Name: a surgical model of heart failure with preserved ejection fraction in tibetan minipigs
Uploaded: 2022-02-18T14:30:00
Description: Watch this Scientific Journal Video about A Surgical Model of Heart Failure with Preserved Ejection Fraction in Tibetan Minipigs at JoVE.com

This work was supported by the Guangdong Science and Technology Program (2008A08003, 2016A020216019, 2019A030317014), the Guangzhou Science and Technology Program (201804010206), the National Natural Science Foundation of China (31672376, 81941002), and the Guangdong Provincial Key Laboratory of Laboratory Animals (2017B030314171).

All animal studies were approved by the Institutional Animal Care and Use Committee of the Guangdong Laboratory Animals Monitoring Institute (approval no. IACUC2017009). All animal experiments were performed following the Guide for the Care and Use of Laboratory Animals (8th Ed., 2011, The National Academies, USA). The animals were housed in an AAALAC-accredited facility at the Guangdong Laboratory Animals Monitoring Institute (license no. SYXK (YUE) 2016-0122, China). Six male Tibetan minipigs (n = 3 each for the sham g...

<ol>
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This study used DAC techniques to develop an HFpEF model for Tibetan minipigs. A step-by-step animal and instrument preparation protocol is presented here, including sedation, tracheal intubation, vein cannulation, surgical procedure, and post-surgery care. The recording techniques for echocardiographic B-mode and M-mode heart images are also presented. After DAC, the heart underwent left ventricular hypertrophy during weeks 4 and 6 and dilation after week 8. LVEF was preserved during the 12-week period. Fibrosis and inf...

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and has become a worldwide public health issue1. Clinical observations have indicated several critical features of HFpEF: (1) ventricular diastolic dysfunction, accompanied by increased systolic stiffness, (2) normal ejection fraction at rest with impaired exercise performance, and (3) cardiac remodeling2. The proposed mechanisms include hormonal dysregulation, systemic microvascular inflammation, metabolic disorders, and abnormalities in sarcomeric and extracellular matrix proteins3. However, experimental studies have shown that heart failure with reduced ejection fraction (HFrEF) causes these alterations. Clinical studies have explored the therapeutic effects of angiotensin receptor inhibitors and drugs for treating HFrEF in HFpEF4,5. However, unique therapeutic approaches for HFpEF are needed. Compared with understanding the clinical symptoms, the alterations in pathology, biochemistry, and molecular biology of HFpEF remain poorly defined.
Animal models of HFpEF have been developed to explore the mechanisms, diagnostic markers, and therapeutic approaches. Laboratory animals, including pigs, dogs, rats, and mice, can develop HFpEF, and diverse risk factors, including hypertension, diabetes mellitus, and aging, were selected as induction factors6,7. For example, deoxycorticosterone acetate alone or combined with a high fat/sugar diet induces HFpEF in pigs8,9. Ventricular pressure overload is another technique used to develop HFpEF in large and small animal models10. In addition, specific EF cut-off values to define HFpEF have been adopted across continents in recent years, as seen in the European Society of Cardiology guidelines, the American College of Cardiology Foundation/American Heart Association11, the Japanese Circulation Society/the Japanese Heart Failure Society12. Thus, many previously established models may become appropriate for HFpEF studies if the clinical criteria are adopted. For example, Youselfi et al. claimed that a genetically modified mouse strain, Col4a3-/-, was an effective HFpEF model. This strain developed typical HFpEF cardiac symptoms, such as diastolic dysfunction, mitochondrial dysfunction, and cardiac remodeling13. A previous study used a high-energy diet to induce cardiac remodeling with a mid-range of EF in aged monkeys14, characterized by a metabolic disorder, fibrosis, and reduced actomyosin MgATPase in the myocardium. Mouse transverse aortic constriction (TAC) is one of the most widely used models to mimic hypertension-induced ventricular cardiomyopathy. The left ventricle progresses from concentric hypertrophy with increased EF to dilated remodeling with reduced EF15,16. The transitional phenotypes between these two typical stages suggest that the aortic constriction technique can be used to study HFpEF.
The pathological features, cellular signaling, and mRNA profiles of a porcine HFpEF model were previously published17. Here, a step-by-step protocol is presented to establish this model and the approaches to evaluate the phenotypes of this model. The procedure is illustrated in Figure 1. Briefly, the surgical plan was made jointly by the principal investigator, surgeons, laboratory technicians, and animal care staff. The minipigs underwent health examinations, including biochemical tests and echocardiography. Following surgery, anti-inflammatory and analgesic procedures were performed. Echocardiography, histological examination, and biomarkers were used to evaluate the phenotypes.

