Method Article

Structured Exercise Regimen in Pulmonary Hypertension-Right Ventricular Failure in an Ovine Model

DOI:

10.3791/70664

⸱

May 5th, 2026

 ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  , 
1Department of Cardiac Surgery, Vanderbilt University Medical Center, 2Vanderbilt University, 3Department of Pulmonary Medicine, Vanderbilt University Medical Center, 4Department of Thoracic Surgery, Vanderbilt University Medical Center, 5Department of Biomedical Engineering, Vanderbilt University

In This Article

Summary

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This manuscript describes the structured exercise regimen developed to study the effects of exercise on the pathophysiology of pulmonary hypertension-right ventricular heart failure in an ovine model.

Abstract

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Right heart failure (RHF) is a significant cause of morbidity and mortality from pulmonary hypertension (PH). To better understand the pathophysiology and implications of exercise-induced stress, we implemented an exercise regimen to further characterize this disease using our previously developed ovine model of chronic pulmonary hypertension-right ventricular failure (PH-RVF). To this end, eight Dorset cross sheep underwent the PH-RVF model via ligation of the left pulmonary artery (LPA) and progressive occlusion of the main pulmonary artery (MPA) with an inflatable cuff. The cuff and right ventricle (RV) pressure lines were subcutaneously tunneled to a port for access. Over eight weeks, each sheep underwent a weekly exercise regimen and cuff check (CC). The exercise regimen consisted of working speeds and recovery speeds for 10 min each. During exercise, we accessed both ports to transduce cuff pressure, hemodynamics, and take RV blood gases. At exercise conclusion, the PA cuff was inflated by 150-200 mmHg to increase RV afterload. A CC and RV blood gas were performed a few days after inflation to confirm cuff pressure and ensure compensation. Over the course of eight weeks, the SvO2 remained relatively stable at maximum intensity at week 1 vs week 8: 62.7 ± 4.5% vs 69.8 ± 4.0% despite the RVSP increasing from week 1 to week 8: 78 ± 8 mmHg vs 96 ± 8 mmHg. Additionally, the distance traveled increased from week 1 to week 8: 1390 ± 297 m vs 1834 ± 189 m, despite the PA cuff pressure at week 8 being increased to 777 ± 98 mmHg. This suggests that despite increased RV afterload, exercise may aid in an adaptive response and compensation to exercise in the setting of PH-RVF. This exercise regimen provides novel information about the effects of exercise in PH-RVF and enables complex studies of exercise physiology in a large animal model of PH-RVF.

Introduction

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Pulmonary hypertension (PH) is a complex disease that causes a wide array of symptoms. Symptoms can be mild, such as dyspnea and exercise intolerance, to severe, such as respiratory decline and overt right ventricle failure (RVF)1. As the right heart afterload increases, the right ventricle (RV) begins to dilate, causing systolic dysfunction and reduced ejection fraction. This mismatch in cardiac demand and output makes activities of daily living and exercise intolerable, leading to both physical and mental decline. Previously, exercise in the setting of pulmonary hypertension was thought to be detrimental2. Recently, many studies have demonstrated that a pulmonary rehabilitation program with exercise could reduce dyspnea and improve overall quality of life both physically and mentally2,3,4. However, the study of exercise in patients with PH has been limited to those with stable disease due to potential cardiopulmonary decompensation.

Rapid decompensation is a feared complication of PH-RVF. Some people with PH may have a period of adequate compensation and only have mild symptoms, with decompensation slowly happening over a period of months to years. Others, unfortunately, may have more severe PH and can decompensate rapidly with any type of exertion. Exercise can exacerbate the disease and cause rapid cardiopulmonary collapse due to a cycle of increased RV metabolic demand, decreased ejection fraction, and ongoing RV ischemia. This is a very serious complication because patients who develop decompensated RVF require hospital admission and have mortality rates as high as 40%5. PH can affect people of any age with most cases developing from left heart disease (Group 2) and lung disease (Group 3). In rare instances, PH can develop from idiopathic causes and is more common in females in their fourth decade of life (Group 1)6. While disease progression can be tempered with medical management, there is no definitive pharmacological cure. Once patients reach end-stage RVF, the only definitive treatment is lung or heart-lung transplantation7.

