Name: induction and phenotyping of acute right heart failure in a large animal model of chronic thromboembolic pulmonary hypertension
Uploaded: 2022-03-17T13:00:00
Description: Watch this Scientific Journal Video about Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension at JoVE.com

This work is supported by a public grant overseen by the French National Research Agency (ANR) as part of the&#160;Investissements d&#39;Avenir Program (reference: ANR-15RHUS0002).

The study complied with the principles of laboratory animal care according to the National Society for Medical Research and was approved by the local ethic committee for animal experiments at Hospital Marie Lannelongue.
1. Chronic thromboembolic PH
<ol>
	<li>Induce chronic thromboembolic PH as previously described6,12.</li>
	<li>Briefly, induce a model of chronic thrombo-embolic PH in around 20 kg large white pigs (sus scrofa</em...

<ol>
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We describe a method to model major pathophysiological features of ARHF on chronic PH in a large animal model including volume and pressure overload and hemodynamic restoration with dobutamine. We also reported how to acquire hemodynamic and imaging data to phenotype the dynamic changes of the right ventricle at each condition created during the protocol. These methods can provide background data to build up future research protocols in the field of ARHF, particularly regarding fluid management and inotropic support....

Acute right heart failure (ARHF) has been recently defined as a rapidly progressive syndrome with systemic congestion resulting from impaired right ventricular (RV) filling and/or reduced RV flow output1. ARHF may occur in several conditions such as left-sided heart failure, acute pulmonary embolism, acute myocardial infarction or pulmonary hypertension (PH). In the case of PH, ARHF onset is associated with a 40% risk of short-term mortality or urgent lung transplantation2,3,4. Here, we describe how to create a large animal model of ARHF in the setting of chronic pulmonary hypertension and how to evaluate the right ventricle using echocardiography and pressure-volume loops.
Pathophysiological features of ARHF include RV pressure overload, volume overload, a decrease in RV output, an increase in central venous pressure and/or a decrease in systemic pressure. In chronic PH, there is an initial increase in RV contractility allowing to preserve cardiac output despite the increase in pulmonary vascular resistance. Therefore, in the context of ARHF on chronic PH, the right ventricle can generate nearly isosystemic pressures, particularly under inotropic support. Taken together, ARHF on chronic PH and hemodynamic restoration with inotropes lead to the development of acute RV ischemic lesions, as recently described in our large animal model5. The increase in inotropes creates an increased energetic demand that may further develop ischemic lesions, and finally lead to the development of end-organ dysfunction and poor clinical outcomes. However, there is no consensus about how to manage patients with ARHF on PH, mainly regarding fluid management, inotropes and the role of extra-corporeal circulatory support. Consequently, a large animal model of acute right heart failure may help to provide pre-clinical data on ARHF clinical management.
As a first step to quantify the response to therapy, simple and reproducible methods to phenotype the right ventricle are needed. To date, there is no consensus about how to better phenotype the RV morphology and function of patients with ARHF. The gold standard method to evaluate RV contractility (i.e., intrinsic capacity to contract) and ventriculo-arterial coupling (i.e., contractility normalized by ventricular afterload; an index of ventricular adaptation) is the analysis of pressure-volume (PV) loops. This method is twice invasive because it requires right heart catheterization and a transient reduction in RV preload using a balloon inserted in the inferior vena cava. In clinical practice, non-invasive and repeatable methods to evaluate the right ventricle are needed. Cardiac magnetic resonance (CMR) is considered as the gold standard for non-invasive evaluation of the right ventricle. In patients with ARHF on chronic PH who are managed in intensive care unit (ICU), the use of CMR may be limited because of the patient&#39;s unstable hemodynamic condition; moreover, repeated CMR evaluations, several times a day, including at night, may be limited because of its cost and limited availability. Conversely, echocardiography allows non-invasive, reproducible and low-cost RV morphology and function evaluations in ICU patients.
Large animal models are ideal to perform preclinical studies focusing on the relationship between invasive hemodynamic parameters and non-invasive parameters. The large white pig anatomy is close to humans. Consequently, most of the echocardiographic parameters described in humans are quantifiable in pigs. Some minor variations exist between human and pig heart that must be taken into account for echocardiographic studies. Pigs present a constitutional dextrocardia and a slightly counterclockwise rotation of the heart axis. As a result, the apical 4-chamber view becomes an apical 5-chamber view and the acoustic window is situated below the xiphoid appendix. Additionally, parasternal long and short axis views acoustic windows are situated on the right side of the sternum.
Here, we describe a novel method to induce ARHF in a large animal model of chronic thromboembolic PH and to restore hemodynamic using dobutamine. We also report RV ischemic lesions present in the model within 2&#8722;3 hours after hemodynamic restoration with dobutamine. Moreover, we describe how to acquire RV PV-loops and echocardiographic RV parameters at each condition providing insights on the dynamic changes in RV morphology and function. As the large animal model of chronic thromboembolic PH and the PV-loop methods were previously described6, these sections will be briefly described. Also, we reported results of echocardiographic evaluations which are deemed potentially difficult in porcine models. We will explain the methods to achieve repeated echocardiographic in the model.
The model of ARHF on chronic PH reported in this study can be used to compare different therapeutic strategies. The methods of RV phenotyping can be used in other large animal models mimicking clinically relevant situations such as acute pulmonary embolism7, RV myocardial infarction8, acute respiratory distress syndrome9 or right heart failure associated with left ventricular failure10 or left ventricular mechanical circulatory support11.

