Name: implantation of human-sized coronary stents into rat abdominal aorta using a trans-femoral access
Uploaded: 2020-11-19T13:00:00
Description: Watch this Scientific Journal Video about Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access at JoVE.com

We would like to thank Mrs. Angela Freund for her invaluable technical assistance with embedding and slides production. We would also like to thank Mr. Tadeusz Stopinski at the Institute for Laboratory Animal Science &#38; Experimental Surgery for his insightful help with the veterinary work.

The experiments were performed in accordance with the German animal welfare law (TSchG) and Directive 2010/63/EU pertaining to the protection of animals used for scientific purposes. The official approval for this study was granted by the Governmental Animal Care and Use Committee (Protocol No.: AZ 87-51.04.2010.A065; Landesamt f&#252;r Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen, Recklinghausen, Germany). The study protocol complied with the Guide for the Care and Use of Laboratory Animals. Postoperative pai...

<ol>
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R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS+2017+Appropriate+Use+Criteria+for+Coronary+Revascularization+in+Patients+With+Stable+Ischemic+Heart+Disease:+A+Report+of+the+American+College+of+Cardiology+Appropriate+Use+Criteria+Task+Force,+American+Association+for+Thoracic+Surgery,+American+Heart+Association,+American+Society+of+Echocardiography,+American+Society+of+Nuclear+Cardiology,+Society+for+Cardiovasular+Angiography+and+Interventions,+Society+of+Cardiovascular+Computed+Tomography,+and+Society+of+Thoracic+Surgeons.">ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease: A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovasular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons.</a> Journal of the American College of Cardiology. 69 (17), 2212-2241 (2017).</li><li>Virmani, R., Farb, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pathology+of+in-stent+restenosis.">Pathology of in-stent restenosis.</a> Current Opinion in Lipidology. 10 (6), 499-506 (1999).</li><li>Buccheri, D., Piraino, D., Andolina, G., Cortese, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Understanding+and+managing+in-stent+restenosis:+a+review+of+clinical+data,+from+pathogenesis+to+treatment.">Understanding and managing in-stent restenosis: a review of clinical data, from pathogenesis to treatment.</a> Journal of Thoracic Disease. 8 (10), 1150-1162 (2016).</li><li>Perkins, L. 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Deviation of man from the usual pattern.</a> Circulation Research. 25 (6), 677-686 (1969).</li><li>Lowe, H. C., James, B., Khachigian, L. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+novel+model+of+in-stent+restenosis:+rat+aortic+stenting.">A novel model of in-stent restenosis: rat aortic stenting.</a> Heart. 91 (3), 393-395 (2005).</li><li>Unthank, J. L., Nixon, J. C., Lash, J. 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This protocol describes the implantation of human-sized coronary stents into the abdominal aorta of apoE-/- rats. Several technical points are worth emphasizing. First, a mismatch between the stent size and the size of the aorta should be avoided. Placing too small a stent can lead to stent malapposition, whereas implantation of a stent that is too large for the aorta can cause overstretch, tearing, and injury of the vessel. Therefore, we recommend using stents between 2.0 and 2.5 mm in diameter, and to keep i...