Due to the morbidity and mortality of PH and subsequent RVF, we previously created a clinically relevant PH-RVF model in sheep to develop novel therapies8. In this model, we ligated the left pulmonary artery (LPA) and placed an inflatable cuff that served as a vascular occluder around the main pulmonary artery (MPA). Over the course of 8 weeks, we increased the pressure inside this cuff to decrease flow through the main pulmonary artery to increase RV afterload and induce RV remodeling. This model has now been further developed by incorporating an exercise regimen to better study the interaction between PH and exercise. This protocol is unique because it captures changes in hemodynamic parameters such as right ventricular systolic pressure (RVSP) and heart rate (HR) in real time. RV blood was used as a surrogate for mixed venous blood to analyze changes in SvO2 to compare oxygen extraction at varying exercise speeds. The exercise regimen and data acquisition methods are outlined below as a resource for investigators to further develop a better understanding of the complex pathophysiology of PH-RVF.

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Protocol

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The Institutional Animal Care and Use Committee at Vanderbilt University Medical Center approved the following protocol. The described procedures were conducted in accordance with the U.S. National Research Council’s Guide for the Care and Use of Laboratory Animals9. All sheep were Dorset cross species, female, weighed 55–65 kg, and were between 1 and 2 years of age. See Figure 1 for the full regimen timeline and exercise session protocol.

1. Treadmill acclimation

  1. After appropriate in-house quarantine and prior to surgery, begin treadmill acclimation.
  2. Transfer sheep to the exercise room via transport cage.
  3. Place the halter on the sheep and gently lead the sheep onto the treadmill.
  4. After the sheep is comfortable, have the sheep place its front legs on the treadmill crate and tie the halter to the front of the treadmill.
  5. Turn the treadmill on, turn the speed dial to its lowest position of 10, and incentivize sheep with animal-approved food.
  6. As the treadmill runs, only the sheep’s back legs should be moving as the front legs are resting on the treadmill crate (Supplementary Video 1).
  7. After a minute of walking, turn the treadmill off. Repeat turning the treadmill on and walking the sheep for a minute, and increase the speed to 30.
  8. Repeat steps 1.2–1.7 two to three times on separate days over the week before surgery.
    NOTE: Exclude the animals that show signs of severe distress or agitation during the acclimation period.

2. Surgical model to initiate the PH-RVF model

  1. Refer to our previous publication that provides details about this surgery, as well as the regular maintenance and titration of the PA cuff8. Nevertheless, this protocol includes the key steps in this first surgery so that the reader can better contextualize them during exercise.
    NOTE: Anesthesia and analgesia are provided according to the previous publication describing the surgical details, and follow the institutional guidelines.
  2. Surgical exposure
    1. Perform a mini left anterior thoracotomy.
    2. Retract the left lung and incise the pericardium longitudinally to expose the key structures: the right ventricle and pulmonary artery.
  3. LPA ligation and MPA occluder placement
    1. Dissect around the main PA and isolate it.
    2. Follow the main PA up to the bifurcation to expose the LPA. Then, isolate and ligate the LPA with umbilical tape.
    3. Place the heavy-duty silicon vascular occluder and perivascular flow probes around the MPA. This occluder is also referred to as the PA cuff.
  4. RV pressure line
    1. Follow the MPA artery down the RV outflow tract free wall to locate the RV.
    2. Select a location where a pressure line can be secured in the middle of the RV. This line will be used for transducing RV pressures and taking blood gas samples.
      ​NOTE: The blood gas taken from the RV will serve as a surrogate mixed venous gas. While blood from the PA is true mixed venous blood, blood from the RV is also a mixture of blood from the systemic circulation and the coronary sinus. In the absence of intracardiac shunting, the difference in SvO2 from a PA or RV source is negligible10,11.
  5. Port tunneling
    1. Bring the RV pressure and PA occluder lines through through one intercostal space below the incision and tunnel in the subcutaneous layer to the left dorsum of the sheep.
    2. Connect both lines to two separate ports and secure the ports under a layer of subcutaneous tissue. The PA port will be closer to the head and the RV port closer to the tail.

