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.

<ol><li>Campo, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Outcomes+of+hospitalization+for+right+heart+failure+in+pulmonary+arterial+hypertension%5BTitle%5D)+AND+%22European+Respiratory+Journal%22%5BJournal%5D)">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/pubmed?term=((Causes+and+circumstances+of+death+in+pulmonary+arterial+hypertension%5BTitle%5D)+AND+%22American+Journal+of+Respiratory+and+Critical+Care+Medicine%22%5BJournal%5D)">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/pubmed?term=((Molecular+and+physiological+characterization+of+RV+remodeling+in+a+murine+model+of+pulmonary+stenosis%5BTitle%5D)+AND+%22American+Journal+of+Physiology-+Heart+and+Circulatory+Physiology%22%5BJournal%5D)">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/pubmed?term=((Large+animal+model+of+chronic+pulmonary+hypertension%5BTitle%5D)+AND+%22ASAIO+Journal%22%5BJournal%5D)">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/pubmed?term=((A+low+mortality+model+of+chronic+pulmonary+hypertension+in+sheep%5BTitle%5D)+AND+%22Journal+of+Surgical+Research%22%5BJournal%5D)">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/pubmed?term=((Chronic+thromboembolic+pulmonary+hypertension+and+assessment+of+right+ventricular+function+in+the+piglet%5BTitle%5D)+AND+%22Journal+of+Visualized+Experiments%3A+JoVE%22%5BJournal%5D)">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/pubmed?term=((Swine+model+of+chronic+postcapillary+pulmonary+hypertension+with+right+ventricular+remodeling%3A+Long-term+characterization+by+cardiac+catheterization%2C+magnetic+resonance%2C+and+pathology%5BTitle%5D)+AND+%22Journal+of+Cardiovascular+Translational+Research%22%5BJournal%5D)">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/pubmed?term=((Large+animal+models+of+heart+failure%3A+A+translational+bridge+to+clinical+success%5BTitle%5D)+AND+%22JACC%3A+Basic+to+Translational+Science%22%5BJournal%5D)">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/pubmed?term=((Left+pulmonary+artery+ligation+and+chronic+pulmonary+artery+banding+model+for+inducing+right+ventricular+-+pulmonary+hypertension+in+sheep%5BTitle%5D)+AND+%22ASAIO+Journal+%28American+Society+for+Artificial+Internal+Organs%3A+1992%22%5BJournal%5D)">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/pubmed?term=((Progression+toward+decompensated+right+ventricular+failure+in+the+ovine+pulmonary+hypertension+model%5BTitle%5D)+AND+%22ASAIO+Journal+%28American+Society+for+Artificial+Internal+Organs%3A+1992%22%5BJournal%5D)">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/pubmed?term=((Piglet+model+of+chronic+pulmonary+hypertension%5BTitle%5D)+AND+%22Pulmonary+Circulation%22%5BJournal%5D)">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/pubmed?term=((Right+ventricular+plasticity+in+a+porcine+model+of+chronic+pressure+overload%5BTitle%5D)+AND+%22Journal+of+Heart+and+Lung+Transplantation%22%5BJournal%5D)">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/pubmed?term=((Incidence+of+pleural+effusions+in+idiopathic+and+familial+pulmonary+arterial+hypertension+patients%5BTitle%5D)+AND+%22Chest%22%5BJournal%5D)">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/pubmed?term=((Frequency+of+pleural+effusions+in+patients+with+pulmonary+arterial+hypertension+associated+with+connective+tissue+diseases%5BTitle%5D)+AND+%22Chest%22%5BJournal%5D)">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/pubmed?term=((Pleural+effusions+occurring+with+right+heart+failure%5BTitle%5D)+AND+%22Current+Opinion+in+Pulmonary+Medicine%22%5BJournal%5D)">Pleural effusions occurring with right heart failure.</a> Current Opinion in Pulmonary Medicine. 17 (4), 226-231 (2011).</li>
<li>Holt, T. N. 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. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Progressive+right+ventricular+dysfunction+in+patients+with+pulmonary+arterial+hypertension+responding+to+therapy%5BTitle%5D)+AND+%22Journal+of+the+American+College+of+Cardiology%22%5BJournal%5D)">Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.</a> Journal of the American College of Cardiology. 58 (24), 2511-2519 (2011).</li>
</ol>

The authors have no conflicts of interest to disclose.

