Die Implantation von Atemwegstents stellt eine therapeutische Option zur Behandlung maligner und benigner Stenosierungen des Tracheobronchialsystems dar. Es handelt sich um ein effektives Verfahren das in spezialisierten Zentren und nach strenger Indikationsstellung durchgeführt werden sollte. Die Bildung von Granulationsgewebe stellt dabei eine der häufigsten Komplikationen dar. In der vorliegenden Arbeit wurden ballonexpandierbare bare-metal stents (BMS) und drug-eluting stents (DES) histologisch und immunhistochemisch untersucht.  Die zellulären und extrazellulären Gewebereaktionen der zentralen Atemwege wurde in New Zealand White Rabbits (3,1 kg bis 4,8 kg) nach Explantation von sieben bare-metal stents (Bx Sonic, Johnson & Johnson Cordis, USA) und vier Sirolimus-eluting stents (Cypher Select, Johnson & Johnson Cordis, USA) untersucht. Die Implantationszeit betrug 12 Monate. Die Implantation  metallischer Stents in die zentralen Atemwege verursachte ähnliche Gewebereaktionen wie nach koronarer Stentimplantation. Die Entzündungsreaktionen waren vergleichsweise stärker ausgeprägt. Nach 12 Monaten konnte bei beiden Stenttypen neugebildetes Gewebe auf der luminalen Seite der Implantate gesehen werden. Dieses war durchsetzt von Entzündungszellen, fibromuskulären Zellen, Kollagenfasern, elastischen Fasern und neu gebildeten Kapillaren. In zwei Stentpräparaten konnten Chondrozyten im neugebildeten Gewebe gesehen werden. Fibromuskuläre Zellen färbten positiv für Smooth Muscle Actin  und Vimentin. Vereinzelt wurde dieses Granulationsgewebe von mehrschichtigem Epithel mit kubisch-polygonalen Zellen, entsprechend einer Epithelmetaplasie, bedeckt. Nicht in die Bronchialwand eingewachsene Stentstreben wurden von Mukus, Granulozyten, Makrophagen und azellulärem Detritus bedeckt. Das Flimmerepithel zeigte sich im gestenteten Bereich deutlich reduziert. Beide Stenttypen zeigten eine vergleichbare Entzündungsreaktion. Granulozyten als Zeichen einer akuten Entzündungsreaktion konnten im neugebildetem Gewebe und an der direkten Stentoberfläche gesehen werden. Weiterhin umgaben Makrophagen und fibromuskuläre Zellen eingewachsene Stentstreben, Lymphozyten und Makrophagen schlossen sich in der unmittelbaren Umgebung an. Einige Lymphozyten wurden als B-Lymphozyten (CD79 +) identifiziert. Fremdkörperriesenzellen wurden in drei Sirolimus-freisetzenden Stentpräparaten und einem bare-metal Stentpräparat gesehen.