3. Postoperative recovery

  1. Allow the sheep to recover for 1 week postoperatively with appropriate pain management and antibiotics per protocol.
  2. Once the sheep recovers appropriately, proceed forward with the first exercise session.

4. Set up for exercise session and cuff check


NOTE: Prepare all the materials aseptically.

  1. Make heparin flushes that will be needed to power flush the RV line.
    1. Acquire 3 normal saline flushes.
    2. Remove 1 mL of normal saline from flushes.
    3. Add 1 mL of heparin (1000 units) to syringes.
    4. Repeat this process to make 3 flushes.
  2. Gather supplies for blood gas samples, a machine for data acquisition, and lab samples.
    1. Prepare two 10 mL syringes: one will be used for waste, and the other will be used to remove 10 mL of blood for labs (CBC, CMP).
    2. Prepare five 1 mL syringes for blood gas samples to be run on the arterial blood gas machine of choice.
  3. Administer heparin and alteplase.
    1. Use a 5 mL syringe to draw up 5 mL of heparin (5000 units) that will be used to lock the RV line at the end of exercise or cuff check to prevent clotting.
    2. Alteplase will only be needed if the RV line has clotted or the waveform is dampened.
    3. If alteplase is needed, it will need to be reconstituted with 2.2 mL of sterile water to make 2 mg of alteplase.
  4. Set up the PA cuff (Figure 2) line access.
    1. Acquire one 1 mL syringe and one 5 mL syringe.
    2. Using a small needle (20–22 G), fill both syringes with hypertonic saline. Use the 1 mL syringe to inflate the cuff and the 5 mL syringe to prime the line.
    3. Acquire a pressure transducer and connect the female Luer end of pressure tubing (at least 36 inches) to the male Luer end of the transducer.
    4. Make sure the bottom Luer end of the transducer is capped (Figure 2A).
    5. Connect the male end of the pressure tubing to the female Luer connection that has the white cap on a three-way stopcock.
    6. Connect a 22-G Huber needle to the male end of the three-way stopcock.
    7. Using the 5 mL syringe of hypertonic saline, access the port on the pressure transducer and open it to the Huber needle set.
    8. Flush the pressure line and Huber needle until hypertonic saline comes out of the needle.
    9. Turn the three-way stopcock toward the Huber needle to lock the stopcock to ensure no air gets into the line for access to the PA cuff (Figure 2B). Turn the three-way stopcock toward the blue cap to open access to the cuff (Figure 2C).
  5. Set up RV line access.
    1. Remove 2 mL of normal saline from a 1 L normal saline bag and add 2 mL of heparin (2000 units) for a total concentration of 2 units/mL.
    2. Place the normal saline bag into a pressure bag and an access bag with an IV spike.
    3. Turn the three-way stopcock on the pressure bag so the handle is perpendicular to the tubing, then inflate the bag using the hand pump until the pressure indicator turns green at approximately 250 mmHg.
    4. Turn the three-way stopcock toward the bag to maintain pressure and place the bag on the IV pole about 2 m above the ground.
    5. Connect the male end of the IV line on the pressure bag to the female end of the pressure transducer.
    6. Connect the female Luer end of the pressure tubing (at least 36 inches) to the male end of the transducer.
    7. Connect the male end of the pressure tubing to the female Luer connection on a three-way stopcock.
    8. Connect a 22 G Huber needle to the male end of the three-way stopcock.
    9. Open the heparin bag IV line and flush the entire line until heparinized saline comes out of the Huber needle. Lock the three-way stopcock connected to the Huber needle by turning it toward the Huber needle to ensure no air gets into the line for access to the RV port.
  6. Transfer the sheep.
    1. Transfer sheep to the exercise room via transport cage.
    2. Gently lead the sheep onto the treadmill and place a halter on the sheep.
    3. Use a halter to keep sheep at the front of the treadmill with the front legs on a small crate.
  7. Access PA and RV ports.
    1. Palpate ports and find the center of the port, and clean overlying skin thoroughly with alcohol wipes.
    2. Access the PA port with a Huber needle.
    3. Repeat steps 4.7.1 and 4.7.2 for RV port access.
  8. Final computer set up.
    1. Turn on the computer, open LabChart, and use the specifications in the supplementary methods (Supplementary File 1, Supplementary Figure 1, Supplementary Figure 2, and Supplementary Figure 3) to set up the following channels: PA Cuff, RV Pressure, RV Systolic Pressure, and Heart Rate (Figure 3A).
    2. Ensure everything is accessed correctly with the PA port closer to the head and the RV port closer to the tail (Figure 3B).
    3. Transducers should be between the computer and the sheep, with transducers at the level of the sheep’s heart (Figure 3C).
    4. Connect both pressure transducers to the interface cable and zero/calibrate the transducers as specified in the supplementary methods (Supplementary File 1, Supplementary Figure 1, Supplementary Figure 2, and Supplementary Figure 3).

