Localized drug delivery in atherosclerotic arteries via a new balloon angioplasty catheter with intramural channels for simultaneous local drug delivery

A dual-purpose angioplasty catheter with intramural channels and exterior pores for local drug delivery (“channeled balloon”) was studied in eight atherosclerotic human necropsy arteries and in 22 rabbits with atherosclerotic peripheral arteries, in which markers (0.005 m?m to 15 m?m) were infused locally at 2 atmospheres during simultaneous angioplasty at 6 atmospheres. Thirteen of the rabbits were sacrificed at 4 or 24 h after procedure to determine the intramural retention over time. Histology confirmed effective angioplasty and revealed presence of markers in the arterial wall in 29 of 43 treated arteries (67%), whereas all control segments without local delivery had no marker staining. Majority of the ineffective local delivery (12/14) occurred when 15 m?m particles were infused (12/13 arteries without intramural markers), especially when examined 4 or 24 h later. Thus, in atherosclerotic arteries, the channeled balloon enabled simultaneous local drug delivery at low pressure during effective angioplasty, although particle size may play a role in successful intramural impregnation and retention.     

Methods and devices for local drug delivery in coronary and peripheral arteries

New developments in catheter design, molecular biology, and polymer chemistry have made it possible to deliver pharmaceutical agents and genetic material directly into the arterial wall to modulate the response to injury. Several local drug delivery catheters of various designs in addition to biodegradable and coated stents are currently being evaluated as devices to facilitate local delivery of agents into the arterial wall. Approaches to locally sustained delivery include the controlled release of medications, the affinity-based delivery of medications administered systemically but accumulated locally, and gene therapy.     

Use of the porous balloon in porcine coronary arteries: rationale for low pressure and volume delivery

Using agents administered systemically, attempts to control the restenotic myoproliferative response associated with angioplasty have been unsuccessful. The porous balloon has the advantage of achieving high local concentrations by directly infusing agents into the arterial wall. The purpose of this study is to identify any acute and chronic morphological changes in swine coronary arteries infused with normal saline through the porous balloon at different driving pressures. In order to establish the safety of local arterial wall infusion through the porous balloon, swine underwent porous balloon infusion of 3,6, or 10 ml of saline at 5 atmospheres, or infusion of 3 ml of normal saline delivered at either 2, 5, or 10 atmospheres of pressure into the normal left anterior descending and left circumflex arteries. To assess the histopathologic alterations induced by the porous balloon, sized 1.1 to 1 with respect to the artery, animals were sacrificed either immediately after porous balloon infusion or 14 days later. Acute vessels were evaluated for the presence of medial injury, disruption and/or dissection, whereas chronic vessels underwent morphometric analysis measuring the residual luminal area (Lumen area/Intimal area + Lumen area) and the maximal intimal thickness. Adequate adventitial penetration was confirmed by infusing as little as 2–3 ml of methylene blue at 2 atmospheres of pressure. Infusion of 3 ml of normal saline at 2 atmospheres resulted in minor focal medial edema and disorganization, detected both acutely and 14 days after porous balloon infusion. At delivery pressures of 5 or 10 atmospheres, proportionally more acute injury was noted and measurable neointimal lesions were observed 2 weeks after infusion. These data indicate that porous balloon infusion of 3 ml of normal saline at 2 atmospheres was safe and resulted in only minimal medial edema of normal swine coronary arteries. Higher pressure or volume delivery proportionally increased the degree of injury and contributed to the development of neointima.© 1993 Wlley-Liss, Inc     

Implantation of paclitaxel-eluting stent impairs the vascular compliance of arteries in porcine coronary stenting model

BackgroundThe impaired compliance of large and medium-sized muscular arteries has been shown to correlate with the risk of adverse cardiovascular events. We assessed coronary artery distensibility using simultaneous intracoronary ultrasound and pressure wire measurements in porcine coronary arteries after implantation of paclitaxel-eluting (PES) and bare metal stents (BMS) and compared this with the histopathology of the arterial wall injury.MethodsPES and BMS were implanted into porcine left coronary arteries under general anesthesia. At 1-month follow-up (FUP) the endothelium-dependent and endothelium-independent vascular compliances were measured after intracoronary infusion of 10^?6 M acetylcholine for 2.5 min, and intracoronary bolus of 100 μg nitroglycerine, respectively. The arterial stiffness index, distensibility and reflexion index were calculated in stented arteries (n = 25 PES and n = 25 BMS), and correlated with histopathologic and histomorphometric changes of the vessel wall.ResultsIn spite of smaller neointimal area, the fibrin deposition, medial thickening, vascular wall inflammation scores and arterial remodeling index were elevated and endothelialization was impaired in arteries with PES. Arteries with PES exhibited significantly worse endothelium-dependent vascular compliance: the stiffness (p < 0.001) and reflexion index (p < 0.001) were significantly higher and the distensibility index (p < 0.001) lower as compared with the arteries with BMS. The endothelium-independent vascular reaction was similarly impaired in arteries with PES, as the stiffness index (p < 0.001) and the distensibility index (p < 0.001) differed significantly between the PES and BMS groups. Incomplete endothelialization (r = 0.617, p < 0.001) was significantly associated with the endothelium-dependent increased vascular stiffness. The increased fibrin score (r = 0.646, p < 0.001), vessel wall inflammation (r = 0.657, p < 0.001) and medial thickening (r = 0.672, p < 0.001) correlated significantly with the endothelium-independent stiffness index.ConclusionsImplantation of PES impairs the coronary artery wall structure and the endothelium-dependent and independent vessel wall dynamics more than does the implantation of BMS.     

