Martin Oberhoff

Stent-Based Delivery of Tissue Inhibitor of Metalloproteinase-3 Adenovirus Inhibits Neointimal Formation in Porcine Coronary Arteries

Background—Stent-based antiproliferative therapy appears to decrease in-stent restenosis. However, alternative approaches might produce equivalent efficacy with better long-term safety. In previous work, an adenovirus capable of expressing the tissue inhibitor of metalloproteinase-3 (RAdTIMP-3) inhibited neointima formation in cell cultures and porcine saphenous vein grafts. RAdTIMP-3 decreased smooth muscle cell migration, stabilized the extracellular matrix, and uniquely promoted apoptosis. The current study developed eluting stent technology to deliver RAdTIMP-3 during stenting of pig coronary arteries. Methods and Results—Binding of virus to and elution from stents and transduction of pig coronary arteries were confirmed using &bgr;-galactosidase as a reporter gene in vitro and in vivo. Deployment of RAdTIMP-3–coated stents increased apoptosis and reduced neointimal cell density, but did not increase inflammation or proliferation compared with &bgr;-galactosidase–expressing adenovirus (RAdlacZ). Neointimal area after 28 days was significantly reduced to 1.27±0.19 mm2 with RAdTIMP-3 versus 2.61±0.31 mm2 with RAdlacZ stents (P<0.001) and 2.12±0.20 mm2 with bare stents (P<0.005). Conclusions—Our results demonstrate for the first time to our knowledge the feasibility of adenovirus-coated stent technology and highlight the potential of TIMP-3 to produce significant inhibition of in-stent neointima formation.

Inhibition of smooth muscle cell proliferation after local drug delivery of the antimitotic drug paclitaxel using a porous balloon catheter

Abstract Percutaneous transluminal coronary angioplasty is an accepted treatment for coronary artery disease. The major limitation, however, is the high incidence of restenosis which limits the long-term benefit of this intervention. Paclitaxel is a new antiproliferative agent that has generated considerable scientific interest since it was introduced in clinical trials in the early 1980s. Recent in vitro studies have shown that paclitaxel has considerable antiproliferative activity in human coculture systems. In the present study the efficacy of paclitaxel was investigated after development of an intimal plaque by electrical stimulation and additional cholesterol diet and subsequent balloon angioplasty in 63 New Zealand White rabbits. Local drug delivery of paclitaxel was accomplished in 30 rabbits with a porous balloon catheter (35 holes, hole diameter 75 μm, 2.5 mm catheter diameter). Paclitaxel was administered locally with 4 ml (solution 10−5 mol/L) using an injection pressure of 2 atm. To study the extent of restenosis and morphological changes, the animals were sacrificed 7, 28 or 56 days after intervention. After staining procedures quantification of SMC proliferation, intimal macrophages and morphological analyses were performed. Paclitaxel plasma concentrations were measured using HPLC technique. One week after balloon angioplasty the arteries treated with local paclitaxel delivery showed an insignificant trend towards a reduction in intimal smooth muscle cell proliferation (untreated 8.4 ± 4.9 % vs paclitaxel treated 2.4 ± 2.4 %, p = NS). However, this resulted in a significant reduction of stenosis degree of 66 % 8 weeks after intervention compared to the untreated group (untreated 41 ± 18 % vs paclitaxel treated 14 ± 11 %, p = 0.005). In conclusion, locally delivered paclitaxel prevented neointimal thickening in the rabbit carotid artery after balloon angioplasty. Local paclitaxel treatment may therefore be a clinical option for the prevention of restenosis after coronary interventions. However, further preclinical studies have to prove long-term efficacy and safety.

Occlusion versus shunting during MIDCAB: effects on left ventricular function and quality of anastomosis

