scholarly journals Use of a right ventricular continuous flow pump to validate the distensible model of the pulmonary vasculature

2019 ◽  
pp. 233-243
Author(s):  
F. Vanden Eynden ◽  
P. Segers ◽  
T. Bové ◽  
F. De Somer ◽  
B. El Oumeiri ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Surface Area ◽  
Continuous Flow ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Flow State ◽  
Mean Flow ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Flow

In the pulmonary circulation, resistive and compliant properties overlap in the same vessels. Resistance varies nonlinearly with pressure and flow; this relationship is driven by the elastic properties of the vessels. Linehanet al. correlated the mean pulmonary arterial pressure and mean flow with resistance using an original equation incorporating the distensibility of the pulmonary arteries. The goal of this study was to validate this equation in an in vivo porcine model. In vivo measurements were acquired in 6 pigs. The distensibility coefficient (DC) was measured by placing piezo-electric crystals around the pulmonary artery (PA). In addition to experiments under pulsatile conditions, a right ventricular (RV) bypass system was used to induce a continuous pulmonary flow state. The Linehanet al. equation was then used to predict the pressure from the flow under continuous flow conditions. The diameter-derived DC was 2.4%/mmHg (+/-0.4%), whereas the surface area-based DC was 4.1 %/mmHg (+/-0.1%). An increase in continuous flow was associated with a constant decrease in resistance, which correlated with the diameter-based DC (r=-0.8407, p=0.044) and the surface area-based DC (r=-0.8986, p=0.028). In contrast to the Linehanet al. equation, our results showed constant or even decreasing pressure as flow increased. Using a model of continuous pulmonary flow induced by an RV assist system, pulmonary pressure could not be predicted based on the flow using the Linehanet al. equation. Measurements of distensibility based on the diameter of the PA were inversely correlated with the resistance.

Abstract 17213: Crizotinib Exacerbates the Severity of Pah in a Preclinical Rat Model

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Francois Potus ◽  
Boucherat Olivier ◽  
Provencher Steeve ◽  
Bonnet Sébastien
Keyword(s):  
Right Ventricular ◽  
Small Cell Lung Carcinoma ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Chemotherapeutic Agents ◽  
Pulmonary Vasculature ◽  
Drug Induced ◽  
Cell Lung Carcinoma ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Introduction: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy histologically associated with remodeling of distal pulmonary arteries and right ventricular failure that is drug-induced in approximately 10% of cases. Recently, PAH induced by chemotherapeutic agents such as RTK inhibitors (e.g. dasatinib) has been described. Crizotinib is a new MET inhibitor increasingly used for the treatment of ALK-positive non-small cell lung carcinoma. Interestingly, crizotinib has been shown to induce endothelial cells (EC) dysfunction (e.g. inhibition of EC survival and angiogenesis) and is symptomatically associated with dyspnea and peripheral oedema in many patients, which are cardinal symptoms of PAH. We thus hypothesized that chronic administration of crizotinib exacerbates PAH. Material and results: We observed a significant increase of mortality rate in PAH rats (Sugen/hypoxia model) treated with daily oral administration of crizotinib (100mg/kg/d for 2 weeks) compared to rats treated with vehicle (6/group; p<0.05). Furthermore, we demonstrated that crizotinib treatment was associated with increases in right ventricular systolic pressure, mean pulmonary arterial pressure and pulmonary vasculature resistance; and decreases in cardiac output and stroke volume (right heart catheterizations in closed chest) compared to vehicle-treated rats with Sugen-induced PAH (4 PAH+crizotinib; 6 PAH+vehicle, 5 PAH and 3 control rats; p<0.05). Histologically, crizotinib administration significantly increased pulmonary arteries wall thickness as well as right ventricular fibrosis (p<0.05). Finally, crizotinib increased macrophage accumulation and size within the lungs of PAH rats (p<0.05). Conclusion: We documented for the first time that crizotinib treatment markedly increases vascular remodeling and macrophage activation with concomitantly marked PAH exacerbation in Sugen rats. This study could have major clinical relevance in the management of patients treated with crizotinib.

