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Advances in Research on Pulmonary Hypertension 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 February 2024) | Viewed by 11277

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Dr. Alberto M. Marra

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Department of Translational Medical Sciences, University of Naples Federico II, 80138 Naples, Italy
Interests: pulmonary hypertension; right heart failure; heart failure with preserved ejection fraction
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Dear Colleagues,

Pulmonary hypertension is a common clinical condition defined by the presence of increased pressure in the pulmonary artery (PH). Several diseases may cause PH, chiefly PH due to left heart disease accounts for ¾ of PH cases, in which an increase in pulmonary pressure in these patients is not only merely due to backward transmission of increased left ventricle filling pressure, but in some cases also to superimposed phenomena of pulmonary vascular remodeling. Similarly to PH caused by lung parenchymal disease, the second most common PH form seems to be not only a consequence of lung parenchymal damage but, similarly to PH, due to left heart disease, a consistent body of evidence suggest a possible role of lung microcirculation. Chronic thromboembolic pulmonary hypertension (CTEPH) can be secondary to steric obstruction of thrombi in the main pulmonary artery but may account also for vascular remodeling due to hyper perfusion of non-obstructed lung segments. Last but not least, pulmonary arterial hypertension (PAH) is a rare but well characterized form of PH, whose hallmark is a progressive and uncontrolled lung vascular remodeling. Endothelial cells (ECs) dysfunction and aberrant proliferation of pulmonary arterial smooth muscle cells (PASMCs) and fibroblasts lead to progressive obliteration of the precapillary vessels which finally results, inexorably, to increased pulmonary vascular resistance, right heart failure and death. Right heart failure is indeed the end stage of all PH forms and is strongly associated with poor outcome.

This Special Issue is a continuation of the Special Issue "Advances Research on Pulmonary Hypertension", focuses on molecular mechanisms in different form of PH and right heart failure. We warmly welcome submissions, including original papers and reviews, on this widely discussed topic.

Dr. Alberto M. Marra
Guest Editor

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Keywords

pulmonary hypertension
right heart Failure
pulmonary arterial hypertension
left heart disease
PH due to lung parenchymal disease
chronic thromboembolic pulmonary hypertension
endothelial dysfunction
lung microcirculation

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Advances Research on Pulmonary Hypertension in International Journal of Molecular Sciences (6 articles)

Published Papers (9 papers)

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Research

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16 pages, 3878 KiB

Open AccessArticle

A Novel Rat Model of Mild Pulmonary Hypertension Associated with Pulmonary Venous Congestion Induced by Left Pulmonary Vein Banding

by Jonas Münks, Athiththan Yogeswaran, Tobiah Kevin Antoine, Leonhard Anton Blumrich, Peter Dorfmüller, Hossein Ardeschir Ghofrani, Birgit Assmus, Ralph Theo Schermuly and Akylbek Sydykov

Int. J. Mol. Sci. 2024, 25(5), 2827; https://doi.org/10.3390/ijms25052827 - 29 Feb 2024

Viewed by 476

Abstract

Pulmonary hypertension (PH) associated with left heart disease (PH-LHD) is the most common form of PH. In PH-LHD, changes in the pulmonary vasculature are assumed to be mainly caused by pulmonary venous congestion. However, the underlying mechanisms of this form of PH are poorly understood. We aimed to establish a model of PH associated with pulmonary venous congestion. Wistar–Kyoto rats underwent partial occlusion of the left pulmonary vein to induce pulmonary venous congestion or sham surgery and were assessed at various time points post-surgery (3, 6, 9, 12 weeks). In vivo cardiopulmonary phenotyping was performed by using echocardiography along with heart catheterization. Histomorphometry methods were used to assess pulmonary vascular remodeling (e.g., wall thickness, degree of muscularization). Left pulmonary vein banding (PVB) resulted in mildly elevated right ventricular systolic pressure and moderate right ventricular hypertrophy. In PVB rats, small- and medium-sized pulmonary vessels in the left lung were characterized by increased wall thickness and muscularization. Taken together, our data demonstrate that left PVB-induced pulmonary venous congestion is associated with pulmonary vascular remodeling and mild PH. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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20 pages, 4782 KiB

