ABSTRACT
AIMS: Atherosclerosis is a well-known cause of cardiovascular disease and is associated with a variety of inflammatory reactions. However, an adequate large-animal model of advanced plaques to investigate the pathophysiology of atherosclerosis is lacking. Therefore, we developed and assessed a swine model of advanced atherosclerotic plaques with macrophage polarization. METHODS: Mini-pigs were fed a 2% high-cholesterol diet for 7 weeks followed by withdrawal periods of 4 weeks. Endothelial denudation was performed using a balloon catheter on 32 coronary and femoral arteries of 8 mini-pigs. Inflammatory proteins (high-mobility group box 1 [HMGB1] or tumor necrosis factor alpha (TNF-α) were injected via a micro-infusion catheter into the vessel wall. All lesions were assessed with angiography and optical coherence tomography and all tissues were harvested for histological evaluation. RESULTS: Intima/plaque area was significantly higher in the HMGB1- and TNF-α-injected groups compared to the saline-injected group (p = 0.002). CD68 antibody detection and polarization of M1 macrophages significantly increased in the inflammatory protein-injected groups (p<0.001). In addition, advanced atherosclerotic plaques were observed more in the inflammatory protein-injected groups compared with the control upon histologic evaluation. CONCLUSION: Direct injection of inflammatory proteins was associated with acceleration of atherosclerotic plaque formation with M1 macrophage polarization. Therefore, direct delivery of inflammatory proteins may induce a pro-inflammatory response, providing a possible strategy for development of an advanced atherosclerotic large-animal model in a relatively short time period.
Subject(s)
Atherosclerosis/metabolism , HMGB1 Protein/metabolism , Macrophages/metabolism , Plaque, Atherosclerotic/metabolism , Tumor Necrosis Factor-alpha/metabolism , Tunica Intima/metabolism , Animals , Atherosclerosis/pathology , Disease Models, Animal , Macrophages/pathology , Plaque, Atherosclerotic/pathology , Swine , Swine, Miniature , Tunica Intima/pathologyABSTRACT
In-stent restenosis (ISR) often occurs after applying drug eluting stents to the blood vessels suffering from atherosclerosis or thrombosis. For treatment of ISR, drug eluting balloons (DEB) have been developed to deliver anti-proliferative drugs to the lesions with ISR. However, there are still limitations of DEB such as low drug delivery efficiency and drug loss to blood flow. Although most researches have focused on alteration of drug formulation for more efficient drug delivery, there are few studies that have attempted to understand and utilize the contact modality of DEB drug delivery. Here, we developed a linear micro-patterned DEB (LMDEB) that applied higher contact pressure to enhance drug stamping to vascular tissue. Ex vivo and in vivo studies confirmed that higher contact pressure from micro-patterns increased the amount of drug delivered to the deeper regions of vessel. Finite element method simulation also showed significant increase of contact pressure between endothelium and micro-patterns. Quantitative analysis by high performance liquid chromatography indicated that LMDEBs delivered 2.3 times higher amount of drug to vascular tissue in vivo than conventional DEBs. Finally, efficacy studies using both atherosclerotic and ISR models demonstrated superior patency of diseased vessels treated with LMDEB compared to those treated with DEB.
Subject(s)
Coronary Restenosis/drug therapy , Drug Delivery Systems/methods , Drug-Eluting Stents/adverse effects , Percutaneous Coronary Intervention/instrumentation , Percutaneous Coronary Intervention/methods , Angioplasty, Balloon, Coronary , Animals , Atherosclerosis/chemically induced , Atherosclerosis/surgery , Chromatography, Liquid , Coronary Angiography , Coronary Restenosis/diagnostic imaging , Disease Models, Animal , Iliac Artery/diagnostic imaging , Iliac Artery/surgery , Male , Mass Spectrometry , Microscopy, Confocal , Microscopy, Fluorescence , Paclitaxel/therapeutic use , Pressure , Rabbits , Swine , Swine, Miniature , Treatment OutcomeABSTRACT
BACKGROUND: LAA occlusion has a similar stroke prevention efficacy compared to anticoagulation treatment for non-valvular atrial fibrillation. OBJECTIVE: The objective of this study was to assess the feasibility and safety of a modified Occlutech® left atrial appendage (LAA) closure device in a canine model. METHODS: The device was implanted in 10 dogs (33±1kg) using fluoroscopy and transesophageal echocardiography (TEE) guidance. The modified Occlutech® LAA occlusion device was compared with the current version, the Watchman device, and the Amplazter cardiac plug (ACP). LAA occlusion and anchoring to the LAA were evaluated. All dogs were assessed using angiography, TEE, and a gross anatomy examination. RESULTS: The 10 LAA occlusion devices were to be implanted into 10 dogs (5 modified Occlutech devices, 3 current version of Occlutech devices, 1 Watchman, and 1 ACP). LAA implantation was not performed in one dog due to transeptal puncture failure. The three current version of Occlutech devices were embolized immediately after implantation, so three modified devices of the same size were implanted securely without embolization. The mean implant size was 20.1±2.0mm. The devices chosen were a mean of 23.3±10.6% larger than the measured landing zone diameters. Post-implant angiography and TEE revealed well-positioned devices without pericardial effusion or impingement on surrounding structures. CONCLUSIONS: The results of this acute animal study suggested that a modified Occlutech® LAA occlusion device was feasible and had greater anchoring performance in canines. Additional large clinical studies are needed to evaluate safety and efficacy.