Right Ventricular Response to Pulmonary Arterial Stiffening in a Canine Model of Acute Embolization

2012 ◽  
Author(s):  
Alessandro Bellofiore ◽  
Alejandro Roldan-Alzate ◽  
Matthieu Besse ◽  
Heidi B. Kellihan ◽  
Daniel W. Consigny ◽  
...  
Keyword(s):  
Heart Failure ◽  
Right Ventricular ◽  
Poor Prognosis ◽  
Pulmonary Arterial Pressure ◽  
Canine Model ◽  
Pulmonary Vasculature ◽  
Mean Pulmonary Arterial Pressure ◽  
Fast Progression ◽  
Ventricular Response ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a devastating disease exhibiting fast progression [1] and poor prognosis [2]. PAH originates from an increased resistance to blood flow in the distal pulmonary vasculature and in the later stages of the disease leads to right ventricular (RV) functional impairment and subsequent heart failure, which in most cases is the direct cause of demise. In PAH, RV failure appears to be correlated to PA stiffening, which is a better predictor of mortality than the direct increases in mean pulmonary arterial pressure (mPAP) and pulmonary vasculature resistance (PVR) [3,4].

Abstract 15665: Can Pulmonary Vasodilators Grow Pulmonary Vasculature in Cases With Bidirectional Glenn for Fontan Candidates?

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kousuke Yonehara
Keyword(s):  
Fontan Procedure ◽  
Pde5 Inhibitor ◽  
Pulmonary Arteries ◽  
Operative Management ◽  
Pulmonary Vasculature ◽  
Endothelin Receptor ◽  
Cross Sectional ◽  
Pulmonary Vasodilators ◽  
Pulmonary Flow ◽  
Fontan Patients

Background: The condition of pulmonary vasculature is a key to determine the outcome of Fontan candidates. The previous reports described no significant growth of pulmonary arteries (PA) after having bi-directional Glenn shunt (BDG), which may influence peri- and post-operative management of Fontan procedure. Aim: We hypothesized the pulmonary vasodilators (PVDs) facilitate to grow small PA even after BDG in Fontan Candidates. Method: The twenty-one cases after BDG, whose PA index (Nakata index) were less than 140 mm 2 /m 2 , were enrolled. The enrolled cases were divided into two group: 15 with PVDs treatment ( PV+) and 6 without (PV-). PVDs used in this study were PDE5 inhibitor, Endothelin-receptor-blocker, oral prostacyclines , and their combination. In addition to measure the hemodynamic parameters ( mean PA pressure(mPAp), indexed pulmonary vascular resistance (Rp), Pulmonary flow (Qp) ), PA index and PA branch index ( a sum of cross-sectional area of first PA branches at both side indexed by body surface area) were measured and compared at the timing of after BDG and at after Fontan completion, respectively. Result: PA index and PA branch index after BDG of (PV+) and (PV-)were 104±33 vs 104±17 mm 2 /m 2 : 151±33 vs 194±45 mm 2 /m 2 . PA index in both groups after Fontan procedure was increased up to 153±42 vs 152±56 mm 2 /m 2 in same fashion, while PA branch index of (PV+) was significantly increased up to 199±60 than that of (PV-) 226±65 mm 2 /m 2 (% increase was 131% vs 116%). Rp and mPAp in both groups were not changed , while Qp in (PV+) was significantly more increased (140%) than that in (PV-)(107%). In conclusion, PVDs facilitates the growth of PA branches by increasing Qp, which brings a favor outcome of Fontan patients.

scholarly journals Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities

2017 ◽  
Vol 8 (2-3) ◽  
pp. 47-64 ◽  
Author(s):  
Jessica B. Badlam ◽  
Todd M. Bull
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Response To Treatment ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
Efficacy Parameters

Pulmonary arterial hypertension (PAH) is a chronic disease that results in narrowing of the small pre-capillary pulmonary arteries leading to elevation of pulmonary artery pressure and pulmonary vascular resistance, subsequent right ventricular failure, and if unchecked, death. Advances in the treatment of PAH over the last two decades have markedly improved survival. These improvements reflect a combination of changes in treatments, improved patient care strategies, and varying disease phenotypes in the PAH population. Currently approved therapies for PAH are directed at the recognized abnormalities within the pulmonary vasculature and include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Most of these drugs have been approved on the basis of short-term trials that mainly demonstrated improvements in exercise capacity. More recently, long-term, event-driven trials of novel drugs have been performed, demonstrating new efficacy parameters. There have also been exciting advances in the understanding of right heart failure pathophysiology in PAH that have the potential to inspire the development of right ventricular targeted therapy and continued discoveries in the heterogeneity of disease and response to treatment has great potential for developing more ‘personalized’ therapeutic options. In this article, we review the current available data regarding the management of PAH, with an emphasis on the pharmacologic therapies and discussion of novel therapeutic directions for the treatment of this fatal disease.