Fundamentos: O implante de stents coronários constitui-se na técnica mais prevalente de revascularização percutânea, em especial pela prevenção da reestenose, quando comparado às intervenções com o balão. No entanto, a reestenose intra-stent, que ocorre em cerca de 25% dos casos, restringe os seus benefícios clínicos e econômicos tardios. Demonstrou-se que a hiperplasia neo-intimal decorrente da reação da parede vascular causada pelo implante do stent, é responsável pelas recidivas. Interroga-se se um protocolo de medicamentos contemplando doses máximas de manutenção de clopidogrel e atorvastatina poderia reduzir a hiperplasia neo-intimal e a reestenose. Objetivos: O objetivo primário foi aferir se esta associação de medicamentos reduziria o volume de hiperplasia neo-intimal (35% ou mais), expressa pela obstrução volumétrica da luz, mensurada pelo ultrassom intracoronário, 12 meses após a intervenção. Os objetivos secundários foram: os resultados da angiografia quantitativa e os eventos cardíacos adversos maiores (óbito, infarto e revascularização do vaso-alvo). Casuística e métodos: Foram incluídos casos eletivos e com lesões primárias nas artérias naturais. Os pacientes foram tratados com stents não farmacológicos e randomizados em dois grupos: A, com 50 pacientes medicados com doses máximas de clopidogrel e atorvastatina; e grupo B com 50 casos, medicados com 75mg de clopidogrel e doses de sinvastatina rotineiramente prescritas para obtenção das metas recomendadas para controle lipídico. Resultados: Ambos os grupos não apresentaram diferenças significantes em relação às características clínicas, angiográficas e técnicas, com exceção do diabetes, mais comum em A (36% vs 16%; p=0,02). Aos 12 meses de evolução, observaram-se eventos cardíacos maiores (12% versus 18%; p = 0,56) e revascularização do vaso-alvo (4% versus 2%; p>0,99) sem diferença significante. Nova angiografia coronária foi obtida em 98% dos casos dos dois grupos, observando-se taxa de reestenose de 8,1% e 8,2% nos grupos A e B (p>0,99). A perda tardia da luz arterial foi semelhante [0,9 mm (DP 0,5 mm) versus 1,1 mm (DP 0,7 mm); p = 0,22], o mesmo acontecendo com o diâmetro mínimo da luz [2,2 mm (DP 0,6 mm) versus 1,9 mm (DP 0,6 mm); p = 0,12]. Realizou-se ultrassom intracoronário em 98% dos pacientes de ambos os grupos, observando-se obstrução do volume da luz de 36,3% (DP 10,3%) no grupo A e de 40,1% (DP 10,9%) no grupo B (p = 0,14). Conclusões: Os resultados deste estudo demonstram que: 1) a terapêutica adjunta utilizando doses máximas de clopidogrel 150 mg/dia e atorvastatina 80 mg/dia não reduz o volume de hiperplasia neo-intimal, expressa pela obstrução volumétrica da luz; 2) as variáveis da angiografia quantitativa e os eventos cardíacos adversos maiores não mostraram diferenças significativas entre os dois grupos. / Coronary stent implantation is the current technique of choice in patients undergoing percutaneous intervention. They effectively reduce acute occlusion and restenosis even in complex lesions. However, instent restenosis occurs in up to 25% of the treated cases and there are several theories elaborating the possible relation between coronary artery thrombosis and inflammation to neointimal proliferation and the mechanism of obstruction recurrence. There are questions whether an optimized medical treatment based on maximum doses of Clopidogrel and Atorvastatin could limit neointimal hyperplasia and restenosis. Objectives: Primary endpoint was to assess the efficacy of this scheme in reducing neointimal hyperplasia volume (XX% or more), according to intravascular ultrasound measurements, 12 months after the index intervention. Secondary endpoints were quantitative angiography measurements and major adverse cardiac events (death, myocardial infarction and target vessel revascularization). Methods: We included patients with de novo lesions undergoing elective implantation of uncoated stents. Patients were divided according to the drug regimen into Group A - 50 patients receiving maximal atorvastatin and clopidogrel doses; and Group B - 50 cases treated with standard clopidogrel and simvastatin doses. Results: Groups were similar concerning clinical and angiographic characteristics, except for diabetes, more frequent in Group A (36% vs 16%, p = 0.02). At the end of 12 months major cardiac events (12% versus 18%, p = 0.56) and target vessel revascularization (4% versus 2%, p> 0.99) did not show differences between groups. Coronary angiography was obtained in 98% of the cases and the restenosis rate was 8.1% (A group) and 8,2% (B group) (p> 0.99). Late luminal loss was similar [0.9 mm (SD 0.5 mm) versus 1.1 mm (SD 0.7 mm), p = 0.22], as well as the minimum lumen diameter [2.2 mm (SD 0.6 mm) versus 1.9 mm (SD 0.6 mm), p = 0.12]. IVUS was done in 98% of patients in both groups, and the volume of neointimal hyperplasia was not significantly different in both groups [61.8 mm 3 (SD 35.4 mm3) mm3 versus 66.3 (SD 31.6 mm3), p = 0.58]. Luminal volume obstruction was 36.3% (SD 10.3%) in group A and 40.1% (SD 10.9%) in group B (p = 0.14). Conclusions: According to our results we may conclude that: 1) the therapeutic regimen using maximum doses of atorvastatin and clopidogrel did not reduce the volume of neointimal hyperplasia, 2) restenosis rate, quantitative angiography results and the rate of major adverse cardiac events were not affected by the treatment regimen.

