Inhibitory effect of n-acetylcysteine on intimal hyperplasia and proliferation of smooth muscle cells in anastomosis performed on the carotid artery of rabbit

Rekonstrüktif vasküler girişimlerden sonra ani tıkanmaya yol açan akut trombüs oluşumundan farklı olarak, geç dönemdeki daralma ve tekrar eden tıkanıklıklarda düz kas hücrelerinin proliferasyonu ve migrasyonu ile birlikte ekstrasellüler matriks birikimi sonucu oluşan neointimal hiperplazi önemli rol oynamaktadır. Hayvan ve insanlarda yapılan arteriyel hasar modellerinde lümen daralmasının temel nedeni intima tabakasındaki düz kas hücre proliferasyonu ve konnektif doku birikiminin olduğu gösterilmiştir.N-Asetilsistein, sahip olduğu nükleofilik serbest tiyol (-SH) grubu aracılığıyla, oksidan radikallerin elektrofilik grubuyla etkileşime girerek direkt antioksidan özellik göstermektedir. N-Asetilsistein, glutatyon sentezini tetiklemekte, glutatyon ise ekzojen veya endojen sitotoksik maddelerin ve oksidan radikallerin hücreye zarar vermesini önleyen, hücre bütünlüğünün ve işlevlerinin devamı için çok önemli bir endosellüler mekanizmada temel rolü olan, yüksek reaktiflikte bir tripeptittir. N-Asetilsistein, sülfidril grupları için kaynak teşkil etmektedir. Sülfidril gruplarının ise, serbest oksijen radikallerinin temizlenmesi ile birlikte Nitrik Oksit'in yarılanma ömrünün düzenlenmesini sağlaması gibi birçok biyolojik fonksiyonu vardır. N-Asetilsistein aynı zamanda nitrogliserin aracılı koroner arter vazodilatasyonunu ve trombosit agregasyonunu önlemeye yönelik etkisini potansiyelize etmektedir. N-Asetilsisteinin vasküler düz kas hücrelerinin hücre döngüsünü ve proliferasyonunu regüle ettiği gösterilmiştir. Nükleer Faktör Kappa-Beta aktivasyonu yoluyla endotel hücreleri ve düz kas hücrelerinin spesifik adezyon moleküllerinin upregulasyonu hasar sonrası vasküler hücre aktivasyonunu destekler. Yapılan güncel çalışmalar N-Asetilsisteinin endotel ve düz kas hücresinde NF-kB aktivitesinin önemli bir regülatörü olduğunu göstermiştir. N-Asetilsistein düz kas hücrelerinin hücre siklus progresyon ve proliferasyonunu düzenler ve endotel hücrelerinde antitrombotik ve antiplatelet aktivasyonunu potansiyelize eder. Tüm bu etkileri nedeniyle, N-Asetilsistein'in tavşan karotid arterlerinde yapılan anastomozlarda intimal hiperplazi ve endotelyal proliferasyon üzerine inhibitör etkisini araştırmayı amaçladık.Materyal - MetodRandomize olarak seçilen 14 adet Yeni Zelanda tipi erkek tavşan kullanıldı. Anestezi olarak 50 mg/kg intramuskuler Ketamin ve 5 mg/kg intramuskuler Ksilazin kullanıldı. Anastomoz için sağ taraf, kontrol için ise sol taraf karotid arteri kullanıldı. Tüm grup tavşanlara sağ vertikal boyun insizyonu yapılarak karotid arter eksplore edildi. 100 IU/kg dozda IV Heparin uygulandı. Karotid arter proksimal ve distalinden buldog klemple klemplendikten sonra transekte edildi ve 8/0 polipropilen sütür ile tek tek dikilerek anastomoz tamamlandı. Grup 1'deki tavşanlar kontrol grubunu oluşturdu. Grup 2'deki deneklere operasyondan hemen sonra ilk doz IV sonraki tüm dozlar IM olmak üzere toplam 21 gün 150 mg/kg/gün N-Asetilsistein uygulandı. Yirmisekizinci gün sonunda anastomoz yapılan taraf ve anastomoz yapılmayan karşı taraf karotid arter segmenti çıkarılarak incelenmek üzere histoloji laboratuarına gönderildi. Mikroskobik örnekler parafin bloklar halinde 5 μm kalınlığında kesildi ve Hematoxylen-Eosin ile boyanarak ışık mikroskobunda