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><tbody><tr><td>&amp;nbsp;0.9% Sodium Chloride Irrigation Pour Bottle by Baxter Healthcare, 1000 mL</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;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>&amp;nbsp;OC-16HD</td><td>Surgical Disposable</td></tr><tr><td>3-mL Skin Prep Applicator</td><td>Medline</td><td>&amp;nbsp;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>07-835-7776</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&quot;, with 0.24 cm Shaft</td><td>Medline</td><td>&amp;nbsp;VALE15516</td><td>Surgical Disposable</td></tr><tr><td>Blades: Stainless-Steel Sterile Surgical Blade, Size #10</td><td>Medline</td><td>&amp;nbsp;B-D371210</td><td>Surgical Disposable</td></tr><tr><td>Blades: Stainless-Steel Sterile Surgical Blade, Size #11</td><td>Medline</td><td>&amp;nbsp;B-D371211</td><td>Surgical Disposable</td></tr><tr><td>Blades: Stainless-Steel Sterile Surgical Blade, Size #15</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;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>&amp;nbsp;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&amp;rsquo;&amp;rsquo;</td><td>V. Mueller</td><td>CH5906</td><td>Surgical Instrument</td></tr><tr><td>Debakey vascular tissue forceps 7 3/4&amp;rsquo;&amp;rsquo;</td><td>V. Mueller</td><td>CH5902</td><td>Surgical Instrument</td></tr><tr><td>Debakey vascular tissue forceps, 9&amp;rsquo;&amp;rsquo;</td><td>V. Mueller</td><td>CH5904</td><td>Surgical Instrument</td></tr><tr><td>Electrosurgical Generator</td><td>Covidien</td><td>&amp;nbsp;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&amp;rdquo; x 13&amp;rdquo;</td><td>V. Mueller</td><td>SU3340</td><td>Surgical Instrument</td></tr><tr><td>Flexsteel ribbon retractor, 2&amp;rdquo; x 13&amp;rdquo;</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&quot; x 4&quot;</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;TP-400</td><td>Equipment</td></tr><tr><td>Heparin</td><td>Fresenius Kabi,</td><td>&amp;nbsp;63323-540-31</td><td>Medication, Chronic PH</td></tr><tr><td>Hospira Primary IV Sets, 80&quot;</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>&amp;nbsp;0338-0054-03</td><td>Medication, Chronic PH</td></tr><tr><td>Hypodermic Needle with Bevel and Regular Wall, 20 G x 1&quot;</td><td>Medline</td><td>B-D305175Z</td><td>Disposable, Chronic PH</td></tr><tr><td>Interface Cable, Edwards LifeScience Transducer to ADInstruments&amp;nbsp; 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>&amp;nbsp;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&amp;rdquo;</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>&amp;nbsp;49427-434-04</td><td>Medication, Chronic PH</td></tr><tr><td>Ligaclip Multiple-Clip Appliers by Ethicon</td><td>Medline</td><td>&amp;nbsp;ETHMCS20</td><td>Surgical Disposable</td></tr><tr><td>Loop, Vessel, Mini, Red, 2/pk, Sterile</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;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&amp;rdquo;</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>&amp;nbsp;ARW45703XP1AH</td><td>Surgical Disposable</td></tr><tr><td>Multi-Parameter Vital Signs Monitor</td><td>Smiths Medical</td><td>&amp;nbsp;SurgiVet Advisor 3</td><td>Equipment</td></tr><tr><td>Needles: Hypodermic Needle with Regular Bevel, Sterile, 18 G x 1.5&quot;</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;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>&amp;nbsp;SWD514604H</td><td>Surgical Disposable</td></tr><tr><td>Perma-Hand Black Braided Silk:&amp;nbsp; 2-0 SH Taperpoint Needle, Control Release, 30&quot;</td><td>Medline</td><td>&amp;nbsp; ETHD8552</td><td>Surgical Disposable</td></tr><tr><td>Perma-Hand Suture, Black Braided, Size 0, 6 x 30&amp;rdquo;</td><td>Medline</td><td>&amp;nbsp; ETHA306H</td><td>Surgical