Tim Vandecasteele

The pulmonary veins of the pig as an anatomical model for the development of a new treatment for atrial fibrillation.

The layout of the porcine atriopulmonary junction and immediately adjacent structures was investigated by gross anatomical and vascular corrosion casting studies to meet the need for more in‐depth anatomical insights when using the pig as an animal model in the development of innovative approaches for surgical cardiac ablation in man. The veins from the right cranial and middle lung lobes drain through a common ostium in the left atrium, whereas a second ostium receives the blood returning from all other lung lobes, although limited variation to this pattern was observed. Surrounding anatomical structures that are most vulnerable to ablation damage as reported in man are located at a safer distance from the pulmonary veins in pigs, yet a certain locations, comparable risks are to be considered. Additionally, it was histologically confirmed that myocardial sleeves extend to over a centimetre in the wall of the pulmonary veins.

The Potential Use of Piglets as Human Pediatric Surrogate for Preclinical Pharmacokinetic and Pharmacodynamic Drug Testing

Pediatric drug research is still substandard, not reaching the same quality level as adult drug research. Despite the efforts made by the Food and Drug Administration and European Medicines Agency to reduce off-label use in children, the lack of clinical studies involving the pediatric population still stands. Pharmacokinetic and pharmacodynamics studies (PK/PD) taking growth and maturation into account are necessary to rationalize dosing strategies in children. Currently, traditional animal models such as rats, mice, dogs and primates are used to conduct pharmacokinetic and pharmacodynamic studies, however age-related trials are rather uncommon. Moreover, these species have several shortcomings as animal models, such as a different physiology and anatomy of the gastrointestinal tract in dogs or the ethical aspects for the use of primates. In contrast, piglets might be potential biomedical pediatric animal models because of the good resemblance with humans, anatomically, physiologically and biochemically. This review summarizes the comparative anatomy and physiology and postnatal development of piglets and infants, focusing on six major topics, namely growth, cardiovascular system, gastrointestinal tract, liver, kidney and integument. Furthermore, the application of piglets as animal model in pediatric PK/PD research is discussed.

Presence of Ganglia and Telocytes in Proximity to Myocardial Sleeve Tissue in the Porcine Pulmonary Veins Wall

Ganglia and telocytes were identified inside the porcine pulmonary veins wall near myocardial sleeve tissue at the atriopulmonary junction. These structures are reported to play a role in the initiation of pulses from outside the heart, which potentially can cause cardiac conduction disorders such as atrial fibrillation. In‐depth knowledge on the fine structure of the pulmonary vein wall is a pre‐requisite to better understand the underlying pathophysiology of atrial fibrillation and the origin and conduction of ectopic pulses. The importance of pulmonary vein myocardial sleeves as triggering foci for atrial fibrillation has been shown in human patients. In this context, the fine structure of the pulmonary vein wall was investigated qualitatively by light and transmission electron microscopy in the pig, which is a frequently used animal model for development of new treatment strategies. Additionally, intra and extramural ganglia, containing telocytes that create a network near the neurone cell bodies, were identified in pigs. Detailed illustration of the distribution and organization of tissues and cell types, potentially involved in the origin and propagation of ectopic stimuli originating from the pulmonary veins, might lead to a better insight on the actual composition of the tissues affected by ablation as studied in pigs.

Topography and ultrasonographic identification of the equine pulmonary vein draining pattern

Information on ultrasound examination of equine pulmonary veins is scarce due to a lack of in-depth anatomical information. Each pulmonary vein drains a specific lung lobe region, after which those veins merge into a collecting antrum, before opening into the left atrium through their respective ostia. The aim of this study was, by using anatomical dissection and silicone casting of equine cardiopulmonary sets, to study the venous drainage of both lungs and the position of the ostia and to investigate whether the ostia can be identified and differentiated using ultrasound. Three out of the four ostia could be observed echocardiographically in the standing horse. The ostium draining the most caudal aspects of both lungs showed little variability, while the ostium draining the rest of the right lung could be used as an easily recognisable landmark, since it was located adjacent to the interatrial septum. The identification of the equine pulmonary vein ostia using ultrasound might allow for the determination of size and flow patterns in the assessment of cardiovascular disease.

