Name: increasing pulmonary artery pulsatile flow improves hypoxic pulmonary hypertension in piglets
Uploaded: 2015-05-11T13:00:00
Description: Watch this Scientific Journal Video about Increasing Pulmonary Artery Pulsatile Flow Improves Hypoxic Pulmonary Hypertension in Piglets at JoVE.com

The authors have nothing to disclose.

NOTE: This study was authorized by Ethics committee number CEEA34.PB.103.12.
1. Use of Piglets as an Animal Model
<ol>
	<li>Perform the in two groups (n = 6 in each group), matched in terms of sex, age (15 &#177; 3 months) and weight (30 &#177; 10 kg) (control group and chronic hypoxia (CH) group). House the CH group for 3 weeks in a hypobaric chamber (0.4 atm), and house the control group in regular normobaric (1 atm) conditions.</li>
	<li>Use a hypobaric chamber consisting of a Plexiglas b...

<ol>
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For the first time, it has been shown that changes in pulmonary pulsatile flow are causally related to the development of PAH secondary to chronic hypoxic exposure. This translational approach provides evidence that inducing an artificial increase in pulmonary pulsatile flow using a specifically designed catheter improves pulmonary hypertension, probably by increasing NO generation.
These findings are not only original, they are also of great therapeutic interest, demonstrating that endogenous...

Pulmonary arterial hypertension is a life-threatening disease affecting the pulmonary vasculature. There is agreement in the field that an imbalance between an increase in vasoconstrictors (endothelin, serotonin) and a decrease in vasodilators (NO, prostacyclin) contributes to the development of PAH. Over time, this pro-constrictive phenotype evolves into a complex pro-proliferative and anti-apoptotic phenotype, contributing to the development of vascular lesions 1.
Prolonged exposure to vasoconstrictors leads to a significant and sustained increase in [Ca2+]i in pulmonary artery smooth muscle cells, allowing the activation of several calcium-regulated transcription factors, such as NFAT 2-4, promoting PASMC proliferation and resistance to an apoptosis phenotype 5. This phenotype leads to pulmonary vascular lesions, contributing to an increase in both PA pressure and pulmonary resistance, which ultimately leads to fatal right heart failure 6.
Currently, there is no treatment available that reverses PAH although there are several that improve patients&#8217; quality of life 7. Among these treatments, the effectiveness of inhaled NO treatment has been demonstrated but because of its short half-life it is difficult to use in clinical practice. For this reason, more stable and durable treatments have been preferred, such as prostacyclin analogs, or endothelin receptor blockers 7. To develop better treatments, it is essential to improve and extend knowledge of the pathophysiology of PAH.
Pulsatility is a well-known stimulus activating shear stress-induced vasodilation, protecting the non-elastic distal artery from high-pressure flow injuries 8,9. In a model of PAH secondary to aortopulmonary surgical shunting, Nour et al. demonstrated intrapulmonary shear stress-mediated endothelial function enhancement 10. Several studies have demonstrated that NO, prostacyclin and ET-1 expression are closely regulated by changes in pulsatile flow. Indeed, a moderate increase in pulsatile flow increases eNOS activity and prostacyclin levels, both of which are reduced in PAH. Pulsatile flow modulation is probably implicated in the etiology of PAH and artificially increasing it is an attractive and novel way of increasing NO and prostacyclin production within the pulmonary circulation.
The present study aims to assess the effects of a 10&#160;min pulsatile flow using a newly developed pulsatile catheter on hemodynamic measurements in a pulmonary hypertension (PH) model in piglets in whom hypoxia has been induced. It has been hypothesized that increasing pulmonary artery pulsatility induces vasorelaxation of the pulmonary arteries, thereby decreasing pulmonary artery pressure.
Right heart catheterization (RHC) is a critical clinical intervention for the diagnosis and follow-up of PAH patients. Indeed, it is the most reliable way of diagnosing PAH and allows physicians to assess vascular reactivity 11,12 as well as disease progression. In fact every PAH patient undergoes RHC several times. The present study in large animals aims to demonstrate the efficacy and safety of pulsatile catheters in assessing and treating PAH during a regular RHC procedure. Because pulsatile catheters are already available and RHC is routinely performed in PAH patients, this study provides all the information required to be able to conduct clinical trials rapidly.