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	<colgroup>
		<col />
		<col />
		<col />
		<col />
	</colgroup>
	<tbody>
		<tr height="40">
			<td height="40" style="height:40px;width:215px;">Radiofocus Introducer II</td>
			<td style="width:123px;">Terumo</td>
			<td style="width:344px;">RS+B80K10MQ</td>
			<td style="width:229px;">catheter sheath</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Equalizer, Occlusion Ballon Catheter</td>
			<td>Boston Scientific</td>
			<td>M001171080</td>
			<td>ballon for inferior vena cava occlusion</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Guidewire</td>
			<td>Terumo</td>
			<td>GR3506</td>
			<td>0.035; angled</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Vigilance monitor</td>
			<td>Edwards</td>
			<td>VGS2V</td>
			<td>Swan-Ganz associated monitor</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Swan-Ganz</td>
			<td>Edwards</td>
			<td>131F7</td>
			<td>Swan-Ganz catheter 7 F; usable lenghth 110 cm</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Echocardiograph; Model: Vivid 9</td>
			<td>General Electrics</td>
			<td>GAD000810 and H45561FG</td>
			<td>Echocardiograph</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Probe for echo, M5S-D</td>
			<td>General Electrics</td>
			<td>M5S-D</td>
			<td>Cardiac ultrasound transducer</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">MPVS-ultra Foundation system</td>
			<td>Millar</td>
			<td>PL3516B49</td>
			<td>Pressure-volume loop unit; includes a powerLab16/35, MPVS-Ultra PV Unit, bioamp and bridge amp and cables</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Ventricath 507</td>
			<td>Millar</td>
			<td>VENTRI-CATH-507</td>
			<td>conductance catheter</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Lipiodol ultra-fluid</td>
			<td>Guerbet</td>
			<td>306 216-0</td>
			<td>lipidic contrast dye</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">BD Insyte Autoguard</td>
			<td>Becton, Dickinson and Company</td>
			<td align="right">381847</td>
			<td>IV catheter</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Arcadic Varic</td>
			<td>Siemens</td>
			<td>A91SC-21000-1T-1-7700</td>
			<td>C-arm</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;">Prolene 5.0</td>
			<td>Ethicon</td>
			<td style="width:344px;">F1830</td>
			<td style="width:229px;">polypropilene monofil</td>
		</tr>
	</tbody>
</table>

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.

Feasibility 
We describe the results of 9 consecutive procedures of ARHF induction in a large animal CTEPH model previously reported5. The duration of the protocol was around 6 hours to complete, including anesthesia induction, installation, vascular access/catheter placements, induction of volume/pressure overload and hemodynamic restoration, data acquisitions and euthanasia. Each hemodynamic condition requires around 40 minutes to achieve in...

Watch this Scientific Journal Video about Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension at JoVE.com

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

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 ...