incelendi.BulgularGrup 1 ile Grup 2'nin lümen alanının karşılaştırılmasında Grup 2'de anlamlı olarak daha fazla [z=-3,13, p=0,002], kontrol gruplarının (Grup 1K ve Grup 2K) karşılaştırılmasında ise anlamlı fark olmadığı saptandı [z=-0,57, p=0,56]. Grup 1 ile Grup 2'nin intima alanının karşılaştırılmasında, Grup 2'de anlamlı olarak daha az olduğu [z=-2,49, p=0,013], kontrol gruplarının (Grup 1K ve Grup 2K) karşılaştırılmasında ise anlamlı fark olmadığı saptandı [z=-0,96, p=0,34]. Grup 1 ile Grup 2'nin intima-media alan oranının karşılaştırılmasında ise Grup 2'de anlamlı olarak daha düşük olduğu [z=-2,236, p=0,025] saptanmıştır.Tartışmaİntimal hiperplazi, tüm arteriyel girişimlerin %15-30'unu etkilemekle birlikte, hasara karşı oluşan bu cevabın kontrolüne yönelik geliştirilen yaklaşımlar, klinik olarak büyük öneme sahiptir. Bugüne kadar ister anastomoz sonrası ister PTCA veya stent sonrası olsun intimal hiperplazinin ve düz kas hücre proliferasyonunun engellenmesi üzerine birçok çalışma yapılmıştır.Çalışmamızda, N-Asetilsistein verilen anastomoz gruplarında lümen alanı, intima alanı ve intima/media alan oranında anlamlı bir düzelme sağlanmıştır. N-Asetilsisteinin bu etkiyi direkt antioksidan etkisi, glutatyon sentezini indüklemesi, Nitrik oksitin yarılanma ömrünü düzenlemesi, kemoatraktanların aktivitesini düzenleme yeteneği, NF-kB aktivitesinin regulasyonu, vasküler düz kas hücrelerinin çoğalma ve migrasyonunu regüle etme özelliği sayesinde yarattığını düşünmekteyiz. Bu doğrultuda vasküler girişimler ve anastomoz sonrası N-Asetilsistein kullanımının intimal hiperplaziyi azaltarak ve vasküler remodellingi sağlayarak damarın açık kalma süresini arttıracağı düşüncesindeyiz.Anahtar kelimeler: N-Asetilsistein, intimal hiperplazi, düz kas hücre proliferasyonu, anastomoz, tavşan. Other than occurence of acute thrombosis leading to sudden occlusion after reconstructive vascular procedures, neointimal hyperplasia, which is accounted for the recurrence of occlusion at late period and which is the result of proliferation and migration of smooth muscle cells together with accmulation of extracellular matrix, plays an important role. It was shown in arterial injury models of animal and human studies that the principal reason for luminal narrowing was smooth muscle cell proliferation and connective tissue accumulation in the intimal layer. N-Acetylcysteine, shows a direct antioxydant characteristic with its free tiyole (-SH) group through an interaction with the electrophilic groups of oxydant radicals. It triggers the synthesis of glutation. As for glutation, which is a high reactive tripeptide, while it protects cells from the harmful effects of endogenous or exogenous cytotoxic substances and oxydant radicals, it also has an important role in endocellular mechanisms for the continuity of the structure and the functionality of cells. N-Acetylcysteine constitudes as a resource for sulphydrile groups. The sulphydril groups has many biologic functions, such as clearance of free oxygen radicals and regulation of the half life of nitric oxide. N-Acetylcysteine also potentialize the vasodilatatory effects of nitroglycerine on coronary arteries and inhibitory effects of it to the aggregation of thrombocytes. It was shown that N-Acetylcysteine regulates the cell cycle and proliferation of smooth muscle cells. Through the activation of nuclear factor Kappa-Beta (NF-kB), the upregulation of