This work was funded by the National Institutes of Health R01HL140231. We thank the Division of Animal Care for their animal husbandry and veterinary care. We thank the SR Light Laboratory and its staff, Jamie Adcock, Susan Fultz, Codi VanRooyen, and Jos&#233; Diaz, for their dedicated technical support with large animal surgeries.

The Institutional Animal Care and Use Committee at Vanderbilt University Medical Center approved the protocol. The described procedures were conducted in accordance with the US National Research Council&#39;s Guide for the Care and Use of Laboratory Animals, 8th edition. The overview and the timeline of the experimental procedure are provided in Figure 1.&#160;Supplementary Table 1&#160; describes the sheep&#8217;s sex, weight, breed, source of sheep, and other rele...

<ol>
	<li>Campo, A., 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=Outcomes+of+hospitalization+for+right+heart+failure+in+pulmonary+arterial+hypertension.">Outcomes of hospitalization for right heart failure in pulmonary arterial hypertension.</a> European Respiratory Journal. 38 (2), 359-367 (2011).</li><li>Tonelli, A. 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=Causes+and+circumstances+of+death+in+pulmonary+arterial+hypertension.">Causes and circumstances of death in pulmonary arterial hypertension.</a> American Journal of Respiratory and Critical Care Medicine. 188 (3), 365-369 (2013).</li><li>Urashima, T., 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=Molecular+and+physiological+characterization+of+RV+remodeling+in+a+murine+model+of+pulmonary+stenosis.">Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis.</a> American Journal of Physiology- Heart and Circulatory Physiology. 295 (3), (2008).</li><li>Sato, H., 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=Large+animal+model+of+chronic+pulmonary+hypertension.">Large animal model of chronic pulmonary hypertension.</a> ASAIO Journal. 54 (4), 396-400 (2008).</li><li>Pohlmann, J. 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=A+low+mortality+model+of+chronic+pulmonary+hypertension+in+sheep.">A low mortality model of chronic pulmonary hypertension in sheep.</a> Journal of Surgical Research. 175 (1), 44-48 (2012).</li><li>Noly, P. -. E., Guihaire, J., Coblence, M., Dorfmuller, P., Fadel, E., Mercier, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chronic+thromboembolic+pulmonary+hypertension+and+assessment+of+right+ventricular+function+in+the+piglet.">Chronic thromboembolic pulmonary hypertension and assessment of right ventricular function in the piglet.</a> Journal of Visualized Experiments: JoVE. (105), e53133 (2015).</li><li>Pereda, D., 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=Swine+model+of+chronic+postcapillary+pulmonary+hypertension+with+right+ventricular+remodeling:+Long-term+characterization+by+cardiac+catheterization,+magnetic+resonance,+and+pathology.">Swine model of chronic postcapillary pulmonary hypertension with right ventricular remodeling: Long-term characterization by cardiac catheterization, magnetic resonance, and pathology.</a> Journal of Cardiovascular Translational Research. 7 (5), 494-506 (2014).</li><li>Silva, K. A. S., Emter, C. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Large+animal+models+of+heart+failure:+A+translational+bridge+to+clinical+success.">Large animal models of heart failure: A translational bridge to clinical success.</a> JACC: Basic to Translational Science. 5 (8), 840-856 (2020).</li><li>Ukita, 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=Left+pulmonary+artery+ligation+and+chronic+pulmonary+artery+banding+model+for+inducing+right+ventricular+-+pulmonary+hypertension+in+sheep.">Left pulmonary artery ligation and chronic pulmonary artery banding model for inducing right ventricular - pulmonary hypertension in sheep.</a> ASAIO Journal (American Society for Artificial Internal Organs: 1992. 67 (1), 44-48 (2020).</li><li>Ukita, 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=Progression+toward+decompensated+right+ventricular+failure+in+the+ovine+pulmonary+hypertension+model.">Progression toward decompensated right ventricular failure in the ovine pulmonary hypertension model.</a> ASAIO Journal (American Society for Artificial Internal Organs: 1992. , (2021).</li><li>Mercier, O., 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=Piglet+model+of+chronic+pulmonary+hypertension.">Piglet model of chronic pulmonary hypertension.</a> Pulmonary Circulation. 3 (4), 908-915 (2013).</li><li>Guihaire, J., 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=Right+ventricular+plasticity+in+a+porcine+model+of+chronic+pressure+overload.">Right ventricular plasticity in a porcine model of chronic pressure overload.</a> Journal of Heart and Lung Transplantation. 33 (2), 194-202 (2014).</li><li>Tang, K. J., Robbins, I. M., Light, R. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Incidence+of+pleural+effusions+in+idiopathic+and+familial+pulmonary+arterial+hypertension+patients.">Incidence of pleural effusions in idiopathic and familial pulmonary arterial hypertension patients.</a> Chest. 136 (3), 688-693 (2009).</li><li>Luo, Y. F., 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=Frequency+of+pleural+effusions+in+patients+with+pulmonary+arterial+hypertension+associated+with+connective+tissue+diseases.">Frequency of pleural effusions in patients with pulmonary arterial hypertension associated with connective tissue diseases.</a> Chest. 140 (1), 42-47 (2011).</li><li>Brixey, A. G., Light, R. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pleural+effusions+occurring+with+right+heart+failure.">Pleural effusions occurring with right heart failure.</a> Current Opinion in Pulmonary Medicine. 17 (4), 226-231 (2011).</li><li>Bovine High-mountain Disease. Merck and the Merck Veterinary Manual Available from: <a target="_blank" href="https://www.merckvetmanual.com/circulatory-system/bovine-high-mountain-disease/bovine-high-mountain-disease">https://www.merckvetmanual.com/circulatory-system/bovine-high-mountain-disease/bovine-high-mountain-disease</a> (2019)</li><li>Van De Veerdonk, M. 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The presented PH-RVF model can reliably induce varying levels of disease severity to match the goals of the investigation. Two different approaches are used in combination to induce this disease model. First, the LPA ligation serves to increase pulmonary vascular resistance and decrease PA capacitance11,12, thereby establishing the starting point of the chronic model at an already increased RV afterload state. Then, the implantation of the PA cuff and its progres...