Disposable</td></tr><tr><td>Perma-Hand Suture, Black Braided, Size 4-0, 12 x 30&quot;</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;SWDE7509</td><td>Surgical Disposable</td></tr><tr><td>Port-A-Cath Huber Needle, Straight, 22 G x 1-1/2&quot;</td><td>Medline</td><td>AAKM21200724</td><td>Disposable, Chronic PH</td></tr><tr><td>PROLENE Monofilament Suture, Blue, Size 4-0, 36&quot;, Double Arm, RB-1 Needle</td><td>Medline</td><td>&amp;nbsp;ETHD7143</td><td>Surgical Disposable</td></tr><tr><td>PROLENE Polypropylene Monofilament Suture, Blue, Double-Armed, RB-1 Needle, Size 5-0, 24&quot;</td><td>Medline</td><td>&amp;nbsp;ETH8555H</td><td>Surgical Disposable</td></tr><tr><td>Regional Block Needles, 22-gauge</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;STAPLER35W</td><td>Surgical Disposable</td></tr><tr><td>Sphygmomanometer</td><td>Patterson Veterinary</td><td>07-815-0464</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&quot; x 18&quot;, 5/Pack</td><td>Medline</td><td>&amp;nbsp;MDS241518HH</td><td>Surgical Disposable</td></tr><tr><td>Sponge, Peanut: X-Ray Detectable Sterile Peanut Sponge, Small, 3/8&quot;</td><td>Medline</td><td>&amp;nbsp;MDS72038</td><td>Surgical Disposable</td></tr><tr><td>Sterile Disposable Deluxe OR Towel, Blue, 17&#039;&#039; x 27&#039;&#039;, 2/Pack</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;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>&amp;nbsp;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>&amp;nbsp;SYR110010Z</td><td>Surgical Disposable</td></tr><tr><td>Thoracic Catheter, Straight, 28 Fr x 20&quot;</td><td>Medline</td><td>SWD570549H</td><td>Surgical Disposable</td></tr><tr><td>Three-quarter surgical drape</td><td>Medline</td><td>&amp;nbsp;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&quot; Bronze-Colored Tubes and 1 Snare, 12 French</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;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&quot; x 12&#039;</td><td>Medline</td><td>&amp;nbsp;OR612</td><td>Surgical Disposable</td></tr><tr><td>Tubing: Pressure Monitoring Tubing with Fixed Male Luer Lock and Female Fitting, Low Pressure, 72&quot; 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&quot; 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&quot;</td><td>Medline</td><td>&amp;nbsp;ETHU12TH</td><td>Surgical Disposable</td></tr><tr><td>Valleylab Button Switch Pencil</td><td>Medline</td><td>&amp;nbsp;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>&amp;nbsp;Matrx VMC</td><td>Equipment</td></tr><tr><td>Veterinary Anesthesia Ventilator</td><td>Hallowell EMC</td><td>&amp;nbsp;Model 2000</td><td>Equipment</td></tr><tr><td>Vicryl: Undyed Coated Vicryl 0 CT-1 36&quot; Suture</td><td>Medline</td><td>&amp;nbsp;ETHVCP946H</td><td>Surgical Disposable</td></tr><tr><td>Vicryl: Undyed Coated Vicryl 2 TP-1 Taper 54&quot; Suture</td><td>Medline</td><td>&amp;nbsp;ETHVCP880T</td><td>Surgical Disposable</td></tr><tr><td>Vicryl: Undyed Coated Vicryl 2-0 CT-1 18&quot; Suture</td><td>Medline</td><td>&amp;nbsp;ETHVCP739D</td><td>Surgical Disposable</td></tr><tr><td>Vital crile-wood needle holder, 10-3/8&amp;rdquo;</td><td>V. Mueller</td><td>CH2427</td><td>Surgical Instrument</td></tr><tr><td>Vital mayo-hegar needle holder, 7-1/4&amp;rdquo;</td><td>V. Mueller</td><td>CH2417</td><td>Surgical Instrument</td></tr><tr><td>Vital metzenbaum dissecting scissors, 14&amp;rsquo;&amp;rsquo;</td><td>V. Mueller</td><td>CH2009</td><td>Surgical Instrument</td></tr><tr><td>Vital metzenbaum dissecting scissors, 9&amp;rdquo;</td><td>V. Mueller</td><td>CH2006</td><td>Surgical Instrument</td></tr><tr><td>Vital ryder needle holder, 9&amp;rdquo;</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>&amp;nbsp;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 ...