5. Port access

  1. Be sure step 4.8 is complete, and click Start on the top right of the software window to start recording the data acquisition software to capture RV and PA cuff pressure waveforms at 400 Hz.
  2. Open the PA cuff by turning the stopcock up to transduce the PA cuff pressure waveform (Figure 4A) and then turn the stopcock off toward the sheep to close the waveform (Figure 4B).
    1. Keep the stopcock for PA cuff pressure off for most of the time to ensure the PA cuff does not deflate due to high pressures.
  3. Place one of the heparin flushes on the three-way stopcock for the RV line and flush line with the entire flush into the RV port.
  4. Gently draw back on the syringe until the return of dark blood.
    1. If it is difficult to draw back blood, power flush with another 5–10 mL of heparinized saline and then draw back with a large empty syringe such as 20 mL or 30 mL.
    2. If the clogging persists, inject 1–2 mg of alteplase into the line and wait about 10 min.
  5. Open the three-way stopcock connected to the RV line to transduce RV pressure and waveform. Waveforms will vary at rest, exercise, and recovery speeds (Figure 4C).

6. Exercise regimen

  1. Draw blood for the baseline blood gas at initial speed 0 by turning the stopcock off towards the transducer, and use an empty 10 mL syringe to draw back 10 mL of RV blood for waste, and then 0.2–0.4 mL of RV blood with a 1 mL syringe for the blood sample.
  2. Use the 1 mL sample of RV blood for blood gas analysis and then return 10 mL of RV blood back to the sheep.
  3. Turn the stopcock to the upward position. Flush the RV line by pulling the blue tab on the RV pressure transducer to open the valve until all blood has cleared from the pressure line.
  4. Start the first exercise speed at the treadmill knob 30, which is 0.46 m/s for 10 min.
  5. Throughout the 10 min, open the PA cuff line periodically to transduce PA cuff pressures.
  6. Near the end of 10 min, obtain blood gas by performing steps 6.1–6.3.
  7. Repeat steps 6.1–6.6 for treadmill settings of 40 (0.78 m/s), 50 (1.1 m/s), 30, and 0.
  8. At the conclusion of the exercise session, use 1 mL of hypertonic saline to inflate the cuff by 150–200 mmHg.
  9. Transduce the RV pressure for a few minutes after inflation to make sure the sheep tolerates inflation.