Decompensated right ventricular (RV) failure is the predominant cause of morbidity and mortality for patients with pulmonary hypertension (PH). RV failure is responsible for over 50% of hospitalizations in patients with PH and is a common cause of death in this patient population1,2. Although current medical treatments for PH can provide temporizing measures, they do not reverse the progression of the disease. As such, the only long-term treatment is lung transplantation. To explore and test novel medical treatments and interventions for PH and RVF, a clinically relevant animal model is needed to recapitulate the disease&#39;s complex pathophysiology. In particular, there is a great clinical need to develop RV-targeted therapeutics for PH patients to improve RV function. To date, most published animal studies of PH and RV dysfunction have relied on small mammals such as mice and rats3. On the other hand, there have only been a handful of large animal models to study the disease and RV pathophysiology from abnormal afterload4,5,6,7. In addition, none of the previously published large animal models include descriptions of experimental procedures for controlled titration of disease severity that differentially leads to compensated versus decompensated RV failure phenotypes. An animal model of PH that can be titrated to induce acute and chronic RV failure with varying degrees of compensation is needed to study disease mechanisms and to develop, test, and translate novel diagnostics and therapeutics for PH and RVF into clinical practice. Such a model in a large animal is especially valuable for the development of mechanical circulatory support devices8.
Here, a chronic, large animal PH-RVF model using left pulmonary artery (PA) ligation and progressive main PA banding in adult sheep is presented9,10. The ligation of the left PA (LPA) increases the pulmonary vascular resistance and decreases PA capacitance11,12. The progressive PA banding approach allows for precise titration of disease severity and RV adaptation. This platform can also be readily utilized for longitudinal investigation of disease progression toward RV decompensation. The procedures and processes required to execute this model are presented as a resource for investigators interested in a large animal platform to develop novel treatments for PH and RVF.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>&#160;0.9% Sodium Chloride Irrigation Pour Bottle by Baxter Healthcare, 1000 mL</td>
			<td>Medline</td>
			<td>&#160;BHL2F7124</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>0.25% Bupivacaine</td>
			<td>Hospira Inc</td>
			<td>0409-1160-18</td>
			<td>Medication, Intra-Operative</td>
		</tr>
		<tr>
			<td>0.9% Normal Saline, 1000 mL</td>
			<td>Baxter Healthcare Corp</td>
			<td>0338-0049-04</td>
			<td>Medication, Intra-Operative</td>
		</tr>
		<tr>
			<td>0.9% Normal Saline, 500 mL</td>
			<td>Baxter Healthcare Corp.,</td>
			<td>&#160;0338-0049-03</td>
			<td>Medication, Chronic PH</td>
		</tr>
		<tr>
			<td>16 mm Heavy Duty Occluder with actuating tubing</td>
			<td>Access Technologies</td>
			<td>&#160;OC-16HD</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>3-mL Skin Prep Applicator</td>
			<td>Medline</td>
			<td>&#160;MDF260400</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>70% isopropyl alcohol prep pads</td>
			<td>Medline</td>
			<td>MDS090670</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Adhesive bandage tape</td>
			<td>Patterson Veterinary</td>
			<td></td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Adson forceps</td>
			<td>V. Mueller</td>
			<td>NL1400</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Allis tissue forceps</td>
			<td>V. Mueller</td>
			<td>CH1560</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Aortic clamp, straight (bainbridge forceps)</td>
			<td>V. Mueller</td>
			<td>SU6001</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Backhaus towel forceps</td>
			<td>V. Mueller</td>
			<td>SU2900</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Bags, Infusion: Nonsterile Novaplus Infusion Bag, 500 mL</td>
			<td>Medline</td>
			<td>TCV4005H</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Berry sternal needle holder</td>
			<td>V. Mueller</td>
