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

Summary

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

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 S_vO₂ 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

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, ma....

Protocol

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 t....

Results

All data are represented as mean±SEM. Over the course of eight weeks, the S_vO₂ 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.......

Discussion

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.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
0.9% Normal Saline, 1000 mL	Baxter Healthcare Corp	0338-0049-04	Medication, Chronic PH
16 mm Heavy Duty Occluder with actuating tubing	Access Technologies	OC-16HD	Disposable, Chronic PH
70% isopropyl alcohol prep pads	Medline	MDS090670	Disposable, Chronic PH
Aluminum Lamb and Goat Treadmill	Livestock Performance Products	DC314	Equipment
Bags, Infusion: Nonsterile Novaplus Infusion Bag, 500 mL	Medline	TCV4005H	Disposable, Chronic PH
Blue Clave	Medline	BOPC1000	Disposable, Chronic PH
Cathflo Activase (alteplase) 2 mg	Cathflo	NDC 50242004164	Medication, Chronic PH
Computer	Dell	Lattitude 7400	Equipment
Data acquisition hardware	ADInstruments	PowerLab 16/30	Equipment
EPOC Point-of-care blood gas analyzer	Siemens Healthineers	Siemens-Epoc-R	Equipment
Flow Meter	Transonic	https://www.transonic.com/tubing-flow-meters-manufacturers
Gauze Sponges: Sterile X-ray Compatible Gauze Sponges, 16-Ply, 4” × 4”	Medline	PRM21430LFH	Disposable, Chronic PH
GEM 7000 with iQM3	Werfen	6000228442	Equipment
Heparin	Fresenius Kabi	63323-540-31	Medication, Chronic PH
Hospira Primary IV Sets, 80”	Patterson Veterinary	07-835-0123	Disposable, Chronic PH
Hypertonic saline 3%	Baxter Healthcare Corp.	0338-0054-03	Medication, Chronic PH
Hypodermic Needle with Bevel and Regular Wall, 20 G × 1”	Medline	B-D305175Z	Disposable, Chronic PH
Interface Cable, Edwards LifeScience Transducer to ADInstruments Bridge Amplifier	Fogg System	0395-2434	Equipment
Labchart software	ADInstruments	Labchart 8	Equipment
Needles: Hypodermic Needle with Regular Bevel, Sterile, 18 G × 1.5”	Medline	B-D305185Z	Disposable, Chronic PH
Octal Bridge Amplifier	ADInstruments	FE228	Equipment
Port-A-Cath Huber Needle, Straight, 22 G × 1-1/2”	Medline	AAKM21200724	Disposable, Chronic PH
Sheep Halter	Weaver Livestock	35-7840-S20	Equipment
Sterile Leur-Lock Syringe, 1 mL	Fisher Scientific	BD309628	Disposable, Chronic PH
Sterile Luer-Lock Syringe, 10 mL	Medline	SYR110010Z	Disposable, Chronic PH
Sterile Luer-Lock Syringe, 3 mL	Medline	SYR103010Z	Disposable, Chronic PH
Sterile Luer-Lock Syringe, 5 mL	Medline	SYR105010Z	Disposable, Chronic PH
Sterile Water	Fresenius Kabi	918550	Medication
Stopcock: 3-Way Stopcock with Handle in OFF Position, Rotating Adaptor Male Collar Fitting, 45 PSI	Medline	DYNJSC301	Disposable, Chronic PH
Transducer clip	Edwards LifeScience	TCLIP05	Equipment
Transonic Perivascular Flow Probe (PAU Series)	ADInstruments	https://www.adinstruments.com/products/perivascular-flowprobes
Transport Cage/ Large Animal Caging	Ancare	ANAT305660SS	Equipment
Trigger Aneroid Gauge (Sphygmomanometer)	Patterson Veterinary	07-815-0464	Equipment
TruWave Disposable Pressure Transducer Kits by Edwards Lifesciences	Medline	VSYPX260	Disposable, Chronic PH
Tubing: Pressure Monitoring Tubing with Fixed Male Luer Lock and Female Fitting, Low Pressure, 72” L	Medline	DYNJPMTBG72MF	Disposable, Chronic PH
Umbilical Tape, Cotton, 3-Strand, 1/8 x 36"	Medline	DYNJPMTBG72MF	Disposable, Chronic PH