scholarly journals Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 638
Author(s):  
Shahood Fazal ◽  
Malik Bisserier ◽  
Lahouaria Hadri
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Genetic Variants ◽  
High Throughput Sequencing ◽  
Molecular Genetic ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Common Genetic Variants ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.

scholarly journals A Novel In Vivo Approach to Assess Radial and Axial Distensibility of Large and Intermediate Pulmonary Artery Branches

2015 ◽  
Vol 137 (4) ◽  
Author(s):  
A. Bellofiore ◽  
J. Henningsen ◽  
C. G. Lepak ◽  
L. Tian ◽  
A. Roldan-Alzate ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Ex Vivo ◽  
Critical Role ◽  
Pulmonary Arteries ◽  
Stretch Ratio ◽  
Mechanical Tests ◽  
Right Heart Catheterization ◽  
Pulmonary Vasculature ◽  
Heart Catheterization

Pulmonary arteries (PAs) distend to accommodate increases in cardiac output. PA distensibility protects the right ventricle (RV) from excessive increases in pressure. Loss of PA distensibility plays a critical role in the fatal progression of pulmonary arterial hypertension (PAH) toward RV failure. However, it is unclear how PA distensibility is distributed across the generations of PA branches, mainly because of the lack of appropriate in vivo methods to measure distensibility of vessels other than the large, conduit PAs. In this study, we propose a novel approach to assess the distensibility of individual PA branches. The metric of PA distensibility we used is the slope of the stretch ratio–pressure relationship. To measure distensibility, we combined invasive measurements of mean PA pressure with angiographic imaging of the PA network of six healthy female dogs. Stacks of 2D images of the PAs, obtained from either contrast enhanced magnetic resonance angiography (CE-MRA) or computed tomography digital subtraction angiography (CT-DSA), were used to reconstruct 3D surface models of the PA network, from the first bifurcation down to the sixth generation of branches. For each branch of the PA, we calculated radial and longitudinal stretch between baseline and a pressurized state obtained via acute embolization of the pulmonary vasculature. Our results indicated that large and intermediate PA branches have a radial distensibility consistently close to 2%/mmHg. Our axial distensibility data, albeit affected by larger variability, suggested that the PAs distal to the first generation may not significantly elongate in vivo, presumably due to spatial constraints. Results from both angiographic techniques were comparable to data from established phase-contrast (PC) magnetic resonance imaging (MRI) and ex vivo mechanical tests, which can only be used in the first branch generation. Our novel method can be used to characterize PA distensibility in PAH patients undergoing clinical right heart catheterization (RHC) in combination with MRI.

α1-Adrenoceptor-dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension

2007 ◽  
Vol 292 (5) ◽  
pp. H2316-H2323 ◽  
Author(s):  
James E. Faber ◽  
Caroline L. Szymeczek ◽  
Susanna Cotecchia ◽  
Steven A. Thomas ◽  
Akito Tanoue ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Pulmonary Arteries ◽  
Vascular Wall ◽  
Ventricular Pressure ◽  
Hypoxic Pulmonary Hypertension ◽  
Oxygen Fraction ◽  
Stimulation Of

