Large Animal Models of Cardiovascular Disease: From Training to Translation.

ARTICLES DISCUSSED: Blanco-Blázquez, V. et al. Swine models of aneurysmal diseases for training and research. Journal of Visualized Experiments. (181), e63616 (2022). Constantin, I., Tabaran, A. F. Dissection techniques and histological sampling of the heart in large animal models for cardiovascular diseases. Journal of Visualized Experiments. (184), e63809 (2022). Hao, Y. et al. Transcatheter pulmonary valve replacement from autologous pericardium with a self-expandable nitinol stent in an adult sheep model. Journal of Visualized Experiments. (184), e63661 (2022). Martínez-Falguera, D. et al. Myocardial infarction by percutaneous embolization coil deployment in a swine model. Journal of Visualized Experiments. (177), e63172 (2021). Tubeeckx, M. R. L. et al. Sterile pericarditis in aachener minipigs as a model for atrial myopathy and atrial fibrillation. Journal of Visualized Experiments. (175), e63094 (2021).

Personalized tissue-engineered veins - long term safety, functionality and cellular transcriptome analysis in large animals.

Tissue engineering is a promising methodology to produce advanced therapy medicinal products (ATMPs). We have developed personalized tissue engineered veins (P-TEV) as an alternative to autologous or synthetic vascular grafts utilized in reconstructive vein surgery. Our hypothesis is that individualization through reconditioning of a decellularized allogenic graft with autologous blood will prime the tissue for efficient recellularization, protect the graft from thrombosis, and decrease the risk of rejection. In this study, P-TEVs were transplanted to vena cava in pig, and the analysis of three veins after six months, six veins after 12 months and one vein after 14 months showed that all P-TEVs were fully patent, and the tissue was well recellularized and revascularized. To confirm that the ATMP product had the expected characteristics one year after transplantation, gene expression profiling of cells from P-TEV and native vena cava were analyzed and compared by qPCR and sequencing. The qPCR and bioinformatics analysis confirmed that the cells from the P-TEV were highly similar to the native cells, and we therefore conclude that P-TEV is functional and safe in large animals and have high potential for use as a clinical transplant graft.

Transcriptome Profile Reveals Differences between Remote and Ischemic Myocardium after Acute Myocardial Infarction in a Swine Model.

Acute myocardial infarction (AMI) is the consequence of an acute interruption of myocardial blood flow delimiting an area with ischemic necrosis. The loss of cardiomyocytes initiates cardiac remodeling in the myocardium, leading to molecular changes in an attempt to recover myocardial function. The purpose of this study was to unravel the differences in the molecular profile between ischemic and remote myocardium after AMI in an experimental model. To mimic human myocardial infarction, healthy pigs were subjected to occlusion of the mid-left anterior descending coronary artery, and myocardial tissue was collected from ischemic and remote zones for omics techniques. Comparative transcriptome analysis of both areas was accurately validated by proteomic analysis, resulting in mitochondrion-related biological processes being the most impaired mechanisms in the infarcted area. Moreover, Immune system process-related genes were up-regulated in the remote tissue, mainly due to the increase of neutrophil migration in this area. These results provide valuable information regarding differentially expressed genes and their biological functions between ischemic and remote myocardium after AMI, which could be useful for establishing therapeutic targets for the development of new treatments.

Intracoronary Administration of Microencapsulated HGF in a Reperfused Myocardial Infarction Swine Model.

Therapy microencapsulation allows minimally invasive, safe, and effective administration. Hepatocyte growth factor (HGF) has angiogenic, anti-inflammatory, anti-apoptotic, and anti-fibrotic properties. Our objective was to evaluate the cardiac safety and effectiveness of intracoronary (IC) administration of HGF-loaded extended release microspheres in an acute myocardial infarction (AMI) swine model. An IC infusion of 5 × 106 HGF-loaded microspheres (MS+HGF, n = 7), 5 × 106 placebo microspheres (MS, n = 7), or saline (SAL, n = 7) was performed two days after AMI. TIMI flow and Troponin I (TnI) values were assessed pre- and post-treatment. Cardiac function was evaluated with magnetic resonance imaging (cMR) before injection and at 10 weeks. Plasma cytokines were determined to evaluate the inflammatory profile and hearts were subjected to histopathological evaluation. Post-treatment coronary flow was impaired in five animals (MS+HGF and MS group) without significant increases in TnI. One animal (MS group) died during treatment. There were no significant differences between groups in cMR parameters at any time (p > 0.05). No statistically significant changes were found between groups neither in cytokines nor in histological analyses. The IC administration of 5 × 106 HGF-loaded-microspheres 48 h post-AMI did not improve cardiac function, nor did it decrease inflammation or cardiac fibrosis in this experimental setting.