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

Research

JoVE Journal

Bioengineering

3.0K Views.  Vanderbilt University Medical Center. Dit protocol is een groot diermodel voor het bestuderen van aanpassing en falen van de rechterventrikel. Dit model is daarom van vitaal belang voor het ontwikkelen van RV-gerichte therapieën om pulmonale hypertensie te behandelen. Dit model verhoogt geleidelijk de juiste RV na belasting die kan worden gebruikt als een strategie om de RV-aanpassing te titreren.Geen enkele eerdere grote diermodellen hebben deze controle over het RV-fenotype. Die chirurgische ingreep zal worden aangetoon...

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

Chronic Thromboembolic Pulmonary Hypertension and Assessment of Right Ventricular Function in the Piglet

An original piglet model of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) associated with chronic Right Ventricular (RV) dysfunction is described. Pulmonary Hypertension (PH) was induced in 3-week-old piglets by a progressive obstruction of the pulmonary vascular bed. A ligation of the left Pulmonary Artery (PA) was performed first through a mini-thoracotomy. Second, weekly embolizations of the right lower pulmonary lobe were done under fluoroscopic guidance with n-butyl-2-cyanoacrylate during 5 weeks. Mean Pulmonary Arterial Pressure (mPAP) measured by ritght heart catheterism, increased progressively, as well as Right Atrial pressure and Pulmonary Vascular Resistances (PVR) after 5 weeks compared to sham animals. Right Ventricular (RV) structural and functional remodeling were assessed by transthoracic echocardiography (RV diameters, RV wall thickness, RV systolic function). RV elastance and RV-pulmonary coupling were assessed by Pressure-Volume Loops (PVL) analysis with conductance method. Histologic study of the lung and the right ventricle were also performed. Molecular analyses on RV fresh tissues could be performed through repeated transcutaneous endomyocardial biopsies. Pulmonary microvascular disease in obstructed and unobstructed territories was studied from lung biopsies using molecular analyses and pathology. Furthermore, the reliability and the reproducibility was associated with a range of PH severity in animals. Most aspects of the human CTEPH disease were reproduced in this model, which allows new perspectives for the understanding of the underlying mechanisms (mitochondria, inflammation) and new therapeutic approaches (targeted, cellular or gene therapies) of the overloaded right ventricle but also pulmonary microvascular disease.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Right Ventricular (RV) dysfunction were induced in piglets by progressive obstruction of the pulmonary arteries. Consequences were remarkably similar to those observed in CTEPH patients. This animal model would be a very useful tool for pathophysiology and therapeutic experiments on CTEPH and RV failure.

An original piglet model of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) associated with chronic Right Ventricular (RV) dysfunction is described. ...

Medicine

Invasive Hemodynamic Monitoring of Aortic and Pulmonary Artery Hemodynamics in a Large Animal Model of ARDS