A preclinical study of an implanted device in the pulmonary veins, intended for the treatment of atrial fibrillation in an ovine model

Atrial fibrillation is the most frequent arrhythmia in adults of which the interventional cure is hampered by high recurrence rates. Recurrence after ablation is due to an incomplete isolation of the pulmonary veins. A new ablation technique was performed, in the antra of ovine pulmonary veins, by device implantation, which was heated through a wireless heat‐generating system.

Stereological and immunogold studies on TIE1 and TIE2 localization in glomeruli indicate angiopoietin signaling in podocytes

Angiopoietins and their TIE receptors are important regulators of vascular stability and remodeling. These molecules are involved not only in the normal development of kidney glomeruli, but also in disease, thus making them promising targets for therapies. Although TIE receptors are mainly found in endothelial cells, some reports observed TIE2 expression in glomerular podocytes as well. This suggests a role of angiopoietins in the regulation of podocytes. In the present study, we aimed to map the subcellular localization of TIE receptors in metanephric glomeruli of fetal pigs using high-resolution immunogold electron microscopy and the relative labeling index stereological approach. TIE1 and TIE2 antibody labeling was detected on the abluminal side of endothelial cell membranes. In endothelial cells, 4.5% of TIE2 was observed close to cell-cell contacts and 11.9% of TIE2 was found in closely associated pairs, which suggests the presence of homodimers. Interestingly, both receptors were also expressed in podocyte foot processes indicating that TIE1 and TIE2 may play a similar role in podocytes as in endothelial cells.

Intussusceptive angiogenesis and expression of Tie receptors during porcine metanephric kidney development.

Intussusceptive angiogenesis (IA) is required for normal embryonic vascular development. The Tie family of receptors and their ligands, the angiopoietins, play an important role in the growth or regression of blood vessels which are important not only during development but also throughout an organisms life. The presence of IA was investigated in glomerular capillaries of the fetal porcine metanephros using Mercox II resin casts. The first signs of IA were observed in stage III glomeruli. Stage IV and V glomeruli showed numerous signs of aligned pillar formation and their successive merging to delineate the vascular entities. Furthermore, immunohistochemistry was used to determine the exact locations of the Tie receptors in the developing porcine metanephric kidneys. Tie1 and Tie2 were found in endothelial cells of all glomeruli. Strong expression of the receptors was found in podocytes of stage V glomeruli whereas a weaker expression was observed in the cuboidal epithelial cells of stage III and IV glomeruli. Remarkably, the receptors were also found in the parietal epithelium of Bowmans capsule. These findings indicate that there might be an association between the Tie receptors and the IA during porcine metanephric development and during glomerulogenesis in particular.

A preliminary study of pulmonary vein implant applicability and safety as a potential ablation platform in a follow-up study in pigs

Recurrence of atrial fibrillation after an ablation procedure remains a major problem which emphasizes the need for improved pulmonary vein isolation techniques.

Isolation of pulmonary veins using a thermoreactive implantable device with external energy transfer : evaluation in a porcine model

Pulmonary vein isolation (PVI) is a well‐established method for the treatment of symptomatic paroxysmal atrial fibrillation, but is only partly successful with a high rate of electrical reconnection. We introduce a novel technique in which PVI is accomplished by noninvasive heating of a dedicated thermoresponse implant inserted into the pulmonary veins (PV), demonstrated in a porcine model.

Intussusceptive Pillar Formation in Developing Porcine Glomeruli

Background/Aims: Intussusceptive angiogenesis (IA) is a dynamic process which contributes to vascular expansion and remodeling. Intraluminal pillars have long been the distinctive structural indicator of IA. However, the mechanism of their formation has not been fully elucidated. Methods: Using light and electron microscopy, we studied intussusceptive vascular growth in the developing porcine metanephric kidney. Results: We observed intraluminal pillars formed by endothelial cells in the vasculature of developing glomeruli. Their diameter was < 2.5 µm, consistent with the diameter of nascent pillars. TEM revealed that the majority of these pillars consisted only of endothelium. However, a central core of extracellular matrix (ECM) covered by endothelium, reminiscent of a more mature intussusceptive pillar, was also found in the lumen of a glomerular capillary. Perivascular cells or pericytes were not involved in the pillar structure during these stages of formation. Conclusion: This study shows ECM presence in a mature intussusceptive pillar without any perivascular cell involvement in the structure. This leads to the hypothesis that ECM deposition precedes the participation of these cells in the formation of intraluminal pillars during IA in porcine metanephric glomerular capillaries.