Effects of Cardiac Stem Cell on Postinfarction Arrhythmogenic Substrate.

Clinical data suggest that cardiosphere-derived cells (CDCs) could modify post-infarction scar and ventricular remodeling and reduce the incidence of ventricular tachycardia (VT). This paper assesses the effect of CDCs on VT substrate in a pig model of postinfarction monomorphic VT. We studied the effect of CDCs on the electrophysiological properties and histological structure of dense scar and heterogeneous tissue (HT). Optical mapping and histological evaluation were performed 16 weeks after the induction of a myocardial infarction by transient occlusion of the left anterior descending (LAD) artery in 21 pigs. Four weeks after LAD occlusion, pigs were randomized to receive intracoronary plus trans-myocardial CDCs (IC+TM group, n: 10) or to a control group. Optical mapping (OM) showed an action potential duration (APD) gradient between HT and normal tissue in both groups. CDCs increased conduction velocity (53 ± 5 vs. 45 ± 6 cm/s, p < 0.01), prolonged APD (280 ± 30 ms vs. 220 ± 40 ms, p < 0.01) and decreased APD dispersion in the HT. During OM, a VT was induced in one and seven of the IC+TM and control hearts (p = 0.03), respectively; five of these VTs had their critical isthmus located in intra-scar HT found adjacent to the coronary arteries. Histological evaluation of HT revealed less fibrosis (p < 0.01), lower density of myofibroblasts (p = 0.001), and higher density of connexin-43 in the IC+TM group. Scar and left ventricular volumes did not show differences between groups. Allogeneic CDCs early after myocardial infarction can modify the structure and electrophysiology of post-infarction scar. These findings pave the way for novel therapeutic properties of CDCs.

Intrapericardial Administration of Secretomes from Menstrual Blood-Derived Mesenchymal Stromal Cells: Effects on Immune-Related Genes in a Porcine Model of Myocardial Infarction.

Acute myocardial infarction (AMI) is a manifestation of ischemic heart disease where the immune system plays an important role in the re-establishment of homeostasis. We hypothesize that the anti-inflammatory activity of secretomes from menstrual blood-derived mesenchymal stromal cells (S-MenSCs) and IFNγ/TNFα-primed MenSCs (S-MenSCs*) may be considered a therapeutic option for the treatment of AMI. To assess this hypothesis, we have evaluated the effect of S-MenSCs and S-MenSCs* on cardiac function parameters and the involvement of immune-related genes using a porcine model of AMI. Twelve pigs were randomly divided into three biogroups: AMI/Placebo, AMI/S-MenSCs, and AMI/S-MenSCs*. AMI models were generated using a closed chest coronary occlusion-reperfusion procedure and, after 72 h, the different treatments were intrapericardially administered. Cardiac function parameters were monitored by magnetic resonance imaging before and 7 days post-therapy. Transcriptomic analyses in the infarcted tissue identified 571 transcripts associated with the Gene Ontology term Immune response, of which 57 were differentially expressed when different biogroups were compared. Moreover, a prediction of the interactions between differentially expressed genes (DEGs) and miRNAs from secretomes revealed that some DEGs in the infarction area, such as STAT3, IGFR1, or BCL6 could be targeted by previously identified miRNAs in secretomes from MenSCs. In conclusion, the intrapericardial administration of secretome early after infarction has a significant impact on the expression of immune-related genes in the infarcted myocardium. This confirms the immunomodulatory potential of intrapericardially delivered secretomes and opens new therapeutic perspectives in myocardial infarction treatment.

Swine Models of Aneurysmal Diseases for Training and Research.