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	<tbody>
		<tr>
			<td>Absorbable surgical suture</td>
			<td>Putong Jinhua Medical Co. Ltd, China</td>
			<td>4-0</td>
			<td></td>
		</tr>
		<tr>
			<td>Aesthesia ventilator station</td>
			<td>Shenzhen Mindray Bio-Medical Electronics Co., Ltd, China</td>
			<td>WATO EX-35vet</td>
			<td></td>
		</tr>
		<tr>
			<td>Aspirator</td>
			<td>Shanghai Baojia Medical Apparatus Co., Ltd, China</td>
			<td>YX930D</td>
			<td></td>
		</tr>
		<tr>
			<td>Benzylpenicillin</td>
			<td>Sichuan Pharmaceutical. INC, China</td>
			<td>H5021738</td>
			<td></td>
		</tr>
		<tr>
			<td>Disposal endotracheal tube with cuff</td>
			<td>Shenzhen Verybio Co., Ltd, China</td>
			<td>20 cm, ID 0.9</td>
			<td></td>
		</tr>
		<tr>
			<td>Disposal transducer</td>
			<td>Guangdong Baihe Medical Technology Co., Ltd, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Dissection blade</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Electrocautery</td>
			<td>Shanghai&#160;Hutong Medical Instruments (Group)&#160;Co., Ltd, China</td>
			<td>GD350-B</td>
			<td></td>
		</tr>
		<tr>
			<td>Enzyme-linked immunosorbent assay ELISA kit</td>
			<td>Cusabio Biotech Co., Ltd, China</td>
			<td>CSB-E08594r</td>
			<td></td>
		</tr>
		<tr>
			<td>Eosin</td>
			<td>Sigma-Aldrich Corp.</td>
			<td>E4009</td>
			<td></td>
		</tr>
		<tr>
			<td>Flunixin meglumine</td>
			<td>Shanghai Tongren Pharmaceutical Co., Ltd., China</td>
			<td>Shouyaozi(2012)-090242103</td>
			<td></td>
		</tr>
		<tr>
			<td>Forceps</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd.,China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Hematoxylin</td>
			<td>Sigma-Aldrich Corp.</td>
			<td>H3136</td>
			<td></td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>RWD Life Science Co., Ltd, China</td>
			<td>Veteasy for animals</td>
			<td></td>
		</tr>
		<tr>
			<td>Laryngoscope</td>
			<td>Taixing Simeite Medical Apparatus and Instruments Limited Co., Ltd, China</td>
			<td>For adults</td>
			<td></td>
		</tr>
		<tr>
			<td>LED surgical lights</td>
			<td>Mingtai Medical Group, China</td>
			<td>ZF700</td>
			<td></td>
		</tr>
		<tr>
			<td>Microplate reader</td>
			<td>Thermo Fisher Scientific, USA</td>
			<td>Multiskan FC</td>
			<td></td>
		</tr>
		<tr>
			<td>Microscope</td>
			<td>Leica, Germany</td>
			<td>DM2500</td>
			<td></td>
		</tr>
		<tr>
			<td>Mobile restraint unit</td>
			<td>Customized</td>
			<td>N/A</td>
			<td>A mobile restraint unit, made by metal frame and wheels, with a canvas cover</td>
		</tr>
		<tr>
			<td>Oxygen</td>
			<td>Local suppliers, Guangzhou, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Paraformaldehyde</td>
			<td>Sigma-Aldrich Corp.</td>
			<td>V900894</td>
			<td></td>
		</tr>
		<tr>
			<td>Patient monitor</td>
			<td>Shenzhen Mindray Bio-Medical Electronics Company, China</td>
			<td>Beneview T5</td>
			<td></td>
		</tr>
		<tr>
			<td>Peripheral Intravenous (IV) Catheter</td>
			<td>Shenzhen Yima Pet Industry Development Co., Ltd., China</td>
			<td>26G X 16 mm</td>
			<td></td>
		</tr>
		<tr>
			<td>Propofol</td>
			<td>Guangdong Jiabo Phamaceutical Co., Ltd.</td>
			<td>H20051842</td>
			<td></td>
		</tr>
		<tr>
			<td>Rib retractor</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd.,China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Ruler</td>
			<td>Deli&#160;Manufacturing&#160;Company, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Scalpel handles</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd.,China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Scissors (g)</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd.,China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Suture</td>
			<td>Medtronic-Coviden Corp.</td>
			<td>3-0, 4-0</td>
			<td></td>
		</tr>
		<tr>
			<td>Ultrasonic gel</td>
			<td>Tianjin Xiyuansi Production Institute, China</td>
			<td>TM-100</td>
			<td></td>
		</tr>
		<tr>
			<td>Veterinary monitor</td>
			<td>Shenzhen Mindray Bio-Medical Electronics Company, China</td>
			<td>ePM12M Vet</td>
			<td></td>
		</tr>
		<tr>
			<td>Veterinary ultrasound system</td>
			<td>Esatoe, Italy</td>
			<td>MyLab30</td>
			<td>Equiped with phased array transducer (3-8 Hz)</td>
		</tr>
		<tr>
			<td>Xylazine hydrochloride injection</td>
			<td>Shenda Animal Phamarceutical Co., Ltd., China</td>
			<td>Shouyaozi(2016)-07003</td>
			<td></td>
		</tr>
		<tr>
			<td>Zoletil injection</td>
			<td>Virbac, France</td>
			<td>Zoletil 50</td>
			<td>Tiletamine and zolazepam for injection</td>
		</tr>
	</tbody>
</table>

