Pulmonary Arteriovenous Pressure Gradient and Time-Averaged Mean Velocity of Small Pulmonary Arteries Can Serve as Sensitive Biomarkers in the Diagnosis of Pulmonary Arterial Hypertension: A Preclinical Study by 4D-Flow MRI

(1) Background: Pulmonary arterial hypertension (PAH) is a serious condition that is associated with many cardiopulmonary diseases. Invasive right heart catheterization (RHC) is currently the only method for the definitive diagnosis and follow-up of PAH. In this study, we sought a non-invasive hemodynamic biomarker for the diagnosis of PAH. (2) Methods: We applied prospectively respiratory and cardiac gated 4D-flow MRI at a 9.4T preclinical scanner on three different groups of Sprague Dawley rats: baseline (n = 11), moderate PAH (n = 8), and severe PAH (n = 8). The pressure gradients as well as the velocity values were analyzed from 4D-flow data and correlated with lung histology. (3) Results: The pressure gradient between the pulmonary artery and vein on the unilateral side as well as the time-averaged mean velocity values of the small pulmonary arteries were capable of distinguishing not only between baseline and severe PAH, but also between the moderate and severe stages of the disease. (4) Conclusions: The current preclinical study suggests the pulmonary arteriovenous pressure gradient and the time-averaged mean velocity as potential biomarkers to diagnose PAH.

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Altered Right Ventricular Kinetic Energy Work Density and Viscous Energy Dissipation in Patients with Pulmonary Arterial Hypertension: A Pilot Study Using 4D Flow MRI

PLoS ONE ◽

10.1371/journal.pone.0138365 ◽

2015 ◽

Vol 10 (9) ◽

pp. e0138365 ◽

Cited By ~ 18

Author(s):

Q. Joyce Han ◽

Walter R. T. Witschey ◽

Christopher M. Fang-Yen ◽

Jeffrey S. Arkles ◽

Alex J. Barker ◽

...

Keyword(s):

Pilot Study ◽

Pulmonary Arterial Hypertension ◽

Energy Dissipation ◽

Kinetic Energy ◽

Arterial Hypertension ◽

Right Ventricular ◽

4D Flow Mri ◽

4D Flow ◽

Flow Mri ◽

Pulmonary Arterial

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Abstract 14367: Abnormal Pulmonary Flow is Associated With Impaired Right Ventricular Coupling in Patients With COPD

Circulation ◽

10.1161/circ.142.suppl_3.14367 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ani Oganesyan ◽

Alex J Barker ◽

Benjamin S Frank ◽

Dunbar D IVY ◽

Lorna Browne ◽

...

Keyword(s):

Strong Association ◽

Pulmonary Arteries ◽

Healthy Controls ◽

4D Flow Mri ◽

4D Flow ◽

Pulmonary Flow ◽

Copd Patients ◽

Flow Mri ◽

Pulmonary Arterial ◽

Rv Function

Introduction: Cor Pulmonale or right ventricular (RV) dysfunction due to pulmonary disease is an expected complication of COPD resulting from increased afterload mediated by hypoxic pulmonary vasoconstriction as well as the destruction of the pulmonary vascular bed. Early detection of elevated RV afterload has been previously demonstrated by visualization of abnormal flow patterns in the proximal pulmonary arteries. Prior quantitative analysis of helicity in the pulmonary arteries of pulmonary hypertension patients has demonstrated a strong association between helicity and increased RV afterload. Hypothesis: Patients with COPD will have abnormal pulmonary flow as evaluated by 4D-Flow MRI and associated with RV function and pulmonary arterial stiffness. Methods: Patients with COPD (n=15) (65yrs ± 6) and controls (n=10) (58yrs ± 9) underwent 4D-Flow MRI to calculate helicity (Figure 1A). The helicity was calculated in 2 segments: 1) the main pulmonary artery (MPA) and 2) along the RV outflow tract (RVOT) - MPA axis. Main pulmonary arterial stiffness was measured using the relative area change (RAC). Results: COPD patients had decreased helicity relative to healthy controls in the MPA (19.4±7.8 vs 32.8±15.9 s -2 , P=0.007) (Figure 1B). Additionally, COPD patients had reduced helicity along the RVOT-MPA axis (33.2±9.0 vs 43.5±8.3 s -2 , P=0.010). The helicity measured in the MPA was associated with RV end-systolic volume (R=0.59, P = 0.002), RVEF (R=0.631, P<0.001), RAC (R=-0.61, P=0.001). e combined helicity along the MPA-RVOT axis was associated with RVEF (R=0.74, P<0.001), RVESV (R=-0.57, P=0.004), and RAC (R=0.42, P=0.005). Conclusion: Patients with COPD show quantitatively abnormal flow hemodynamics, when compared with healthy controls, as assessed by 4D-Flow MRI. A strong association between helicity along the MPA-RV outflow tract axis and RV function suggests that 4D-Flow MRI might be a sensitive tool in evaluating RV - pulmonary arterial coupling in COPD.

