Acute Inflammatory Response after Novolimus Eluting Bioresorbable Scaffold and Novolimus Eluting Stent Implantation in Al-Najaf Cardiac Center Patients: A Comparative Study View PDF

In recent years, the effectiveness of the treatments for atherosclerosis in the coronary artery has increased significantly. Initially, the technique of balloon angioplasty had several adverse effects. In some cases, the dissection flaps formed by the effect of the balloon led to acute recoil and acute vessel occlusion [1]. To address these problems, devices called coronary stents were developed and applied to treat the coronary atherosclerosis. The first coronary stent design was a bare-metal stent (BMS). These devices proved helpful in preventing negative or harmful remodeling of the artery and reduction of the restenosis ratio associated with balloon angioplasty [2]. The most significant drawback of using the BMS device was the initiation of a severe neoproliferative response which was considered the other reason lead to restenosis [3]. In response to the limited efficacy of BMS devices, drug-eluting stents (DES) were tested. These DES devices were applied in interventional cardiology, in conjunction with an anti- proliferative drug to decrease the restenosis rates associated with BMS. When treated in this manner, irregular endothelialization, the main adverse effect linked with DES, occurred in some patients. Since endothelialization can lead to late or very late stent thrombosis, patients must be treated with double anti-platelet therapy to decrease this adverse effect [4]. The most commonly used anti-proliferative agents that are combined with drug eluting stents are Sirolimus, Zotarolimus, and everolimus [5]. A newly modified agent in the commonly uses Elixir DESyne coronary stent system is Novolimus, a metabolite of Sirolimus that has analogous efficacy to presented agents. Since the advantages of using Novolimus include a reduction in the required drug doses and polymer loads, this agent was believed to be safer when compared with previously used agents [6]. Additionally, Bioresorbable stents are a further advancement in interventional cardiology, as these stents were found in long-term follow-ups to reduce the risk of stent thrombosis associated with metallic stent complications [7]. The primary benefit of a resorbable scaffold include the elimination of complications caused by the presence of a foreign body inside the vessel wall, such as the development of stent thrombosis and the formation of atherosclerosis due to the persistent inflammation intra- coronary artery [8]. If the stent dissolves, the late malapposition associated with stent thrombosis would be reduced or eliminated [9]. Also, the use of Bioresorbable stents was found to reduce the risk of bleeding related to use of antiplatelet agents especially in elderly patients, because the need for extended double antiplatelet therapy was diminished. Further, when the Bioresorbable stent is removed upon completion of the absorption process, the artery is freed from constriction to begin the healing process, increasing the viability of endothelial function of the vessel and react with vasoactive therapy for a second time [10]. Constructed from polymers, a Bioresorbable stent possesses higher levels of plasticity, flexibility, and conformability than metallic stents. Also, polymer Bioresorbable stents are more resilient against shear stress which can affect the neointimal distribution post stent placement. The absorption of the stent allows patients future surgical options if needed and facilitates access to side branches that are caged by the stent. This advantage is particularly important in case of children or young patients who are still growing, as the change of vessel size can create a differential between the device size and vessel size. Lastly, many patients prefer to use absorbable devices in their arteries, because of concerns regarding the adverse effects of the presence of a permanent device inside their bodies [11]. Several inflammatory factors serve as predictors of adverse cardiac events. IL-6 is an inflammatory factor that is implicated in the development of atherosclerosis in the vascular system [12]. The immune cells that are responsible for the production of IL-6 include monocytes and macrophages, in addition to cardiovascular components such as smooth muscle cells and endothelial cells [13]. There is a relationship between increased levels of IL-6 and acute ischemic conditions, and high IL-6 levels are predictors in CAD patients for repeated cardiac events [14]. Further, the IL-6 factor has been linked with adverse clinical outcomes in unstable angina and ST-elevated myocardial infarction (STEMI) patients [15]. However, Pentraxin- 3 (PTX3) may be a more dependable inflammatory marker used in patients post drug eluting stent implantation to investigate long-term cardiovascular events [16]. The role of PTX3 in prediction of cardiovascular disease (CVD) risk is confirmed by the fact that it localizes in atherosclerotic plaques [17]. Matrix metalloproteinase (MMP-9) is one of the matrix metalloproteinase types responsible for the regulation of pathological remodeling processes that involve inflammation in cardiovascular disease. The function of MMP-9 is the degradation of the extracellular matrix (ECM) proteins and to trigger both cytokines and Chemokines in order to regulate tissue remodeling [18]. There is an association between several cardiovascular diseases such as atherosclerosis, MI, and elevated MMP-9 levels [19]. Cardiac troponin is a highly sensitive and specific biomarker used for myocardial injury [20]. The elevation of cardiac troponin in non-ST segment elevation acute coronary syndromes refers to a presence of thrombus at culprit lesions. This elevation can indicate a consequent thromboembolization at distal vascular beds [21]. This may happen spontaneously and in the treatment of the artery by balloon angioplasty and stent implantation [22]. The complement system, including numbers of proteins, has been shown to contribute to atherosclerosis [23]. There is an association between high levels of C5a and an increased risk in atherosclerotic patients [24]. C5a acts as a chemotactic agent for T-lymphocytes, monocytes, and mast cells in order to catalyze and develop the atherosclerosis process and stimulate the expression of adhesion molecules on monocytes in addition to endothelial cells [25].