Σκοπός: Η μελέτη είχε ως σκοπό την διερεύνηση της ασφάλειας και της αποτελεσματικότητας των sirolimus-eluting stent, σε σχέση με τα απλά μεταλλικά stent, στα πλαίσια αγγειοπλαστικής των κνημιαίων αγγείων, σε ασθενείς με χρόνια κρίσιμη ισχαιμία του κάτω άκρου. Πρόκειται για μια προοπτική ελεγχόμενη, κλινική μελέτη με διπλό σκέλος. Τα stent τοποθετήθηκαν σε περιπτώσεις μη ικανοποιητικής αγγειοπλαστικής (δηλ. σε περιπτώσεις ελαστικής επαναφοράς-υπολειμματικής στένωσης >30% και σε περιπτώσεις διαχωρισμού). Οι ασθενείς ελέγχθηκαν κλινικά και αγγειογραφικά στο εξάμηνο και στο 1 έτος. Ασθενείς και μέθοδοι: 29 ασθενείς, εκ των οποίων 8 γυναίκες και 21 άνδρες, με μέση ηλικία τα 68,7 έτη υποβλήθηκαν σε αγγειοπλαστική στα κνημιαία αγγεία, με απλά μεταλλικά stent, ομάδα Β. Σε αυτή την ομάδα τοποθετήθηκαν απλά stent σε 65 αλλοιώσεις, εκ των οποίων 38 στενώσεις και 27 αποφράξεις σε συνολικά 40 κνημιαία αγγεία. Άλλοι 29 ασθενείς, 8 γυναίκες και 21 άνδρες, με μέση ηλικία τα 68,8 έτη αντιμετωπίστηκαν με sirolimus-eluting stent, ομάδα S. Σε αυτή την ομάδα αντιμετωπίστηκαν 66 αλλοιώσεις εκ των οποίων 46 στενώσεις και 20 αποφράξεις, σε 41 συνολικά αγγεία. Οι ασθενείς επανελέγχθηκαν κλινικά και με ενδαρτηριακή αγγειογραφία στους 6 μήνες και στο 1 έτος, μετά την αρχική επέμβαση. Έγινε στατιστική ανάλυση των αποτελεσμάτων. Αποτελέσματα: Οι συνοδές νόσοι ήταν περισσότερες στην ομάδα S (όπως η συμπτωματική νόσος από την καρδιά και τις καρωτίδες, καθώς και η υπερλιπιδαιμία, p<0.05). Η τεχνική επιτυχία ήταν 96,6% (28/29 άκρα) στην ομάδα Β έναντι 100% (29/29 άκρα) στην ομάδα S (p=0.16) Στον επανέλεγχο εξαμήνου: Η βατότητα ήταν 68,1% στην ομάδα Β και 92,0% στην ομάδα S, (p<0.002). Τα μεγαλύτερα ποσοστά βατότητας των sirolimus-eluting stent, μετά από πολυπαραγοντική regression analysis είχαν OR 5.625, με 95% CI 1.711- 18.493, που ήταν στατιστικά σημαντικό (p=0.004). Η δυαδική επαναστένωση εντός του stent ήταν 55,3% ενώ η επαναστένωση στα άκρα του stent ήταν 66,0% στους ασθενείς με τα απλά μεταλλικά stent. Αντιθέτως τα ποσοστά στους ασθενείς με sirolimus-eluting stent ήταν 4,0% και 32,0% αντίστοιχα. Συγκεκριμένα η επαναστένωση εντός του stent είχε OR 0.067, με 95% CI 0.021-0.017, και η επαναστένωση στα άκρα του stent είχε OR 0.229 με 95% CI 0.099-0.533. Και τα δύο ήταν ήταν στατιστικά σημαντικά με p<0.001 και p=0.001, αντίστοιχα. Τα συνολικά ποσοστά επανεπέμβασης (TLR) στο εξάμηνο ήταν 17,0% στην ομάδα Β έναντι 4,0% στην ομάδα S, (OR 0.057, με 95% CI 0.008-0.426). Το αποτέλεσμα ήταν επίσης στατιστικά σημαντικό υπέρ των sirolimus stent. (p=0.02) Η διάσωση του άκρου ήταν 100% και στις δύο ομάδες. Η θνησιμότητα και ο ελάσσων ακρωτηριασμός στο εξάμηνο ήταν 6,9% και 17,2% στην ομάδα Β έναντι 10,3% και 3,4% στην ομάδα S (p=0.32 και p=0.04, αντίστοιχα). Στον επανέλεγχο έτους: Τα sirolimus-eluting stent σχετίζoνταν και πάλι με καλύτερη πρωτογενή βατότητα (OR 10.401, με 95% CI 3.425-31.589, p<0.001) και σημαντικά μειωμένη δυαδική επαναστένωση εντός του stent (OR 0.156, με 95% CI 0.060-0.407, p<0.001), καθώς και στα άκρα του stent. (OR 0.089, με 95% CI 0.023-0.349, p=0.001) Τα ποσοστά επανεπέμβασης στις βλάβες (TLR) ήταν πολύ μικρότερα στην ομάδα του sirolimus (OR 0.238, με 95% CI 