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	<tbody>
		<tr height="17">
			<td height="17" style="height:17px;width:311px;">Drugs for anesthesia</td>
			<td style="width:336px;"></td>
			<td style="width:141px;"></td>
			<td style="width:224px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">sodium thiopental, THIOPENTAL SODIUM</td>
			<td>Abbott, France</td>
			<td>0000071-73-8</td>
			<td>powder 
			3 place Gustave Eiffe 94518 RUNGIS CEDEX.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">&#160;isoflurane, FORANE</td>
			<td>Abbott, France</td>
			<td style="width:141px;">05260-05</td>
			<td>glass bottle 250 ml 
			3 place Gustave Eiffe 94518 RUNGIS CEDEX.</td>
		</tr>
		<tr height="17">
			<td height="17" style="height:17px;">midazolam, Hypnovel</td>
			<td>Accord Healthcare&#160;</td>
			<td>Vidal</td>
			<td>injectable ampoules 1mg/ml 
			45 Rue du Faubourg de Roubaix 59000 Lille France</td>
		</tr>
		<tr height="17">
			<td height="17" style="height:17px;">pramocaine,TRONOTHANE 1 %&#160;</td>
			<td>Laboratoires LISAPHARM</td>
			<td>Vidal</td>
			<td>Gel appl locale T/30g 
			3, rue Scheffer. 75016 Paris.</td>
		</tr>
		<tr height="17">
			<td height="17" style="height:17px;">morphine chlohydrate Lavoisier</td>
			<td>CMD Lavoisier Laboratoires CHAIX et DU MARAIS</td>
			<td>Vidal</td>
			<td>injectable ampoules&#160; 
			7, rue Labie -75017 Paris - France</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:311px;">Acrylates Copolymer-Carbopol&#174; Aqua SF-1 Polymer</td>
			<td>Lubrizol</td>
			<td></td>
			<td>gel appl local 
			Elys&#233;es La D&#233;fense 19 le Parvis 92073 Paris la d&#233;fense</td>
		</tr>
		<tr height="17">
			<td height="17" style="height:17px;">Material&#160;</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Ventilateur Harvard 683</td>
			<td>Harvard apparatus</td>
			<td>Harvard apparatus</td>
			<td>DRIM 75 rue des Anglais - 78700 Conflans Ste Honorine &#160;&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Echographe Voluson E8 with a 3,5 MHz probe</td>
			<td>General Electric</td>
			<td>GEHealthcare</td>
			<td>DRIM 75 rue des Anglais - 78700 Conflans Ste Honorine &#160;&#160;</td>
		</tr>
		<tr height="17">
			<td height="17" style="height:17px;">Pulsatil Catheter</td>
			<td>Cardio inovating system</td>
			<td></td>
			<td>Cardio innovative systems, 33 rue Vivienne, Paris, France 75002</td>
		</tr>
		<tr height="17">
			<td height="17" style="height:17px;">NO breath Analyseur</td>
			<td>Respur</td>
			<td>Respur</td>
			<td>26 rue Felix Rouget 95490 Vaureal France</td>
		</tr>
	</tbody>
</table>

increasing pulmonary artery pulsatile flow improves hypoxic pulmonary hypertension in piglets

Pulmonary arterial hypertension (PAH) is a disease affecting distal pulmonary arteries (PA). These arteries are deformed, leading to right ventricular failure. Current treatments are limited. Physiologically, pulsatile blood flow is detrimental to the vasculature. In response to sustained pulsatile stress, vessels release nitric oxide (NO) to induce vasodilation for self-protection. Based on this observation, this study developed a protocol to assess whether an artificial pulmonary pulsatile blood flow could induce an NO-dependent decrease in pulmonary artery pressure. One group of piglets was exposed to chronic hypoxia for 3 weeks and compared to a control group of piglets. Once a week, the piglets underwent echocardiography to assess PAH severity. At the end of hypoxia exposure, the piglets were subjected to a pulsatile protocol using a pulsatile catheter. After being anesthetized and prepared for surgery, the jugular vein of the piglet was isolated and the catheter was introduced through the right atrium, the right ventricle and the pulmonary artery, under radioscopic control. Pulmonary artery pressure (PAP) was measured before (T0), immediately after (T1) and 30 min after (T2) the pulsatile protocol. It was demonstrated that this pulsatile protocol is a safe and efficient method of inducing a significant reduction in mean PAP via an NO-dependent mechanism. These data open up new avenues for the clinical management of PAH.

Increasing Pulmonary Artery Pulsatile Flow Improves Induced Chronic Hypoxic Pulmonary Hypertension in Piglets
Prior to exposing animals to an increase in pulsatile flow, ultrasound was used non-invasively to check that the piglets had developed pulmonary hypertension. As shown in Figure 2, three weeks of chronic hypoxia induced the development of pulmonary hypertension in piglets, characterized by a significant reduction in pulmonary artery acceleration time (Doppler) and an i...

Watch this Scientific Journal Video about Increasing Pulmonary Artery Pulsatile Flow Improves Hypoxic Pulmonary Hypertension in Piglets at JoVE.com

Increasing Pulmonary Artery Pulsatile Flow Improves Hypoxic Pulmonary Hypertension in Piglets

Pulmonary hypertension is associated with a significant reduction in pulmonary artery pulsatility, contractility and elasticity, contributing to an increase in pulmonary artery pressure and pulmonary resistance. Using a hypoxic piglet model, this study demonstrated that improving pulmonary artery plasticity using a newly developed pulsatile catheter improves hypoxic pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a disease affecting distal pulmonary arteries (PA). These arteries are deformed, leading to right ventricular ...

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