Materials and instruments, materials, Novolimus eluting Bioresorbable coronary scaffold system (DESolve/USA), Novolimus eluting coronary stent system (DESyne USA), Lidocaine HCL 1% (APP), Iohexol 240mg/ml (OMNIPAQUE), Heparine vial (Pharmacia and Upjohn) ,Clot activator gel tube (Sun /Jordan), EDTA tube (AFCO/Jordan), Eppendorf tube 1.5 ml /Jordan. Human urea, creatinine, sugar, PT, PTT, INR kits (Human/Germany), Human Interleukine-6 (IL-6), Pentraxin 3 (PTX3), Cardiac Troponin–I (cTn-I), Matrix metalloproteinase’s (MMP-9), Complement component 5a (C5a) enzyme linked immunosorbent assay (ELISA) kits were produced by Elabscience/china/Wuhan. Instruments/Deep freeze (-80?), (GFL/Germany), Centrifuge (K centrifuge Tiwan), ECG monitor (City Med. China), Catheterization tools (Ireland, Germany), Bio-Elisa Reader, BioTek Instruments (USA).

Patients

A total of forty four diabetic patients (type II) with unstable angina (29 men and 15 women, aged 43 to 70 years old) were included in this study, all patients submitted to elective PCI at Al-Najaf center for cardiac surgery and trans catheter therapy between January and July 2015. The patients were randomized into two groups in a single -blind study. One day prior to the PCI procedure, the following were measured: blood pressure, blood oxygen saturation (SPo₂) levels, Electrocardiography (ECG), Heart rate, blood urea, serum creatinine, fasting blood sugar, and coagulation factors. International normalized ratios (INR), Prothrombin time (PT), activated partial thromboplastin time (APTT) were also measured. All participants were given the following viral screening tests: an anti-Hepatitis C virus antibody (Anti HCV Ab), a Hepatitis B surface antigen (HBsAg), and a Human immunodeficiency virus (HIV) test. Patient demographic information including gender, age, diabetes treatment history, and medication details were recorded for each participant.

Exclusion and Inclusion Criteria for Study

Patients, Novolimus Bioresorbable coronary scaffold implantation should be excluded in the following patients: Elderly patients (older than 65 years old), Non-diabetic patients, Patients undergoing long term steroid therapy or receiving immune suppressant agents, Patients with renal impairment, Patients for whom anti-platelet or anticoagulant therapy is contraindicated, those with hypersensitivity to poly L-Lactide, Novolimus, heparin or contrast medium, as well as patients with severely calcified lesions that prevent complete balloon inflation of an angioplasty. While Novolimus Bioresorbable coronary scaffold implantation should be performed in the following patients: Patients with myocardial ischemia (unstable angina), Patients for whom coronary artery lesion with vessel diameters between (2.75-3.5 mm). Novolimus eluting coronary stent implantation should be excluded in the following patients: Non diabetic patients, Patients undergoing long-term steroid therapy or receiving immune suppressant agents, Patients with renal impairment, Patients for whom anti-platelet or anticoagulant therapy is contraindicated, those with hypersensitivity to poly n- butyl methacrylate, Novolimus, heparin or contrast medium, as well as patients with severely calcified lesion that prevent complete balloon inflation of an angioplasty. While Novolimus eluting coronary stent implantation should be performed in the following patients: Patients with myocardial ischemia (unstable angina), Patients for whom coronary artery lesion with vessel diameters between (2.5-3.5 mm).