			<td>CH2540</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Blades, Electrode: Electrode Blade, 6.5&#34;, with 0.24 cm Shaft</td>
			<td>Medline</td>
			<td>&#160;VALE15516</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Blades: Stainless-Steel Sterile Surgical Blade, Size #10</td>
			<td>Medline</td>
			<td>&#160;B-D371210</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Blades: Stainless-Steel Sterile Surgical Blade, Size #11</td>
			<td>Medline</td>
			<td>&#160;B-D371211</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Blades: Stainless-Steel Sterile Surgical Blade, Size #15</td>
			<td>Medline</td>
			<td>&#160;B-D371215</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>BNC Male to BNC Male Cable</td>
			<td>Digi-Key</td>
			<td>415-0198-036</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Castroviejo needle holder</td>
			<td>V. Mueller</td>
			<td>CH8589</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Cefazolin</td>
			<td>Apotex Corp</td>
			<td>60505-6142-0</td>
			<td>Medication, Intra-Operative</td>
		</tr>
		<tr>
			<td>Ceftiofur Crystalline Free Acid</td>
			<td>Zoetis Inc</td>
			<td>54771-5223-1</td>
			<td>Medication, Post-Operative</td>
		</tr>
		<tr>
			<td>Chest Drain, with Dry Suction, Adult-Pediatric</td>
			<td>Medline</td>
			<td>&#160;DEKA6000LFH</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Chest tube passer</td>
			<td>V. Mueller</td>
			<td>CH04189</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>COnfidence Flowprobes for Research (PAU-Series)</td>
			<td>Transonic</td>
			<td>24PAU</td>
			<td>Equipment, Perivascular Flow Probe</td>
		</tr>
		<tr>
			<td>Cooley tangential occlusion clamp</td>
			<td>V. Mueller</td>
			<td>CH6572</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Data Acquisition Hardware</td>
			<td>ADInstruments</td>
			<td>&#160;PowerLab 16/30</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>DeBakey Aorta clamp</td>
			<td>V. Mueller</td>
			<td>CH7247</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>DeBakey multi-purpose clamp</td>
			<td>V. Mueller</td>
			<td>CH7276</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Debakey tissue forceps, 12&#8217;&#8217;</td>
			<td>V. Mueller</td>
			<td>CH5906</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Debakey vascular tissue forceps 7 3/4&#8217;&#8217;</td>
			<td>V. Mueller</td>
			<td>CH5902</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Debakey vascular tissue forceps, 9&#8217;&#8217;</td>
			<td>V. Mueller</td>
			<td>CH5904</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Electrosurgical Generator</td>
			<td>Covidien</td>
			<td>&#160;Force FX-C</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Endotracheal Tube, 10mm</td>
			<td>Patterson Veterinary</td>
			<td>07-882-9008</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Enrofloxacin</td>
			<td>Norbrook Laboratories Limited</td>
			<td>55529-152-05</td>
			<td>Medication, Intra-Operative</td>
		</tr>
		<tr>
			<td>Fentanyl Transdermal Patch</td>
			<td>Apotex Corp</td>
			<td>60505-7007-2</td>
			<td>Medication, Pre-Operative</td>
		</tr>
		<tr>
			<td>Ferris smith tissue forceps</td>
			<td>V. Mueller</td>
			<td>SU2510</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Finochietto rib spreaders, large</td>
			<td>V. Mueller</td>
			<td>CH1220-1</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Finochietto rib spreaders, medium</td>
			<td>V. Mueller</td>
			<td>CH1215-1</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Flexsteel ribbon retractor, 1&#8221; x 13&#8221;</td>
			<td>V. Mueller</td>
			<td>SU3340</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Flexsteel ribbon retractor, 2&#8221; x 13&#8221;</td>
			<td>V. Mueller</td>
			<td>SU3346</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Foerster sponge forceps, curved</td>
			<td>V. Mueller</td>
			<td>GL660</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Gauze Sponges: Sterile X-ray Compatible Gauze Sponges, 16-Ply, 4&#34; x 4&#34;</td>
			<td>Medline</td>
			<td>&#160;PRM21430LFH</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Gerald-DeBakey forceps</td>
			<td>V. Mueller</td>
			<td>CH04242</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Glassman Allis</td>