This model of acute right heart failure in the context of coronary pulmonary hypertension can help to better understand the pathophysiology of this clinically relevant situation. Induction of acute right heart failure by the mean of volume and pressure overload is easily reproducible and duplicates the main pathophysiological aspects of the corresponding clinical situation. After confirming an appropriate level of sedation, place a central venous catheter through the jugular vein up to the superior vena cava using the Seldinger method.Next, make a four centimeter transverse incision at the groin and insert a Beckman retractor into the incision. Using Debakey forceps and Metzenbaum scissors, divide the anterior face of the femoral vein and artery and place a 20 gauge catheter into the femoral artery. Then connect the catheter to a disposable transducer with a fluid-filled catheter to obtain systemic and central venous blood pressure.Using an 18 gauge catheter and a fluoroscope with a C-arm and an interior-posterior view, insert a guidewire into the femoral vein through the inferior vena cava. Place a balloon dilation catheter over the guidewire at the intrapericardial level and place the visible markers of the balloon immediately above the diaphragm level. Then remove the guidewire.Immediately after the catheters have been placed, acquire an apical five-chamber view under the xiphoid process in two dimensions and in the tissue Doppler mode. Acquire the parasternal short and long axis views on the right side of the sternum in 2D and tissue Doppler modes and an image of the valvular flow using continuous and pulsed Doppler modes. Then acquire tissue Doppler signals of the lateral tricuspid annulus and the lateral and septal mitral annulus.For catheterization of the right heart, introduce the Swan-Ganz catheter into the jugular 8 French sheath inserted into the jugular vein and acquire the mean right atrial, right ventricular, and pulmonary artery pressures. Next, measure the cardiac output with the thermodilution method according to the manufacturer's instructions while simultaneously measuring the heart rate for the stroke volume calculation. Connect the disposable transducer to the pressure volume loop workstation for live acquisitions of the pressures derived from the fluid-filled catheters and use fluoroscopy to introduce the conductance catheter into the right ventricle.Then verify the quality signal using in live acquisition of the pressure volume loops and acquire pressure volume loop families in the steady state and during acute preload reduction induced by inflating the balloon inserted into the inferior vena cava during end expiratory apnea. To induce acute right heart failure, first use a free flow infusion output to start a 15 milliliters per kilogram saline infusion. Five minutes after hemodynamic stabilization and at the end of each infusion, obtain the right heart catheterism, pressure volume loop, and echocardiographic measurements.Then start the second infusion of 15 milliliters per kilogram of saline immediately after the end of the measurements and start the third infusion of 30 milliliters per kilogram of saline immediately after the end of the second set of measurements. To induce hemodynamic pressure overload, use the fluoroscope to insert a 5 French angiographic catheter through the jugular sheath into the right lower lobe pulmonary artery. Embolize the right lower lobe pulmonary artery with a 150 microliter bolus containing n-butyl-2-cyanoacrylate lipidic contrast dye, washing out the catheter with 10 milliliters of saline once the bolus has been delivered.Two minutes after the embolization, measure the systemic and pulmonary artery pressures to evaluate the hemodynamic response, then repeat the bolus delivery every two minutes until hemodynamic compromise is achieved. After reaching hemodynamic compromise, acquire pressure volume loop and echocardiographic measurements before starting a dobutamine infusion at 2.5 micrograms per kilogram per minute. Wait 10-15 minutes for hemodynamic stabilization before performing right heart catheterization, pressure volume loop, and echocardiographic measurements.When all of the measurements have been acquired, increase the dobutamine infusion dose to five micrograms per kilogram per minute and repeat the right heart catheterization, pressure volume loop, and echocardiographic measurements once hemodynamic stabilization has been achieved as just demonstrated. Then increase the dobutamine infusion dose to 7.5 micrograms per kilogram per minute. Acute volume loading does not induce acute right heart failure, but rather highlights the adaptive phenotype of the chronic pulmonary hypertension model.With volume loading, the cardiac output increases without an increase in the right atrial pressure and with ventriculo-arterial coupling remaining stable. Hemodynamic compromise is associated with a significant decrease in cardiac output, stroke volume, and ventriculo-arterial coupling, whereas right ventricle contractility remained stable. A twofold increase in the right atrial pressure and mean pulmonary artery pressure are also typically observed.Dobutamine delivery as demonstrated restores cardiac output, stroke volume, and ventriculo-arterial coupling within the normal range. Echocardiography can be used to quantify dynamic changes in right ventricle size and function throughout the experiment. Pressure volume loop analysis allows the dynamic quantification of right ventricle end-systolic elastins and ventriculo-arterial coupling.In this representative study, the two deaths that occurred immediately after acute pulmonary embolism were associated with acute thrombosis of the right heart cavities. After hematoxylin eosin and saffron staining, right ventricular ischemic lesions characterized by clusters of hypereosinophilic cardiomyositis with pyknotic nuclei can be observed in the sub-endocardial and sub-pericardial layers of the right ventricle free wall. The magnitude of acute volume and pressure overload required to induce acute right heart failure phenotype of the right ventricle in the context of pulmonary hypertension.Hemodynamic restoration could be used by drugs or intervention in order to determine the best therapeutic option.

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

Induction and Characterization of Pulmonary Hypertension in Mice using the Hypoxia/SU5416 Model

Pulmonary Hypertension (PH) is a pathophysiological condition, defined by a mean pulmonary arterial pressure exceeding 25 mm Hg at rest, as assessed by ...

Invasive Hemodynamic Assessment for the Right Ventricular System and Hypoxia-Induced Pulmonary Arterial Hypertension in Mice

Pulmonary arterial hypertension (PAH) is a chronic and severe cardiopulmonary disorder. Mice are a popular animal model used to mimic this disease. ...