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BACKGROUND In vitro experiments have shown that holmium laser energy can effectively ablate even calcified plaque in human arterial vessels. Because high-energy densities from holmium lasers can easily be transmitted through quartz fibers, this solid-state laser has been suggested as an alternative intraluminal treatment of atherosclerotic plaque. METHODS AND RESULTS To develop an intimal plaque, 35 New Zealand White rabbits underwent electrical stimulation of their right carotid artery for 28 days. Subsequently, in 25 rabbits, holmium laser angioplasty (wavelength, 2.12 microns; pulse duration, 150 microseconds; energy density, 350 mJ/mm2) was performed. To study the morphological results, the vessels were excised after 7, 14, 28, and 42 days. Cross sections were analyzed in regard to laser-specific injury. Staining of alpha-actin was used to identify smooth muscle cells (SMCs). After bromodeoxyuridine labeling, the extent of proliferation (number of cells undergoing DNA synthesis) was determined by using a monoclonal antibody. Holmium laser ablation resulted in an initial decrease of the numbers of intimal cell layers in the early group (7 days after treatment: 5 +/- 1 cell layers with 76 +/- 39 microns; control: 13 +/- 3 cell layers with 144 +/- 44 microns). Quantification of SMCs undergoing DNA synthesis in the intima (control: 51 +/- 19 cells/mm2) showed a significant increase of labeled cells after 7 (216 +/- 74 cells/mm2, p = 0.003) and 14 days (281 +/- 139 cells/mm2, p = 0.011). Integrity of the internal elastic lamina was disrupted in all animals after intervention. Seven and 14 days after treatment, a considerable reduction of medial cell nuclei was found in 10 of 12 animals. SMC proliferation in the medial layer was increased within the first 2 weeks after laser ablation (168 +/- 113 cells/mm2; control: 8 +/- 4 cells/mm2; p = 0.023). Six weeks after holmium laser angioplasty, SMC proliferation had returned to control levels in the intima and remained increased in the medial layer. This proliferative response resulted in a significant increase of intimal thickening within 6 weeks after laser ablation (30 +/- 6 cell layers, 375 +/- 97 microns resp.; p = 0.001 each). CONCLUSIONS Holmium laser treatment leads to considerable vessel wall injury and results in SMC proliferation in the intimal and medial layer with a maximum of proliferative activity within the first 2 weeks. Subsequently, this results in considerable intimal and medial hyperplasia within 6 weeks after treatment.

BACKGROUND The proliferative response induced by balloon angioplasty is known to be an important factor in the development of restenosis after successful coronary angioplasty. METHODS AND RESULTS To study the effects of low-molecular-weight heparin (LMWH) on cellular proliferation after experimental balloon angioplasty, LMWH (3.9 kd, 400 anti-Xa units/kg/day) was given to 20 male New Zealand White rabbits. After an intimal fibromuscular plaque was induced by electrical stimulation in the right carotid artery, LMWH was applied during the 7 days after balloon dilatation. As the control group, 20 other rabbits underwent balloon angioplasty without application of LMWH. The vessels were excised 3, 7, 14, and 28 days after balloon treatment. During the final 18 hours before the rabbits were killed, bromodeoxyuridine was applied. Intimal wall thickness increased from 13 +/- 5 cell layers (preangioplasty control group) to 20 +/- 6 cell layers in the LMWH-treated group at 28 days (p less than 0.05). In contrast, histological examination of control animals 28 days after angioplasty revealed a significant increase to 35 +/- 15 cell layers (p less than 0.01). Immunohistological quantification showed a significant increase (p less than 0.001) of cells undergoing DNA synthesis at 3 (10.2 +/- 4.2%) and 7 (7.7 +/- 4.8%) days after balloon dilatation in control animals. In contrast, at 3 and 7 days after balloon treatment, the percentage of cells undergoing DNA synthesis in LMWH-treated rabbits was lower (3 days, 2.7 +/- 1.8%; 7 days, 1.9 +/- 0.3%) than the corresponding untreated controls but showed a significant increase (p less than 0.01) compared with the preangioplasty controls. The differences between the two groups were statistically significant, however (3 days, p less than 0.01; 7 days, p less than 0.05). As early as 14 days after angioplasty, the extent of cellular proliferation was normalized and was comparable to the preintervention levels in both groups. CONCLUSIONS Our data indicate that the proliferative response after balloon angioplasty can be reduced in vivo by early treatment with LMWH and thus encourage further clinical investigations.

