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Advances Research on Pulmonary Hypertension
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Advances Research on Pulmonary Hypertension

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 (31 March 2022) | Viewed by 24137

Special Issue Editor

Dr. Alberto M. Marra

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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 that 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. Like PH due to 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 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

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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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Related Special Issue

Published Papers (6 papers)

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Research

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17 pages, 1974 KiB  
Article
Reversal of Right Ventricular Hypertrophy and Dysfunction by Prostacyclin in a Rat Model of Severe Pulmonary Arterial Hypertension
by Rebecca R. Vanderpool, Anastasia Gorelova, Yiran Ma, Mohammad Alhamaydeh, Jeffrey Baust, Sruti Shiva, Stevan P. Tofovic, Jian Hu, Seyed Mehdi Nouraie, Mark T. Gladwin, Maryam Sharifi-Sanjani and Imad Al Ghouleh
Int. J. Mol. Sci. 2022, 23(10), 5426; https://doi.org/10.3390/ijms23105426 - 12 May 2022
Cited by 8 | Viewed by 2916
Abstract
Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has [...] Read more.
Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague–Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure–volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses. Full article
(This article belongs to the Special Issue Advances Research on Pulmonary Hypertension)
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17 pages, 15472 KiB  
Article
Congestive Hepatopathy Secondary to Right Ventricular Hypertrophy Related to Monocrotaline-Induced Pulmonary Arterial Hypertension
by Douglas Mesadri Gewehr, Allan Fernando Giovanini, Beatriz Alvarez Mattar, Anelyse Pulner Agulham, Andressa de Souza Bertoldi, Seigo Nagashima, Fernando Bermudez Kubrusly and Luiz Fernando Kubrusly
Int. J. Mol. Sci. 2021, 22(21), 11891; https://doi.org/10.3390/ijms222111891 - 2 Nov 2021
Cited by 5 | Viewed by 2989
Abstract
Heart dysfunction and liver disease often coexist. Among the types of cardiohepatic syndrome, Type 2 is characterized by the chronic impairment of cardiac function, leading to chronic liver injury, referred to as congestive hepatopathy (CH). In this study, we aimed to establish a [...] Read more.
Heart dysfunction and liver disease often coexist. Among the types of cardiohepatic syndrome, Type 2 is characterized by the chronic impairment of cardiac function, leading to chronic liver injury, referred to as congestive hepatopathy (CH). In this study, we aimed to establish a rat model of CH secondary to right ventricular hypertrophy (RVH) related to monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Fifty male Wistar rats were divided into four groups and randomly assigned to control and experimental groups. Three experimental groups were submitted to intraperitoneal MCT inoculation (60 mg/kg) and were under its effect for 15, 30 and 37 days. The animals were then sacrificed, obtaining cardiac and hepatic tissues for anatomopathological and morphometric analysis. At macroscopic examination, the livers in the MCT groups presented a nutmeg-like appearance. PAH produced marked RVH and dilatation in the MCT groups, characterized by a significant increase in right ventricular free wall thickness (RVFWT) and chamber area. At histological evaluation, centrilobular congestion was the earliest manifestation, with preservation of the hepatocytes. Centrilobular hemorrhagic necrosis was observed in the groups exposed to prolonged MCT. Sinusoidal dilatation was markedly increased in the MCT groups, quantified by the Sinusoidal Lumen Ratio (SLR). The Congestive Hepatic Fibrosis Score and the Centrilobular Fibrosis Ratio (CFR) were also significantly increased in the MCT30 group. Hepatic atrophy, steatosis, apoptotic bodies and, rarely, hydropic swelling were also observed. SLR correlated strongly with CFR and RVFWT, and CFR correlated moderately with RVFWT. Our rat model was able to cause CH, related to monocrotaline-induced PAH and RVH; it was feasible, reproducible, and safe. Full article
(This article belongs to the Special Issue Advances Research on Pulmonary Hypertension)
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21 pages, 6217 KiB  
Article
miR-29a-3p/THBS2 Axis Regulates PAH-Induced Cardiac Fibrosis
by Chih-Hsin Hsu, I-Fan Liu, Hsuan-Fu Kuo, Chia-Yang Li, Wei-Shiung Lian, Chia-Yuan Chang, Yung-Hsiang Chen, Wei-Lun Liu, Chi-Yu Lu, Yu-Ru Liu, Tzu-Chieh Lin, Tsung-Ying Lee, Chi-Yuan Huang, Chong-Chao Hsieh and Po-Len Liu
Int. J. Mol. Sci. 2021, 22(19), 10574; https://doi.org/10.3390/ijms221910574 - 30 Sep 2021
Cited by 23 | Viewed by 4207
Abstract
Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression; however, its role in PAH-induced fibrosis remains unclear. In this study, we [...] Read more.
Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression; however, its role in PAH-induced fibrosis remains unclear. In this study, we aimed to investigate the role of miR-29a-3p in cardiac fibrosis progression in PAH and its influence on ECM protein thrombospondin-2 (THBS2) expression. The diagnostic and prognostic values of miR-29a-3p and THBS2 in PAH were evaluated. The expressions and effects of miR-29a-3p and THBS2 were assessed in cell culture, monocrotaline-induced PAH mouse model, and patients with PAH. The levels of circulating miR-29a-3p and THBS2 in patients and mice with PAH decreased and increased, respectively. miR-29a-3p directly targets THBS2 and regulates THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis. The circulating levels of miR-29a-3p and THBS2 were correlated with PAH diagnostic parameters, suggesting their independent prognostic value. miR-29a-3p targeted THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis, indicating miR-29a-3p acts as a messenger with promising therapeutic effects. Full article
(This article belongs to the Special Issue Advances Research on Pulmonary Hypertension)
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Review