7. Disconnecting from ports

  1. Remove the Huber needle from the PA cuff port quickly to prevent a pressure leak of the cuff.
  2. Inject 5 mL of heparin into the RV line, but do not flush the line so that heparin stays in the RV line and port.
  3. Remove access to the RV port quickly and clean both ports with alcohol wipes.

8. Cuff check

  1. Transfer the sheep to a small enclosure.
  2. Repeat steps 4.1–4.8, omitting the extra 10 mL syringe from step 4.2.1, as labs are only obtained during exercise sessions.
  3. Repeat steps 5.1–5.5 and transduce PA cuff pressure and RV waveform.
  4. Draw blood from the RV port as outlined in steps 6.1–6.3.
  5. Open the PA cuff line to ensure that the PA cuff is retaining its pressure from the previous exercise session inflation by turning the stopcock perpendicular to the pressure line.
  6. Inflate the PA cuff as needed following step 6.8 to reinflate to the cuff pressure that was obtained at that week’s exercise session.
  7. Transduce the RV pressure for a few minutes after inflation to make sure the sheep tolerates cuff inflation.
  8. Follow steps 7.1–7.3 to conclude the cuff check.

9. Complete the entire regimen

  1. Repeat exercise and cuff checks weekly over the course of 8 weeks (Figure 1A,B).

10. Ending the exercise session early

  1. If during exercise SvO2 drops below 30% or baseline SvO2 is below 50%, immediately end the exercise session and deflate the cuff to mitigate the risk for acute irreversible decompensation of the sheep.
  2. Additionally, if the animal displays symptoms of pallor, tachypnea, grunting, teeth grinding, or mouth breathing, end the exercise session and deflate the cuff. These could be early signs of decompensation.

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Results

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All data are represented as mean±SEM. Over the course of eight weeks, the SvO2 remained relatively stable at maximum treadmill speed at week 1 vs week 8: 62.7 ± 4.5% vs 69.8 ± 4.0% (Figure 5A), despite the RVSP increasing from week 1 to week 8: 78 ± 8 mmHg vs 96 ± 8 mmHg (Figure 5B). The distance traveled during exercise increased from week 1 to week 8: 1390 ± 297 m vs 1834 ± 189 m (Figure 5C), despite the PA c...

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Discussion

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The presented sheep PH-RVF model has been updated from the previous version by combining it with a treadmill exercise platform to study the interaction between exercise and disease development8. Because each animal may respond differently to cuff inflation, for consistent exercise conditioning across animals, treadmill speeds during an exercise session were adjusted to include working speeds and recovery speeds. Increasing treadmill speed gradually with three progressive working speeds and then tw...

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Disclosures

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The authors have no conflicts of interest to disclose.

Acknowledgements

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This work was funded by the following institutions and awards: National Institutes of Health R01HL171577, National Institute of General Medical Sciences of the NIH grant T32 GM007347, National Institutes of Health grant T32 HL160508, Vanderbilt Faculty Research Scholar Award, American Heart Association Second Century Early Faculty Independence Award 24SCEFIA1255079, Vanderbilt University Medical Center Cardiothoracic Research Fund, Vanderbilt University Medical Center Mrs. Shelley F. Kleiner and Dr. Fredric Kleiner Fund, Vanderbilt University Medical Center Ms. Dorothy Thomas Research Fund, and the Vanderbilt University Medical Center David M. Livingston Lung Transplant Memorial Fund. Additionally, this work would not have been possible without the Vanderbilt University Animal Care and Use Program and the staff of the S.R. Light Laboratory: Jamie Adcock, Susan Fultz, Azia Tanks, and Eiman Barsoum for their technical support.

