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Biomedical subjects

Christoph Hehrlein

Publications and source records attributed to Christoph Hehrlein.

17 recordsLinked to original sources
PubMed2006

Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter.

BACKGROUND: Treatment of coronary in-stent restenosis is hampered by a high incidence of recurrent in-stent restenosis. We assessed the efficacy and safety of a paclitaxel-coated balloon in this setting. METHODS: We enrolled 52 patients with in-stent restenosis in a randomized, double-blind, multicenter trial to compare the effects of a balloon catheter coated with paclitaxel (3 microg per square millimeter of balloon surface area) with those of an uncoated balloon catheter in coronary angioplasty. The primary end point was late luminal loss as seen on angiography. Secondary end points included the rates of restenosis (a binary variable) and major adverse cardiac events. RESULTS: Multivessel disease was present in 80% of patients in both groups. Quantitative coronary angiography revealed no significant differences in baseline measures. At 6 months, angiography showed that the mean (+/-SD) in-segment late luminal loss was 0.74+/-0.86 mm in the uncoated-balloon group versus 0.03+/-0.48 mm in the coated-balloon group (P=0.002). A total of 10 of 23 patients (43%) in the uncoated-balloon group had restenosis, as compared with 1 of 22 patients (5%) in the coated-balloon group (P=0.002). At 12 months, the rate of major adverse cardiac events was 31% in the uncoated-balloon group and 4% in the coated-balloon group (P=0.01). This difference was primarily due to the need for target-lesion revascularization in six patients in the uncoated-balloon group (P=0.02). CONCLUSIONS: Treatment of coronary in-stent restenosis with paclitaxel-coated balloon catheters significantly reduced the incidence of restenosis. These data suggest that the inhibition of restenosis by local drug delivery may not require stent implantation and sustained drug release at the site of injury. (ClinicalTrials.gov number, NCT00106587 [ClinicalTrials.gov].).

Aged↗
PubMed2006

Reoxygenation of human coronary smooth muscle cells suppresses HIF-1alpha gene expression and augments radiation-induced growth delay and apoptosis.

BACKGROUND AND PURPOSE: Catheter-based coronary brachytherapy with beta- and gamma-radiation is an evidence-based method to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) and stent implantation, but the outcome may be subject to improvements. Physiological studies suggest that most of the target cells of brachytherapy in coronary arteries after PTCA are hypoxic. A lack of oxygen decreases the effect of low LET (linear energy transfer) irradiation. The authors assumed that reoxygenation of hypoxic human coronary smooth muscle cells (HCSMCs) improves the results of coronary brachytherapy. The expression of hypoxia-inducible factor 1alpha (HIF-1alpha) gene, and the rates of growth and apoptosis of hypoxic and reoxygenated HCSMCs after gamma-irradiation were therefore analyzed. MATERIAL AND METHODS: An in vitro model of megacolonies of HCSMCs was developed. After exposure to chronic hypoxia the HCSMCs were irradiated with graded doses of 2, 4, 8, and 16 Gy using a (60)Co source either under hypoxia (pO(2) < 3 mmHg) or after reoxygenation (pO(2) approximately 150 mmHg). RT-PCR (reverse transcription-polymerase chain reaction) analysis was used to quantify HIF-1alpha gene expression and the growth of HCSMC megacolonies was measured serially. The oxygen enhancement ratio (OER) was calculated from the specific growth delay. Apoptosis of HCSMCs was quantified by counting cells with specific DNA strand breaks using the TUNEL assay. RESULTS: HIF-1alpha gene expression was markedly suppressed in reoxygenated cells versus hypoxic cells 30 min after gamma-irradiation at all radiation doses (158 +/- 46% vs. 1,675 +/- 1,211%; p < 0.01). Apoptosis was markedly increased in reoxygenated HCSMCs. The OER was 1.8 (95% CI [confidence interval] 1.3-2.4). Therefore, reoxygenated HCSMCs require 44% less radiation dose to achieve the equivalent biological radiation effect compared to hypoxic HCSMCs. CONCLUSION: Reoxygenation of coronary smooth muscle cells should be considered an option to increase efficacy of coronary brachytherapy. This could be used to reduce radiation dose and associated late side effects.