Open AccessArticle

Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants

by Mei-Tzu Wang, Ken-Pen Weng, Sheng-Kai Chang, Wei-Chun Huang and Lee-Wei Chen

Int. J. Mol. Sci. 2024, 25(5), 2734; https://doi.org/10.3390/ijms25052734 - 27 Feb 2024

Viewed by 568

Abstract

Asians have a higher carrier rate of pulmonary arterial hypertension (PAH)-related genetic variants than Caucasians do. This study aimed to identify PAH-related genetic variants using whole exome sequencing (WES) in Asian idiopathic and heritable PAH cohorts. A WES library was constructed, and candidate variants were further validated by polymerase chain reaction and Sanger sequencing in the PAH cohort. In a total of 69 patients, the highest incidence of variants was found in the BMPR2, ATP13A3, and GDF2 genes. Regarding the BMPR2 gene variants, there were two nonsense variants (c.994C>T, p. Arg332*; c.1750C>T, p. Arg584*), one missense variant (c.1478C>T, p. Thr493Ile), and one novel in-frame deletion variant (c.877_888del, p. Leu293_Ser296del). Regarding the GDF2 variants, there was one likely pathogenic nonsense variant (c.259C>T, p. Gln87*) and two missense variants (c.1207G>A, p. Val403Ile; c.38T>C, p. Leu13Pro). The BMPR2 and GDF2 variant subgroups had worse hemodynamics. Moreover, the GDF2 variant patients were younger and had a significantly lower GDF2 value (135.6 ± 36.2 pg/mL, p = 0.002) in comparison to the value in the non-BMPR2/non-GDF2 mutant group (267.8 ± 185.8 pg/mL). The BMPR2 variant carriers had worse hemodynamics compared to the patients with the non-BMPR2/non-GDF2 mutant group. Moreover, there was a significantly lower GDF2 value in the GDF2 variant carriers compared to the control group. GDF2 may be a protective or corrected modifier in certain genetic backgrounds. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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23 pages, 5207 KiB

Open AccessArticle

In the Search for Biomarkers of Pulmonary Arterial Hypertension, Are Cytokines IL-2, IL-4, IL-6, IL-10, and IFN-Gamma the Right Indicators to Use?

by Michał Tomaszewski, Paulina Mertowska, Martyna Janczewska, Agnieszka Styczeń, Sebastian Mertowski, Kamil Jonas, Ewelina Grywalska and Grzegorz Kopeć

Int. J. Mol. Sci. 2023, 24(18), 13694; https://doi.org/10.3390/ijms241813694 - 05 Sep 2023

Cited by 1 | Viewed by 1127

Abstract

Pulmonary arterial hypertension (PAH) is a complex disorder characterized by increased pressure in the pulmonary arteries, leading to right heart failure. While the exact mechanisms underlying PAH are not fully understood, cytokines have been implicated in the pathogenesis of the disease. Cytokines play a crucial role in regulating immune responses and inflammation. These small proteins also play a key role in shaping the immunophenotype, which refers to the specific characteristics and functional properties of immune cells, which can have a significant impact on the development of PAH. The aim of this study was to determine the immunophenotype and the concentration of selected cytokines, IL-2, IL-4, IL-6, IL-10, and IFN-gamma, in patients diagnosed with PAH (with particular emphasis on subtypes) in relation to healthy volunteers. Based on the obtained results, we can conclude that in patients with PAH, the functioning of the immune system is deregulated as a result of a decrease in the percentage of selected subpopulations of immune cells in peripheral blood and changes in the concentration of tested cytokines in relation to healthy volunteers. In addition, a detailed analysis showed that there are statistically significant differences between the PAH subtypes and the tested immunological parameters. This may indicate a significant role of the immune system in the pathogenesis of PAH. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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12 pages, 2125 KiB

Open AccessArticle

Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity

by Miguel A. Olivencia, Marta Villegas-Esguevillas, Maria Sancho, Bianca Barreira, Elena Paternoster, Rui Adão, María Jesús Larriba, Angel Cogolludo and Francisco Perez-Vizcaino

Int. J. Mol. Sci. 2023, 24(15), 12350; https://doi.org/10.3390/ijms241512350 - 02 Aug 2023