BACKGROUNDnMinimally invasive direct coronary artery bypass is an established clinical procedure for revascularization of the left anterior descending coronary artery. Mechanical stabilization and temporary occlusion is currently used to perform the anastomosis of the internal thoracic artery to the left anterior descending coronary artery. However, critical reduction of cardiac function can occur as a result of temporary ischemia. The purpose of this study was to evaluate whether ischemic sequelae can be avoided by using temporary intraluminal shunts and whether this alters early outcome.nnnMETHODSnThirty-five patients underwent minimally invasive direct coronary artery bypass revascularization using a mechanical stabilizer. In group A (n = 20), the anastomotic site was temporarily occluded by tourniquets. In group B (n = 15), temporary intraluminal shunts were inserted into the anastomotic site without any occlusion of the left anterior descending coronary artery. Anastomosis of the internal thoracic artery to the left anterior descending coronary artery was performed in an identical fashion. A Swan-Ganz catheter was inserted, and transesophageal echocardiographic measurements were obtained for analysis of left ventricular (LV) function. Regional wall motion, cardiac index, stroke volume index, systolic and diastolic LV diameters, and fractional area change were measured during four periods: at the start of the operation (baseline), placement of the stabilizer (stabilization), left anterior descending coronary artery occlusion (occlusion) or insertion of temporary intraluminal shunts (shunt), and 30 minutes after reperfusion (reperfusion). Angiograms were obtained 4 to 6 days postoperatively.nnnRESULTSnIn group A, LV performance, cardiac index, stroke volume index, and fractional area change decreased during occlusion whereas systolic diameters increased. Almost two myocardial segments per patient developed severe hypokinesia in the perfusion area. These changes disappeared after 30 minutes of reperfusion, with increased LV function. In group B, LV function remained stable whereas hypokinetic wall motion was only detected in 2 patients. Early angiograms revealed 90% of the grafts were patent in group A versus 100% in group B. The need for percutaneous intervention during the first 6 months was 20% in group A versus 6.7% in group B.nnnCONCLUSIONSnThe use of temporary intraluminal shunts resulted in reduced acute ischemia and revealed wall motion abnormalities and maintained LV function. Furthermore, this technique suggests an improvement of early graft patency and a lower reintervention rate within the first 6 postoperative months. Thus, use of temporary intraluminal shunts appears to be superior to the occlusion technique early after minimally invasive direct coronary artery bypass procedures.

Multislice computed tomography coronary angiography in patients admitted with a suspected acute coronary syndrome

ObjectivesThe aim of this prospective clinical study was to assess the accuracy and clinical relevance of multislice computed tomography coronary angiography (MSCTCA) in patients presenting with acute chest pain.BackgroundMultislice computed tomography coronary angiography has shown ability to detect accurately coronary artery disease (CAD) in selected elective patient groups.MethodsOne hundred and twenty patients presenting with acute chest pain (<24xa0h) underwent MSCTCA (Siemens Sensation 16) before a scheduled inpatient conventional coronary angiogram (CCA). Exclusion criteria included patients with STEMI, non-sinus rhythm, contraindication to β blockers and renal impairment. Blinded visual assessment of MSCTCA to detect CAD was performed on an 11-segment model. The accuracy of MSCTCA was compared to CCA to detect significant stenoses (≥50%).ResultsOne hundred and thirteen patients underwent both investigations. The prevalence of significant CAD was 74%. 1,243 native segments were assessed by MSCTCA. The overall ability of MSCTCA to detect the presence of ≥1 significant stenosis in all native segments had a sensitivity of 92% (95%CI 83–97%), specificity of 55% (95%CI 35–74%), positive predictive value of 86% (95%CI 76–93%) and negative predictive value of 70% (95%CI 47–87%). 22% of all segments (mostly distal) were non-analyzable. Coronary calcification was a major cause of false positivity.ConclusionIn a prospective study of unselected patients presenting with acute chest pain, the diagnostic accuracy of 16-slice CT coronary angiography was moderate and less than reported from studies in elective patients. The clinical relevance of this technology to screen patients with acute chest pain is limited.Condensed AbstractMultislice CT coronary angiography (MSCTCA) and conventional coronary angiography (CCA) were used to assess 120 patients presenting with acute chest pain. MSCTCA was compared to CCA to detect significant stenoses (≥50%). In 113 directly comparable patients MSCTCA had a sensitivity of 92% (95%CI 83–97%) and specificity of 55% (95%CI 35–74%) to detect the presence of ≥1 significant stenosis in all native segments. In this patient cohort with a high prevalence of coronary disease and coronary calcification, the accuracy and clinical relevance of 16 slice MSCTCA to screen and risk stratify patients with acute chest pain is limited.