One of the leading causes of morbidity and mortality in patients with heart failure is right ventricular (RV) dysfunction, especially if it is due to pulmonary hypertension. For a better understanding and treatment of this disease, precise hemodynamic monitoring of left and right ventricular parameters is important. For this reason, it is essential to establish experimental pig models of cardiac hemodynamics and measurements for research purpose. 
This article shows the induction of ARDS by using oleic acid (OA) and consequent right ventricular dysfunction, as well as the instrumentation of the pigs and the data acquisition process that is needed to assess hemodynamic parameters. To achieve right ventricular dysfunction, we used oleic acid (OA) to cause ARDS and accompanied this with pulmonary artery hypertension (PAH). With this model of PAH and consecutive right ventricular dysfunction, many hemodynamic parameters can be measured, and right ventricular volume load can be detected. 
All vital parameters, including respiratory rate (RR), heart rate (HR) and body temperature were recorded throughout the whole experiment. Hemodynamic parameters including femoral artery pressure (FAP), aortic pressure (AP), right ventricular pressure (peak systolic, end systolic and end diastolic right ventricular pressure), central venous pressure (CVP), pulmonary artery pressure (PAP) and left arterial pressure (LAP) were measured as well as perfusion parameters including ascending aortic flow (AAF) and pulmonary artery flow (PAF). Hemodynamic measurements were performed using transcardiopulmonary thermodilution to provide cardiac output (CO). Furthermore, the PiCCO2 system (Pulse Contour Cardiac Output System 2) was used to receive parameters such as stroke volume variance (SVV), pulse pressure variance (PPV), as well as extravascular lung water (EVLW) and global end-diastolic volume (GEDV). Our monitoring procedure is suitable for detecting right ventricular dysfunction and monitoring hemodynamic findings before and after volume administration.

We present a protocol of creating right ventricular dysfunction in a pig model by inducing ARDS. We demonstrate invasive monitoring of left and right ventricular cardiac output using flow probes around the aorta and the pulmonary artery, as well as blood pressure measurements in the aorta and pulmonary artery.

One of the leading causes of morbidity and mortality in patients with heart failure is right ventricular (RV) dysfunction, especially if it is due to ...

A Pulmonary Trunk Banding Model of Pressure Overload Induced Right Ventricular Hypertrophy and Failure

Right ventricular (RV) failure induced by sustained pressure overload is a major contributor to morbidity and mortality in several cardiopulmonary disorders. Reliable and reproducible animal models of RV failure are therefore warranted in order to investigate disease mechanisms and effects of potential therapeutic strategies. Banding of the pulmonary trunk is a common method to induce isolated RV hypertrophy but in general, previously described models have not succeeded in creating a stable model of RV hypertrophy and failure.
We present a rat model of pressure overload induced RV hypertrophy caused by pulmonary trunk banding (PTB) that enables different phenotypes of RV hypertrophy with and without RV failure. We use a modified ligating clip applier to compress a titanium clip around the pulmonary trunk to a pre-set inner diameter. We use different clip diameters to induce different stages of disease progression from mild RV hypertrophy to decompensated RV failure.
RV hypertrophy develops consistently in rats subjected to the PTB procedure and depending on the diameter of the applied banding clip, we can accurately reproduce different disease severities ranging from compensated hypertrophy to severe decompensated RV failure with extra-cardiac manifestations.
The presented PTB model is a valid and robust model of pressure overload induced RV hypertrophy and failure that has several advantages to other banding models including high reproducibility and the possibility of inducing severe and decompensated RV failure.

We present a surgical method to induce right ventricular hypertrophy and failure in rats.

Right ventricular (RV) failure induced by sustained pressure overload is a major contributor to morbidity and mortality in several cardiopulmonary ...

Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension

The development of acute right heart failure (ARHF) in the context of chronic pulmonary hypertension (PH) is associated with poor short-term outcomes. The morphological and functional phenotyping of the right ventricle is of particular importance in the context of hemodynamic compromise in patients with ARHF. Here, we describe a method to induce ARHF in a previously described large animal model of chronic PH, and to phenotype, dynamically, right ventricular function using the gold standard method (i.e., pressure-volume PV loops) and with a non-invasive clinically available method (i.e., echocardiography). Chronic PH is first induced in pigs by left pulmonary artery ligation and right lower lobe embolism with biological glue once a week for 5 weeks. After 16 weeks, ARHF is induced by successive volume loading using saline followed by iterative pulmonary embolism until the ratio of the systolic pulmonary pressure over systemic pressure reaches 0.9 or until the systolic systemic pressure decreases below 90 mmHg. Hemodynamics are restored with dobutamine infusion (from 2.5 &#181;g/kg/min to 7.5 &#181;g/kg/min). PV-loops and echocardiography are performed during each condition. Each condition requires around 40 minutes for induction, hemodynamic stabilization and data acquisition. Out of 9 animals, 2 died immediately after pulmonary embolism and 7 completed the protocol, which illustrates the learning curve of the model. The model induced a 3-fold increase in mean pulmonary artery pressure. The PV-loop analysis showed that ventriculo-arterial coupling was preserved after volume loading, decreased after acute pulmonary embolism and was restored with dobutamine. Echocardiographic acquisitions allowed to quantify right ventricular parameters of morphology and function with good quality. We identified right ventricular ischemic lesions in the model. The model can be used to compare different treatments or to validate non-invasive parameters of right ventricular morphology and function in the context of ARHF.

