Coronary bare metal stent implantation in homozygous LDL receptor deficient swine induces a neointimal formation pattern similar to humans

Téllez, Armando; Krueger, Christian G.; Seifert, Paul S.; Winsor-Hines, Dawn; Piedrahita, Cristian; Cheng, Yanping; Milewski, Krzysztof; Aboodi, Michael S.; Yi, Geng–Hua; McGregor, Jennifer; Crenshaw, T. D.; Reed, Jess D.; Huibregtse, Barbara; Kałuża, Greg L.; Granada, Juan F.

doi:10.1016/j.atherosclerosis.2010.09.021

Cited by 29 publications

(25 citation statements)

References 32 publications

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“…Finally, the WT background for RFH swine was only recently developed, and this study used the most aged animals available from this herd. None of the previous publications describing the use of RFH swine as models for atherosclerosis and restenosis have included a background‐matched WT control 24, 25, 26, 27…”

Section: Discussionmentioning

confidence: 99%

“…RFH swine express elevated LDL levels as a result of a mutation in the gene encoding the LDL receptor (LDL‐R),24 as is commonly observed in humans with FH. Due to their ability to develop complex atherosclerotic lesions that closely mimic those found in humans, these animals have been used extensively in the study of atherosclerosis over the past 2 decades,25 as well as in the development and validation of therapeutic and diagnostic cardiovascular technologies 26, 27. However, the heart valves of RFH swine have not previously been evaluated.…”

Section: Introductionmentioning

confidence: 99%

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Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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BackgroundFamilial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non‐FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined.Methods and ResultsAortic valve leaflets were isolated from wild‐type (0.25‐ and 1‐year‐old) and RFH (0.25‐, 1‐, 2‐, and 3‐year‐old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation‐related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD.ConclusionsAdult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non‐FH individuals. The development of advanced atherosclerotic lesions, but only early‐stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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“…As the arteries of RFH swine exist within the physiological milieu of the disease process, their responses to interventions are remarkably different to those in conventional swine models of induced atherosclerosis. The efficacy of antiproliferative agents (Tellez et al 2010b) coated on stents to counteract the phenomena of restenosis is greater in RFH swine than in the conventional swine model (Buszman et al 2014;Buszman et al 2013;Milewski et al 2011;Granada et al 2009). Because RFH swine better model this effect, this supports our assertion that models need to replicate the complexity of pathophysiology in order to mimic the safety and biocompatibility as it would be in humans.…”

Section: Cardiovascular Systemmentioning

confidence: 99%

“…The RFH swine (Rapacz et al 1994;Hasler-Rapacz et al 1998;Prescott et al 1991), a model of atherosclerosis developed and miniaturized at the University of WisconsinMadison, produces plaques spontaneously as a function of age in a manner remarkably similar to the human disease in time course, location, and phenotypic complexity, making it a platform for the development of cardiovascular imaging and interventional devices Tellez et al 2010b). Mature RFH mini-swine (Thim 2010), like humans (Finn et al 2010;Hansson and Libby 2006), display a large stenotic atherosclerotic burden with thin fibrous cap, a large necrotic core, presence of inflammatory infiltrates led by macrophages and foam cells, and intraplaque hemorrhages accompanied by adventitial and intraplaque neovascularization.…”

Section: Cardiovascular Systemmentioning

confidence: 99%

Miniature Swine for Preclinical Modeling of Complexities of Human Disease for Translational Scientific Discovery and Accelerated Development of Therapies and Medical Devices

Schomberg

Téllez²,

Meudt

et al. 2016

Toxicol Pathol

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Noncommunicable diseases, including cardiovascular disease, diabetes, chronic respiratory disease, and cancer, are the leading cause of death in the world. The cost, both monetary and time, of developing therapies to prevent, treat, or manage these diseases has become unsustainable. A contributing factor is inefficient and ineffective preclinical research, in which the animal models utilized do not replicate the complex physiology that influences disease. An ideal preclinical animal model is one that responds similarly to intrinsic and extrinsic influences, providing high translatability and concordance of preclinical findings to humans. The overwhelming genetic, anatomical, physiological, and pathophysiological similarities to humans make miniature swine an ideal model for preclinical studies of human disease. Additionally, recent development of precision gene-editing tools for creation of novel genetic swine models allows the modeling of highly complex pathophysiology and comorbidities. As such, the utilization of swine models in early research allows for the evaluation of novel drug and technology efficacy while encouraging redesign and refinement before committing to clinical testing. This review highlights the appropriateness of the miniature swine for modeling complex physiologic systems, presenting it as a highly translational preclinical platform to validate efficacy and safety of therapies and devices.

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“…The majority of published studies have used total loading doses of aspirin and clopidogrel of approximately 300 mg, followed by maintenance daily doses of 75 to 100 mg of aspirin and 75 mg of clopidogrel (Seifert et al, 2007;Chung et al, 2010;Posa et al, 2010;Tellez et al, 2010). We use similar dosing schedules to those in humans undergoing stent deployment and load with 150 mg of aspirin and 150 mg of clopidogrel on both the day before and the day of the procedure, and then give 75 mg of each agent on a daily basis until the time of sacrifice.…”

Section: Procedural Techniquementioning

confidence: 99%

Coronary angiography and percutaneous coronary intervention in the porcine model: a practical guide to the procedure

Williams

Malik

Kingston

2012

Animal

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Assessment of safety and efficacy within the porcine coronary artery model remains a standard requirement for new therapies delivered to the coronary arteries before proceeding to clinical testing. Human coronary procedures carry a very low mortality rate; however, procedural mortality for porcine experiments is often high, despite these animals being young and free of atherosclerosis. Some of these deaths are due to poor technique, and therefore avoidable. However, despite the wide use of this model, a systematic description of the procedure has never been published. This article will detail how porcine angiography and stent implantation is performed in our institution and will discuss the relevant differences between humans and pigs with regard to anaesthesia, pharmacotherapy, vascular access, catheter selection and angiographic views. Important variations to the technique that have been reported are also covered.

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Coronary bare metal stent implantation in homozygous LDL receptor deficient swine induces a neointimal formation pattern similar to humans

Cited by 29 publications

References 32 publications

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Miniature Swine for Preclinical Modeling of Complexities of Human Disease for Translational Scientific Discovery and Accelerated Development of Therapies and Medical Devices

Coronary angiography and percutaneous coronary intervention in the porcine model: a practical guide to the procedure

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