Large animal models, specifically swine, are widely used to research cardiovascular diseases and therapies, as well as for training purposes. This paper describes two different aneurysmal swine models that may help researchers to study new therapies for aneurysmal diseases. These aneurysmal models are created by surgically adding a pouch of tissue to carotid arteries in swine. When the model is used for research, the pouch must be autologous; for training purposes, a synthetic pouch suffices. First, the right external jugular vein (EJV) and right common carotid artery (CCA) must be surgically exposed. The EJV is ligated and a vein pouch fashioned from a short segment. This pouch is then sutured to an elliptical arteriotomy performed in the CCA. Animals must be kept heparinized during model creation, and local vasodilators may be used to decrease vasospasms. Once the suture is completed, correct blood flow should be inspected, checking for bleeding from the suture line and vessel patency. Finally, the surgical incision is closed by layers and an angiography performed to image the aneurysmal model. A simplification of this aneurysmal carotid model that decreases invasiveness and surgical time is the use of a synthetic, rather than venous, pouch. For this purpose, a pouch is tailored in advance with a segment of a polytetrafluoroethylene (PTFE) prosthesis, one end of which is sutured close using polypropylene vascular suture and sterilized prior to surgery. This "sac" is then attached to an arteriotomy performed in the CCA as described. Although these models do not reproduce many of the physiopathological events related to aneurysm formation, they are hemodynamically similar to the situation found in the clinical setting. Therefore, they can be used for research or training purposes, allowing physicians to learn and practice different endovascular techniques in animal models that are close to the human system.

The epicardial delivery of cardiosphere derived cells or their extracellular vesicles is safe but of limited value in experimental infarction.

The epicardial administration of therapeutics via the pericardial sac offers an attractive route, since it is minimally invasive and carries no risks of coronary embolization. The aim of this study was to assess viability, safety and effectiveness of cardiosphere-derived cells (CDCs), their extracellular vesicles (EVs) or placebo administered via a mini-thoracotomy 72 h after experimental infarction in swine. The epicardial administration was completed successfully in all cases in a surgery time (knife-to-skin) below 30 min. No significant differences between groups were found in cardiac function parameters evaluated using magnetic resonance imaging before therapy and at the end of the study, despite a trend towards improved function in CDC-treated animals. Moreover, infarct size at 10 weeks was smaller in treated animals, albeit not significantly. Arrhythmia inducibility did not differ between groups. Pathological examination showed no differences, nor were there any pericardial adhesions evidenced in any case 10 weeks after surgery. These results show that the epicardial delivery of CDCs or their EVs is safe and technically easy 3 days after experimental myocardial infarction in swine, but it does not appear to have any beneficial effect on cardiac function. Our results do not support clinical translation of these therapies as implemented in this work.

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model.

The administration of cardiosphere-derived cells (CDCs) after acute myocardial infarction (AMI) is very promising. CDC encapsulation in alginate-poly-l-lysine-alginate (APA) could increase cell survival and adherence. The intrapericardial (IP) approach potentially achieves high concentrations of the therapeutic agent in the infarcted area. We aimed to evaluate IP therapy using a saline vehicle as a control (CON), a dose of 30 × 106 CDCs (CDCs) or APA microcapsules containing 30 × 106 CDCs (APA-CDCs) at 72 h in a porcine AMI model. Magnetic resonance imaging (MRI) was used to determine the left ventricular ejection fraction (LVEF), infarct size (IS), and indexed end diastolic and systolic volumes (EDVi; ESVi) pre- and 10 weeks post-injection. Programmed electrical stimulation (PES) was performed to test arrhythmia inducibility before euthanasia. Histopathological analysis was carried out afterwards. The IP infusion was successful in all animals. At 10 weeks, MRI revealed significantly higher LVEF in the APA-CDC group compared with CON. No significant differences were observed among groups in IS, EDVi, ESVi, PES and histopathological analyses. In conclusion, the IP injection of CDCs (microencapsulated or not) was feasible and safe 72 h post-AMI in the porcine model. Moreover, CDCs APA encapsulation could have a beneficial effect on cardiac function, reflected by a higher LVEF at 10 weeks.

Intracoronary Delivery of Porcine Cardiac Progenitor Cells Overexpressing IGF-1 and HGF in a Pig Model of Sub-Acute Myocardial Infarction.

Human cardiac progenitor cells (hCPC) are considered a good candidate in cell therapy for ischemic heart disease, demonstrating capacity to improve functional recovery after myocardial infarction (MI), both in small and large preclinical animal models. However, improvements are required in terms of cell engraftment and efficacy. Based on previously published reports, insulin-growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) have demonstrated substantial cardioprotective, repair and regeneration activities, so they are good candidates to be evaluated in large animal model of MI. We have validated porcine cardiac progenitor cells (pCPC) and lentiviral vectors to overexpress IGF-1 (co-expressing eGFP) and HGF (co-expressing mCherry). pCPC were transduced and IGF1-eGFPpos and HGF-mCherrypos populations were purified by cell sorting and further expanded. Overexpression of IGF-1 has a limited impact on pCPC expression profile, whereas results indicated that pCPC-HGF-mCherry cultures could be counter selecting high expresser cells. In addition, pCPC-IGF1-eGFP showed a higher cardiogenic response, evaluated in co-cultures with decellularized extracellular matrix, compared with native pCPC or pCPC-HGF-mCherry. In vivo intracoronary co-administration of pCPC-IGF1-eGFP and pCPC-HFG-mCherry (1:1; 40 × 106/animal), one week after the induction of an MI model in swine, revealed no significant improvement in cardiac function.