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Why septal motion is a marker of right ventricular failure in pulmonary arterial hypertension: mechanistic analysis using a computer model

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00596.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. H691-H700 ◽

Cited By ~ 14

Author(s):

Georgina Palau-Caballero ◽

John Walmsley ◽

Vanessa Van Empel ◽

Joost Lumens ◽

Tammo Delhaas

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pressure Gradient ◽

Right Ventricular ◽

Left Ventricular ◽

Contractile Dysfunction ◽

Ventricular Relaxation ◽

Pulmonary Arterial ◽

Rv Function ◽

Septal Motion

Rapid leftward septal motion (RLSM) during early left ventricular (LV) diastole is observed in patients with pulmonary arterial hypertension (PAH). RLSM exacerbates right ventricular (RV) systolic dysfunction and impairs LV filling. Increased RV wall tension caused by increased RV afterload has been suggested to cause interventricular relaxation dyssynchrony and RLSM in PAH. Simulations using the CircAdapt computational model were used to unravel the mechanism underlying RLSM by mechanistically linking myocardial tissue and pump function. Simulations of healthy circulation and mild, moderate, and severe PAH were performed. We also assessed the effects on RLSM when PAH coexists with RV or LV contractile dysfunction. Our results showed prolonged RV shortening in PAH causing interventricular relaxation dyssynchrony and RLSM. RLSM was observed in both moderate and severe PAH. A negative transseptal pressure gradient only occurred in severe PAH, demonstrating that negative pressure gradient does not entirely explain septal motion abnormalities. PAH coexisting with RV contractile dysfunction exacerbated both interventricular relaxation dyssynchrony and RLSM. LV contractile dysfunction reduced both interventricular relaxation dyssynchrony and RLSM. In conclusion, dyssynchrony in ventricular relaxation causes RLSM in PAH. Onset of RLSM in patients with PAH appears to indicate a worsening in RV function and hence can be used as a sign of RV failure. However, altered RLSM does not necessarily imply an altered RV afterload, but it can also indicate altered interplay of RV and LV contractile function. Reduction of RLSM can result from either improved RV function or a deterioration of LV function. NEW & NOTEWORTHY A novel approach describes the mechanism underlying abnormal septal dynamics in pulmonary arterial hypertension. Change in motion is not uniquely induced by altered right ventricular afterload, but also by altered ventricular relaxation dyssynchrony. Extension or change in motion is a marker reflecting interplay between right and left ventricular contractility.

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A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension

European Respiratory Journal ◽

10.1183/13993003.02638-2017 ◽

2018 ◽

Vol 51 (6) ◽

pp. 1702638 ◽

Cited By ~ 78

Author(s):

Anna R. Hemnes ◽

Anandharajan Rathinasabapathy ◽

Eric A. Austin ◽

Evan L. Brittain ◽

Erica J. Carrier ◽

...

