Hugh Zhao

Vascular Response to Zotarolimus-Coated Balloons in Injured Superficial Femoral Arteries of the Familial Hypercholesterolemic Swine

Background— Drug-coated balloons are rapidly emerging as a therapeutic alternative for the interventional treatment of peripheral vascular disease. The purpose of this study was to test the hypothesis that an angioplasty balloon coated with the mTOR inhibitor zotarolimus (ZCB) would inhibit neointimal hyperplasia in a novel injury-based superficial femoral artery model in the familial hypercholesterolemic swine. Methods and Results— A total of 44 familial hypercholesterolemic swine were included (12 designated to study tissue pharmacokinetics and 32 to study safety and efficacy). Fogarty balloon denudation was performed in all superficial femoral artery segments, followed by balloon angioplasty. In the pharmacokinetic study, a total of 24 ZCBs (300 &mgr;g/cm2) were used. Zotarolimus was detected in arterial tissue at 5 minutes (162 ng/mg of tissue), 24 hours (5.9 ng/mg of tissue), and 28 days (0.007 ng/mg of tissue) after ZCB inflation. In the safety and efficacy study, superficial femoral artery segments were randomized to either high-dose (600 &mgr;g/cm2, n=16), low-dose (300 &mgr;g/cm2, n=16), or paired uncoated balloons (high-dose ZCB control, n=16; low-dose ZCB control, n=16). At 28 days, the percentage of angiographic stenosis was similar among all tested groups. Histological analysis demonstrated a reduction in neointimal formation in both ZCB groups compared with controls (high-dose ZCB 44% reduction, P=0.007; low-dose ZCB 22% reduction, P=0.08). There was no evidence of delayed arterial healing or vascular toxicity in any of the ZCB groups. Conclusions— The single delivery of zotarolimus via coated balloon is feasible, and therapeutic levels are maintained up to 28 days. The ZCB technology appears to be effective in the reduction of neointimal proliferation in the superficial femoral artery of the familial hypercholesterolemic swine.

Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy

Background— Drug-coated balloons are increasingly used for peripheral vascular disease, and, yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined zotarolimus pharmacokinetics. Methods and Results— Animal studies, bench-top experiments, and computational modeling were integrated to quantify arterial distribution after zotarolimus-coated balloon use. Drug diffusivity and binding parameters for use in computational modeling were estimated from the kinetics of zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like paclitaxel, zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with zotarolimus concentration decreasing with transmural depth as opposed to the multiple peaks displayed by paclitaxel. Drug release kinetics was measured by inflating zotarolimus-coated balloons in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion, but binding determined drug retention. Conclusions— A large bolus of zotarolimus releases during balloon inflation, some of which pervades the tissue, and a fraction of the remaining drug adheres to the tissue–lumen interface. As a result, the duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively.

A theoretical model to characterize the drug release behavior of drug-eluting stents with durable polymer matrix coating †

The time-dependent local drug delivery from drug-eluting stents (DES) plays a critical role in reducing restenosis in intravascular stenting. To better understand the basic mechanism of drug release for certain polymer-drug-coated DES platforms, a cylindrical diffusion model was applied successfully to quantitatively describe the experimental drug release data of Dynalink-E in vitro and in vivo. The results showed that the profiles of Dynalink-E everolimus release could be controlled by such characteristic parameters as coating thickness and diffusion coefficient. The model could be used to quantitatively characterize the drug release profiles and IVIV correlations.

Assessment of self-expanding nitinol stent deformation after chronic implantation into the femoropopliteal arteries.

AIMS The purpose of this prospective clinical investigation was to quantify the degree and range of compressive and bending deformations sustained by self-expanding nitinol stents when implanted into the femoropopliteal arteries of patients with symptomatic peripheral vascular disease (PVD). METHODS AND RESULTS Twenty-three nitinol self-expanding stents (Absolute; Abbott Vascular, Santa Clara, CA, USA) with diameters ranging from 5-10 mm and lengths ranging from 40-100 mm were implanted in 19 lesions in 18 extremities of 17 patients. Two days following implantation, in vivo stent compression and bending were assessed by measurement of stent length and deflection angle via lateral view radiographs. The results showed that leg flexion was associated with significant stent bending; popliteal stents bent almost 90° while SFA stents bent only minimally. Leg flexion was also associated with stent shortening (compression), the greatest amount being observed for stents implanted into the popliteal artery (popliteal 8.5% ± 3.2%; SFA/prox pop 5.3% ± 0.5%; SFA 3.1% ± 1.8%). After a mean follow-up of 7.1 ± 1.3 months, the degree of stent deformation during leg flexion was essentially unchanged as compared to immediate post-procedure levels. CONCLUSIONS Indwelling nitinol stents are routinely bent and compressed during leg flexion, with most bending observed in stents implanted near the popliteal artery. The degree of deformation observed immediately after implantation appears to be predictive of the chronic state, as repeat measurements obtained after a mean of seven months were essentially unchanged from baseline.