Excessive proliferation of vascular wall cells underlies the development of elevated vascular resistance in hypoxic pulmonary hypertension (PH), but the responsible mechanisms remain unclear. Growth-promoting effects of catecholamines may contribute. Hypoxemia causes sympathoexcitation, and prolonged stimulation of α1-adrenoceptors (α1-ARs) induces hypertrophy and hyperplasia of arterial smooth muscle cells and adventitial fibroblasts. Catecholamine trophic actions in arteries are enhanced when other conditions favoring growth or remodeling are present, e.g., injury or altered shear stress, in isolated pulmonary arteries from rats with hypoxic PH. The present study examined the hypothesis that catecholamines contribute to pulmonary vascular remodeling in vivo in hypoxic PH. Mice genetically deficient in norepinephrine and epinephrine production [dopamine β-hydroxylase−/− (DBH−/−)] or α1-ARs were examined for alterations in PH, cardiac hypertrophy, and vascular remodeling after 21 days exposure to normobaric 0.1 inspired oxygen fraction (FiO2). A decrease in the lumen area and an increase in the wall thickness of arteries were strongly inhibited in knockout mice (order of extent of inhibition: DBH−/− = α1D-AR−/− > α1B-AR−/−). Distal muscularization of small arterioles was also reduced (DBH−/− > α1D-AR−/− > α1B-AR−/− mice). Despite these reductions, increases in right ventricular pressure and hypertrophy were not attenuated in DBH−/− and α1B-AR−/− mice. However, hematocrit increased more in these mice, possibly as a consequence of impaired cardiovascular activation that occurs during reduction of FiO2. In contrast, in α1D-AR−/− mice, where hematocrit increased the same as in wild-type mice, right ventricular pressure was reduced. These data suggest that catecholamine stimulation of α1B- and α1D-ARs contributes significantly to vascular remodeling in hypoxic PH.

scholarly journals A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism

2019 ◽  
Vol 116 (8) ◽  
pp. 1500-1513
Author(s):  
Carly Jones ◽  
Malik Bisserier ◽  
Carlos Bueno-Beti ◽  
Guillaume Bonnet ◽  
Susana Neves-Zaph ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Adenosine Monophosphate ◽  
Cell Types ◽  
Pulmonary Vasculature ◽  
Intracellular Camp ◽  
Camp Pathway ◽  
Extracellular Camp

Abstract Aims Cyclic adenosine monophosphate (cAMP) is the predominant intracellular second messenger that transduces signals from Gs-coupled receptors. Intriguingly, there is evidence from various cell types that an extracellular cAMP pathway is active in the extracellular space. Herein, we investigated the role of extracellular cAMP in the lung and examined whether it may act on pulmonary vascular cell proliferation and pulmonary vasculature remodelling in the pathogenesis of pulmonary hypertension (PH). Methods and results The expression of cyclic AMP-metabolizing enzymes was increased in lungs from patients with PH as well as in rats treated with monocrotaline and mice exposed to Sugen/hypoxia. We report that inhibition of the endogenous extracellular cAMP pathway exacerbated Sugen/hypoxia-induced lung remodelling. We found that application of extracellular cAMP induced an increase in intracellular cAMP levels and inhibited proliferation and migration of pulmonary vascular cells in vitro. Extracellular cAMP infusion in two in vivo PH models prevented and reversed pulmonary and cardiac remodelling associated with PH. Using protein expression analysis along with luciferase assays, we found that extracellular cAMP acts via the A2R/PKA/CREB/p53/Cyclin D1 pathway. Conclusions Taken together, our data reveal the presence of an extracellular cAMP pathway in pulmonary arteries that attempts to protect the lung during PH, and suggest targeting of the extracellular cAMP signalling pathway to limit pulmonary vascular remodelling and PH.

17β-Estradiol increases nitric oxide-dependent dilation in rat pulmonary arteries and thoracic aorta

2001 ◽  
Vol 280 (3) ◽  
pp. L555-L564 ◽  
Author(s):  
Rayna J. Gonzales ◽  
Benjimen R. Walker ◽  
Nancy L. Kanagy
Keyword(s):  
Nitric Oxide ◽  
Rnase Protection Assay ◽  
Pulmonary Arteries ◽  
Treated Group ◽  
Pulmonary Vasculature ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Rnase Protection ◽  
17Β Estradiol