Benefits of cryopreservation as long-term storage method of encapsulated cardiosphere-derived cells for cardiac therapy: A biomechanical analysis.

Cardiosphere-derived cells (CDCs) encapsulated within alginate-poly-L-lysine-alginate (APA) microcapsules present a promising treatment alternative for myocardial infarction. However, clinical translatability of encapsulated CDCs requires robust long-term preservation of microcapsule and cell stability, since cell culture at 37 °C for long periods prior to patient implantation involve high resource, space and manpower costs, sometimes unaffordable for clinical facilities. Cryopreservation in liquid nitrogen is a well-established procedure to easily store cells with good recovery rate, but its effects on encapsulated cells are understudied. In this work, we assess both the biological response of CDCs and the mechanical stability of microcapsules after long-term (i.e., 60 days) cryopreservation and compare them to encapsulated CDCs cultured at 37 °C. We investigate for the first time the effects of cryopreservation on stiffness and topographical features of microcapsules for cell therapy. Our results show that functionality of encapsulated CDCs is optimum during 7 days at 37 °C, while cryopreservation seems to better guarantee the stability of both CDCs and APA microcapsules properties during longer storage than 15 days. These results point out cryopreservation as a suitable technique for long-term storage of encapsulated cells to be translated from the bench to the clinic.

Prostatic artery embolization: magnetic resonance image (MRI) findings in the early detection of prostate infarction in a canine spontaneous benign prostatic hyperplasia model.

BACKGROUND: The purpose was to assess the association between prostate infarction and prostate volume (PV) reduction after prostatic artery embolization (PAE) and define the best time point in detection of prostate infarction. METHODS: Ten male beagles (3.5-6.4 years) with spontaneous benign prostatic hyperplasia (BPH) underwent PAE. Magnetic resonance image (MRI) was conducted immediately before and 1 week, 2 weeks and 1 month after PAE to document prostate infarcts and measure PV. The sum of infarct areas (SUMIA) was measured and calculated using OsiriX software. Spearman's rank correlation was used to estimate the relationship of PV reduction rate with infarction percentage and SUMIA reduction. RESULTS: In comparison with baseline data, significant PV reduction (P<0.001) occurred at 2 weeks and continued to decrease substantially (P=0.004) from 2 weeks to 1 month after PAE. In the same fashion, significant decrease in both SUMIA and infarction percentage was observed from 1 to 2 weeks (P=0.002), and subsequently to 1 month (P=0.039 and P=0.016, respectively). Spearman's rank correlation test demonstrated infarction percentage at 1 week had a stronger correlation (r=0.880, P=0.001) with PV reduction rate at 1 month than infarction percentage at 2 weeks (r=0.733, P=0.016). PV reduction rate had a significant correlation with decrease in SUMIA (r=0.854, P=0.002) at 1 month after PAE. CONCLUSIONS: One week after PAE is an ideal time point to evaluate prostate infarction. Prostate infarction percentage at 1 week is a good predictor for prostate shrinkage at 1 month after PAE.

Prostatic artery embolization with polyethylene glycol microspheres: evaluation in a canine spontaneous benign prostatic hyperplasia model.