Pharmacokinetics and tissue localization of antisense oligonucleotides in balloon-injured pig coronary arteries after local delivery with an iontophoretic balloon catheter

When delivered locally to the arterial wall by passive fluid transfer systems such as perforated balloons, water-soluble compounds in aqueous solution are not readily taken up by tissue, show low levels of cellular localization, and are quickly lost by wash-out. One approach to improve delivery is addition of an “active” component to the catheter system to change the nature of the drug-to-tissue interaction. Using an iontophoretic balloon catheter to deliver antisense oligonucleotide (ODN) to pig coronary arteries after balloon angioplasty, we determined the quantity and localization of ODN in the tissue. By radiolabeling, 7.3 ± 2.4 μg ODN was present at 30 min, 1.5 ± 0.6 at 2 h, 0.52 ± 0.35 at 24 h, and 0.26 ± 0.11 at 7 d. By fluorescent labeling, circumferential medial uptake and adventitial delivery at the site of medial injury was observed, with primarily cellular localization. The iontophoretic catheter thus appears to be a useful device for ODN delivery to arterial tissue. Cathet. Cardiovasc. Diagn. 41:354–359, 1997. © 1997 Wiley-Liss, Inc.     

Use of monorail PTCA balloon catheter for local drug delivery

We report the use of monorail coronary balloon as an infusion catheter to give bailout abciximab selectively into the site of stent thrombosis as an adjunct to plain old balloon angioplasty (POBA) in a patient of subacute stent thrombosis of the left anterior descending coronary artery. The balloon component (polyamide material) of the monorail balloon catheter was shaved off the catheter so that abciximab injected through the balloon port of the catheter exited out the shaft of the balloon catheter at the site from where the balloon material was shaved off. We believe that selective infusion with abciximab along with POBA established antegrade flow and relieved the patient's ischemia. In the absence of essential hardware to give intracoronary drugs in an emergency situation, one may employ our technique of infusion through a monorail balloon catheter after shaving the balloon component from the catheter.     

New multifunctional percutaneous transluminal coronary angioplasty catheter device capable of balloon inflation, local drug delivery and coronary perfusion

A new percutaneous transluminal coronary angioplasty catheter with multiple functions of balloon inflation, local drug delivery and coronary perfusion has been devised. The device consists of an inflatable lumen, a drug delivery lumen, and a perfusion (or guide wire) lumen. A drug can be infused from the port located distal to the inflated balloon during continuous blood perfusion via the perfusion lumen. Fluorescence-labeled heparin and peroxidase administered using the device permeated into denuded vessel tissues during ongoing perfusion and remained there for over 24 hr. This prototype device indicates the potential therapeutic implications of the concepts of the device.     

Restenosis after balloon angioplasty. A practical proliferative model in porcine coronary arteries

A model of proliferative human restenosis was developed in domestic pigs by using deep injury to the coronary arterial media. Metal wire coils were delivered percutaneously to the coronary arteries of 11 pigs with an oversized, high-pressure (14 atm) balloon and were left in place for times ranging from 28 to 70 days. During placement, the balloon expanded the coils and delivered them securely within the arterial lumen. Light microscopic examination of the vessels confirmed fracture of the internal elastic lamina by the coil. An extensive proliferative response occurred in 10 of the 11 pigs and was associated with a luminal area narrowing of at least 50% in all but one pig. The histopathologic features of the proliferative response were identical to those observed in human cases of restenosis after angioplasty. Immunohistochemical studies confirmed the prominence of smooth muscle cells in the proliferative tissue. A similar response was obtained in two of five porcine coronary arteries in which balloon inflation only was performed, without coil implant. This model is practical and inexpensive and closely mimics the proliferative portion of human restenosis both grossly and microscopically. Thus, it may be useful for understanding human restenosis and for testing therapies aimed at preventing restenosis after balloon angioplasty or other coronary interventional procedures.     

