High-blood-flow related pulmonary hypertension and heart disease after pulmonary resection surgery : pathophysiology, cellular and molecular mechanisms, new targeted therapies

Autor: Sentenac, Pierre
Přispěvatelé: STAR, ABES, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier, Saadia Eddahibi, Sylvain Richard
Jazyk: francouzština
Rok vydání: 2020
Předmět:
Zdroj: Médecine humaine et pathologie. Université Montpellier, 2020. Français. ⟨NNT : 2020MONTT034⟩
Popis: The objective was to investigate the consequences of right pneumonectomy (PN) on the pulmonary vascular bed in rats, and to explore in vitro the involved mechanisms in human cells. In patients, the objective was to determine the incidence of right ventricular (RV) dysfunction during the first three days after major pulmonary resection surgery, assessed by the RV lateral wall (RVLW) longitudinal strain, a new marker of RV function.Sixty Sprague-Dawley male rats randomly underwent either a right PN or sham surgery. Ten rats per group were sacrificed on postoperative days 3, 7 and 28 (D3, D7, D28). Cardiopulmonary alterations were investigated by echocardiographic, hemodynamic and histological analyses. A competitive antagonist of the platelet-derived growth factor (PDGF)-receptor β (named A4 inhibitor) was administered between D0 and D28 in ten rats to prevent PH development. In vitro, the shear stress was reproduced using a FlexCell™ Tension system. A pathological cyclic stretch (18% elongation) was applied on cultured human pulmonary endothelial cells (P-ECs) to investigate the impact on pulmonary artery smooth muscle cell (PA-SMC) growth. Growth factors were dosed in P-ECs using qRT-PCR. A prospective study was conducted in the Montpellier University Hospital (France). All patients undergoing a major pulmonary resection surgery, without pre-existing PH or RV dysfunction, were eligible. A standardized echocardiography (GE® Vivid iq™) was performed preoperatively and then on postoperative days 1, 2 and 3 by the same examiner. The endpoint was the occurrence of a RV dysfunction, defined by a RV lateral wall (RVLW) longitudinal strain greater than -15%.Mean pulmonary arterial pressure (mPAP) gradually increased in the PN group to reach 35 ±7 mmHg on D28 vs 18 ±4 in sham (P = 0.001), likewise the proportion of muscularized distal pulmonary arteries, 83 ±1% vs 5 ± 1 respectively (P < 0.001), related to in situ PA-SMC proliferation. The RV enddiastolic area and RV lateral wall thickness were doubled in the PN group on D28. The left ventricle ejection fraction decreased on D7 and D28 while the RV systolic function was maintained. In vitro, the human PA-SMC growth was significantly greater when seeded with stretched vs non stretched P-EC media, highlighting the role of shear stress on the P-EC paracrine function. The qRT PCR highlighted that the PDGF was the main growth factor involved. In rats, a treatment by PDGFR-β antagonist decreased the systolic PAP after pneumonectomy, from 69 ±10 (PN) to 46 ±6 mmHg (PN+A4) (P = 0.0005), and the RV hypertrophy index from 0.52 ± 0.09 to 0.42 ± 0.06 respectively (P = 0.004). Between February 2017 and July 2018, 110 patients were included, 92 were analyzed, mean age 65 ±10 years, 59% male, COPD in 41% of cases, 74 lobectomy (80%), 8 pneumonectomy (9%), 6 bilobectomy (7%). In the early postoperative period, the RVLW longitudinal strain was altered in 55% of patients (CI 0.44—0.66), and dropped from -20 ±7% (D0) to -16 ±6 (D3) (P = 0.002). The longitudinal strain of the RVLW segments (basal, middle and apex) was homogeneously altered. An altered TAPSE (less than 17 mm) was observed in 15% of patients, preferentially after pneumonectomy or bilobectomy than after lobectomy (P = 0.04). Pulmonary hypertension (defined by systolic PAP >35 mmHg) occurred in 11% of patients, and the systolic PAP increased from 19 ±9 (D0) to 21 ±11 (D3) mmHg (P = 0.006). CONCLUSIONS: In rats, right pneumonectomy led to PH related to high muscularisation of distal pulmonary arteries, and was associated with a selective RV remodeling. In vitro, the shear stress related to high blood flow altered the pulmonary endothelial paracrine control of SMC growth. Selective PDGFR-β inhibition could be a therapeutic target. After major pulmonary resection surgery, the RVLW longitudinal strain showed an early RV dysfunction in approximately 50% of patients.
L'objectif était d'étudier le remodelage vasculaire pulmonaire après pneumonectomie droite (PN) chez le rat, et d'explorer in vitro les mécanismes impliqués sur des cellules humaines soumises à un shear stress. Chez les patients, l'objectif était de déterminer l'incidence de dysfonctionnement ventriculaire droite (VD) précoce après résection pulmonaire majeure, évaluée par le strain longitudinal de la paroi latérale du VD (RVLW).Soixante rats mâles Sprague-Dawley ont subi soit une PN droite ou une chirurgie sham. Dix rats par groupe ont été sacrifiés au 3ème, 7ème et 28ème jours postopératoires (J3, J7, J28). Les altérations cardio-pulmonaires ont été étudiées par des analyses échocardiographiques, hémodynamiques et histologiques. Un antagoniste compétitif du récepteur β du facteur de croissance dérivé des plaquettes (PDGFR- β), appelé inhibiteur A4, a été administré entre J0 et J28 chez dix rats en prévention de l’HTP. In vitro, le shear stress a été reproduit à l'aide d'un système FlexCell ™ Tension. Un étirement cyclique pathologique (allongement de 18%) a été appliqué sur des cellules endothéliales pulmonaires (P-ECs) humaines pour évaluer l'impact sur la croissance des cellules musculaires lisses artérielles pulmonaires (PA-SMCs). Une étude prospective a été menée au CHU de Montpellier (France). Tous les patients opérés d’une chirurgie de résection pulmonaire majeure, sans hypertension pulmonaire ni dysfonction VD préexistante, étaient éligibles. Une échocardiographie standardisée (GE® Vivid iq ™) a été réalisée en préopératoire puis aux jours 1, 2 et 3 postopératoires par le même examinateur. Le critère d'évaluation était la survenue d'une dysfonction VD définie par un RVLW longitudinal strain supérieur à -15%. La pression artérielle pulmonaire (PAP) moyenne a progressivement augmenté dans le groupe PN pour atteindre 35 ±7 mmHg à J28 vs 18 ±4 (sham) (P=0.001), de même que la proportion d'artères pulmonaires distales muscularisées, 83 ±1% vs 5 ±1 respectivement (P
Databáze: OpenAIRE
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