Keyword(s):

Pilot Study ◽

Pulmonary Arterial Hypertension ◽

Angiotensin Converting Enzyme ◽

Arterial Hypertension ◽

Pulmonary Arteries ◽

Converting Enzyme ◽

Open Label ◽

Angiotensin Converting Enzyme 2 ◽

Markers Of Inflammation ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1–7) (Ang-(1–7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1–7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg−1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2–4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

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Abstract 3570: A Critical and Novel Role of Nogo (Neurite Outgrowth Inhibitor) in Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circ.118.suppl_18.s_446-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Gopinath Sutendra ◽

Sebastien Bonnet ◽

Paulette Wright ◽

Peter Dromparis ◽

Alois Haromy ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Nuclear Translocation ◽

Pulmonary Arteries ◽

Over Expression ◽

Nfat Activation ◽

Pulmonary Arterial ◽

Systemic Arteries

Nogo was first identified as an inhibitor of neuronal axonal regeneration. Recently, Nogo-B was implicated in the proliferative and anti-apoptotic remodeling in systemic arteries; reduced Nogo-B expression was seen in remodeled mouse femoral arteries following injury. Pulmonary arterial hypertension (PAH) is also characterized by proliferative/anti-apoptotic remodeling in pulmonary arteries (PA), sparing systemic vessels. PAH PA smooth muscle cells (PASMC) are characterized by mitochondrial hyperpolarization (increased ΔΨm), decreased production of reactive oxygen species (ROS) (suppressing mitochondria-dependent apoptosis), down-regulation of Kv1.5 and activation of the transcription factor NFAT (promoting contraction and proliferation). We found that in contrast to systemic vessels, Nogo-B expression is significantly increased in vivo and in vitro in PAs and PASMCs from patients (n=6) and mice (n=42) with PAH, compared to normals. We hypothesized that Nogo is involved in the pathogenesis of PAH . Nogo −/− mice (n=7) had a normal phenotype and, in contrast to Nogo +/+ , did not develop chronic hypoxia (CH)-induced PAH assessed invasively (catheterization, RV/LV+Septum) and non-invasively (pulmonary artery acceleration time and treadmill performance) (n=7, Table ). CH- Nogo +/+ PASMC had the expected increase in ΔΨm (measured by TMRM), decreased ROS (MitoSOX), increased [Ca ++ ] i (FLUO3), decreased Kv1.5 (immunohistochemistry) and NFAT activation (nuclear translocation). None of these changes occurred in CH- Nogo −/− PASMC while all were induced in normoxic Nogo +/+ PASMC by adenoviral over-expression of Nogo-B . Heterozygote CH- Nogo +/− (n=7) values were between Nogo −/− and Nogo +/+ suggesting a gene dose-dependent effect. Nogo is over-expressed in human and rodent PAH and induces critical features of the PAH phenotype. Nogo targeting might represent a novel and selective therapeutic strategy for PAH. Table

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Abstract 15120: Nanoparticle-Mediated Delivery of Pitavastatin into Small Pulmonary Arteies by Intravenous Administration Attenuated the Progression of Already Established Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Circulation ◽

10.1161/circ.130.suppl_2.15120 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Kenzo Ichimura ◽

Tetsuya Matoba ◽

Ryoji Nagahama ◽

Kaku Nakano ◽

Kenji Sunagawa ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Intravenous Administration ◽