			<td>V. Mueller</td>
			<td>SU6152</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Halsted mosquito forceps</td>
			<td>V. Mueller</td>
			<td>SU2702</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Harken clamp</td>
			<td>V. Mueller</td>
			<td>CH6462</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Heat Therapy Pump</td>
			<td>Gaymar/Stryker</td>
			<td>&#160;TP-400</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Heparin</td>
			<td>Fresenius Kabi,</td>
			<td>&#160;63323-540-31</td>
			<td>Medication, Chronic PH</td>
		</tr>
		<tr>
			<td>Hospira Primary IV Sets, 80&#34;</td>
			<td>Patterson Veterinary</td>
			<td>07-835-0123</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Hypertonic saline 3%</td>
			<td>Baxter Healthcare Corp.,</td>
			<td>&#160;0338-0054-03</td>
			<td>Medication, Chronic PH</td>
		</tr>
		<tr>
			<td>Hypodermic Needle with Bevel and Regular Wall, 20 G x 1&#34;</td>
			<td>Medline</td>
			<td>B-D305175Z</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Interface Cable, Edwards LifeScience Transducer to ADInstruments&#160; Bridge Amplifier</td>
			<td>Fogg System</td>
			<td>0395-2434</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Intravenous Infusion Pump</td>
			<td>Heska</td>
			<td>&#160;Vet/IV 2.2 Infusion Pump</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>Patterson Veterinary</td>
			<td>14043-704-06</td>
			<td>Medication, Pre-Operative</td>
		</tr>
		<tr>
			<td>Kantrowitz thoracic clamp, 9-1/2&#8221;</td>
			<td>V. Mueller</td>
			<td>CH1722</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Kelly hemostats</td>
			<td>V. Mueller</td>
			<td>88-0314</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Lidocaine HCl, 2.46%</td>
			<td>PRN Pharmacal,</td>
			<td>&#160;49427-434-04</td>
			<td>Medication, Chronic PH</td>
		</tr>
		<tr>
			<td>Ligaclip Multiple-Clip Appliers by Ethicon</td>
			<td>Medline</td>
			<td>&#160;ETHMCS20</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Loop, Vessel, Mini, Red, 2/pk, Sterile</td>
			<td>Medline</td>
			<td>&#160;DYNJVL12</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Lorna non-perforating towel forceps</td>
			<td>V. Mueller</td>
			<td>SU2937</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Mayo dissecting scissors, curved</td>
			<td>V. Mueller</td>
			<td>SU1826</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Mayo dissecting scissors, straight</td>
			<td>V. Mueller</td>
			<td>SU1821</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Medipore Dress-It Pre-Cut Dressing Covers by 3M</td>
			<td>Medline</td>
			<td>&#160;MMM2955Z</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Meloxicam</td>
			<td>Patterson Veterinary</td>
			<td>14043-909-10</td>
			<td>Medication, Post-Operative</td>
		</tr>
		<tr>
			<td>Mixter thoracic forceps, 9&#8221;</td>
			<td>V. Mueller</td>
			<td>CH1730-003</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Mosquito hemostats</td>
			<td>V. Mueller</td>
			<td>88-0301</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Multi-Channel Research Consoles</td>
			<td>Transonic</td>
			<td>T402/T403</td>
			<td>Equipment, Perivascular Flow Meter</td>
		</tr>
		<tr>
			<td>Multi-Lumen Central Venous Catheterization Kits</td>
			<td>Medline</td>
			<td>&#160;ARW45703XP1AH</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Multi-Parameter Vital Signs Monitor</td>
			<td>Smiths Medical</td>
			<td>&#160;SurgiVet Advisor 3</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Needles: Hypodermic Needle with Regular Bevel, Sterile, 18 G x 1.5&#34;</td>
			<td>Medline</td>
			<td>&#160;B-D305185Z</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>No. 3 knife handle</td>
			<td>V. Mueller</td>
			<td>SU1403-001</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>No. 7 knife handle</td>
			<td>V. Mueller</td>
			<td>SU1407</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Non-Vented Male Luer Cap</td>
			<td>Qosina</td>
			<td>13614</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Octal Bridge Amplifier</td>
			<td>ADInstruments</td>
			<td>&#160;FE228</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Ophthalmic Ointment</td>
			<td>Akorn Animal Health</td>
			<td>59399-162-35</td>