specific adesion molecules on endotel and smooth muscle cells support the activation of vascular cells after injury. Recently performed studies of N-Acetylcysteine showed that it has been an important regulator of the activity of NF-kB in endotel and smooth muscle cells. N-Acetylcysteine regulates the progression and proliferation of smooth muscle cells and potentializes the antithrombotic and antiplatelet activation in endotel cells. Due to the all abovementioned effects of N-Acetylcysteine, we aimed to investigate the inhibitory effects of N-Acetylcysteine on intimal hyperplasia and endothelial proliferation in the anastomosis models of rabbit carotid arteries. Material and MethodIn this study, randomly selected fourteen New Zealand type male rabbits were used. As for anesthesia, 50 mg/kg intramuscular ketamine and 5 mg/kg intramuscular Ksilazine were used. Right common carotid artery for anastomozis and left common carotid artery for control was used. Common carotid artery was explored with vertical neck incision in all rabbits. 100 IU/kg intravenous heparin were used. After the proximal and distal carotid arterial segments were clamped, it was transected and anastomozed end-to-end with 8/0 polipropilene sutures. Group 1 pertained the control group. First dose of N-Acetylcysteine was given intravenously initially after the surgical procedure, and the remaining doses intramuscularly with total of 150 mg/kg/day. At the end of twentyeighth day, carotid artery segments of both sides (anastomozis side and opposing control side) were removed and transfered to the hystology laboratory. Specimens were cut as paraphine blocks of 5 µm and painted with Hematoxylene-Eosine in order to be evaluated under microscobe. ResultsThe comparison of luminal area in group 1 and 2 revealed that, the luminal area was significantly higher in group 2 [z=3,13, p=0,002]. This comparison between contrlateral control groups (Group 1K and 2K) was not significantly different [z=-0,57, p=0,56]. While the intimal area was significantly lower in group 2 [z=-2,49, p=0,013], no significant difference was found on the comparison of control groups [z=0,96, p=0,34]. The comparison of the ratio of intimal to medial area showed that it was significantly lower in group 2 [z=-2,236, p=0,025].ConclusionIntimal hyperplasia has an influence on15-30% of all arterial revascularizations. Improvements in management strategies in order to control the healing process to injury have a great clinical importance. Until today, either after anastomozis or after PTCA or stenting, many articles have been published regarding the inhibition of intimal hyperplasia and smooth muscle cell proliferation. In our study, significant improvements in parameters of luminal area, intimal area and ratio of intimal-to-media were achieved in groups which were given N-Acetylcysteine. This favorible influence of N-Acetylcesteine was thought to be achieved with the direct antioxydant effect, induction of synthesis of glutation, regulation of the half life of nitric oxide, regulation of the activities of chemoattractants and regulation of the proliferation and migration of smooth muscle cells. With this manner, in our opinion, the usage of N-Acetylcysteine after surgical and interventional revascularizations lessen the load of intimal hyperplasia, improve the remodelling process and finally increase the patency period of revascularizations procedures