0.067-0.841, p=0.026) . Δεν υπήρξαν στατιστικά σημαντικές διαφορές ανάμεσα στις δύο ομάδες Β και S όσον αφορά στα ποσοστά θνησιμότητας 10,3% έναντι 13,8%, στη διάσωση του άκρου 100% έναντι 96% και στους ελάσσονες ακρωτηριασμούς 17,2% έναντι 10,3% αντίστοιχα. Συμπεράσματα: Τα sirolimus-eluting stents περιορίζουν την ενδοθηλιακή υπερπλασία στα κνημιαία αγγεία. Η εφαρμογή τους έχει ως αποτέλεσμα την σημαντική μείωση των ποσοστών επαναστένωσης και μειώνει την ανάγκη για επανεπεμβάσεις. / Aim : The purpose of our study was to investigate the 6-month and 1-year angiographic and clinical outcome in the setting of a controlled clinical study. The study examined the safety and relative effectiveness of sirolimus-eluting stents opposed to conventional metal stents, in the infrapopliteal vessels, in patients with critical limb ischemia (CLI). The stents were used in a bail-out setting during infrapopliteal endovascular procedures, i. e. stenting was carried out in cases of suboptimal angioplasty results (recoil - residual stenosis >30%, or in cases of dissection, after angioplasty). Patients and Methods: Twenty-nine patients comprising 8 women and 21 men with a mean age of 68.7 years were submitted to infrapopliteal revascularization with conventional (bare) metal stents, called group B. In these patients 65 lesions were treated with bare stents, of whom 38 stenoses and 27 occlusions, in a total of 40 infrapopliteal vessels. Another 29 patients, again 8 women and 21 men, with a mean age of 68.8 years were treated with sirolimus-eluting stents, named group S. There were 66 lesions in this group with 46 of them stenoses and 20 occlusions, in a total of 41 arteries. Patients were followed-up with clinical examination and intrarterial angiography 6 months and 1 year after the procedure. Both results were subsequently analyzed statistically. 135 Results: Co morbidities like symptomatic cardiac and carotid disease, as well as hyperlipidemia were more prominent in group S (p<0.05). Technical success was 96.6% (28/29 limbs) in group B against 100.0% (29/29 limbs) in group S (p=0.16). During 6-month patient follow-up: Primary patency was 68.1% in group B opposed to 92.0% in group S (p<0.002). Sirolimus-eluting stents exhibited higher primary patency with OR 5.625 and 95% CI 1.711-18.493, which was statistically significant (p=0.004). Binary in-stent restenosis rate was 55.3% while in-segment restenosis was 66.0%, in patients who had received bare metal stents. In opposition the respective restenosis rates, in patients with sirolimus-eluting stents were 4.0% and 32.0%. Diminished in-stent (OR 0.067 with 95% CI 0.021-0.017) and insegment (OR 0.229 with 95% CI 0.099-0.533) binary restenosis were both statistically significant with p values being p<0.001 and p=0.001 respectively. Collective target lesion re-intervention (TLR) at 6 month follow-up was 17.0% in group B against 4.0% (OR 0.057 with 95% CI 0.008-0.426) in group S, which proved again statistically significant for sirolimus stents (p=0.02). Six-month limb salvage rate was 100% in both groups. Six-month mortality and minor amputation rates were respectively 6.9% and 17.2%, in group B versus 10.3% and 3.4%, in group S (p=0.32 and p=0.04, respectively). During 1-year patient follow-up: 136 SES were still related with better primary patency rate (OR 10.401 with 95% CI 3.425-31.589, p<0.001) and considerably lesser events of in-stent binary restenosis (OR 0.156, 95% CI 0.060-0.407, p<0.001) as well as insegment (OR 0.089, 95% CI 0.023-0.349, p=0.001) binary restenosis. Target lesion re-intervention (TLR), was much lower in the SES patients group during 1-year follow-up (OR 0.238 with 95% CI 0.067-0.841, p=0.026) . At 1 year follow-up there were no statistically significant differences among group B and group S regarding mortality (10.3% against 13.8%), limb salvage rates (100% vs. 96%) and minor amputation (17.2% vs. 10.3%). Conclusions: Sirolimus-eluting stents appear to limit intimal hyperplasia in the infrapopliteal vessels. The use of sirolimus-eluting stents decreases considerably restenosis rates in the infrapopliteal vessels and reduces the need for repeat interventions

Fundamentos: O implante de stents coronários constitui-se na técnica mais prevalente de revascularização percutânea, em especial pela prevenção da reestenose, quando comparado às intervenções com o balão. No entanto, a reestenose intra-stent, que ocorre em cerca de 25% dos casos, restringe os seus benefícios clínicos e econômicos tardios. Demonstrou-se que a hiperplasia neo-intimal decorrente da reação da parede vascular causada pelo implante do stent, é responsável pelas recidivas. Interroga-se se um protocolo de medicamentos contemplando doses máximas de manutenção de clopidogrel e atorvastatina poderia reduzir a hiperplasia neo-intimal e a reestenose. Objetivos: O objetivo primário foi aferir se esta associação de medicamentos reduziria o volume de hiperplasia neo-intimal (35% ou mais), expressa pela obstrução volumétrica da luz, mensurada pelo ultrassom intracoronário, 12 meses após a intervenção. Os objetivos secundários foram: os resultados da angiografia quantitativa e os eventos cardíacos adversos maiores (óbito, infarto e revascularização do vaso-alvo). Casuística e métodos: Foram incluídos casos eletivos e com lesões primárias nas artérias naturais. Os pacientes foram tratados com stents não farmacológicos e randomizados em dois grupos: A, com 50 pacientes medicados com doses máximas de clopidogrel e atorvastatina; e grupo B com 50 casos, medicados com 75mg de clopidogrel e doses de sinvastatina rotineiramente prescritas para obtenção das metas recomendadas para controle lipídico. Resultados: Ambos os grupos não apresentaram diferenças significantes em relação às características clínicas, angiográficas e técnicas, com exceção do diabetes, mais comum em A (36% vs 16%; p=0,02). Aos 12 meses de evolução, observaram-se eventos cardíacos maiores (12% versus 18%; p = 0,56) e revascularização do vaso-alvo (4% versus 2%; p>0,99) sem diferença significante. Nova angiografia coronária foi obtida em 98% dos casos dos dois grupos, observando-se taxa de reestenose de 8,1% e 8,2% nos grupos A e B (p>0,99). A perda tardia da luz arterial foi semelhante [0,9 mm (DP 0,5 mm) versus 1,1 mm (DP 0,7 mm); p = 0,22], o mesmo acontecendo com o diâmetro mínimo da luz [2,2 mm (DP 0,6 mm) versus 1,9 mm (DP 