An Update on Clinical and Pharmacological Aspects of Drug-Eluting Stents

The introduction of stents to clinical practice was the major breakthrough in the field of percutaneous coronary intervention. The introduction of stents was associated with two serious complications, the first was increase in subacute thrombosis within the first 30 days of stent implantation later controlled with the use of high pressure inflation and dual antiplatelet therapy, the second was the phenomenon of in-stent restenosis that was primarily caused by smooth muscle proliferation. While coronary stenting eliminates elastic recoil, it is unable to inhibit excessive neointimal formation. Stents were associated with an increase of neointimal formation compared to balloon angioplasty as a result of excessive injury to the vessel wall and the inflammatory process from interaction of metal with vessel wall. Local delivery of the potential agents for inhibition of neointimal formation to the site of the lesion was considered the desired approach. Several compounds have been tested for stent coating, primarily with the aim of the inhibition of SMC proliferation. Recently, new stents have emerged which are loaded with anti-inflammatory, anti-migratory, anti-proliferative or pro-healing drugs. In this review article the results of clinical studies investigating drug-eluting stents are discussed from pharmacological and clinical points of view, reviewing the current literature and the future prospective.

Local delivery of a low molecular weight heparin following stent implantation in the pig coronary artery

Background: The low molecular weight heparin Reviparin reduces smooth muscle cell proliferation in cell culture experiments. Clinical studies with systemic application of the substance did not show a reduction of the incidence of restenosis following balloon angioplasty. Local delivery, by achieving higher local concentrations of the drug, may have the potential to decrease smooth muscle cell proliferation in the treated arterial segment. Objectives: The aim of this study was to investigate the effects of local delivery of reviparin following stent implantation in the pig coronary artery. Methods: A coronary stent was implanted in the LAD of 34 pigs. In the treatment group 5 ml reviparin was injected with the Infusasleeve catheter at a proximal pressure of 80 psi. After 28 days the animals were sacrificed. Quantitative morphometric analysis comprised the intimal area, medial area and the lumen. The extent of vessel injury and the intimal thickness were assessed separately for each stent strut region. The correlation of injury and neointimal thickness was analysed using linear regression. Results: There was no relevant difference in the extent of vessel injury (1.9 ± 0.7 vs. 1.6 ± 0.6), the neointimal areas (2.4 ± 0.9 vs. 2.4 ± 1.0 mm2) and the resulting stenosis (46 ± 18 vs. 47 ± 17%). The medial area was larger in the animals treated with local delivery (2.2 ± 0.4 vs. 1.6 ± 0.4 mm2; p < 0,01). The correlation of injury and neointimal thickness was comparable in both groups. In two animals the passage of the stent area with the delivery system resulted in stent dislocation and fatal subacute thrombosis. Conclusion: In this animal model, local delivery of reviparin with the Infusasleeve catheter did not result in a reduction of neointimal proliferation following stent implantation. Local delivery after stent implantation carries the risk of stent dislocation as a result of the passage with the delivery system.

Vascular contractile function following experimental excimer laser angioplasty

The aim of this study was to determine the vasomotor response to in vivo excimer laser irradiation with regard to laser-induced tissue effects. Transfemoral excimer laser angioplasty was performed in the right carotid artery of 11 New Zealand white rabbits. In four additional rabbits (sham group), the procedure was performed without the application of laser energy. Angiography documented vessel dissection in five laser-treated animals. Perforation occurred in one animal. Rings of the treated artery and controls of the contralateral artery were investigated in a contraction chamber. The passive stress-strain relation (PSS) and the maximum contraction force (MCF) after stimulation with noradrenaline, serotonin and potassium chloride were determined. The treated vessels had a higher PSS than the control (p=0.05). The MCF was lower in the treated vessels (p<0.05). The contraction force of the sham-operated vessels was higher, although statistically not significant, compared to the laser-irradiated segments. In a subset analysis, performed to compare vessels with moderate and severe trauma, MCF was significantly reduced in vessels with severe laser-induced injury. Experimental in vivo excimer laser angioplasty in this model resulted in heterogeneous structural changes, including dissections and perforation. Post-mortem assessment of vasomotor response showed no significant difference between laser-treated and sham-operated animals. However, the contractile function of the target vessel seems to be reduced following extensive laser-induced vessel injury.