Study Design

The Patients in this study were divided into two groups as per the following: Group 1 includes twenty diabetic patients with coronary stenosis undergoing Novolimus Bioresorbable coronary scaffold implantation and Group 2 includes twenty four diabetic patients with coronary stenosis undergoing Novolimus eluting stent implantation.

Study Procedure

The Elixir DESolve Novolimus eluting Bioresorbable coronary scaffold is comprised of Bioresorbable poly L-Lactide (PLLA) based polymer and available in 3, 3.25, and 3.5 mm (diameter), and in 14, 18, and 28 mm (length) with a nominal strut thickness of 0.15 mm (150 microns). The system should be stored at (0-8?). While the Elixir DESyne Novolimus eluting coronary stent system is comprised of durable poly n-butyl methacrylate (PBMA) polymer and available in 2.5, 3, and 3.5 mm (diameter), and in 14, 18, 23, and 28 mm (length) with a nominal strut thickness of 0.081 mm (80 microns). The system should be stored at exactly 25? or below. All patients received 100 mg of aspirin and 75 mg of clopidogrel daily, beginning seven days prior to implantation and continuing for one year. During the procedure of implantation, patients received 7000-9000 units of Heparine intravenously and 150-200 ml of a contrast medium Iohexol 240. The sheath was placed in a femoral or radial artery using 1% lidocaine hydrochloride as a local anesthetic. A 6 F (0.071”) minimum guiding catheter was used with Bioresorbable scaffold implantation patients; while a 5F (0.058”) minimum guiding catheter was used in cases of Novolimus eluting stent implantation. The intervention performed was determined according to standard guidelines for all patients applying routine techniques [26]. In accordance with these guidelines, the length of the scaffold covered at minimum 2 mm of healthy vessel before and after the stenosis. If the stenosis was long in lesion, more than one scaffold (two) was used in this lesion. During scaffold implantation, this device was inflated slowly by 2 atm every 5 sec [27]. If the pre-dilatation resulted in an unacceptable result or the balloon could not be completely expanded, the implantation was progressed step by step until total expansion of the scaffold was obtained. The objective of implantation at end of procedure was to achieve a remaining stenosis less than 10% with complete scaffold expansion and best strut apposition, in order to prevent the complications linked with implantation such as acute and sub acute stent thrombosis [28]. The pressure used in Bioresorbable vascular scaffold (BVS) implantation should not exceed 16 atm. In cases of suboptimal implantation, post-dilations were performed until optimal stent implantation was achieved [29].

Collection of Samples 5ml of blood were drawn from peripheral veins directly before implantation, as well as 12 and 24 hrs. after implantation. Blood samples were placed in a clot activator gel tube at 37?. The samples were then centrifuged at 3000 rpm at 15 min. The samples were stored in deep freeze (-80?) following collection in order to use for the measurement of IL-6, PTX3, MMP-9, cTn-I and C5a according to the sandwich ELISA method.

Statistical analyses were performed by using SPSS (statistical package for social sciences) version 20. Data were expressed as mean ± SEM. T-test was used to compare the mean values between group1 & group 2, while Chi square test used to compare between the categorical data. In all tests P-value of less than 0.05 was designated as statistically significant.

Table 1: Shows the baseline demographic characteristics, risk factors, investigations, medications of the patients who submitted to Novolimus BVS and DES implantation.