We present a protocol to induce and phenotype an acute right heart failure in a large animal model with chronic pulmonary hypertension. This model can be used to test therapeutic interventions, to develop right heart metrics&#160;or to improve the understanding of acute right heart failure pathophysiology.

The development of acute right heart failure (ARHF) in the context of chronic pulmonary hypertension (PH) is associated with poor short-term outcomes. The ...

The Left Pneumonectomy Combined with Monocrotaline or Sugen as a Model of Pulmonary Hypertension in Rats

In this protocol, we detail the correct procedural steps and necessary precautions to successfully perform a left pneumonectomy and induce PAH in rats with the additional administration of monocrotaline (MCT) or SU5416 (Sugen). We also compare these two models to other PAH models commonly used in research. In the last few years, the focus of animal PAH models has moved towards studying the mechanism of angioproliferation of plexiform lesions, in which the role of increased pulmonary blood flow is considered as an important trigger in the development of severe pulmonary vascular remodeling. One of the most promising rodent models of increased pulmonary flow is the unilateral left pneumonectomy combined with a "second hit" of MCT or Sugen. The removal of the left lung leads to increased and turbulent pulmonary blood flow and vascular remodeling. Currently, there is no detailed procedure of the pneumonectomy surgery in rats. This article details a step-by-step protocol of the pneumonectomy surgical procedure and post-operative care in male Sprague-Dawley rats. Briefly, the animal is anesthetized and the chest is opened. Once the left pulmonary artery, pulmonary vein, and bronchus are visualized, they are ligated and the left lung is removed. The chest then closed and the animal recovered. Blood is forced to circulate only on the right lung. This increased vascular pressure leads to a progressive remodeling and occlusion of small pulmonary arteries. The second hit of MCT or Sugen is used one week post-surgery to induce endothelial dysfunction. The combination of increased blood flow in the lung and endothelial dysfunction produces severe PAH. The primary limitation of this procedure is that it requires general surgical skills.

The rodent left pneumonectomy is a valuable technique in pulmonary hypertension research. Here, we present a protocol to describe the rat pneumonectomy procedure and postoperative care to ensure minimal morbidity and mortality.

In this protocol, we detail the correct procedural steps and necessary precautions to successfully perform a left pneumonectomy and induce PAH in rats ...

Quantification of Biventricular Function and Morphology by Cardiac Magnetic Resonance Imaging in Mice with Pulmonary Artery Banding

Right ventricular (RV) function and failure are major determinants of outcome in acquired and congenital heart diseases, including pulmonary hypertension. Assessment of RV function and morphology is complex, partly due to the complex shape of the RV. Currently, cardiac magnetic resonance (CMR) imaging is the golden standard for noninvasive assessment of RV function and morphology. The current protocol describes CMR imaging in a mouse model of RV pressure load induced by pulmonary artery banding (PAB). PAB is performed by placing a 6-0 suture around the pulmonary artery over a 23 G needle. The PAB gradient is determined using echocardiography at 2 and 6 weeks. At 6 weeks, the right and left ventricular morphology and function is assessed by measuring both end-systolic and end-diastolic volumes and mass by ten to eleven cine slices 1 mm thick using a 9.4 T magnetic resonance imaging scanner equipped with a 1,500 mT/m gradient. Representative results show that PAB induces a significant increase in RV pressure load, with significant effects on biventricular morphology and RV function. It is also shown that at 6 weeks of RV pressure load, cardiac output is maintained. Presented here is a reproducible protocol for the quantification of biventricular morphology and function in a mouse model of RV pressure load and may serve as a method for experiments exploring determinants of RV remodeling and dysfunction.