Angioplasty, Balloon, Coronary↗
PubMed2005

Contrast ultrasound perfusion imaging of lower extremities in peripheral arterial disease: a novel diagnostic method.

AIMS: The purpose of this study was to establish contrast-enhanced ultrasound perfusion imaging (CUPI) of the lower extremities as a novel non-invasive diagnostic tool for patients with peripheral arterial disease (PAD). METHODS AND RESULTS: Ultrasound contrast agent (SonoVue) was injected into a peripheral vein of 16 control subjects and 16 PAD patients and its appearance in the calf muscle was detected by low-energy harmonic ultrasound. Analysis of the wash-in curves revealed that PAD patients had a significantly longer time to peak intensity (TTP), i.e. duration of maximum contrast perfusion [37 s (19-79 s) in control subjects vs. 56 s (32-104 s) in PAD patients at rest, age-adjusted P=0.002]. Exercise stress test of the calf muscle resulted in a decrease of the TTP, maintaining the significant difference in TTP between the groups [19 s (8-37 s) in control subjects vs. 32 s (18-48 s) in PAD patients after exercise, age-adjusted P=0.004]. Neither ankle-brachial index and TTP nor age and TTP showed a significant correlation. CONCLUSION: CUPI reflects the regional blood circulation of the calf muscle. In this pilot study, PAD patients show a significantly longer TTP than control subjects. The clinical relevance of CUPI is topic of ongoing studies.

Adult↗
PubMed2005

Particle debris from a nanoporous stent coating obscures potential antiproliferative effects of tacrolimus-eluting stents in a porcine model of restenosis.

Polymer stent coatings may not be suitable for drug elution because of inherent proinflammatory effects. A previous study suggested a beneficial effect of a stent eluting tacrolimus from a nanoporous ceramic aluminum oxide coating in a rabbit restenosis model. We investigated whether this stent is effective in preventing in-stent restenosis in a porcine restenosis model. Thirty-four juvenile swine underwent balloon overstretch injury and were subjected to implantation of either stainless steel (bare) stents, bare stents coated with nanoporous aluminum oxide alone, and coated stents eluting 50 and 180 mug of tacrolimus (FK506). In-stent restenosis was quantified at 1 and 3 months after stent placement by histomorphometry. A significant increase of neointimal hyperplasia was noted with the stents coated with aluminum oxide alone compared with bare stents (2.92 +/- 1.02 and 1.38 +/- 0.51 mm(2), respectively; P < 0.02). In all arteries containing coated stents, particle debris was found in the media and neointima, resulting in augmented vascular inflammation. In the group of stents coated with aluminum oxide, FK506 elution at a dose 180 mug reduced neointimal hyperplasia vs. no drug elution (1.66 +/- 0.49 vs. 2.92 +/- 1.02 mm(2); 180 mug vs. ceramic alone; P < 0.03). At a dose of 50 mug stent-based delivery of FK506, no reduction of neointimal hyperplasia was found (2.88 +/- 1.31 and 2.92 +/- 1.02 mm(2), respectively; P = NS; FK506 vs. ceramic alone). In summary, particle debris shed from a drug-eluting aluminum oxide coating of a stainless steel stent counteracts potential antiproliferative effects of stent-based tacrolimus delivery in a porcine model of restenosis. We propose that stent coatings eluting drugs need to be routinely tested for being tightly anchored into the stent surface. Alternatively, omission of any coating used as a drug reservoir may eliminate inflammatory particle debris after placement of drug-eluting stents.

Aluminum Oxide↗
PubMed2004

Reoxygenation of hypoxic coronary smooth muscle cells amplifies growth-retarding effects of ionizing irradiation.