Cited by 1 | Viewed by 1061

Abstract

Recent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (Vdr⁻^/−). PAs were dissected and mounted in a wire myograph. Potassium membrane currents were recorded in freshly isolated PA smooth muscle cells (PASMCs) using the conventional whole-cell configuration of the patch-clamp technique. Potential vitamin D response elements (VDREs) in Kv7 channels coding genes were studied, and their protein expression was analyzed. Vdr⁻^/− mice did not show a pulmonary hypertensive phenotype, as neither right ventricular hypertrophy nor endothelial dysfunction was apparent. However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice. Furthermore, the current sensitive to XE991, a Kv7 inhibitor, was also higher in PASMCs from knockout mice. A possible VDRE was found in the gene coding for KCNE4, the regulatory subunit of Kv7.4. Accordingly, Vdr⁻^/− mice showed an increased expression of KCNE4 in the lungs, with no changes in Kv7.1 and Kv7.4. These results indicate that the absence of Vdr in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr^−/− mice, resembling animals and humans suffering from PAH. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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12 pages, 2771 KiB

Open AccessArticle

Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload

by Vitaly O. Kheyfets, Sushil Kumar, Paul M. Heerdt, Kenzo Ichimura, R. Dale Brown, Melissa Lucero, Ilham Essafri, Sarah Williams, Kurt R. Stenmark and Edda Spiekerkoetter

Int. J. Mol. Sci. 2023, 24(11), 9746; https://doi.org/10.3390/ijms24119746 - 05 Jun 2023

Viewed by 1455

Abstract

This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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12 pages, 522 KiB

Open AccessArticle

Incidence of Bloodstream Infection in Patients with Pulmonary Hypertension under Intravenous Epoprostenol or Iloprost—A Multicentre, Retrospective Study

by Raquel Paulinetti Camara, Francisco das Neves Coelho, Natália Cruz-Martins, Patrícia Marques-Alves, Graça Castro, Rui Baptista and Filipa Ferreira

Int. J. Mol. Sci. 2023, 24(7), 6434; https://doi.org/10.3390/ijms24076434 - 29 Mar 2023

Cited by 2 | Viewed by 1176

Abstract

Intravenous synthetic prostacyclin analogs (iPCAs), such as epoprostenol, treprostinil and iloprost have been widely used for the treatment of pulmonary arterial hypertension (PAH). Despite having good outcomes, continuous infusion of iPCAs has been associated with some adverse effects. Bloodstream infection (BSI) is one of the most severe complications, although poorly recognized, especially under iloprost administration, which few studies have addressed. This study aimed to compare the BSI incidence rates between intravenous iloprost and epoprostenol administration. Patients with pulmonary hypertension (PH) functional class III or IV receiving intravenous iloprost or epoprostenol through Hickman catheter, between 2004 and 2019, were retrospectively selected from two PH treatment centers. From a total of 36 patients (13 for iloprost and 23 for epoprostenol), 75% (n = 27) fulfilled the PAH criteria, mainly belonging to the idiopathic group. Overall BSI rate was 1.5/1000 days of treatment (3.38 and 0.09/1000 days for iloprost and epoprostenol, respectively). Patients receiving iloprost were at a higher risk of developing BSI than those receiving epoprostenol (HR: 12.5; 95% CI: 1.569–99.092). A higher mortality rate from BSI was also identified in the iloprost group (p = 0.04). Twenty-seven patients developed BSI, with 92% of them requiring hospitalization. A total of 29 agents were found, 10 Gram-positive (mainly Staphylococcus aureus; n = 5) and 19 Gram-negative (mainly Pseudomonas aeruginosa; n = 6) bacteria. Iloprost administration was linked to a significantly higher incidence of BSI, worse prognosis, and more BSI-related deaths than epoprostenol. BSI due to Gram-negative, commensal, low-virulence bacteria was also higher in the iloprost group. In short, physicians should be aware when prescribing iPCA to guarantee their patients’ safety and best medical care. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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10 pages, 4907 KiB

Open AccessArticle

No Placebo Effect beyond Regression to the Mean on the Six Minute Walk Test in Pulmonary Arterial Hypertension Trials

by Dennis Anheyer, Till Johannes Bugaj, Rainer Lüdtke, Sebastian Appelbaum, Hubert Trübel and Thomas Ostermann

Int. J. Mol. Sci. 2023, 24(2), 1069; https://doi.org/10.3390/ijms24021069 - 05 Jan 2023