Pulmonary Arteries ◽

Intratracheal Instillation ◽

Poly Lactic Acid ◽

Bolus Administration ◽

Sprague Dawley ◽

Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) is an intractable disease of small pulmonary artery in which multiple pathogenetic factors are involved. We have previously reported that poly(lactic acid/glycolic acid) (PLGA) nanoparticle (NP)-mediated targeting of pitavastatin into lungs by intratracheal instillation attenuated the development of PAH. In the present study we examined the effects of intravenous treatment with pitavastatin-NPs on the progression of already established PAH induced by monocrotaline (MCT). Methods and Results: Male Sprague-Dawley rats (200 to 230 g) were injected subcutaneously with 60 mg/kg MCT to induce PAH. At day 17 after MCT injection when PAH had been already established, animals were randomly divided into 4 groups, which treated with intravenous daily bolus administration of the following drugs for consecutive 4 days from 17 to 20 days after MCT injection; 1) vehicle, 2) FITC-NPs, 3) pitavastatin alone (1, 3, 10 or 30 mg/kg), or 4) pitavastatin-NPs (containing 1 or 3 mg/kg pitavastatin). Treatment with pitavastatin-NPs, but not with pitavastatin alone attenuated the progression of established PAH (Fig. A) associated with the reduction of inflammation and small pulmonary artery remodeling (stenosis and obstruction of pulmonary arterial branches) (Fig. B). In trace experiments, intravenous administration of FITC-NPs revealed the targeting of FITC-NPs into small pulmonary artery in rats with MCT-induced PAH, but not in normal animals. Importantly, in a separate protocol, treatment with pitavastatin-NPs improved the survival rate at day 35 (30% in pitavastatin-NP group vs. 61% in FITC-NP group, P<0.05 by Kaplan-Meier). Conclusion: A novel NP-mediated targeting of pitavastatin into small pulmonary arteries by intravenous administration attenuated the progression of established PAH and improved survival associated with anti-inflammatory and anti-remodeling effects in a rat model of MCT-induced PAH.

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Echocardiography and Pulmonary Arterial Hypertension

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2007.440 ◽

2016 ◽

Vol 68 (4) ◽

Author(s):

Eduardo Bossone ◽

Rodolfo Citro ◽

Alberto Ruggiero ◽

Bettina Kuersten ◽

Giovanni Gregorio ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Structural Changes ◽

Pulmonary Arteries ◽

Progressive Increase ◽

Accurate Estimate ◽

Therapeutic Interventions ◽

Wide Range ◽

Advanced Stages ◽

Pulmonary Arterial

Pulmonary Arterial Hypertension (PAH) is an heterogeneous condition brought on by a wide range of causes. It is characterized by structural changes in small pulmonary arteries, that produce a progressive increase in pulmonary artery pressure and pulmonary vascular resistance, ultimately leading to right ventricle failure and death. Given the non-specific nature of its early symptoms and signs, PAH is often diagnosed in its advanced stages. Along with a careful clinical assessment and an accurate electrocardiogram/Chest X-ray interpretation, echocardiography is an essential test in the evaluation of patient with PAH. In fact it not only provides an accurate estimate of pulmonary pressure at rest and during exercise, but may also help to exclude any secondary causes, predict the prognosis, monitor the efficacy of specific therapeutic interventions and detect the preclinical stage of the disease.

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At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension

Genes ◽

10.3390/genes11111371 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1371

Author(s):

Meghan M. Cirulis ◽

Mark W. Dodson ◽

Lynn M. Brown ◽

Samuel M. Brown ◽

Tim Lahm ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Bone Morphogenetic Protein ◽

Pulmonary Arteries ◽

Bmp Signaling ◽

Signaling Cascades ◽

Estrogen Signaling ◽

Protein Receptor ◽

Morphogenetic Protein ◽

Pulmonary Arterial

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

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Estrogen metabolites in a small cohort of patients with idiopathic pulmonary arterial hypertension

Pulmonary Circulation ◽

10.1177/2045894020908783 ◽

2020 ◽

Vol 10 (1) ◽

pp. 204589402090878

Author(s):

Nina Denver ◽

Natalie Z.M. Homer ◽

Ruth Andrew ◽

Katie Y. Harvey ◽

Nicholas Morrell ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Arteries ◽

Metabolite Profile ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Proof Of Concept ◽

Increased Risk ◽

Small Cohort ◽

Pulmonary Arterial ◽

Estradiol Metabolism

Increased risk and severity of idiopathic pulmonary arterial hypertension (iPAH) is associated with elevated estradiol in men and postmenopausal women. Pulmonary arteries synthesise estradiol via aromatase and metabolise it via CYP1B1 to mitogenic metabolites; SNPs in aromatase and CYP1B1 have been associated with PAH. This suggests that estradiol metabolism could be altered in iPAH. This proof-of-concept study profiles estradiol and several metabolites of estradiol simultaneously in serum from iPAH patients and controls. We show that the estradiol and metabolite profile is altered in iPAH and that 16-hydroxyestrone and 16-hydroxyestradiol accumulate in iPAH patients with 16-hydroxyestrone levels relating to disease severity.

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