BACKGROUND: Prostatic artery embolization (PAE) is a minimally invasive technique for the management of symptomatic benign prostatic hyperplasia (BPH) relieving the lower urinary tract symptoms in patients. Various embolic agents have been tested in animal models and subsequently used in human patients. The purpose of this study was to evaluate the technical feasibility, effectiveness, and safety of PAE with polyethylene glycol microspheres in a canine spontaneous BPH model. RESULTS: Five adult male Beagle dogs (4.78 ± 1.11 years) were diagnosed by tranrectal ultrasonography of spontaneous BPH (prostate volume > 18 ml) and underwent PAE with polyethylene glycol microspheres (400 ± 75 µm). PAE procedures were performed successfully in all dogs. After PAE, all dogs were inspected for potential procedure-related complications during 1 month of follow-up. No major complications were observed any animal. Follow-up angiography was performed in each animal at 1 month of follow-up. Recanalization was demonstrated in all the embolized prostatic arteries or main branches at the end of the study. Magnetic Resonance Imaging (MRI) evaluations were performed immediately before PAE as baseline data, and 1 week, 2 weeks and 1 month after PAE. MRI study showed that the prostate shrank substantially with ischemic necrosis in each dog. There was a significant reduction in the mean prostate volume at 2 weeks and 1 month compared with the baseline data, from 19.95 ± 1.89 mL to 13.14 ± 2.33 and 9.35 ± 2.69 mL (p < 0.001), respectively. Histopathological study was conducted after 1-month follow-up angiography and confirmed the therapeutic responses with diffuse glandular atrophy and interstitial fibrosis. CONCLUSIONS: The findings of the present study support that PAE with the use of polyethylene glycol microspheres is a safe and feasible procedure that may induce a significant shrinkage of prostate due to the local ischemia and secondary glandular atrophy. Early recanalization of target arteries remains to be further addressed in both laboratory investigation and clinical practice.

Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model.

Insulin-like growth factor-1 (IGF-1) has demonstrated beneficial effects after myocardial infarction (MI). Microencapsulation of IGF-1 could potentially improve results. We aimed to test the effect of an intracoronary (IC) infusion of microencapsulated IGF-1 in a swine acute MI model. For that purpose IC injection of a 10 ml solution of 5 × 106 IGF-1 loaded microspheres (MSPs) (n = 8, IGF-1 MSPs), 5 × 106 unloaded MSPs (n = 9; MSPs) or saline (n = 7; CON) was performed 48 hours post-MI. Left ventricular ejection fraction (LVEF), indexed ventricular volumes and infarct size (IS) were determined by cardiac magnetic resonance at pre-injection and 10 weeks. Animals were euthanized at 10 weeks, and myocardial fibrosis and vascular density were analysed. End-study LVEF was significantly greater in IGF-1 MSPs compared to MSPs and CON, while ventricular volumes exhibited no significant differences between groups. IS decreased over time in all groups. Collagen volume fraction on the infarct area was significantly reduced in IGF-1 MSPs compared to CON and MSPs. Vascular density analysis of infarct and border zones showed no significant differences between groups. In conclusion, the IC injection of 5 × 106 IGF-1 loaded MSPs in a porcine acute MI model successfully improves cardiac function and limits myocardial fibrosis, which could be clinically relevant.

Altered hematological, biochemical and immunological parameters as predictive biomarkers of severity in experimental myocardial infarction.

Preclinical studies in cardiovascular medicine are necessary to translate basic research to the clinic. The porcine model has been widely used to understand the biological mechanisms involved in cardiovascular disorders for which purpose different closed-chest models have been developed in the last years to mimic the pathophysiological events seen in human myocardial infarction. In this work, we studied hematological, biochemical and immunological parameters, as well as Magnetic resonance derived cardiac function measurements obtained from a swine myocardial infarction model. We identified some blood parameters which were significantly altered after myocardial infarction induction. More importantly, these parameters (gamma-glutamyl transferase, glutamic pyruvic transaminase, red blood cell counts, hemoglobin concentration, hematocrit, platelet count and plateletcrit) correlated positively with cardiac function, infarct size and/or cardiac enzymes (troponin I and creatine kinase-MB). Thus several blood-derived parameters have allowed us to predict the severity of myocardial infarction in a clinically relevant animal model. Therefore, here we provide a simple, affordable and reliable way that could prove useful in the follow up of myocardial infarction and in the evaluation of new therapeutic strategies in this animal model.

Canine prostate models in preclinical studies of minimally invasive interventions: part I, canine prostate anatomy and prostate cancer models.

The high prevalence of prostate cancer (PCa) in elderly men and technical advances in early detection of localized PCa have led to continued efforts to develop new therapeutic options of minimally invasive nature in current urologic oncology community. Increasing newly emerging therapies are undergoing preclinical tests on the technical feasibility, efficacy and safety in animal experiments. The dog is an ideal large animal because of its similar anatomy to human and the capability allowing the use of the same medical devices applied in future clinical trials. Awareness of the local anatomy, microvascular structure, and histological features of the prostate in dogs is essential to experimental design and performance of the tested procedures and techniques. Although dogs with spontaneous PCa may be used in preclinical investigation, the low incidence and pathological features limit its utility. Alternatively, canine orthotopic PCa models have a great potential in preclinical research for this purpose. The goal of this review is to provide detailed anatomic and histological information of the canine prostate, outline the pathological and clinical characteristics of spontaneous PCa in dogs and discuss the current status of canine orthotopic PCa models.