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of coronary artery disease1. The long-term success of stents, however, can be limited by the occurrence of in-stent restenosis (ISR) that is determined by an excessive proliferation of neointimal tissue within the stent2,3. ISR may require a re-intervention either with coronary artery bypass or re-PCI. A variety of animal models have been suggested for the study of ISR, each of them featuring advantages and shortcomings. The major drawbacks of the most commonly used porcine coronary and rabbit iliac artery models, albeit developing lesions markedly similar to humans after stent implantation4,5, are large animal and housing costs which brings up logistical difficulties especially in long-term studies, as well as limitations in handling and equipment. Furthermore, availability of antibodies to cellular proteins of swine and rabbits is limited. On the other hand, murine models provide the major advantages of high throughput and reproducibility, as well as ease of handling, housing, and therefore cost-effectiveness. Furthermore, a higher number of antibodies are available. However, while apolipoprotein E-deficient (apoE-/-) mice have been broadly used for the study of atherosclerosis6,7,8, they are unsuitable for the study of ISR as stents have to be miniaturized to be implanted into mice, potentially changing the stents&#8217; mechanical properties. Moreover, the aortic wall of mice measures between 50 &#181;m in young mice and 85 &#181;m in old mice9, and stents have to be deployed using pressure levels as low as 2 atm, which might lead to malapposition of the stent10. Rats, however, allow for the implantation of commercially available human coronary stents, and demonstrate a vascular healing course similar to larger animals after aortic stent implantation, first reported by Langeveld et al.11. This technique originally required a trans-abdominal access, which necessitated a physical constriction of the aorta to achieve a temporary interruption of blood flow. To avoid the potentially associated vessel injury and inflammatory reactions, the technique was later refined by the introduction of a trans-iliac access, which additionally resulted in a higher survival rate of the animals12.
Because wildtype rats do not develop atherosclerotic lesions13, apoE-/- rats have been generated using nuclease techniques such as Transcription Activator-Like Effector Nuclease (TALEN)14, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9)15, and Zinc Finger (ZF)16. ApoE-/- rats have been commercially available since 2011. Providing an atherogenic background, apoE-/- rats allow for a more realistic evaluation of human-sized coronary stents, especially with regards to ISR.
Herein, we describe the method via the transfemoral access route and using a commercially available thin-strut cobalt-chromium drug-eluting stent (DES), however, it can also be applied for the study of other stent types, such as bare metal stents (BMS) or biodegradable stents.