BACKGROUND: Hypoxic human coronary smooth muscle cells (HCSMCs) are possible targets for brachytherapy to prevent restenosis after percutaneous transluminal coronary angiography. It is unclear whether growth kinetics and gene expression of these cells undergoing gamma-irradiation are changed by reoxygenation. METHODS AND RESULTS: Hypoxic (H) and hypoxia-reoxygenated (H-R) HCSMCs were irradiated with gamma-radiation at single doses of 4, 8, and 16 Gy using a 60Co-source. Vascular endothelial growth factor gene expression of HCSMCs was dramatically suppressed in H-R versus H cells independent of the radiation dose (15+/-7% versus 2183+/-2023%, P<0.01, H-R versus H cells). An oxygen enhancement ratio of 1.8 was calculated after irradiation from the retarded growth of H-R versus hypoxic HCSMCs. Production of reactive oxygen species by HCSMCs after irradiation increased by 15+/-2% in H-R cells versus 7+/-1% in H cells (P<0.05). CONCLUSIONS: Reoxygenation of hypoxic HCSMCs markedly amplifies growth-retarding effects of ionizing irradiation. On the basis of these findings, oxygenating radiosensitizers should be analyzed with regard to suitability for coronary brachytherapy to prevent restenosis.

Brachytherapy↗
PubMed2002

The IST registry.

Intracoronary brachytherapy has been established in Europe and the US as an evidence-based treatment of in-stent restenoses. The objective of the IST Registry is to register all patients treated in Germany with intracoronary radiation and to observe the clinical outcome for a duration of 5 years. The required set of data for each patient is kept to a minimum to encourage participation. All data are entered online. In the internet, each participating site can, at any time, check their most important parameters and compare them with those of other sites. Presently, the Novoste System is used in 58 catheter labs and the Guidant System in 16, while several sites use both. The requirements regarding radiation safety in intracoronary application of gamma radiation are very strict in Germany, so the Cordis-Gamma System is used in only one German lab. In a first analysis of 332 radiated stenoses, it was observed that late vessel occlusion could occur even after 6-month administration of clopidogrel (in addition to ASA)--without new stents being implanted within the brachytherapy session. Clopidogrel should thus be administered in addition to aspirin for at least a year. Ca. 270 patients per month receive intracoronary radiation in Germany, so the IST Registry will provide important data regarding long-term observation and a foundation for future negotiations with insurance companies potentially bearing the costs. At present, neither the physician's service nor the material costs are reimbursed. The IST Registry can furthermore be used as a comparative database regarding long-term outcome following implantation of antiproliferative-coated stents.

Angioplasty, Balloon, Coronary↗
PubMed2002

Drug-eluting stent: the "magic bullet" for prevention of restenosis?

The need for repeat interventions after initially successful PTCA due to restenosis has been called the "Archilles heel" of a percutaneous revascularization procedure. The incidence of restenosis varies between 20-50 % depending on the stent material, the presence of risk factors, and the location of vascular disease. Some risk factors such as diabetes have been clearly identified, others are currently debated. After years of failures trying to reduces restenosis rates, locally administered antiproliferative means have been shown to successfully inhibit excessive cell growth in response to PTCA. Local radiotherapy of in-stent restenosis results in a reduction of recurrent stenosis versus a conventional PTCA procedure. However, long-term evaluation indicated that restenosis may only be delayed with radiation therapy. Moreover, the restenosis rates were reduced, but the restenotic process was not eliminated. Coronary stents eluting the anti-proliferative agent rapamycin have demonstrated for the first time, that restenosis rates of zero percent are achievable after percutaneous revascularization procedures. Thus, it is intriguing to believe that the elimination of restenosis may have become reality. The purpose of this review is to discuss, whether a stent eluting drugs should be considered as the "magic bullet" for prevention of restenosis after PTCA.

Angioplasty, Balloon, Coronary↗
PubMed2002

[Radioactive stents: problems and potential solutions].