Who wants his plaque sealed

There are some lessons to be learned from 25 yearsof coronary interventional cardiology. One of themost fundamental and important lessons learnt hasbeen the need for an extensive understanding andknowledge of a specific disease process prior to thesuccessful design of a targeted interventionaltreatment. The rapid development of sophisticatedimaging equipment in interventional cardiology hasresulted in a much better outcome for patientsundergoing percutaneous interventions. The im-proved understanding of the pathology and patho-physiology of atherosclerosis and restenosis hasresulted in the development of effective treatmentstrategies, e.g. GP IIb/IIIa antagonists, ADP inhibi-tors and coated stents. These continuing develop-ments significantly raise the standard and safety ofinterventional cardiology.The concept of plaque sealing is an example ofanapproachtotreatcoronaryarterydisease,whichlacks this fundamental understanding of pathologyand pathophysiology. Although it might be an inter-estingclinicalhypothesisandmighthavethepoten-tial to fulfil the desperate wish of interventionalcardiologists to stabilize the life threatening‘vulnerable’ plaque the odds for success are slim.Currently, we do not have sufficient experimentalor clinical information to justify such a thera-peutic approach. There is only a vague knowledgeabout natural stabilization of vulnerable plaques.Recently, the first experimental models of spon-taneous plaque rupture have been developed.

Initial clinical experience with a modified excimer laser for coronary angioplasty

A clinical study was conducted in 32 patients to evaluate the efficacy and safety of a modified excimer laser system for percutaneous transluminal coronary angioplasty. In this system, the laser beam is scanned and transmitted into eight fibre bundles of the catheter device, consisting of 20 50 μm fibres, each. Twenty-eight patients were treated with 1.5 mm laser catheters, four patients with 1.8 mm laser catheters. Mean time of energy delivery was 82±39 s using a mean energy fluence of 49±2 mJ mm−2. In all 32 patients in whom laser angioplasty was attempted, laser irradiation resulted in a stenosis reduction from 85±10% (mean±s.d.) before to 57±20% after laser treatment. In 16 patients, additional balloon angioplasty had to be performed, either due to an insufficient angiographic result in 11 patients or due to abrupt vessel closure in five patients. In these 16 patients, percent stenosis decreased after balloon angioplasty to 35±14%, corresponding to a luminal diameter of 1.6±0.5 mm. In 10 patients, dissection was observed. In one of these patients, the dissection resulted in a reduction in antegrade flow, necessitating balloon dilatation. One perforation occurred which did not require surgery. There were no deaths, bypass surgery or myocardial infarction. During the time of follow-up, restenosis occurred in 14 patients; in two of these patients bypass surgery was performed and five patients were treated with conventional balloon angioplasty.These results suggest that this form of modified excimer energy delivery provides effective therapy for patients with coronary artery disease. Due to the small catheter sizes, however, one-half of the patients still required additional balloon dilatation. To increase the number of stand-alone laser procedures and to address the issue of restenosis in this patient population appropriately, larger catheter devices will be necessary.

Effect of a Dihydropyridine-Type Calcium Channel Blocker on Vascular Remodelling after Experimental Balloon Angioplasty

OBJECTIVEnAim of the study was to evaluate the influence of the dihydropyridine derivative BW 9798 on intimal hyperplasia in a carotid artery injury model of New Zealand White rabbits on a high cholesterol diet.nnnMETHODSnIn carotid arteries of 50 New Zealand White rabbits atherosclerotic lesions were induced by cholesterol diet and electrostimulation of the artery. In 40 animals the resulting primary lesion was subjected to balloon angioplasty (BA). Three days prior to BA animals received BW 9798 or placebo per os until sacrifice three days or 28 days after BA.nnnRESULTSnBW 9798 lead to increased cross sectional area by 128.3% and an increased luminal area by 157% after 28 days after BA compared with placebo. However the degree of stenosis did not significantly decrease. The cell count of the different layers of the arteries decreased by 64.5% in the intima and by 62.6% compared with placebo treated animals after BA. Additionally the number of smooth muscle cell (SMC) layers in the neointima was significantly lower in BW 9798 treated animals than in placebo animals (8±3 vs 14±9, p<0.05) although the proliferation was not changed by BW 9798 treatment 3 days after BA.nnnCONCLUSIONnBW 9798 leads to significant changes in vessel wall geometry although the influence on vascular remodeling of this compound is unclear. It can be speculated that the compound affects the homeostasis of extracellular matrix, invasion of inflammatory cells into the vessel wall and the expression of cytokines. However, further investigation needs to clarify the role of BW 9798 on remodelling after BA.