			<td>Medication, Pre-Operative</td>
		</tr>
		<tr>
			<td>Penrose Tubing, 6 mm x 46 cm, 11 mm Flat</td>
			<td>Medline</td>
			<td>&#160;SWD514604H</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Perma-Hand Black Braided Silk:&#160; 2-0 SH Taperpoint Needle, Control Release, 30&#34;</td>
			<td>Medline</td>
			<td>&#160; ETHD8552</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Perma-Hand Suture, Black Braided, Size 0, 6 x 30&#8221;</td>
			<td>Medline</td>
			<td>&#160; ETHA306H</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Perma-Hand Suture, Black Braided, Size 4-0, 12 x 30&#34;</td>
			<td>Medline</td>
			<td>&#160;ETHA303H</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Phenylephrine</td>
			<td>West-Ward</td>
			<td>0641-6142-25</td>
			<td>Medication, Intra-Operative</td>
		</tr>
		<tr>
			<td>Polyhesive Cordless Patient Return Electrodes, Adult</td>
			<td>Medline</td>
			<td>&#160;SWDE7509</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Port-A-Cath Huber Needle, Straight, 22 G x 1-1/2&#34;</td>
			<td>Medline</td>
			<td>AAKM21200724</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>PROLENE Monofilament Suture, Blue, Size 4-0, 36&#34;, Double Arm, RB-1 Needle</td>
			<td>Medline</td>
			<td>&#160;ETHD7143</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>PROLENE Polypropylene Monofilament Suture, Blue, Double-Armed, RB-1 Needle, Size 5-0, 24&#34;</td>
			<td>Medline</td>
			<td>&#160;ETH8555H</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Regional Block Needles, 22-gauge</td>
			<td>Medline</td>
			<td>&#160;B-D408348Z</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Schnidt tonsil artery forceps</td>
			<td>V. Mueller</td>
			<td>M01700</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Skin staple extractor</td>
			<td>Medline</td>
			<td>CND3031</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Skin stapler 35 wide, with counter</td>
			<td>Medline</td>
			<td>&#160;STAPLER35W</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Sphygmomanometer</td>
			<td>Medline</td>
			<td></td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Sponge bowl</td>
			<td>V. Mueller</td>
			<td>GE-75</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Sponge, Lap: X-Ray Detectable Sterile Lap Sponge, 18&#34; x 18&#34;, 5/Pack</td>
			<td>Medline</td>
			<td>&#160;MDS241518HH</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Sponge, Peanut: X-Ray Detectable Sterile Peanut Sponge, Small, 3/8&#34;</td>
			<td>Medline</td>
			<td>&#160;MDS72038</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Sterile Disposable Deluxe OR Towel, Blue, 17&#39;&#39; x 27&#39;&#39;, 2/Pack</td>
			<td>Medline</td>
			<td>&#160;MDT2168202</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Sterile Luer-Lock Syringe, 3 mL</td>
			<td>Medline</td>
			<td>SYR103010Z</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Sterile Luer-Lock Syringe, 5 mL</td>
			<td>Medline</td>
			<td>SYR105010Z</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Sterile Surgical Equipment Probe Covers</td>
			<td>Medline</td>
			<td>&#160;DYNJE5930</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Stopcock: 3-Way Stopcock with Handle in OFF Position, Rotating Adaptor Male Collar Fitting, 45 PSI</td>
			<td>Medline</td>
			<td>&#160;DYNJSC301</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Stopcock: 3-Way Stopcock with Handle in OFF Position, Rotating Adaptor Male Collar Fitting, 45 PSI</td>
			<td>Medline</td>
			<td>DYNJSC301</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Subcutaneous Port with 5-French Connector and Blue Boot</td>
			<td>Access Technologies</td>
			<td>CP2AC-5NC</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Super cut metzenbaum dissecting scissors</td>
			<td>V. Mueller</td>
			<td>CH2032-S</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Super cut nelson-metzenbaum dissecting scissors</td>
			<td>V. Mueller</td>
			<td>CH2025-S</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Syringes: Sterile Luer-Lock Syringe, 10 mL</td>
			<td>Medline</td>
			<td>&#160;SYR110010Z</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Thoracic Catheter, Straight, 28 Fr x 20&#34;</td>
			<td>Medline</td>