Effect of Novolimus Bioresorbable Scaffold and Novolimus eluting stent implantation on levels of IL-6, PTX3 and MMP-9

This comparison of Novolimus eluting stent and Novolimus Bioresorbable scaffold implantation showed significant increase in all levels of IL-6, PTX3 at (12,24) hrs., MMP-9 at 24 hrs. (p<0.05) post implantation, as shown in figure 1 to figure 3.

There is a significant higher increase in IL-6 at 12 and 24 hrs. (p<0.05) in group 1 as compared with group 2.

There is a significant higher increase in PTX3 at 12 and 24 hrs. (p<0.05) in group 1 as compared with group 2.

There is a significant higher increase in MMP-9 at 24 hrs. (p<0.05) in group 1 as compared with group 2.

Effect of Novolimus Bioresorbable Scaffold and Novolimus eluting stent implantation on levels of cTn-I & C5a.

This comparison of Novolimus eluting stent and Novolimus Bioresorbable scaffold implantation showed insignificant increase in both levels of cTn-I & C5a at 12 and 24 hrs. (p>0.05) post implantation, as shown in figure 4 and figure 5.

There is insignificant difference at 12 and 24 hrs. (p>0.05) between group 1 & group 2.

There is insignificant difference at 12 and 24 hrs. (p>0.05) between group 1 & group 2.

Coronary intervention stimulates a local injury in the wall of a coronary artery followed by molecular and cellular actions [30]. Inflammatory markers can provide crucial information about inflammatory events induced by PCI and its effect in progression of ISR [31]. Drug eluting coronary stent is considered to be a recent advancement in interventional cardiology. Anti-proliferative drugs released from this design of stent causes inhibition of neointimal growth followed by reduction in ISR [32]. In spite of this advantage, anti-proliferative drugs have been shown to impede healing and have been implicated in late strut coverage, malposition, and late stent thrombosis [33]. Novolimus is a metabolite of Sirolimus (macro cyclic lactones). The advantage of Novolimus over other anti-proliferative drugs is that it is effective in lower doses of drug and polymer required for neointimal proliferation inhibition, especially in patients hypersensitive to the presence of a polymer [34].

Effect of Novolimus Bioresorbable Scaffold and Novolimus eluting stent implantation on levels of IL-6, PTX3 &MMP-9