<table>
	<tbody>
		<tr>
			<td>Diet</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>SNIFF High Fat diet + Clopidogrel (15 mg/kg)</td>
			<td>SNIFF Spezialdi&#228;ten GmbH, Soest</td>
			<td>custom prepared</td>
			<td>Western Diet</td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Drugs and Anesthetics</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Buprenorphine</td>
			<td>Essex Pharma</td>
			<td>997.00.00</td>
			<td></td>
		</tr>
		<tr>
			<td>ISOFLO (Isoflurane Vapor) vaporiser</td>
			<td>Eickemeyer</td>
			<td>4802885</td>
			<td></td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>Forene Abbott</td>
			<td>B 506</td>
			<td></td>
		</tr>
		<tr>
			<td>Isotonic (0.9%) NaCl solution</td>
			<td>DeltaSelect GmbH</td>
			<td>PZN 00765145</td>
			<td></td>
		</tr>
		<tr>
			<td>Ringer&#39;s lactate solution</td>
			<td>Baxter Deutschland GmbH</td>
			<td>3775380</td>
			<td></td>
		</tr>
		<tr>
			<td>(S)-ketamine</td>
			<td>CEVA Germany</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Xylazine</td>
			<td>Medistar Germany</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Consumable supplies</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>10 mL syringes</td>
			<td>BD Plastipak</td>
			<td>4606108V</td>
			<td></td>
		</tr>
		<tr>
			<td>2 mL syringes</td>
			<td>BD Plastipak</td>
			<td>4606027V</td>
			<td></td>
		</tr>
		<tr>
			<td>6-0 prolene suture</td>
			<td>ETHICON</td>
			<td>N-2719K</td>
			<td></td>
		</tr>
		<tr>
			<td>4-0 silk suture</td>
			<td>Seraflex</td>
			<td>IC 158000</td>
			<td></td>
		</tr>
		<tr>
			<td>Bepanthen Eye and Nose Ointment</td>
			<td>Bayer Vital GmbH</td>
			<td>6029009.00.00</td>
			<td></td>
		</tr>
		<tr>
			<td>Cotton Gauze swabs</td>
			<td>Fuhrmann GmbH</td>
			<td>32014</td>
			<td></td>
		</tr>
		<tr>
			<td>Durapore silk tape</td>
			<td>3M</td>
			<td>1538-1</td>
			<td></td>
		</tr>
		<tr>
			<td>Poly-Alcohol Skin Desinfection Solution</td>
			<td>Antiseptica GmbH</td>
			<td>72PAH200</td>
			<td></td>
		</tr>
		<tr>
			<td>Sterican needle 18 G</td>
			<td>B. Braun</td>
			<td>304622</td>
			<td></td>
		</tr>
		<tr>
			<td>Sterican needle 27 3/4 G</td>
			<td>B.Braun</td>
			<td>4657705</td>
			<td></td>
		</tr>
		<tr>
			<td>Tissue Paper</td>
			<td>commercially available</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Surgical instruments</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Graefe forceps curved x1</td>
			<td>Fine Science Tools Inc.</td>
			<td>11151-10</td>
			<td></td>
		</tr>
		<tr>
			<td>Graefe forceps straight</td>
			<td>Fine Science Tools Inc.</td>
			<td>11050-10</td>
			<td></td>
		</tr>
		<tr>
			<td>Needle holder Mathieu</td>
			<td>Fine Science Tools Inc.</td>
			<td>12010-14</td>
			<td></td>
		</tr>
		<tr>
			<td>Scissors</td>
			<td>Fine Science Tools Inc.</td>
			<td>14074-11</td>
			<td></td>
		</tr>
		<tr>
			<td>Semken forceps</td>
			<td>Fine Science Tools Inc.</td>
			<td>11008-13</td>
			<td></td>
		</tr>
		<tr>
			<td>Small surgical scissors curved</td>
			<td>Fine Science Tools Inc.</td>
			<td>14029-10</td>
			<td></td>
		</tr>
		<tr>
			<td>Small surgical scissors straight</td>
			<td>Fine Science Tools Inc.</td>
			<td>14028-10</td>
			<td></td>
		</tr>
		<tr>
			<td>Standard pattern forceps</td>
			<td>Fine Science Tools Inc.</td>
			<td>11000-12</td>
			<td></td>
		</tr>
		<tr>
			<td>Vannas spring scissors</td>
			<td>Fine Science Tools Inc.</td>
			<td>15000-08</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Equipment</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Dissecting microscope</td>
			<td>Leica MZ9</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Temperature controlled heating pad</td>
			<td>Sygonix</td>
			<td>26857617</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Equipment for stent implantation</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Drug-eluting stent Xience 2,25mm x 8mm</td>
			<td>Abbott Vascular USA</td>
			<td>1009544-18</td>
			<td></td>
		</tr>
		<tr>
			<td>Guide wire Fielder XT PTCA guide wire: 0.014&#34; x 300cm</td>
			<td>ASAHI INTECC CO., LTD Japan</td>
			<td>AGP140302</td>
			<td></td>
		</tr>
		<tr>
			<td>Inflation syringe system</td>
			<td>Abbott 20/30 Priority Pack</td>
			<td>1000186</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Tissue processing and analysis</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>30% H2O2</td>
			<td>Roth</td>
			<td>9681</td>
			<td>Histology</td>
		</tr>
		<tr>
			<td>Ethanol</td>
			<td>Roth</td>
			<td>K928.1</td>
			<td>Histology</td>
		</tr>
		<tr>
			<td>Giemsas Azur-Eosin-Methylenblau</td>
			<td>Merck</td>
			<td>109204</td>
			<td>Histology</td>
		</tr>
		<tr>
			<td>Graphic Drawing Tablet</td>
			<td>WACOM Europe GmbH</td>
			<td>CTL-6100WLK-S</td>
			<td></td>
		</tr>
		<tr>
			<td>Roti Histofix, Formaldehyd 4% buffered</td>
			<td>Roth</td>
			<td>P087</td>
			<td>Histology</td>
		</tr>
		<tr>
			<td>Technovit 9100</td>
			<td>Morphisto</td>
			<td>12225.K1000</td>
			<td>Histology</td>
		</tr>
	</tbody>
</table>

implantation of human-sized coronary stents into rat abdominal aorta using a trans-femoral access

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of coronary artery disease. In-stent restenosis (ISR) is determined by an excessive proliferation of neointimal tissue within the stent and limits the long-term success of stents. A variety of animal models have been used to elucidate pathophysiological processes underlying in-stent restenosis (ISR), with the porcine coronary and the rabbit iliac artery models being the most frequently used. Murine models provide the advantages of high throughput, ease of handling and housing, reproducibility, and a broad availability of molecular markers. The apolipoprotein E deficient (apoE-/- ) mouse model has been widely used to study cardiovascular diseases. However, stents must be miniaturized to be implanted into mice, involving important changes of their mechanical and (potentially) biological properties. The use of apoE-/- rats can overcome these shortcomings as apoE-/- rats allow for the evaluation of human-sized coronary stents while at the same time providing an atherogenic phenotype. This makes them an excellent and reliable model to investigate ISR after stent implantation. Here, we describe, in detail, the implantation of commercially available human coronary stents into the abdominal aorta of rats with an apoE-/- background using a trans-femoral access.

