vs 11%, P = 0.008) than control lesions. The volume of control lesions, however, was larger (358.4 ± 56.2 vs 174.7 ± 18.6 mm3, P = 0.002) due to a significantly larger cross‐sectional area at the endocardium (0.548 ± 0.04 vs 0.151 ± 0.01 cm2, P < 0.001). At depths > 6 mm, the needle electrode lesions had a greater cross‐sectional area (0.136 ± 0.01 vs 0.005 ± 0.004 cm2, P < 0.001). Catheter‐based needle ablation is feasible and allows creation of deeper lesions that can be transmural. Although deep, the lesions had a small cross‐sectional area such that precise targeting would be required for success. (PACE 2004; 27:594–599)

Coronary artery perforation by cutting balloon resulting in dissecting subepicardial hematoma and avulsion of the vasculature

We report a case of perforation caused by cutting balloon angioplasty of in‐stent restenosis in a saphenous vein coronary bypass graft. This was complicated by a subepicardial hematoma leading to avulsion of the penetrating arteries and cardiogenic shock. Despite surgical evacuation and percutaneous left ventricular assist‐device support, death ensued. Catheter Cardiovasc Interv 2005;64:163–168.

Kissing sirolimus-eluting stents for the treatment of left main coronary artery stenosis

We present a case of kissing drug‐eluting stent deployment in the left main coronary artery in a 43‐year‐old male with failed previous bypass grafting. We discuss the technique used for stent deployment and the rationale for using this technique in the drug‐eluting stent era. Catheter Cardiovasc Interv 2004;61:206–210.

Stent-based release of paclitaxel to prevent restenosis

Paclitaxel ist eine die Mikrotubuli stabilisierende Substanz mit antiproliferativen Eigenschaften. Sowohl in experimentiellen Untersuchungen als auch in klinischen Studien hat sich Paclitaxel als vielversprechender Wirkstoff zur Restenosehemmung erwiesen. Intrinsische Effekte, einschließlich einer Abschwächung der Migration sowie der Proliferation glatter Muskelzellen und eine Inhibition zellulärer und subzellulärer Komponenten der Entzündung, interagieren mit den hauptsächlichen Mechanismen der Restenoseentstehung. Darüberhinaus prädestinieren die biophysikalischen Eigenschaften – besonders die Lipophilie – Paclitaxel für eine Freisetzung aus einer polymeren Matrix und eine selektive Verteilung in lipidreichen Atheromen der Arterienwand ohne wesentliche systemische Anreicherung und Toxizität. Die in vitro gezeigte Eigenschaft einer selektiven Inhibition der Proliferation von glatten Muskelzellen, nicht jedoch von Endothelzellen lässt vermuten, dass Paclitaxel die fibromuskuläre Proliferation nach Gefäßverletzung ohne Störung der Reendothelialisierung zu hemmen vermag. In einem Tiermodell einer Gefäßverletzung von New Zealand White Rabbits resultierte die Implantation von NIR-Stents, die mit pLA/pCL bioabbaubarem Polymer und Paclitaxel (200 μg, Freisetzung über 56 Tage) beschichtet waren, im Vergleich zu Kontrollen in einer nahezu vollständigen Hemmung der Neointimaformation. Der Effekt auf die Wundheilung hielt noch nach sechs Monaten an, lange nachdem die Freisetzung des Paclitaxel und der Abbau des Polymers abgeschlossen waren. In einem weiteren Versuch wurden NIR-Stents, die mit einem nicht abbaubarem Polymer beschichtet wurden und entweder mit einer größeren Dosis einer rasch freigesetzten Pacitaxel-Zubereitung (Hochdosisgruppe) oder einer niedrigeren Dosis einer langsam freigesetzten Paclitaxel-Zubereitung versehen wurden, in Schweinekoronararterien implantiert. Die mit einer hohen Dosis von Paclitaxel behandelten Gefäße entwickelten ausgedehnte Gewebsnekrosen, unvollständige Heilung, zeigten späte Stentmalapposition und späte Stentthrombose in 25 % der Fälle. Die Niedrig-Dosis-Gruppe entwickelte minimale Neointimaformation, zeigte vollständige Endothelialisierung und Wundheilung nach 90 Tagen. Komplikationen traten nicht auf. Die Ergebnisse dieser Tierexperimente zeigten, dass eine stent-basierte Paclitaxelfreisetzung einen profunden und dauerhaften Effekt hat, jedoch eine relativ geringe therapeutische Breite besteht. Klinische Pilotstudien einschließlich TAXUS I (unter Verwendung des NIR-Stents mit dem oben beschriebenen Niedrigdosisprofil) an humanen Koronararterien zeigten eine erstaunlich Reduktion der Restenoserate. Weitere Studien mit größeren Fallzahlen sind erforderlich, um die Sicherheit und Effektivität einer stent-basierten Paclitaxel-Freisetzung im Rahmen der alltäglichen klinischen Anwendung auch an komplexen Läsionen wie beispielsweise Bifurkationsstenosen und der Hauptstammerkrankung zu überprüfen. Außerdem müssen die Wirkungen von sich überlappenden Stents untersucht und die adäquate Dauer einer antithrombozytären Therapie definiert werden. Paclitaxel, a microtubule-stabilizing agent with potent antiproliferative effects, has shown great promise as a locally delivered, antirestenotic therapy in both experimental and pilot clinical trials. Its protean effects, including attenuation of smooth muscle cell migration and proliferation and inhibition of cellular and subcellular components of inflammation, interfere with major elements of restenosis. In addition, paclitaxels biophysical attributes – particularly its lipophilicity – allow for ready delivery from a polymer matrix, selective partitioning into lipid-rich atheroma in the arterial wall, with minimal systemic delivery and toxicity. In vitro selective inhibition of smooth muscle cell versus endothelial cell proliferation suggests that paclitaxel may reduce the fibromuscular proliferation following vascular injury without disrupting endothelialization. In a New Zealand White rabbit model of arterial injury, implantation of NIR stents coated with pLA/pCL bioerodible polymer loaded with paclitaxel (200 mcg, delivered over 56 days) resulted in near-total abolition of neointimal proliferation compared to vessels treated with control stents. The impact on wound healing was sustained for at least six months, long after drug delivery and polymer degradation were complete. NIR stents coated with a non-erodible polymer loaded with either a high dose of rapidly-delivered paclitaxel (“high dose” group) or a low dose of slowly-delivered paclitaxel (“low dose” group) were implanted in pig coronary arteries. “High dose” stented vessels developed wide-spread tissue necrosis, incomplete healing, late stent malapposition, and late stent thrombosis in 25 % of treated vessels. “Low dose” stented vessels developed minimal neointima, complete endothelialization and wound healing by 90 days, and no thrombotic complications. From rabbit and porcine data, it is clear that stent-based paclitaxel delivery may have a profound and durable effect, but that tissue dosimetry must be carefully contained within the therapeutic window. Pilot clinical trials including TAXUS I (using the NIR stent “low dose” profile described above) have demonstrated an astonishing effect on restenosis reduction in human coronaries. Furthermore, larger-scale trials will be needed to confirm the safety and efficacy of stent-based paclitaxel delivery and its applicability to more complex, “real world” clinical situations including bifurcation lesions, left main disease, the use of overlapping stents, and the potential need for extended anti-platelet therapy.