Increasing Pulmonary Artery Pulsatile Flow Improves Hypoxic Pulmonary Hypertension in Piglets

Summary

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.

Abstract

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.

Introduction

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, allowin....

Protocol

NOTE: This study was authorized by Ethics committee number CEEA34.PB.103.12.

1. Use of Piglets as an Animal Model

1. Perform the in two groups (n = 6 in each group), matched in terms of sex, age (15 ± 3 months) and weight (30 ± 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.
2. Use a hypobaric chamber consisting of a Plexiglas box with a 2 square meter footprint and a height of 1.6 meters, as shown in Figure 1.
3. Continuously monitor and maintain a te....

Results

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.......

Discussion

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.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Drugs for anesthesia
sodium thiopental, THIOPENTAL SODIUM	Abbott, France	0000071-73-8	powder 3 place Gustave Eiffe 94518 RUNGIS CEDEX.
isoflurane, FORANE	Abbott, France	05260-05	glass bottle 250 ml 3 place Gustave Eiffe 94518 RUNGIS CEDEX.
midazolam, Hypnovel	Accord Healthcare	Vidal	injectable ampoules 1mg/ml 45 Rue du Faubourg de Roubaix 59000 Lille France
pramocaine,TRONOTHANE 1%	Laboratoires LISAPHARM	Vidal	Gel appl locale T/30g 3, rue Scheffer. 75016 Paris.
morphine chlohydrate Lavoisier	CMD Lavoisier Laboratoires CHAIX et DU MARAIS	Vidal	injectable ampoules  7, rue Labie -75017 Paris - France
Acrylates Copolymer-Carbopol® Aqua SF-1 Polymer	Lubrizol		gel appl local Elysées La Défense 19 le Parvis 92073 Paris la défense
Material
Ventilateur Harvard 683	Harvard apparatus	Harvard apparatus	DRIM 75 rue des Anglais - 78700 Conflans Ste Honorine
Echographe Voluson E8 with a 3.5 MHz probe	General Electric	GEHealthcare	DRIM 75 rue des Anglais - 78700 Conflans Ste Honorine
Pulsatil Catheter	Cardio inovating system		Cardio innovative systems, 33 rue Vivienne, Paris, France 75002
NO breath Analyseur	Respur	Respur	26 rue Felix Rouget 95490 Vaureal France