Viewed by 1811

Abstract

In drug studies, patients are often included when the disease activity is high. This will make any treatment appear to lessen disease activity, although the improvement is biased by selection. This effect is known as regression towards the mean (RTM). We aimed at investigating drug trials in Pulmonary Arterial Hypertension (PAH) using the 6-minute walking distance test (6MWD) as a primary outcome for the phenomenon of RTM. An existing registry of 43 open label studies and 23 randomized controlled trials conducted between 1990 and 2009 was used as the data source. Data analysis was carried out for 18 randomized controlled trials (RCTs) and 24 open label studies out of this registry. Data were analyzed for verum and placebo arms of the RCTs separately, as well as for the open label arms. In the verum arms, the overall effect given as 33.2 m (95% CI: 25.7; 40.6]); 6MWD was slightly lower than the effect in the observational studies, with 44.6 m (95% CI: [25.4; 63.8]). After studying and interpreting the data, we found that regression towards the mean plays only a minor role in PAH studies. In particular, placebo effects in the RCTs were negligibly small, with a mean 6MWD of −2.5 m (95% CI: [−9.8; 4.7]) in the placebo arm. Therefore, our analysis indicates that results of non-randomized observational studies can be regarded as valid tools for gaining valid clinical effects in patients with PAH. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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13 pages, 2781 KiB

Open AccessArticle

Role of Endothelin-1 in Right Atrial Arrhythmogenesis in Rabbits with Monocrotaline-Induced Pulmonary Arterial Hypertension

by Yen-Yu Lu, Fong-Jhih Lin, Yao-Chang Chen, Yu-Hsun Kao, Satoshi Higa, Shih-Ann Chen and Yi-Jen Chen

Int. J. Mol. Sci. 2022, 23(19), 10993; https://doi.org/10.3390/ijms231910993 - 20 Sep 2022

Cited by 7 | Viewed by 1726

Abstract

Atrial arrhythmias are considered prominent phenomena in pulmonary arterial hypertension (PAH) resulting from atrial electrical and structural remodeling. Endothelin (ET)-1 levels correlate with PAH severity and are associated with atrial remodeling and arrhythmia. In this study, hemodynamic measurement, western blot analysis, and histopathology were performed in the control and monocrotaline (MCT, 60 mg/kg)-induced PAH rabbits. Conventional microelectrodes were used to simultaneously record the electrical activity in the isolated sinoatrial node (SAN) and right atrium (RA) tissue preparations before and after ET-1 (10 nM) or BQ-485 (an ET-A receptor antagonist, 100 nM) perfusion. MCT-treated rabbits showed an increased relative wall thickness in the pulmonary arterioles, mean cell width, cross-sectional area of RV myocytes, and higher right ventricular systolic pressure, which were deemed to have PAH. Compared to the control, the spontaneous beating rate of SAN–RA preparations was faster in the MCT-induced PAH group, which can be slowed down by ET-1. MCT-induced PAH rabbits had a higher incidence of sinoatrial conduction blocks, and ET-1 can induce atrial premature beats or short runs of intra-atrial reentrant tachycardia. BQ 485 administration can mitigate ET-1-induced RA arrhythmogenesis in MCT-induced PAH. The RA specimens from MCT-induced PAH rabbits had a smaller connexin 43 and larger ROCK1 and phosphorylated Akt than the control, and similar PKG and Akt to the control. In conclusion, ET-1 acts as a trigger factor to interact with the arrhythmogenic substrate to initiate and maintain atrial arrhythmias in PAH. ET-1/ET-A receptor/ROCK signaling may be a target for therapeutic interventions to treat PAH-induced atrial arrhythmias. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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15 pages, 1419 KiB

Open AccessReview

Modulating NO–GC Pathway in Pulmonary Arterial Hypertension

by Anna D’Agostino, Lorena Gioia Lanzafame, Lorena Buono, Giulia Crisci, Roberta D’Assante, Ilaria Leone, Luigi De Vito, Eduardo Bossone, Antonio Cittadini and Alberto Maria Marra

Int. J. Mol. Sci. 2024, 25(1), 36; https://doi.org/10.3390/ijms25010036 - 19 Dec 2023

Viewed by 963

Abstract

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH. Full article

(This article belongs to the Special Issue Advances in Research on Pulmonary Hypertension 2.0)

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