药物涂层球囊在冠状动脉小血管原发病变的临床效果评价

目的:评价药物涂层球囊对冠状动脉小血管原发病变(SVD)的临床效果。方法:前瞻性选取2017年1月至2017年12月,我院收治的SVD患者166例作为研究对象,分为药物洗脱支架(DES)组78例和药物涂层球囊(DCB)组88例,观察两组治疗效果、血管再狭窄(ISR)和不良事件。结果:DCB组治疗后最窄直径、病变长度和直径狭窄率均较治疗前明显改善(DCB组:t=32.963、3.420、28.346;DES组:t=17.613、2.089、9.862,P0.05);DCB组治疗后最窄直径、病变长度和直径狭窄率改善情况均优于DES组(t=7.672、2.593、8.619,P0.05)。至随访结束时,两组均有部分病例出现病变血管ISR,其中DES组进展比例高于DCB组(χ~2=34.901,P0.05),而维持、好转比例低于DCB组(χ~2=18.769、8.448,P0.05);DES组不良事件发生率(25.6%)高于DCB组(14.8%),但组间比较差异无统计学意义(χ~2=3.067,P0.05)。结论:DCB治疗冠状动脉SVD的临床疗效优于DES,同时降低远期ISR,不良事件无显著增加。     

Saline infusion via local drug delivery catheters is associated with increased neointimal hyperplasia in a porcine coronary in-stent restenosis model

BACKGROUND: Catheter-based local drug delivery at the site of stent implantation has been proposed to reduce in-stent restenosis. We examined whether local delivery itself may cause additional vessel wall injury and negate the potential benefit of local drug delivery in a porcine coronary in-stent restenosis model. METHODS: Pigs were randomly assigned to no local delivery (controls, n = 10) or local saline infusion (5 ml) using commercially available catheters (n = 39; Dispatch catheter, Microporous Infusion catheter, and InfusaSleeve) prior to oversized (stent:artery ratio 1.2) coronary stent implantation. The amount of in-stent neointima was evaluated 4 weeks later with angiography and histology. RESULTS: There was no difference in vessel size or stent: artery ratio. However, at follow-up the local saline delivery group had significantly greater diameter stenosis (50 +/- 19% versus 25 +/- 17% in the controls, P < 0.01). Histology revealed similar injury scores but significantly greater neointimal area in the local saline group (3.61 +/- 1.11 mm2 versus 1.96 +/- 0.82 mm2 in the controls, P < 0.01). In a multivariate linear regression analysis, the use of the local delivery catheter was the only independent variable which was positively correlated with the amount of neointima (P = 0.0001). CONCLUSIONS: In this in-stent restenosis model, catheter-based local saline delivery was associated with significantly increased neointimal hyperplasia. Thus, for local drug delivery to reduce in-stent restenosis, the antiproliferative agent should be potent enough to compensate for the additional neointimal hyperplasia from the infusion itself.     

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.     

Long-term endothelial dysfunction is more pronounced after stenting than after balloon angioplasty in porcine coronary arteries

Objectives. To compare percutaneous transluminal coronary angioplasty (PTCA) and stent implantation with respect to the long-term changes they induce in the newly formed endothelium in porcine coronary arteries by studying both morphological and functional parameters of the endothelium at 2 weeks and 3 months after intervention.Background. Problems affecting PTCA or stent implantation have been overcome to a large extent by means of better techniques and the availability of new drugs. Late problems, however, still exist in that restenosis affects a large number of patients. With an increasing number of patients being treated with stents, the problem of in-stent restenosis is of even greater concern, as this seems difficult to treat. A functional endothelial lining is thought to be important in controlling the growth of the underlying vascular tissue. We hypothesized that the enhanced neointimal hyperplasia observed after stenting is associated with a more pronounced and prolonged endothelial dysfunction.Methods. Arteries were analyzed using a dye-exclusion test and planimetry of permeable areas. Thereafter, the arteries were processed for light and scanning electron microscopy for assessment of morphology and proliferative response.Results. Leakage of the endothelium for molecules such as Evans blue-albumin as well as prolonged endothelial proliferation is observed as late as 3 months after the intervention, and is more pronounced after stenting. Permeability is associated with distinct morphologic characteristics: endothelial retraction, the expression of surface folds, and the adhesion of leukocytes.Conclusions. Stenting especially decreases long-term vascular integrity with respect to permeability and endothelial proliferation, and is associated with distinct morphologic characteristics.     

Vascular imaging balloon with local drug delivery for the treatment of renal artery recurrent in-stent restenosis

Renal artery stenosis is a common finding among patients with atherosclerotic disease and its percutaneous treatment with stent implantation is frequently performed by interventional cardiologists and vascular radiologists. However, renal artery in-stent restenosis is not a rare complication and its management is not straightforward. We describe and report angiographic follow-up of an innovative approach to renal artery in-stent restenosis based on combined intravascular ultrasound and drug-eluting balloon treatment.     

Novel use of a local drug delivery catheter for coronary perforation

Coronary perforation is a complication of percutaneous coronary intervention that may be fatal. Conventionally, a perfusion balloon catheter is used for treatment, but may not always be available. We report a case in which bleeding due to coronary perforation was successfully treated without induction of ischemia using a local drug delivery catheter as a perfusion device.