Inhibition of experimental neointimal hyperplasia and neoatherosclerosis by local, stent-mediated delivery of everolimus

INTRODUCTION A novel self-expanding, drug-eluting stent (DES) was designed to slowly release everolimus in order to prevent restenosis after percutaneous peripheral intervention. The purpose of this experimental animal study was to test the hypothesis that long-term local, stent-mediated delivery of everolimus would reduce neointimal hyperplasia in porcine iliac arteries. METHODS The iliac arteries of 24 Yucatan mini-swine were percutaneously treated with overlapping 8- × 28-mm self-expanding nitinol stents loaded with everolimus (225 μg/cm2 stent surface area) formulated in a poly(ethylene-co-vinyl alcohol) copolymer intended to deliver the drug in a sustained fashion over about 6 months (DES). Bare nitinol self-expanding stents (bare metal stent [BMS]) were implanted in an identical fashion on the contralateral side to serve as controls. After 3, 6, or 12 months, the animals were sacrificed and the stented arteries perfusion-fixed for histomorphometric analysis. RESULTS The chronic presence of everolimus in arterial tissue reduced stent-induced inflammation after 3 months (inflammation score: BMS 2.29±0.44 vs DES 0.17±0.17; P=.001) and 6 months (BMS 2.06±0.43 vs DES 0.50±0.5; P=.007), although some late inflammation was observed after drug exhaustion (BMS 1.00±0.25 vs DES 2.56±0.62 after 12 months; P=not significant [NS]). Treatment with locally delivered everolimus significantly reduced neointimal hyperplasia after 3 months (neointimal thickness: BMS 0.79±0.20 vs DES 0.37±0.04 mm; P=.03) and 6 months (BMS 0.73±0.14 vs DES 0.41±0.08 mm; P=.05), although the effect had dissipated after 12 months (BMS 0.68±0.11 vs DES 0.67±0.11 mm; P=NS). Remarkably, stent-induced neoatherosclerosis, characterized by the histologic presence of foamy macrophages and cholesterol clefts, was significantly attenuated by treatment with everolimus (atherogenic change scores at 3 months: BMS 0.56±0.15 vs DES 0.04±0.04; P=.003; 6 months: BMS 0.84±0.23 vs DES 0.00±0.00; P=.004; and 12 months: BMS 0.09±0.10 vs DES 0.19±0.19; P=NS). CONCLUSIONS In this experimental animal model, local arterial stent-mediated delivery of everolimus inhibited the formation of neointimal hyperplasia and neoatherosclerosis during the first 6 months. The effect was transient, however, as arterial morphology and histology appeared similar to control stented arteries after 12 months.

In-Vitro Modeling of the Dynamic Forces in the Femoropopliteal Artery

The use of intravascular stents in the femoropopliteal artery (FPA) continues to be controversial due to the potential fractures in the dynamic environment. The purpose of this study was to (1) develop a representative in-vitro model that simulates physiological motion of the FPA during knee and hip flexion and (2) use the model to characterize the types and ranges of stent distortion produced by extremity movement. This model eliminates inconsistencies often observed in cadaveric models and clinical subjects due to individual anatomical differences, and allows testing with large sample sizes in a controlled environment for variable (tubing length, material, diameter, and thickness) modification. A comparative evaluation of axial mechanical property and elasticity was conducted between the tubing intended to simulate arteries and the ex-vivo porcine carotid arteries, favoring the selection of silicone tubing. The model was assessed for its unstented and stented arterial bending and axial compression under three physiological motions: straight leg, walking (knee/hip flexion 70°/20°), and sitting/stair climbing (knee/hip flexion 90°/90°). Self-expanding nitinol stents implanted in the simulated mid-superficial femoral artery and popliteal artery (PA) of the model exhibit axial compression of 4.5±0.3 % and 7±0.3 % (knee/hip flexion 70°/20°), and 8.4±0.7 % and 8±0.2 % (knee/hip flexion 90°/90°). Stents implanted in the simulated PA exhibit bending of 40° and 74° from knee/hip angle changes to 70°/20° and to 90°/90°, respectively. The model demonstrated stent bending and compression as previously observed in cadaver studies. Additional analysis of stent motion (torsion, localized bending, radial compression) may be evaluated with more advanced imaging techniques and additional model development. The data generated in these analyses could support appropriate modes and parameters for stent fatigue testing, and better understanding of vascular device performance in the dynamic FPA.