This protocol describes stent implantation in the abdominal aorta of rats using a trans-femoral access route (Figure 1). The first central point of this animal model is that it allows for the deployment of human-sized coronary stents. A commercially available crimped and balloon-mounted coronary stent can be placed into the abdominal aorta of rats. Thus, in addition, the same principle of stent deployment as in humans can be applied. Another advantage of the use of rats is the availability o...

Watch this Scientific Journal Video about Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access at JoVE.com

Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access

This protocol describes the implantation of human coronary stents into the abdominal aorta of rats with an apoE-/- background using a trans-femoral access. Compared with other animal models, murine models carry the advantages of high throughput, reproducibility, ease of handling and housing, and a broad availability of molecular markers.

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of ...

This protocol uses an animal model to establish an accessible method for characterizing the effects of human coronary stents on vascular pathology. The main advantages of our model are that is minimally invasive, highly reproducible, and easily performed even by researchers with little operative experience. Demonstrating the the procedure will be Roberta Florescu, a physician from our laboratory.Following this procedure, other clinical and pathology diagnostic tools can be used, such as optical coherence tomography or histological analysis. After confirming a lack of response to pedal reflex in an anesthetized adult rat, place the rat on a heating pad in the supine position with the right hind limb fully extended and in line with the spine, and fix the upper and lower limbs with medical tape. Apply ointment to the animal's eyes and shave the fur from the groin and lower abdomen.Then sterilize the exposed skin with a povidone iodine solution. For implantation of the stent, make a 0.5 to one centimeter medial incision in the right groin to open the skin and underlying fascia, and bluntly dissect and probe the tissue until the pulsating left femoral artery is located. Using very fine forceps, gently remove the connective tissue surrounding the artery and carefully insert the top of the forceps under the vessel.Thread pieces of 4-0 silk suture under the distal and proximal parts of the artery to form slings and clamp the ends of each of the two threads slings between the branches of a surgical clamp. Use the surgical clamps to control the artery and gently stretch and lift the artery to temporarily interrupt the blood flow. Using sharp micro-scissors, quickly perform in arteriotomy in the middle of the femoral artery and introduce a guide wire into the arteriotomy.When the proximal thread sling is reached, move the surgical clamp to release the tension of the thread and advance the guide wire toward the abdominal aorta. Introduce a 2.25 by eight millimeter crimped and balloon-mounted coronary stent over the guide wire into the femoral artery. Advance the stent to the abdominal aorta until it is just above the aortic bifurcation, but below the renal arteries.When the stent is in place, use an inflation syringe system to inflate the balloon catheter to its nominal pressure. After 15 seconds, deflate the balloon catheter and maintain negative pressure according to the manufacturer's recommendations for the stent in use. Next, slowly withdraw the deflated catheter while leaving the stent in place.Just before removing the guide wire, use the surgical clamp to create tension on the threaded loop above the incision to interrupt the blood flow and remove the guide wire. Directly ligate the vessel proximally and tie the proximal and distal thread loops to ligate the femoral artery. Then confirm adequate hemostasis of the arteriotomy and use 6-O non-resorbable sutures to close the muscle overlying the artery and the skin incision.In this representative analysis, human-sized coronary stents were successfully deployed with no sign of malapposition or vessel injury. Homozygous apolipoprotein E knockout rats developed markedly elevated neointimal hyperplasia and in-stent restenosis compared to wild type rats. Although the apolipoprotein E knockout background renders animals more susceptible to atherosclerosis, no antecedent atherosclerotic plaques were observed in these rats.Selecting the proper stent size for each animal and using rats weighing over 500 grams for the human coronary stent implantation are critical to the success of the procedure.

Research

JoVE Journal

Medicine

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Direct Re-implantation of Left Coronary Artery into the Aorta in Adults with Anomalous Origin of Left Coronary Artery from the Pulmonary Artery (ALCAPA)

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Balloon-based Injury to Induce Myointimal Hyperplasia in the Mouse Abdominal Aorta

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Ultrasound Imaging of the Thoracic and Abdominal Aorta in Mice to Determine Aneurysm Dimensions

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A Murine Model of Hemodialysis Access-Related Hand Dysfunction

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