a surgical model of heart failure with preserved ejection fraction in tibetan minipigs

More than half of heart failure (HF) cases are classified as heart failure with preserved ejection fraction (HFpEF) worldwide. Large animal models are limited for investigating the fundamental mechanisms of HFpEF and identifying potential therapeutic targets. This work provides a detailed description of the surgical procedure of descending aortic constriction (DAC) in Tibetan minipigs to establish a large animal model of HFpEF. This model used a precisely controlled constriction of the descending aorta to induce chronic pressure overload in the left ventricle. Echocardiography was used to evaluate the morphological and functional changes in the heart. After 12 weeks of DAC stress, the ventricular septum was hypertrophic, but the thickness of the posterior wall was significantly reduced, accompanied by dilation of the left ventricle. However, the LV ejection fraction of the model hearts was maintained at &gt;50% during the 12-week period. Furthermore, the DAC model displayed cardiac damage, including fibrosis, inflammation, and cardiomyocyte hypertrophy. Heart failure marker levels were significantly elevated in the DAC group. This DAC-induced HFpEF in minipigs is a powerful tool for investigating molecular mechanisms of this disease and for preclinical testing.

Echocardiography 
Cardiac structure and function were evaluated at weeks 0, 2, 4, 6, 8, 10, and 12. The B-mode and M-mode recordings of the parasternal short-axis view are displayed in Figure 4A. The echocardiographic measurement included the ventricular septum thickness (VST), posterior wall thickness (PWT), and left ventricular internal dimension (LVID). The VST at end-diastole increased in the DAC hearts, whereas the PWT at end-diastole increased and then decreased d...

Watch this Scientific Journal Video about A Surgical Model of Heart Failure with Preserved Ejection Fraction in Tibetan Minipigs at JoVE.com

A Surgical Model of Heart Failure with Preserved Ejection Fraction in Tibetan Minipigs

The present protocol describes a step-by-step procedure to establish a minipig model of heart failure with preserved ejection fraction using descending aortic constriction. The methods for evaluating cardiac morphology, histology, and function of this disease model are also presented.

More than half of heart failure (HF) cases are classified as heart failure with preserved ejection fraction (HFpEF) worldwide. Large animal models are ...