BACKGROUND: The implantation of radioactive stents was the first procedure of a coronary brachytherapy in Europe examined in multicenter clinical trials. PROBLEMS OF RADIOACTIVE STENTS: After more than 400 patients with radioactive stents were analyzed, it became clear that overall restenosis rates were not reduced. A new phenomenon called the "edge effect" or "candy-wrapper" effect was discovered, which later was also described for catheter-based brachytherapy. Currently, the implantation of radioactive stents for the prevention of restenosis cannot be recommended. DRUG ELUTING STENTS: Although technical improvements of radioactive stents are theoretically possible, novel drug coated stents may overcome any future research of stent-based radiotherapy. Drug eluting stents induce antiproliferative effects beyond the stent margins. Edge effects were not observed in preliminary trials. However, long-term results need to be awaited.

Angioplasty, Balloon, Coronary↗
PubMed2002

Role of the "dogbone" effect of balloon-expandable stents: quantitative coronary analysis of DUET and NIR stent implantation introducing a novel indexing system.

UNLABELLED: Stent design and deployment characteristics of balloon-expandable stents may play an important role in determining both early and late outcomes of stenting. The purpose of this study was to compare the percent residual stenosis (RS) of two new-generation stent delivery systems, DUET and NIR, in patients with CAD. From September 1998 1999, a total of 100 consecutive patients with CAD receiving either a DUET (18 or 23 mm length; n = 50) or NIR stent (16 or 25 mm length; n = 50) using a 3.0 or 3.5 mm stent delivery system were compared by quantitative coronary analysis. The ability of each balloon delivery system to fully expand the stent was assessed using a new scoring index entitled the stent delivery balloon expansion ratio (SDBR; %). A high SDBR correlates with the angiographic appearance of a "dogbone" that is sometimes seen during stent deployment. A stent "scalloping" score was developed to quantitatively assess the cobblestone appearance observed angiographically with plaque protrusion after stent implantation. Mean deployment pressures were 14 +/- 2 atm (DUET) and 13 +/- 2 atm (NIR) (p=NS). Extent of elastic recoil was similar (6 +/- 5% for DUET vs. 6 +/- 4% for NIR; (p=NS). "Scalloping" was more pronounced in the DUET stent (score, 0.66 +/- 0.6 for DUET vs. 0.24 +/- 0.4 for NIR; p < 0.001). SDBR and RS were higher with DUET than with NIR stent implantation (SDBR, 15 +/- 5% vs. 12 +/- 5%; RS, 14 +/- 5% vs. 11 +/- 6%; p < 0.01). Multivariate analysis showed that SDBR and stent recoil, but not "scalloping", were associated with increased RS after stent implantation (r = 0.45 and p < 0.001 for "dogbone" effect; r = 0.39 and p < 0.001 for stent recoil). CONCLUSION: The second-generation DUET and NIR stents and their respective delivery systems show angiographically different acute performance characteristics. Insufficient deployment of stents visualized by the "dogbone" effect plays a role in the extent of RS after stenting. The introduced angiographic indexes require further validation.

Age Factors↗
PubMed1999

Long period of balloon inflation and the implantation of stents potentiate smooth muscle cell death. Possible role of chronic vascular injury in restenosis.