			<td>SWD570549H</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Three-quarter surgical drape</td>
			<td>Medline</td>
			<td>&#160;DYNJP2414H</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Tiletamine + Zolazepam</td>
			<td>Zoetis Inc</td>
			<td>54771-9050-1</td>
			<td>Medication, Pre-Operative</td>
		</tr>
		<tr>
			<td>TourniKwik Tourniquet Set with Four 7.5&#34; Bronze-Colored Tubes and 1 Snare, 12 French</td>
			<td>Medline</td>
			<td>&#160;CVR79013</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Transducer clip</td>
			<td>Edwards LifeScience</td>
			<td>TCLIP05</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Trigger Aneroid Gauge (Sphygmomanometer)</td>
			<td>Patterson Veterinary</td>
			<td>07-815-0464</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>TruWave Disposable Pressure Transducer Kits by Edwards Lifesciences</td>
			<td>Medline</td>
			<td>&#160;VSYPX260</td>
			<td>Surgical Disposable and Chronic PH</td>
		</tr>
		<tr>
			<td>TS420 Perivascular Flow Module</td>
			<td>Transonic</td>
			<td>TS420</td>
			<td>Equipment, Perivascular Flow Meter</td>
		</tr>
		<tr>
			<td>Tubing, Suction: Sterile Universal Suction Tubing with Straight Ribbed Connectors, 1/4&#34; x 12&#39;</td>
			<td>Medline</td>
			<td>&#160;OR612</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Tubing: Pressure Monitoring Tubing with Fixed Male Luer Lock and Female Fitting, Low Pressure, 72&#34; L</td>
			<td>Medline</td>
			<td>DYNJPMTBG72MF</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Tubing: Pressure Monitoring Tubing with Fixed Male Luer Lock and Female Fitting, Low Pressure, 72&#34; L</td>
			<td>Medline</td>
			<td>DYNJPMTBG72MF</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Tubular Elastic Dressing Retainer</td>
			<td>Medline</td>
			<td>DERGL711</td>
			<td>Disposable, Chronic PH</td>
		</tr>
		<tr>
			<td>Tuffier rib retractor</td>
			<td>V. Mueller</td>
			<td>CD1101</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Tygon E-3603 Flexible Tubings</td>
			<td>Fisher Scientific</td>
			<td>14-171-227</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>U.S.A retractor</td>
			<td>V. Mueller</td>
			<td>SU3660</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Umbilical Tape, Cotton, 3-Strand, 1/8 x 36&#34;</td>
			<td>Medline</td>
			<td>&#160;ETHU12TH</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Valleylab Button Switch Pencil</td>
			<td>Medline</td>
			<td>&#160;VALE2516H</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Vanderbilt deep vessel forceps</td>
			<td>V. Mueller</td>
			<td>CH1687</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Veterinary Anesthesia Machine</td>
			<td>Midmark</td>
			<td>&#160;Matrx VMC</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Veterinary Anesthesia Ventilator</td>
			<td>Hallowell EMC</td>
			<td>&#160;Model 2000</td>
			<td>Equipment</td>
		</tr>
		<tr>
			<td>Vicryl: Undyed Coated Vicryl 0 CT-1 36&#34; Suture</td>
			<td>Medline</td>
			<td>&#160;ETHVCP946H</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Vicryl: Undyed Coated Vicryl 2 TP-1 Taper 54&#34; Suture</td>
			<td>Medline</td>
			<td>&#160;ETHVCP880T</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Vicryl: Undyed Coated Vicryl 2-0 CT-1 18&#34; Suture</td>
			<td>Medline</td>
			<td>&#160;ETHVCP739D</td>
			<td>Surgical Disposable</td>
		</tr>
		<tr>
			<td>Vital crile-wood needle holder, 10-3/8&#8221;</td>
			<td>V. Mueller</td>
			<td>CH2427</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Vital mayo-hegar needle holder, 7-1/4&#8221;</td>
			<td>V. Mueller</td>
			<td>CH2417</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Vital metzenbaum dissecting scissors, 14&#8217;&#8217;</td>
			<td>V. Mueller</td>
			<td>CH2009</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Vital metzenbaum dissecting scissors, 9&#8221;</td>
			<td>V. Mueller</td>
			<td>CH2006</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Vital ryder needle holder, 9&#8221;</td>
			<td>V. Mueller</td>
			<td>CH2510</td>
			<td>Surgical Instrument</td>
		</tr>
		<tr>
			<td>Yankauer, Bulb Tip: Sterile Rigid Yankauer with Bulb Tip, No Vent</td>
			<td>Medline</td>
			<td>&#160;DYND50130</td>
			<td>Surgical Disposable</td>
		</tr>
	</tbody>
</table>