The purpose of this experimental in vivo study was to determine the time course of smooth muscle cell proliferation early and late after intravascular stenting compared to conventional balloon angioplasty in normal vessels. A balloon expandable 2·0 mm tantalum Strecker stent was placed in the right carotid artery of 33 male New Zealand White rabbits after they had been fed a 0·5% cholesterol diet for 28 days. In addition, balloon angioplasty was performed in 27 of the animals; 19 contralateral vessels served as controls without treatment. The vessels were excised at 7, 14, 28, 42 or 90 days after treatment. During the final 18 h before the rabbits were killed, bromodeoxyuridine (BrdU) was applied and proliferating cells were detected by using a monoclonal antibody against BrdU. In histological cross sections the proportion of cells undergoing DNA synthesis was determined. Analysis was performed separately in the intimal and medial layers. Additionally, the area adjacent to the stent wire was compared with the intermediate area. Smooth muscle cells were identified by alpha-actin staining. Intimal wall thickness increased from 23 ± 28,μm (control group without intervention) to 323 ± 84μm within 42 days after slenting (P

Ziel der Untersuchung war die Bestimmung der proliferativen Reaktion glatter Muskelzellen in der Intima sowie der Haufigkeit thrombotischer Verschlusse nach Stentimplantation im Vergleich zur konventionellen Ballondilatation. Hierzu wurden an der Arteria carotis von 27 Neuseeland-Kaninchen ballonexpandierbare Strecker-Stents implantiert beziehungsweise bei 29 Tieren eine Ballonangioplastie durchgefuhrt. Zehn Tiere dienten als Kontrollgruppe ohne Intervention. Die Tiere erhielten unmittelbar praoperativ sowie postoperativ fur insgesamt drei Tage unfraktioniertes Heparin. Die Gefase wurden 7, 14, 28 und 42 Tage nach Intervention entnommen und histologisch aufgearbeitet. Die Gabe von Bromdesoxyuridin ermoglichte die immunhistologische Bestimmung der neointimalen Proliferationsrate, wobei die glatten Muskelzellen mit einem Antikorper gegen a-Aktin identifiziert wurden. Am 7. Tag nach Intervention zeigte sich eine stark gesteigerte Proliferation glatter Muskelzellen sowohl nach Stentimplantation (16,2 ± 3,7%) als auch nach konventioneller Ballon-angioplastie (12,5 ± 4,8%). Wahrend die Proliferationsrate nach Ballon-angioplastie am 42. Tag jedoch auf den Wert der Kontrollgruppe (0,3 ± 0,4%) zuruckgekehrt war, fand sich nach Stentimplantation eine immer noch signifikante Erhohung der Proliferation (2,7 ± 0,3%; p < 0,0001). Auserdem war die Inzidenz thrombotischer Komplikationen nach Stentimplantation deutlich hoher (25,9% vs. 6,8%). Zusammenfassend weisen unsere Daten auf eine gesteigerte und prolongierte proliferative Reaktion glatter Muskelzellen nach Stentimplantation im Vergleich zur Ballondilatation hin.

Ziel der vorliegenden Studie war es, die intimalen Makrophagen im zeitlichen Verlauf nach experimenteller Ballonangioplastie quantitativ zu erfassen. Nach Erzeugung einer Plaque in der Arteria carotis durch Elektrostimulation wurde bei 32 Kaninchen eine Ballonangioplastie durchgefuhrt. Die Gefase wurden 3, 7, 14, 21, 28 bzw. 42 Tage nach Intervention histologisch aufgearbeitet. Unter Verwendung eines monoklonalen Antikorpers (RAM 11) erfolgte die prozentuale Bestimmung der Makrophagen in der Neointima. Ausgehend von 2,4± 2,6 % in der Kontrollgruppe fand sich ein signifikanter Anstieg der Makrophagen vom 7. (7,9± 2,1 %) bis zum 21. (6,9± 3,1 %) Tag nach Intervention. Am 28. und 42. Tag nach Dilatation war die Anzahl der intimalen Makrophagen wieder mit der Kontrollgruppe vergleichbar.