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25 pages, 1839 KiB  
Review
AMPK and the Challenge of Treating Hypoxic Pulmonary Hypertension
by Karen Flores, Patricia Siques, Julio Brito and Silvia M. Arribas
Int. J. Mol. Sci. 2022, 23(11), 6205; https://doi.org/10.3390/ijms23116205 - 1 Jun 2022
Cited by 15 | Viewed by 3692
Abstract
Hypoxic pulmonary hypertension (HPH) is characterized by sustained elevation of pulmonary artery pressure produced by vasoconstriction and hyperproliferative remodeling of the pulmonary artery and subsequent right ventricular hypertrophy (RVH). The search for therapeutic targets for cardiovascular pathophysiology has extended in many directions. However, [...] Read more.
Hypoxic pulmonary hypertension (HPH) is characterized by sustained elevation of pulmonary artery pressure produced by vasoconstriction and hyperproliferative remodeling of the pulmonary artery and subsequent right ventricular hypertrophy (RVH). The search for therapeutic targets for cardiovascular pathophysiology has extended in many directions. However, studies focused on mitigating high-altitude pulmonary hypertension (HAPH) have been rare. Because AMP-activated protein kinase (AMPK) is involved in cardiovascular and metabolic pathology, AMPK is often studied as a potential therapeutic target. AMPK is best characterized as a sensor of cellular energy that can also restore cellular metabolic homeostasis. However, AMPK has been implicated in other pathways with vasculoprotective effects. Notably, cellular metabolic stress increases the intracellular ADP/ATP or AMP/ATP ratio, and AMPK activation restores ATP levels by activating energy-producing catabolic pathways and inhibiting energy-consuming anabolic pathways, such as cell growth and proliferation pathways, promoting cardiovascular protection. Thus, AMPK activation plays an important role in antiproliferative, antihypertrophic and antioxidant pathways in the pulmonary artery in HPH. However, AMPK plays contradictory roles in promoting HPH development. This review describes the main findings related to AMPK participation in HPH and its potential as a therapeutic target. It also extrapolates known AMPK functions to discuss the less-studied HAPH context. Full article
(This article belongs to the Special Issue Advances Research on Pulmonary Hypertension)
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12 pages, 570 KiB  
Review
Structural and Hemodynamic Changes of the Right Ventricle in PH-HFpEF
by Maria Barilli, Maria Cristina Tavera, Serafina Valente and Alberto Palazzuoli
Int. J. Mol. Sci. 2022, 23(9), 4554; https://doi.org/10.3390/ijms23094554 - 20 Apr 2022
Cited by 7 | Viewed by 4285
Abstract
One of the most important diagnostic challenges in clinical practice is the distinction between pulmonary hypertension (PH) due to primitive pulmonary arterial hypertension (PAH) and PH due to left heart diseases. Both conditions share some common characteristics and pathophysiological pathways, making the two [...] Read more.
One of the most important diagnostic challenges in clinical practice is the distinction between pulmonary hypertension (PH) due to primitive pulmonary arterial hypertension (PAH) and PH due to left heart diseases. Both conditions share some common characteristics and pathophysiological pathways, making the two processes similar in several aspects. Their diagnostic differentiation is based on hemodynamic data on right heart catheterization, cardiac structural modifications, and therapeutic response. More specifically, PH secondary to heart failure with preserved ejection fraction (HFpEF) shares features with type 1 PH (PAH), especially when