Retrograde Popliteal Access and Balloon Dilatation of Chronic Total Occlusion of Superficial Femoral Arteries

Background: The objective of the study was to evaluate the effectiveness of retrograde popliteal access in subjects with chronic total occlusion of the superficial femoral artery

Comparison of paclitaxel-coated balloon angioplasty with femoropopliteal bypass surgery in treating femoropopliteal lesions

Objective To compare drug (paclitaxel)-coated balloon angioplasty with femoropopliteal bypass surgery in the treatment of femoropopliteal lesions. Methods A retrospective study was performed between January 2015 and January 2019, covering a four-year period. All subjects who underwent femoropopliteal bypass surgery and drug-coated balloon angioplasty over a four-year period were evaluated. The subjects' demographic characteristics, lesion characteristics, treatment outcomes and disease-free survival were collected. Subjects were divided into the femoropopliteal bypass group (Group A) and the drug-coated balloon angioplasty (Group B) group. Results In total, 220 subjects were enrolled. Both Group A and Group B consisted of 110 subjects. The proportion of patients with a claudication distance between 0 and 50 m was significantly higher in Group A, and the proportion of patients with a claudication distance between 50 and 100 m was significantly higher in Group B (p = 0.001). In terms of the Rutherford levels, moderate claudication was significantly higher in Group B, and severe claudication was significantly higher in Group A (p = 0.001). The lesion length for the subjects in Group A was significantly longer than that in Group B (24.61 +/- 2.79 mm for Group A and 18.59 +/- 3.95 mm for Group B,p = 0.001). The stenosis degree in Group A was also significantly higher than that in Group B (96.82 +/- 4.32% for Group A and 94.85 +/- 4.55% for Group B,p = 0.001). The duration of the procedure, duration of hospitalization and rate of bleeding in Group A were significantly higher than those in Group B. The incidence of overall morbidity and reintervention rates in Group B were significantly higher than that in Group A. The preoperative ankle brachial index values of the subjects in Group B were statistically significantly higher than those in Group A (0.56 +/- 0.08 for Group A and 0.61 +/- 0.08 for Group B,p = 0.001). The change in the ankle brachial index measurement of the subjects in Group A with respect to the preprocedure value was significantly greater than that in Group B (p = 0.001). For primary patency, there was a significant difference between the groups in the distribution of the duplex ultrasound results at the 3rd, 6th, 9th and 12th month control points (p = 0.001). At all control points, Group A had better primary patency rates, whereas the secondary patency rates did not differ. In total, among the 220 patients, 125 (56.8%) were disease free, and 95 (43.2%) experienced recurrence. The mean disease-free survival times for Group A and Group B were 10.45 +/- 0.28 months and 9.11 +/- 0.37 months, respectively. The disease-free survival rates were significantly higher in Group A (p = 0.001,p < 0.05). Conclusion Femoropopliteal bypass resulted in better disease-free survival rates than drug-coated balloon angioplasty and serves as an effective modality for the treatment of femoropopliteal lesions

Effect of N-acetylcysteine on intimal hyperplasia and endothelial proliferation in rabbit carotid artery anastomosis

Introduction: Neointimal hyperplasia due to smooth muscle cell migration and proliferation, as well as extracellular matrix accumulation, plays an important role in stenosis and restenosis that develop after reconstructive vascular interventions. Various agents are being tested to reduce neointimal hyperplasia and to prevent lumen stenosis. In the present study, the effect of N-acetylcysteine (NAC) on intimal hyperplasia and endothelial hyperplasia after carotid anastomosis was investigated in a rabbit model

Comparison of del Nido Cardioplegia and Blood Cardioplegia in Aortic Root Surgery

Aim: To compare del Nido cardioplegia (DNC) with conventional blood cardioplegia (BC) in aortic root surgery

Surgical Treatment of Rare Giant Inferoposterior Left Ventricular Aneurysm: A Case Report

We present the case of a 63-year-old male with post-myocardial infarction causing a giant left ventricular aneurysm and describe the surgical treatment via Dor Procedure

Comparison of del Nido Cardioplegia and Blood Cardioplegia in Aortic Root Surgery

Aim: To compare del Nido cardioplegia (DNC) with conventional blood cardioplegia (BC) in aortic root surgery

Mid and Long Term Results in Patients with Endovenous Radiofrequancy Ablation in Lower Extremity Venous Insufficiency

Objective: Lower extremity venous insufficiency is a condition in which the flow of venous blood returns to the heart and the normal one-way rotation of the venous blood is reversed. As an alternative to open surgery in varicose veins, non-surgical endovascular procedures and hybrid endovascular procedures have emerged in the last decade. In this study, we aimed to evaluate the mid and long term results of endovenous radiofrequency ablation (RF) as an endovascular method

A mandatory modification in extracorporeal biventricular assist device (BIVAD) implantation: intercostal tunnel application: a case report

In this case, our patient was a heart transplant candidate connected to a respiratory system. An extracorporeal biventricular assist device (BIVAD) was the only option in order to bridge to transplantation. In routine procedures, it is recommended that Berlin Heart Excor cannulas be removed through the subfascial subcostal tunnel. As the severely dilated right ventricle compressed the apex of the left ventricle, which was also dilated to the mid-back zone of the left hemithorax, the whole length of the Extracorporeal BIVAD apical cannula had to remain within the thorax; however, the cannula was removed from the body by creating a tunnel at the 7th intercostal space. In the long-term follow-up, this compulsory modification has proven to be safe and effective