a large animal model for pulmonary hypertension and right ventricular failure: left pulmonary artery ligation and progressive main pulmonary artery banding in sheep

Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing novel therapeutics for PH requires a clinically relevant large animal model of increased pulmonary vascular resistance and RVF. This manuscript discusses the latest development of the previously published ovine PH-RVF model that utilizes left pulmonary artery (PA) ligation and main PA occlusion. This model of PH-RVF is a versatile platform to control not only the disease severity but also the RV&#39;s phenotypic response.
Adult sheep (60-80 kg) underwent left PA (LPA) ligation, placement of main PA cuff, and insertion of RV pressure monitor. PA cuff and RV pressure monitor were connected to subcutaneous ports. Subjects underwent progressive PA banding twice per week for 9 weeks with sequential measures of RV pressure, PA cuff pressures, and mixed venous blood gas (SvO2). At the initiation and endpoint of this model, ventricular function and dimensions were assessed using echocardiography. In a representative group of 12 animal subjects, RV mean and systolic pressure increased from 28 &#177; 5 and 57 &#177; 7 mmHg at week 1, respectively, to 44 &#177; 7 and 93 &#177; 18 mmHg (mean &#177; standard deviation) by week 9. Echocardiography demonstrated characteristic findings of PH-RVF, notably RV dilation, increased wall thickness, and septal bowing. The longitudinal trend of SvO2 and PA cuff pressure demonstrates that the rate of PA banding can be titrated to elicit varying RV phenotypes. A faster PA banding strategy led to a precipitous decline in SvO2 &#60; 65%, indicating RV decompensation, whereas a slower, more paced strategy led to the maintenance of physiologic SvO2 at 70%-80%. One animal that experienced the accelerated strategy developed several liters of pleural effusion and ascites by week 9. This chronic PH-RVF model provides a valuable tool for studying molecular mechanisms, developing diagnostic biomarkers, and enabling therapeutic innovation to manage RV adaptation and maladaptation from PH.