To understand the pathophysiology of right ventricular (RV) adaptation to abnormal loading, experimental models are crucial. However, assessment of RV dimensions and function is complex and challenging. This protocol provides a method to perform cardiac magnetic resonance imaging (CMR) as a noninvasive benchmark procedure in mice subjected to RV pressure load.

Right ventricular (RV) function and failure are major determinants of outcome in acquired and congenital heart diseases, including pulmonary hypertension. ...

Chronic Ovine Model of Right Ventricular Failure and Functional Tricuspid Regurgitation

The pathophysiology of severe functional tricuspid regurgitation (FTR) associated with right ventricular dysfunction is poorly understood, leading to suboptimal clinical results. We set out to establish a chronic ovine model of FTR and right heart failure to investigate the mechanisms of FTR. Twenty adult male sheep (6-12 months old, 62 &#177; 7 kg) underwent a left thoracotomy and baseline echocardiography. A pulmonary artery band (PAB) was placed and cinched around the main pulmonary artery (PA) to at least double the systolic pulmonary artery pressure (SPAP), inducing right ventricular (RV) pressure overload and signs of RV dilatation. PAB acutely increased the SPAP from 21 &#177; 2 mmHg to 62 &#177; 2 mmHg. The animals were followed for 8 weeks, symptoms of heart failure were treated with diuretics, and surveillance echocardiography was used to assess for pleural and abdominal fluid collection. Three animals died during the follow-up period due to stroke, hemorrhage, and acute heart failure. After 2 months, a median sternotomy and epicardial echocardiography were performed. Of the surviving 17 animals, 3 developed mild tricuspid regurgitation, 3 developed moderate tricuspid regurgitation, and 11 developed severe tricuspid regurgitation. Eight weeks of pulmonary artery banding resulted in a stable chronic ovine model of right ventricular dysfunction and significant FTR. This large animal platform can be used to further investigate the structural and molecular basis of RV failure and functional tricuspid regurgitation.

Right ventricular failure and functional tricuspid regurgitation are associated with left-sided heart disease and pulmonary hypertension, which contribute significantly to morbidity and mortality in patients. Establishing a chronic ovine model to study right ventricular failure and functional tricuspid regurgitation will help in understanding their mechanisms, progression, and possible treatments.

The pathophysiology of severe functional tricuspid regurgitation (FTR) associated with right ventricular dysfunction is poorly understood, leading to ...

Ascending Aortic Banding for Studying Pressure-Overload Induced Heart Failure

A Minimally Invasive Model of Aortic Stenosis in Swine

Large animal models of heart failure play an essential role in the development of new therapeutic interventions due to their size and physiological similarities to humans. Efforts have been dedicated to creating a model of pressure-overload induced heart failure, and ascending aortic banding while still supra-coronary and not a perfect mimic of aortic stenosis in humans, closely resembling the human condition.
The purpose of this study is to demonstrate a minimally invasive approach to induce left ventricular pressure overload by placing an aortic band, precisely calibrated with percutaneously introduced high-fidelity pressure sensors. This method represents a refinement of the surgical procedure (3Rs), resulting in homogenous trans-stenotic gradients and reduced intragroup variability. Additionally, it enables swift and uneventful animal recovery, leading to minimal mortality rates. Throughout the study, animals were followed for up to 2 months after surgery, employing transthoracic echocardiography and pressure-volume loop analysis. However, longer follow-up periods can be achieved if desired. This large animal model proves valuable for testing new drugs, particularly those targeting hypertrophy and the structural and functional alterations associated with left ventricular pressure overload.

Author Spotlight: Development of a Minimally Invasive Large-Animal Model for Reliable and Reproducible Cardiovascular Research 

This protocol describes a minimally invasive surgical procedure for ascending aortic banding in swine.

Large animal models of heart failure play an essential role in the development of new therapeutic interventions due to their size and physiological ...