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Materials

List of materials used in this article
NameCompanyCatalog NumberComments
0.9% Normal Saline, 1000 mLBaxter Healthcare Corp0338-0049-04Medication, Chronic PH
16 mm Heavy Duty Occluder with actuating tubingAccess TechnologiesOC-16HDDisposable, Chronic PH
70% isopropyl alcohol prep padsMedlineMDS090670Disposable, Chronic PH
Aluminum Lamb and Goat TreadmillLivestock Performance Products DC314Equipment
Bags, Infusion: Nonsterile Novaplus Infusion Bag, 500 mLMedlineTCV4005HDisposable, Chronic PH
Blue ClaveMedlineBOPC1000Disposable, Chronic PH
Cathflo Activase (alteplase) 2 mgCathfloNDC 50242004164Medication, Chronic PH
Computer Dell Lattitude 7400Equipment
Data acquisition hardwareADInstrumentsPowerLab 16/30Equipment
EPOC Point-of-care blood gas analyzerSiemens HealthineersSiemens-Epoc-REquipment
Flow MeterTransonichttps://www.transonic.com/tubing-flow-meters-manufacturers
Gauze Sponges: Sterile X-ray Compatible Gauze Sponges, 16-Ply, 4” × 4”MedlinePRM21430LFHDisposable, Chronic PH
GEM 7000 with iQM3Werfen6000228442Equipment
HeparinFresenius Kabi63323-540-31Medication, Chronic PH
Hospira Primary IV Sets, 80”Patterson Veterinary07-835-0123Disposable, Chronic PH
Hypertonic saline 3%Baxter Healthcare Corp.0338-0054-03Medication, Chronic PH
Hypodermic Needle with Bevel and Regular Wall, 20 G × 1”MedlineB-D305175ZDisposable, Chronic PH
Interface Cable, Edwards LifeScience Transducer to ADInstruments Bridge AmplifierFogg System0395-2434Equipment
Labchart softwareADInstrumentsLabchart 8Equipment
Needles: Hypodermic Needle with Regular Bevel, Sterile, 18 G × 1.5”MedlineB-D305185ZDisposable, Chronic PH
Octal Bridge AmplifierADInstrumentsFE228Equipment
Port-A-Cath Huber Needle, Straight, 22 G × 1-1/2”MedlineAAKM21200724Disposable, Chronic PH
Sheep HalterWeaver Livestock 35-7840-S20Equipment
Sterile Leur-Lock Syringe, 1 mLFisher ScientificBD309628Disposable, Chronic PH
Sterile Luer-Lock Syringe, 10 mLMedlineSYR110010ZDisposable, Chronic PH
Sterile Luer-Lock Syringe, 3 mLMedlineSYR103010ZDisposable, Chronic PH
Sterile Luer-Lock Syringe, 5 mLMedlineSYR105010ZDisposable, Chronic PH
Sterile WaterFresenius Kabi918550Medication
Stopcock: 3-Way Stopcock with Handle in OFF Position, Rotating Adaptor Male Collar Fitting, 45 PSIMedlineDYNJSC301Disposable, Chronic PH
Transducer clipEdwards LifeScienceTCLIP05Equipment
Transonic Perivascular Flow Probe (PAU Series)ADInstrumentshttps://www.adinstruments.com/products/perivascular-flowprobes
Transport Cage/ Large Animal CagingAncare ANAT305660SSEquipment
Trigger Aneroid Gauge (Sphygmomanometer)Patterson Veterinary07-815-0464Equipment
TruWave Disposable Pressure Transducer Kits by Edwards LifesciencesMedlineVSYPX260Disposable, Chronic PH
Tubing: Pressure Monitoring Tubing with Fixed Male Luer Lock and Female Fitting, Low Pressure, 72” LMedlineDYNJPMTBG72MFDisposable, Chronic PH
Umbilical Tape, Cotton, 3-Strand, 1/8 x 36"MedlineDYNJPMTBG72MFDisposable, Chronic PH

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Tags

Chronic Pulmonary HypertensionRight Heart FailureHemodynamic MonitoringPulmonary Artery CuffExercise PhysiologyRV Blood Gases

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