A representative group of 12 sheep is used to show the efficacy of this model for developing varying degrees of PH-RVF. Among these sheep, the mean PA cuff pressure increased from 32 &#177; 20 mmHg at week 1 to 1002 &#177; 429 mmHg at week 9. This resulted in increasing the RV mean and systolic pressures from 28 &#177; 5 and 57 &#177; 7 mmHg at week 1, respectively, to 44 &#177; 7 and 93 &#177; 18 mmHg by week 9. Furthermore, PA cuff pressure profile was superimposed onto mixed venous oxygen saturation (SvO2) ...

Watch this Scientific Journal Video about A Large Animal Model for Pulmonary Hypertension and Right Ventricular Failure: Left Pulmonary Artery Ligation and Progressive Main Pulmonary Artery Banding in

A Large Animal Model for Pulmonary Hypertension and Right Ventricular Failure: Left Pulmonary Artery Ligation and Progressive Main Pulmonary Artery Banding in Sheep

This manuscript describes the surgical technique and experimental approach to develop severe right ventricular pressure overload to model their adaptive and maladaptive phenotypes.

Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing ...

This protocol is a large animal model for studying right ventricular adaptation and failure. This model is therefore vital for developing RV-targeted therapeutics to treat pulmonary hypertension. This model progressively increases the right RV after load which can be used as a strategy to titrate the RV adaptation.No previous large animal models have this control over the RV phenotype. Demonstrating that surgical procedure will be Dr.Matthew Bacchetta, the laboratory director and the surgical fellows doctors John Stokes, Kelly Wu and Yatrik Patel. I will be demonstrating the pulmonary artery banding procedure.After anesthetization, begin by shaving the surgical field from the sheep's neck to its upper abdomen. Clean the surgical field off dirt and other contaminants using soap or a scrub brush. Prep the neck in the chest with chlorhexidine or betaine solution and drape the surgical field in a sterile fashion.To obtain media style exposure perform a muscle sparing mini thoracotomy at the left fourth intercostal space with incision length less than eight centimeters. Use a small or medium Finochietto retractor to separate the ribs in a tuffier retractor to sit perpendicular to the Finochietto within the intercostal space which will retract the soft tissue within the intercostal space, improving exposure without injuring the phrenic nerve incise the pericardia interior to it and create a pericardial well with 2/0 silk sutures to expose the main pulmonary artery and right ventricle. Identify the left atrial appendage within the exposure as a landmark for the level of the pulmonary artery bifurcation dissect around the main pulmonary artery and isolate it with a umbilical tape.Perform intrapericardial dissection of the left pulmonary artery and encircle with a umbilical tape. Place a heavy duty silicone vascular occluder around the main pulmonary artery. Using an 0 silk suture on a Keith needle.Secure the end to the vascular occluder together with a U-stitch. Once secured around the main pulmonary artery slide the occluder distally along the main pulmonary artery. To establish a right ventricular pressure line, start by placing a 5/0 monofilament non-absorbable polypropylene purser suture with pledgets surrounding the selected location and see a vascular snare.Prepare the right ventricular pressure line by cutting off the male end of a sterile 36 inch pressure tubing at a 30 degree angle to facilitate insertion through the myocardium. Then use a 2/0 silk tie to mark the pressure line at an optimal depth for placement within the right ventricle. Using a biopsy punch, make a small cardiotomy in the right ventricular outflow tract or RVOT free wall within the previously placed purser string suture.Control the bleeding with manual pressure or by tightening the snare on the purser suture. Insert and secure the cut end of the pressure tubing into the RVOT. Tie down the purse string then secure the purse string to the pressure tubing to secure the pressure line.Extend the RVOT tubing by connecting an additional pressure tubing to the RVOT pressure line. Monitor for the measurement of the baseline, right ventricular pressure. Carefully dissect around the left pulmonary artery Encircle the left pulmonary artery with umbilical tape tying it down to ligate it.Bring the RVOT pressure line and pulmonary artery occluder tubing out of the chest one intercostal space below the thoracotomy incision. To mark sites for indwelling ports form two subdural pockets along the fascia layer on the left dorsum of the sheep as far posteriorly toward the spine as feasible within sterile field. Use a chest tube polar to tunnel the RVOT pressure line and occluder tubing from the chest incision out to the left dorsum port sites.Secure both the occluder tubing and right ventricular pressure line to the port's barb connections. Anchor the occluder and pressure tubing around the port connectors with additional ties. To prevent port migration anchor the ports in three locations around their rims to the underlying fascia with 3/0 polypropylene sutures.Reapproximate the subcutaneous tissue dermis and skin in layers with polyglactin 910 sutures. Flush the RVOT port with five milliliters of heparin sodium. Close the thoracotomy with figure of eight number two polyglactin 910 sutures Then close the pectorals muscle layer with a running number 0 polyglactin 910.Finally, close the subcutaneous tissue in layers of running number 2/0 polyglactin 910 sutures and staple the skin. Prepare two pressure transducers for monitoring, right ventricular and occluder cuff pressures. After the animal is mildly restrained insert the Huber needle from the right ventricular pressure transducer to the right ventricular port.Attach a five milliliter syringe to the three-way stop cock and attempt to draw blood back into the syringe from the right ventricular port. Once the right ventricular pressure line is established, connect the Huber needle from the pulmonary artery cuff transducer. Capture the starting values of rip ventricular and pulmonary artery cuff pressures, noting any drastic changes from previous readings.Slowly inject 3%hypertonic saline into the occluder port while paying attention to rip ventricular and cuff pressures. The once the PA cuff is inflated to the desired amount remove the Huber needle from the cuff port. Flush the right ventricular port with 10 milliliters of saline then flush the port with five milliliters of 1000 units per milliliter of heparin sodium.Among the 12 sheep. The mean pulmonary artery cuff pressure increased with an increase in time from the first to the ninth week. Faster pulmonary artery banding lead to a more rapid decline in venous oxygen saturation.In contrast, those that experienced a more gradual pulmonary artery banding strategy maintain a physiologic range of venous oxygen saturation between 70 and 80%By controlling the pulmonary artery cuff pressure. This model has ability to control and titrate ride ventricular adaptation and phenotype.

a-large-animal-model-for-pulmonary-hypertension-right-ventricular

Research

JoVE Journal

Bioengineering

2.9K 조회수.  Vanderbilt University Medical Center. 이 프로토콜은 우심실 적응과 실패를 연구하기위한 대규모 동물 모델입니다. 따라서이 모델은 폐 고혈압을 치료하기위한 RV 표적 치료제 개발에 필수적입니다. 이 모델은 로드 후 오른쪽 RV를 점진적으로 증가시키며, 이는 RV 적응을 적정하기 위한 전략으로 사용될 수 있다.이전의 어떤 대형 동물 모델도 RV 표현형에 대한 이러한 통제권을 가지고 있지 않다. 외과 수술이 ?...

비디오: A Large Animal Model for Pulmonary Hypertension and Right Ventricular Failure: Left Pulmonary Artery Ligation and Progressive Main Pulmonary Artery Banding in Sheep