Creating a Murine Model of RV Hypertrophy and Failure by Pulmonary Trunk Banding

A Murine Model of Pressure Overload-Induced Right Ventricular Hypertrophy and Failure by Pulmonary Trunk Banding

Right ventricular (RV) failure caused by pressure overload is strongly associated with morbidity and mortality in a number of cardiovascular and pulmonary diseases. The pathogenesis of RV failure is complex and remains inadequately understood. To identify new therapeutic strategies for the treatment of RV failure, robust and reproducible animal models are essential. Models of pulmonary trunk banding (PTB) have gained popularity, as RV function can be assessed independently of changes in the pulmonary vasculature.
In this paper, we present a murine model of RV pressure overload induced by PTB in 5-week-old mice. The model can be used to induce different degrees of RV pathology, ranging from mild RV hypertrophy to decompensated RV failure. Detailed protocols for intubation, PTB surgery, and phenotyping by echocardiography are included in the paper. Furthermore, instructions for customizing instruments for intubation and PTB surgery are given, enabling fast and inexpensive reproduction of the PTB model.
Titanium ligating clips were used to constrict the pulmonary trunk, ensuring a highly reproducible and operator-independent degree of pulmonary trunk constriction. The severity of PTB was graded by using different inner ligating clip diameters (mild: 450 &#181;m and severe: 250 &#181;m). This resulted in RV pathology ranging from hypertrophy with preserved RV function to decompensated RV failure with reduced cardiac output and extracardiac manifestations. RV function was assessed by echocardiography at 1 week and 3 weeks after surgery. Examples of echocardiographic images and results are presented here. Furthermore, results from right heart catheterization and histological analyses of cardiac tissue are shown.

Author Spotlight: Investigating the Underlying Mechanisms of Right Ventricular Failure in Pulmonary Hypertension

We describe a murine model of right ventricular pressure overload-induced by pulmonary trunk banding. Detailed protocols for intubation, surgery, and phenotyping by echocardiography are included in the paper. Custom-made instruments are used for intubation and surgery, allowing for fast and inexpensive reproduction of the model.

Right ventricular (RV) failure caused by pressure overload is strongly associated with morbidity and mortality in a number of cardiovascular and pulmonary ...

Optimizing Pulmonary Artery Banding for Consistent Right Heart Failure Induction

Rat Model of Right-Sided Cardiac Remodeling and Arrhythmia Using Pulmonary Artery Banding

Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle pressure overload and progressive right heart failure (RHF). RHF can be identified by right-sided cardiac hypertrophy and dilation associated with abnormal myocardial function affecting the RV and the right atrium (RA). We recently demonstrated that severe RHF is accompanied by an increased risk of atrial inflammation, atrial fibrosis, and atrial fibrillation (AF), the most common type of cardiac arrhythmia (CA). Recent studies have shown that RV and RA inflammation plays an important role in the arrhythmogenesis of CA, including AF. However, the impact of inflammation in the development of CA and AF in RHF is poorly described.
Experimental models of RHF are required to better understand the association between right-sided myocardial inflammation and CA. The rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH) is well-established to provoke RHF. However, MCT triggers severe pneumo-toxicity and pulmonary inflammation. Hence, MCT-induced RHF does not help to distinguish whether the subsequent myocardial inflammation originates from the RHF per se or circulating inflammatory signals secreted by the injured lung.
In this article, a mechanical method involving pulmonary artery trunk banding (PAB) was used to provoke right-sided cardiac arrhythmogenesis. The PAB consists of performing a permanent suture of the pulmonary artery trunk for 3 weeks. Such an approach generates increased right-sided pressure overload. At D21 post-PAB, the suture results in hypertrophied, dilated, and inflamed RV and RA. The PAB-induced RHF is also accompanied by vulnerability to ventricular and atrial arrhythmias, including AF.

Right heart failure (RHF) is characterized by right-sided cardiac dilation and hypertrophy, leading to ventricular and atrial malfunction. Cardiopulmonary conditions associated with RHF are accompanied by an increased risk for cardiac arrhythmias. This article describes a standardized model of pulmonary artery banding-induced RHF associated with enhanced ventricular and atrial arrhythmogenesis.

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

Samenvatting

Meer video's verkennen