More than half of heart failure cases worldwide are classified as heart failure with preserved blood ejection fraction or HFpEF. This video presents a step by statist procedure to model HFpEF minipigs as well as echocardiography techniques for assessing cardiac function. This model has a single predisposing filter.There is aortic constriction, induced pressure overload. Hence, the model is helpful for studying a certain type of HFpEF. In addition to surgical technique per operation planning, animal quality control and post-operation animal care are critical steps.The biochemical tests and electrocardiography help in monitoring animal health and changes in her structure and function. Xiaohui Li, a clinical cardiac surgeon. Weijiang Tan, a trained animal surgeon.Xiang Li, a trained anesthetist for this operation. Shuang Chen, a trained operating room nurse. And Honghua Chen, a trained operating room nurse will be demonstrating the procedure.To begin acclimatize the animals to the facility for 14 days before surgery. Prepare the surgical room and devices. Restrain and place the minipig in the right lateral recumbent position on the operating surgery table.Turn on the heating system to maintain the body temperature of the animal. Perform the echocardiography and collect a two milliliter blood sample. Initiate the ventilation at eight milliliters per kilograms of tidal volume and 30 breaths per minute.Establish intravenous cannulation using a peripheral intravenous catheter from an ear vein. Then connect the animal to a veterinary monitor. Shave the left thoracic area.Apply 0.7%iodine and 75%alcohol to aseptically prepare the skin from the scapula to the diaphragm. Place sterile drapes over the surgical area. Mark approximately a 15 centimeter long incision along the fourth intercostal space.Then make the skin incision using electrocautery. Open the chest using a combination of cautery and blunt dissection of the muscle and connective tissue. Use a rib retractor to spread the ribs.Locate the thoracic descending aorta segment and determine the constriction site and use two three OTT surgical sutures to loop around the segment twice. Set up pressure measurement units. To determine the degree of constriction, tighten the surgical suture surrounding the descending aorta segment gradually to achieve the desired constriction degree.Allow the pressure readings to stabilize for 20 minutes and permanently tighten the surgical knots. Use a drainage chest tube to evacuate the air and excess fluids in the chest cavity. Monitor the presence of eye blinking and limb movement of the animal.Disconnect the ventilator, but leave the endotracheal tube and monitor the presence of spontaneous breathing. Place the animal in a mobile restraint unit with a canvas cover. Shave the left chest of the animal.Place fingers on the left center of the chest to feel the epical pulse. Apply the ultrasonic gel to the surrounding area. Place the ultrasound system's phased array transducer in the third intercostal space.Move the transducer toward an anterior or posterior direction and adjust the notch angle. Identify the atria, ventricles and aorta and record the B mode and M mode perasternal long axis images. Next in the parasternal short axis view, identify the interventricular septum, left ventricular posterior wall and papillary muscle, and record the B mode and M mode images.Use the workstation provided by the manufacturer of the ultrasound system to assess the cardiac structure and function. The cardiac structure and function evaluation showed the displayed B mode and M mode recordings of the perasternal short axis. The ventricular septum thickness increased in the descending aortic constriction hearts, whereas the posterior wall thickness increased and then decreased during the observation period, suggesting the hypertrophic remodeling in the left ventricle of the descending aortic constriction minipigs.The left ventricular internal dimension at end diastole decreased in weeks four and six, and then gradually increased after week eight, suggesting that the ventricles underwent concentric hypertrophy before dilation. The left ventricular ejection fraction of the model hearts was maintained at more than 50%during the 12 weeks. Compared with sham hearts, enlargement of the descending aortic constriction hearts was observed.The heart failure marker, cardiac troponin I, was significantly higher at weeks 4, 8 and 12 in the descending aortic constriction group than in the sham group at the corresponding time points. Cardiomyocytes in the atria ventricular septum and ventricles displayed hypertrophy with pignosis. Muscular layers were reduced in endometrial valve and vascular endothelial hyperplasia was observed in the aorta.Moreover, descending aortic constriction induced extensive fibrosis in the myocardium of the minipigs, accompanied by infiltration of inflammatory cells in the left ventricles, right atrium, and aortic walls. This model is a powerful tool to study tissues damage, fibrosis, inflammation, and concentric dysfunction in pressure overload induced HFpEF.

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