BACKGROUND: It has been suggested that the severity of acute vascular injury immediately after percutaneous transluminal coronary angioplasty (PTCA) or stent implantation correlates with the extent of neointimal hyperplasia and restenosis. However, the influence of prolonged or chronic vessel injury on the pathogenesis of restenosis is unclear. METHODS: Rabbit iliac arteries were balloon dilated for a short (1 min) or prolonged (10 min) period of time, or were chronically dilated and received a Palmaz-Schatz stent (balloon inflation for 1 min). All arteries were overexpanded to a balloon:artery ratio of 1.2:1 as determined by angiography. The arteries were removed 30 min and 4 weeks after the angioplasty procedures. The sites of injury were evaluated by gross histology and transmission electron microscopy (TEM). Cell death of medial smooth muscle cells (SMCs) was specified by TEM images 30 min after the procedures. Computer-assisted quantification of the neointimal cross-sectional areas was performed after 4 weeks using a light microscope connected to a digital image analyser. RESULTS: The results show that prolonged balloon dilatation and stent implantation increased necrotic SMC death compared with balloon dilatation for 1 min. After 30 min, increased staining of SMC nuclei, enlarged intercellular spaces and changes in SMC shape in the media indicated cell death induced by prolonged balloon dilatation or chronic stent injury. Stent implantation markedly augmented vessel damage by persistent compression of the media, compared with a balloon dilatation for 1 or 10 min. Both prolonged balloon dilatation and stent implantation increased neointimal hyperplasia at 4 weeks compared with balloon dilatation for 1 min (0.6 3 0.2 and 1.0 3 0.2 mm(2) versus 0.2 3 0.1 mm(2), P < 0.001 versus dilatation for 1 min). CONCLUSION: Prolonged or chronic vascular expansion due to long balloon-inflation periods or the implantation of stents increases medial SMC death, which subsequently stimulates neointimal growth in this restenosis model. Chronic vascular injury may be an important stimulus for restenosis after angioplasty procedures.

Journal Article↗
PubMed1998

Radioisotope stents for the prevention of restenosis: what did we learn from pre-clinical studies?

This article will discuss the lessons learned by using stents implanted with low activities of radioisotopes to prevent in-stent restenosis. A continuous low-dose rate radiation delivered by radioisotope stents has been shown to reduce the proliferative activity of smooth muscle cells and to inhibit neointimal growth. However, the radiation also delays endothelialization of the stents. Both the dose rate and the cumulative dose delivered by radioisotope stents appear to affect outcome. The neointima covering radioactive stents is characterized by a reduced cellularity, increased amounts of fibrin and extracellular matrix proteins. Aneurysm formation or excessive tissue destruction due to the radiation were not observed. Animals studies including up to 1 year follow-up periods suggest that beta-particle-radiation as well as gamma-radiation are effective in reducing neointimal hyperplasia. It is still unknown, however, which range of activities are needed and if a combination of radioisotopes, i.e. with short and long halflives, further reduce neotima formation over the long-term. An appropriate stent design for homogenous dose distribution around the stent may be important, i.e. articulations or large cell sizes may have disadvantages. Augmented neointima formation at the ends of radioactive stents, in particular when using beta-particle emitting stents, has been observed in animal models. Future studies will focus on the effects of increasing activity levels at the stent ends, optimal stent designs, alternative isotopes and different dosing strategies.

Journal Article↗
PubMedDate not supplied

Neointima formation after stent implantation in an experimental model of restenosis: polytetrafluoroethylene-covered versus uncovered stainless steel stents.

The aim of the study was to assess whether stents covered with a membrane of polytetrafluoroethylene spanned over the mashes of a sandwich-configured double stent (n = 15) prevent migration of smooth muscle cells through stent spaces, leading to less neointima formation compared with uncovered stainless steel stents (n = 14) in iliac arteries of male Chinchilla Bastard rabbits (n = 18). Lumen stenosis was assessed by quantitative angiography immediately before the animals were killed 5 weeks after stent deployment. Neointima formation was quantified by histomorphometric analysis. There were large regional and individual differences in neointima formation, leading locally to a significantly higher degree of stenosis in covered stents (histologically, 76.0 +/- 13.7 vs. 62.9 +/- 12.9%; angiographically, 33.5 +/- 21.1 vs. 7.8 +/- 8.8%) compared with uncovered stents, though mean neointimal and lumen area values were not significantly different. In conclusion, polytetrafluoroethylene-covered stents do not prevent neointima formation compared with uncovered stents. Although the membrane reduces local smooth muscle cell migration, the neointima hyperplasia at the proximal and distal ends of a covered stent stimulates migration along its longitudinal axis. In this stent-restenosis model, regional and individual proliferation processes and not the membrane-covering strut-to-strut distances determine lumen restenosis.

Animals↗