0,6 mm); p = 0,12]. Realizou-se ultrassom intracoronário em 98% dos pacientes de ambos os grupos, observando-se obstrução do volume da luz de 36,3% (DP 10,3%) no grupo A e de 40,1% (DP 10,9%) no grupo B (p = 0,14). Conclusões: Os resultados deste estudo demonstram que: 1) a terapêutica adjunta utilizando doses máximas de clopidogrel 150 mg/dia e atorvastatina 80 mg/dia não reduz o volume de hiperplasia neo-intimal, expressa pela obstrução volumétrica da luz; 2) as variáveis da angiografia quantitativa e os eventos cardíacos adversos maiores não mostraram diferenças significativas entre os dois grupos. / Coronary stent implantation is the current technique of choice in patients undergoing percutaneous intervention. They effectively reduce acute occlusion and restenosis even in complex lesions. However, instent restenosis occurs in up to 25% of the treated cases and there are several theories elaborating the possible relation between coronary artery thrombosis and inflammation to neointimal proliferation and the mechanism of obstruction recurrence. There are questions whether an optimized medical treatment based on maximum doses of Clopidogrel and Atorvastatin could limit neointimal hyperplasia and restenosis. Objectives: Primary endpoint was to assess the efficacy of this scheme in reducing neointimal hyperplasia volume (XX% or more), according to intravascular ultrasound measurements, 12 months after the index intervention. Secondary endpoints were quantitative angiography measurements and major adverse cardiac events (death, myocardial infarction and target vessel revascularization). Methods: We included patients with de novo lesions undergoing elective implantation of uncoated stents. Patients were divided according to the drug regimen into Group A - 50 patients receiving maximal atorvastatin and clopidogrel doses; and Group B - 50 cases treated with standard clopidogrel and simvastatin doses. Results: Groups were similar concerning clinical and angiographic characteristics, except for diabetes, more frequent in Group A (36% vs 16%, p = 0.02). At the end of 12 months major cardiac events (12% versus 18%, p = 0.56) and target vessel revascularization (4% versus 2%, p> 0.99) did not show differences between groups. Coronary angiography was obtained in 98% of the cases and the restenosis rate was 8.1% (A group) and 8,2% (B group) (p> 0.99). Late luminal loss was similar [0.9 mm (SD 0.5 mm) versus 1.1 mm (SD 0.7 mm), p = 0.22], as well as the minimum lumen diameter [2.2 mm (SD 0.6 mm) versus 1.9 mm (SD 0.6 mm), p = 0.12]. IVUS was done in 98% of patients in both groups, and the volume of neointimal hyperplasia was not significantly different in both groups [61.8 mm 3 (SD 35.4 mm3) mm3 versus 66.3 (SD 31.6 mm3), p = 0.58]. Luminal volume obstruction was 36.3% (SD 10.3%) in group A and 40.1% (SD 10.9%) in group B (p = 0.14). Conclusions: According to our results we may conclude that: 1) the therapeutic regimen using maximum doses of atorvastatin and clopidogrel did not reduce the volume of neointimal hyperplasia, 2) restenosis rate, quantitative angiography results and the rate of major adverse cardiac events were not affected by the treatment regimen.