Canine prostate models in preclinical studies of minimally invasive interventions: part II, benign prostatic hyperplasia models.

Canine prostate is widely used as animal model in the preclinical evaluation of emerging therapeutic interventions. Spontaneous benign prostatic hyperplasia (BPH) is common in adult intact male dogs with two distinct pathological types: glandular and complex form of prostatic hyperplasia. The complex form of prostatic hyperplasia, usually occurring in older dogs, represents an ideal model because of its unique pathologic feature, including not only glandular hyperplasia but also an increase in prostate stromal components. The limited commercial availability of adult dogs with spontaneous BPH motivates experimentally induced BPH in young dogs. Hormone-induced canine BPH model has been well established with various hormonal treatment regimens and administration approaches. The goal of this review is to provide the veterinary background in spontaneous BPH in dogs, summarize the techniques in hormonal induction of canine BPH, and highlight the pathological and clinical limitations of the canine models that may lead to distinct therapeutic responses compared to clinical trials in humans.

Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are among the most promising growth factors for promoting cardiorepair. Here, we evaluated the combination of cell- and gene-based therapy using mesenchymal stem cells (MSC) genetically modified to overexpress IGF-1 or HGF to treat acute myocardial infarction (AMI) in a porcine model. METHODS: Pig MSC from adipose tissue (paMSC) were genetically modified for evaluation of different therapeutic strategies to improve AMI treatment. Three groups of infarcted Large White pigs were compared (I, control, non-transplanted; II, transplanted with paMSC-GFP (green fluorescent protein); III, transplanted with paMSC-IGF-1/HGF). Cardiac function was evaluated non-invasively using magnetic resonance imaging (MRI) for 1 month. After euthanasia and sampling of the animal, infarcted areas were studied by histology and immunohistochemistry. RESULTS: Intramyocardial transplant in a porcine infarct model demonstrated the safety of paMSC in short-term treatments. Treatment with paMSC-IGF-1/HGF (1:1) compared with the other groups showed a clear reduction in inflammation in some sections analyzed and promoted angiogenic processes in ischemic tissue. Although cardiac function parameters were not significantly improved, cell retention and IGF-1 overexpression was confirmed within the myocardium. CONCLUSIONS: The simultaneous administration of IGF-1- and HGF-overexpressing paMSC appears not to promote a synergistic effect or effective repair. The combined enhancement of neovascularization and fibrosis in paMSC-IGF-1/HGF-treated animals nonetheless suggests that sustained exposure to high IGF-1 + HGF levels promotes beneficial as well as deleterious effects that do not improve overall cardiac regeneration.

Common swine models of cardiovascular disease for research and training.

Cardiovascular diseases are a major health concern and therefore an important topic in biomedical research. Large animal models allow researchers to assess the safety and efficacy of new cardiovascular procedures in systems that resemble human anatomy; additionally, they can be used to emulate scenarios for training purposes. Among the many biomedical models that are described in published literature, it is important that researchers understand and select those that are best suited to achieve the aims of their research, that facilitate the humane care and management of their research animals and that best promote the high ethical standards required of animal research. In this resource the authors describe some common swine models that can be easily incorporated into regular practices of research and training at biomedical institutions. These models use both native and altered vascular anatomy of swine to carry out research protocols, such as testing biological reactions to implanted materials, surgically creating aneurysms using autologous tissue and inducing myocardial infarction through closed-chest procedures. Such models can also be used for training, where native and altered vascular anatomy allow medical professionals to learn and practice challenging techniques in anatomy that closely simulates human systems.

Prostatic Artery Embolization (PAE) for Symptomatic Benign Prostatic Hyperplasia (BPH): Part 2, Insights into the Technical Rationale.

Rationale of prostatic artery embolization (PAE) in the treatment of symptomatic benign prostatic hyperplasia is conventionally believed to include two parts: shrinkage of the enlarged prostate gland as a result of PAE-induced ischemic infarction and potential effects to relax the increased prostatic smooth muscle tone by reducing the number and density of α1-adrenergic receptor in the prostate stroma. This review describes new insights into the likely mechanisms behind PAE, such as ischemia-induced apoptosis, apoptosis enhanced by blockage of androgens circulation to the embolized prostate, secondary denervation following PAE, and potential effect of nitric oxide pathway immediately after embolization. Studies on therapeutic mechanisms in PAE may shed light on potentially new treatment strategies and development of novel techniques.