Past studies have demonstrated that 17β-estradiol (E2β) increases endothelial nitric oxide (NO) synthase (eNOS) activity in uterine, heart, and skeletal muscle and in cultured human endothelial cells. However, little is known about E2β regulation of NO synthesis in the pulmonary vasculature. The present study evaluated E2β regulation of eNOS function in pulmonary arteries and thoracic aortas. We hypothesized that E2β upregulates vascular NO release by increasing eNOS expression. To test this, NO-dependent vasodilation was assessed in isolated perfused lungs and aortic rings from ovariectomized Sprague-Dawley rats treated for 1 wk with 20 μg/24 h of E2β or vehicle. Expression of eNOS was evaluated by Western blot and immunohistochemistry. Also, a RNase protection assay determined eNOS mRNA levels in lung and aortic homogenates from control and treated rats. Vasodilation to ionomycin in lungs from the E2β-treated group was enhanced compared with that in control animals. Endothelium-intact aortic rings from E2β-treated animals also demonstrated augmented endothelium-dependent dilation. Both responses were blocked with NOS inhibition. Immunostaining for eNOS was greater in pulmonary arteries and aortas from E2β-treated compared with control rats. However, mRNA levels did not differ between groups. Thus we conclude that in vivo E2β treatment augments endothelium-dependent dilation in aorta and lung, increasing expression of eNOS independently of sustained augmented gene transcription.

scholarly journals Морфологические изменения в динамике легочной артериальной гипертензии, индуцированной монокроталином в эксперименте in vivo

2020 ◽  
Author(s):  
I.E. Adzericho ◽  
O.N. Jacevich ◽  
T.E. Vladimirskaja ◽  
D.L. Mihnevich
Keyword(s):  
Right Ventricular ◽  
Time Windows ◽  
Pulmonary Arteries ◽  
Male Rats ◽  
Aseptic Necrosis ◽  
Morphological Alterations ◽  
Morphological Studies ◽  
Perivascular Inflammation ◽  
Medial Hypertrophy

Цель исследования - изучение временной динамики морфологических изменений легочной ткани и миокарда правого желудочка у крыс на модели легочной артериальной гипертензии, индуцированной монокроталином. Методика. Исследование выполнено на 80 беспородных белых крысах. Для моделирования легочной артериальной гипертензии крысам вводили подкожно монокроталин в дозе 60 мг/кг. Материал для морфологического исследования (образцы тканей легких и миокарда) брали через 2, 4, 6 и 8 нед после введения монокроталина. Контролем служили образцы соответствующих тканей интактных животных. Результаты. В течение первых 4 нед эксперимента выявлялись начальные признаки структурного ремоделирования легочной ткани и миокарда. Это проявлялось гипертрофией медиального слоя легочных артерий с сохранением сосудистого просвета на фоне незначительных периваскулярных лимфоцитарных инфильтратов, появлением признаков активации апоптотической гибели эндотелиоцитов, а также сегментарными повреждениями кардиомиоцитов с развитием гипертрофии правого желудочка. К концу эксперимента наблюдались необратимые прогрессирующие во времени патологические изменения в исследуемых тканях. В легочной ткани появлялись участки плексиформной артериопатии, а также полное закрытие просвета легочных сосудов с выраженной околососудистой реакцией. Облитерация просвета сосудов обусловлена как гипертрофией медии, так и выраженным фиброзом интимы. В правом желудочке были обнаружены признаки мелкоочагового некроза кардиомиоцитов с участками заместительного фиброза и развитием дилатации правых отделов сердца. Заключение. В эксперименте in vivo установлены временные интервалы обратимости морфологических изменений легочной ткани и миокарда правых отделов сердца, характерные для легочной артериальной гипертензии.Objective. To investigate the dynamics of pathomorphological changes in lung and right ventricular tissues in rats following injections of 60 mg/kg monocrotaline for 8 weeks. Methods. The study was performed on white mongrel male rats treated with monocrotaline 60 mg/kg, s.c. Samples of lung and heart tissues were collected for morphological studies every two weeks following the monocrotaline treatment. Results. In the first four weeks of the experiment, initial signs of structural remodeling were observed in the lungs and myocardium. These signs were evident as medial hypertrophy of pulmonary arteries with preserved lumen and minor perivascular infiltrates; increased apoptosis of endothelial cells; and segmental injury of cardiomyocytes with right ventricular hypertrophy. Irreversible, progressive pathology was observed in studied tissues by the end of experiment, which included occlusion of the vascular lumen in pulmonary arteries due to intimal fibrosis and medial hypertrophy in the lung tissue affected by perivascular inflammation. Plexiform arteriopathy was established in some samples at 8 weeks. Right ventricular cardiomyocytes showed aseptic necrosis with transformation into reactive fibrosis and right heart dilatation. Conclusion. This in vivo study established the time windows for reversibility of morphological alterations in lung and myocardial tissues characteristic of pulmonary arterial hypertension.

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