the combined pre- and post-capillary form (CpcPH) takes place in advanced stages of the disease. Right ventricular (RV) dysfunction is a common consequence related to worse prognosis and lower survival. This condition has recently been identified with a new classification based on clinical signs and progression markers. The role and prevalence of PH and RV dysfunction in HFpEF remain poorly identified, with wide variability in the literature reported from the largest clinical trials. Different parenchymal and vascular alterations affect the two diseases. Capillaries and arteriole vasoconstriction, vascular obliteration, and pulmonary blood fluid redistribution from the basal to the apical district are typical manifestations of type 1 PH. Conversely, PH related to HFpEF is primarily due to an increase of venules/capillaries parietal fibrosis, extracellular matrix deposition, and myocyte hypertrophy with a secondary “arteriolarization” of the vessels. Since the development of structural changes and the therapeutic target substantially differ, a better understanding of pathobiological processes underneath PH-HFpEF, and the identification of potential maladaptive RV mechanisms with an appropriate diagnostic tool, become mandatory in order to distinguish and manage these two similar forms of pulmonary hypertension. Full article
(This article belongs to the Special Issue Advances Research on Pulmonary Hypertension)
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22 pages, 1572 KiB  
Review
Cannabinoids—A New Perspective in Adjuvant Therapy for Pulmonary Hypertension
by Anna Krzyżewska, Marta Baranowska-Kuczko, Krzysztof Mińczuk and Hanna Kozłowska
Int. J. Mol. Sci. 2021, 22(18), 10048; https://doi.org/10.3390/ijms221810048 - 17 Sep 2021
Cited by 8 | Viewed by 4170
Abstract
Currently, no treatment can completely cure pulmonary hypertension (PH), which can lead to right ventricular failure and, consequently, death. Therefore, searching for new therapies remains important. Increased resistance in pulmonary circulation is mainly caused by the excessive contraction and proliferation of small pulmonary [...] Read more.
Currently, no treatment can completely cure pulmonary hypertension (PH), which can lead to right ventricular failure and, consequently, death. Therefore, searching for new therapies remains important. Increased resistance in pulmonary circulation is mainly caused by the excessive contraction and proliferation of small pulmonary arteries. Cannabinoids, a group of lipophilic compounds that all interact with cannabinoid receptors, exert a pulmonary vasodilatory effect through several different mechanisms, including mechanisms that depend on vascular endothelium and/or receptor-based mechanisms, and may also have anti-proliferative and anti-inflammatory properties. The vasodilatory effect is important in regulating pulmonary resistance, which can improve patients’ quality of life. Moreover, experimental studies on the effects of cannabidiol (plant-derived, non-psychoactive cannabinoid) in animal PH models have shown that cannabidiol reduces right ventricular systolic pressure and excessive remodelling and decreases pulmonary vascular hypertrophy and pulmonary vascular resistance. Due to the potentially beneficial effects of cannabinoids on pulmonary circulation and PH, in this work, we review whether cannabinoids can be used as an adjunctive therapy for PH. However, clinical trials are still needed to recommend the use of cannabinoids in the treatment of PH. Full article
(This article belongs to the Special Issue Advances Research on Pulmonary Hypertension)
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