This comparison of Novolimus eluting stent and Novolimus Bioresorbable scaffold implantation showed significant increase in all levels of IL-6, PTX3 at 12 and 24 hrs. MMP-9 at 24 hrs. (p<0.05) post implantation in group 1 as compared with group 2. Previous studies provided important information about increases in the release of inflammatory markers after PCI, regardless the type of stent, this increase being attributed to implantation techniques including Predilation [35]. Stent implantation activates inflammatory responses subsequent to the injury in the vascular wall caused by the implantation technique [36]. Acute inflammatory responses have been shown to appear within (0-72) hrs after stent implantation [37]. The stent stimulates inflammatory responses by the disturbance of the endothelial layer in coronary artery, activating the inflammatory cells, and early recruitment of Neutrophil to the site of the injury, results in subsequent macrophage accumulation [38]. Kang WC, et al. (2009) found that after Sirolimus-eluting stent (SES) & paclitaxel-eluting stent (PES) implantation, interleukin 6 (IL-6) levels increased significantly in both types of stents at 24 hrs post PCI [39]. Kotooka N, et al. (2008) also demonstrated that after 15 min of stent implantation, the plasma level of PTX3 increased significantly related to an inflammatory response [40]. Dai F, et al. (2009) showed that MMP-9 levels increased significantly in acute myocardial infarction (AMI) patients post PCI at 24 hrs. [41]. In this study as compared with Novolimus eluting stent, Bioresorbable scaffold implantation showed greater increases in inflammatory mediators mentioned above as found in DES. One possible explanation for the differences between two types of coronary systems is the presence of two factors. The first factor is the possession of the Bioresorbable scaffold thick strut (150 microns) as compared with Novolimus eluting stent with thin strut (80 microns). The second is the incidence of partial malapposition in the Bioresorbable scaffold due to its plastic nature as compared with the properties of the metallic stent. The scaffold technology has a number of limitations which should be taken into consideration; one major limitation is that the struts are characterized by increased thickness which increases the risk of fracture. Further, the device can become bulky (crossing profile>1mm), resulting in an obstructed passage, especially if the scaffold across lesion is not prepared optimally or in a calcified lesion. When the thick struts are compared with thin struts, the thick struts are found to be more thrombogenic and less forgiving regarding malapposition [42]. In Bioresorbable scaffold, strut thickness may cause injury in the vessel wall, flow with non-laminar property, or deposition in platelets. In addition, the shear stress is reduced from the strut of BVS with high thickness which may lead to platelet activation [43]. Due to the polymeric nature of scaffolds, it is necessary to produce the strut with highest thickness, because it has less radial strength as shown in stainless steel type [44]. Stent thrombosis (ST) is considered a fatal complication of PCI that appears following implantation and can continue for years with DES. The implantation of stent can lead to changes in luminal flow, stimulate foreign materials, and produce a nidus for clot accumulation [45]. So, when the strut of a stent is doubled in thickness it augments a foreign material and increases flow disruptions such as flow separation and stagnation. This results in an increase of platelet accumulation and thrombin formation [46]. Cassese et al., 2015, observed in patients submitted to an everolimus-eluting BVS and an everolimus-eluting metallic stent implantation an increase of sub acute stent thrombosis at one day to one month post implantation in BVS treated patients than metallic stent patients [47]. Byrne & Kastrati, 2015, found the rates of ST at six to twelve months post BVS implantation appeared higher compared with recent generations of metallic DES, especially in the first thirty days following implantation [48]. Another possible explanation for the increase in inflammatory markers post implantation of Bioresorbable coronary scaffold regarding to Novolimus eluting stent is partial malapposition of BVS may be due to its plastic nature. An additional limitation of this specific quality (polymeric nature) makes BVS less agreeable to post-dilatation with forceful state due to the possibility of strut fracture. The polymeric nature of BVS predisposes it to stimulate scaffold abnormality resulting in incomplete scaffold apposition (ISA). During implantation time, when scaffold post dilation occurred in an aggressive manner, this led to overstretching of the device. In addition, the nature of the scaffold and the properties of the material prevent overexpansion, with the possibility of under expansion and malapposition [49]. Tissue injury, stent malapposition, or under expansion can cause ST in addition to ISR [50]. Results of previous studies show that there are still some problems to be resolved prior to frequent use of the Bioresorbable device in interventional cardiology [51].

Effect of Novolimus Bioresorbable Scaffold and Novolimus eluting stent implantation on levels of cTn-I &C5a

This comparison of Novolimus eluting stent and Novolimus Bioresorbable scaffold implantation showed insignificant increase in both levels of cTn-I & C5a at (12,24) hrs (p>0.05) post implantation. In both types of systems there is a similar increase in levels of cTn-I and C5a at 12 and 24 hrs. post implantation. Garbarz E, et al. (1999), found that the level of cTn-I post stent implantation increased in comparison with the baseline, and this increase is common post-procedure [52]. Cantor WJ, et al. (2002) observed that post PCI, there is an increase in cTn-I levels, and these levels are associated with an increased risk for cardiac disease [53]. Speidl WS, et al. (2010), showed that post drug eluting stent implantation there is increase in serum levels of C5a at twenty four hours after the procedure, an increase related to stent restenosis at the time of follow up [54]. As a result, Bioresorbable scaffold possess thick struts (150 microns), twice as thick as those of DES with thin struts. So, they activate the pro inflammatory pathways and encourage thrombus formation to a greater extent than the DES, as evidenced by the elevated inflammatory markers. Therefore, large, randomized, long period studies are required to estimate the safety and efficacy of BVS as compared with DES. For the advancement of interventional cardiology, data from these studies should be taken into consideration in order to know if these new steps in cardiology overcome the shortcomings and disadvantages of previous stents.

Based on the results of this study, it can be concluded that the Novolimus Bioresorbable scaffold with thick struts may cause more marked inflammatory responses as compared with Novolimus eluting stent with thin struts.

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