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1
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Ghofrani HA, Gomberg-Maitland M, Zhao L, Grimminger F. Mechanisms and treatment of pulmonary arterial hypertension. Nat Rev Cardiol 2025; 22:105-120. [PMID: 39112561 DOI: 10.1038/s41569-024-01064-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2024] [Indexed: 11/28/2024]
Abstract
Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research.
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Affiliation(s)
- Hossein-Ardeschir Ghofrani
- Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany.
| | - Mardi Gomberg-Maitland
- George Washington University School of Medicine and Health Sciences, Department of Medicine, Washington, DC, USA
| | - Lan Zhao
- National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK
| | - Friedrich Grimminger
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), German Center for Lung Research (DZL), Giessen, Germany
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2
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Corboz MR, Nguyen TL, Stautberg A, Cipolla D, Perkins WR, Chapman RW. Current Overview of the Biology and Pharmacology in Sugen/Hypoxia-Induced Pulmonary Hypertension in Rats. J Aerosol Med Pulm Drug Deliv 2024; 37:241-283. [PMID: 39388691 PMCID: PMC11502635 DOI: 10.1089/jamp.2024.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 07/03/2024] [Indexed: 10/12/2024] Open
Abstract
The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.
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Dhoble S, Patravale V, Weaver E, Lamprou DA, Patravale T. Comprehensive Review on Novel Targets and Emerging Therapeutic Modalities for Pulmonary Arterial Hypertension. Int J Pharm 2022; 621:121792. [PMID: 35513217 DOI: 10.1016/j.ijpharm.2022.121792] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/17/2022] [Accepted: 04/28/2022] [Indexed: 01/17/2023]
Abstract
Pulmonary Arterial Hypertension (PAH) is the progressive increase in mean pulmonary arterial pressure (mPAP) (≥ 20 mmHg at rest). Current treatment strategies include the drugs targeting at nitric oxide pathway, endothelin receptors, prostaglandin receptors, thromboxane receptors and phosphodiesterase inhibitors, which provides the symptomatic relief. Despite of these treatments, the mortality amongst the PAH patients remains high due to non-reversal of the condition. This review primarily covers the introduction of PAH and the current treatments of the disease. This is followed by the newer disease targets expressed in the pathobiology of the disease like Rho Kinase Pathway, Vasoactive Intestinal Peptide Pathway, Receptor Tyrosine Kinases, Serotonin signalling pathway, Voltage-gated potassium (Kv) channel pathway. Newer formulation strategies for targeting at these specific receptors were covered and includes nano formulations like liposomes, Micelles, Polymeric Nanoparticles, Solid Lipid Nanoparticles (SLN), Bioresorbable stents, NONOates, Cell-Based Therapies, miRNA therapy for PAH. Novel targets were identified for their role in the pathogenesis of the PAH and needs to be targeted with new molecules or existing molecules effectively. Nanosystems have shown their potential as alternative carriers on the virtue of their better performance than traditional drug delivery systems.
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Affiliation(s)
- Sagar Dhoble
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai 400 019, India
| | - Vandana Patravale
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai 400 019, India.
| | - Edward Weaver
- School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, United Kingdom
| | - Dimitrios A Lamprou
- School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, United Kingdom.
| | - Tanmay Patravale
- Department of General Surgery, Jawaharlal Nehru Medical College, KLE Academy of Higher Education and Research, Belagavi 590 010, India
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4
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Wilkins MR, Mckie MA, Law M, Roussakis AA, Harbaum L, Church C, Coghlan JG, Condliffe R, Howard LS, Kiely DG, Lordan J, Rothman A, Suntharalingam J, Toshner M, Wort SJ, Villar SS. Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy. Pulm Circ 2021; 11:20458940211052823. [PMID: 34868551 PMCID: PMC8642118 DOI: 10.1177/20458940211052823] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/19/2021] [Indexed: 12/21/2022] Open
Abstract
Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm-5, success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm-5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.
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Affiliation(s)
- Martin R. Wilkins
- National Heart and Lung Institute, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - Mikel A. Mckie
- MRC Biostatistics Unit, School of Clinical Medicine, Cambridge Institute of Public Health, Cambridge, UK
| | - Martin Law
- MRC Biostatistics Unit, School of Clinical Medicine, Cambridge Institute of Public Health, Cambridge, UK
| | | | - Lars Harbaum
- Golden Jubilee National Hospital, University of Glasgow, Scotland, UK
| | - Colin Church
- Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK
| | - J Gerry Coghlan
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
| | - Robin Condliffe
- Sheffield Pulmonary Vascular Disease Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Luke S Howard
- National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - David G Kiely
- Newcastle Freeman Hospital, Freeman Road, High Heaton, Newcastle Upon Tyne, UK
| | - Jim Lordan
- Royal United Hospital, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK
| | - Alexander Rothman
- Heart Lung Research Institute, University of Cambridge, Cambridge, UK
| | | | - Mark Toshner
- Royal Brompton Hospital, Guy’s and St Thomas’s Trust, London, UK
| | - Stephen J Wort
- Royal Brompton Hospital, Guy’s and St Thomas’s Trust, London, UK
| | - Sofía S. Villar
- MRC Biostatistics Unit, School of Clinical Medicine, Cambridge Institute of Public Health, Cambridge, UK
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Abstract
KIT is a receptor tyrosine kinase that after binding to its ligand stem cell factor activates signaling cascades linked to biological processes such as proliferation, differentiation, migration and cell survival. Based on studies performed on SCF and/or KIT mutant animals that presented anemia, sterility, and/or pigmentation disorders, KIT signaling was mainly considered to be involved in the regulation of hematopoiesis, gametogenesis, and melanogenesis. More recently, novel animal models and ameliorated cellular and molecular techniques have led to the discovery of a widen repertoire of tissue compartments and functions that are being modulated by KIT. This is the case for the lung, heart, nervous system, gastrointestinal tract, pancreas, kidney, liver, and bone. For this reason, the tyrosine kinase inhibitors that were originally developed for the treatment of hemato-oncological diseases are being currently investigated for the treatment of non-oncological disorders such as asthma, rheumatoid arthritis, and alzheimer's disease, among others. The beneficial effects of some of these tyrosine kinase inhibitors have been proven to depend on KIT inhibition. This review will focus on KIT expression and regulation in healthy and pathologic conditions other than cancer. Moreover, advances in the development of anti-KIT therapies, including tyrosine kinase inhibitors, and their application will be discussed.
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Özgür Yurttaş N, Eşkazan AE. Dasatinib-induced pulmonary arterial hypertension. Br J Clin Pharmacol 2018; 84:835-845. [PMID: 29334406 PMCID: PMC5903230 DOI: 10.1111/bcp.13508] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 12/29/2017] [Accepted: 01/03/2018] [Indexed: 12/19/2022] Open
Abstract
Drug-induced (group 1) pulmonary hypertension (PH) is an important subgroup of PH involving dasatinib as a likely related agent, which is a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML). The mechanism of dasatinib-induced pulmonary arterial hypertension (PAH) is unclear. However, the occurrence of PAH with late onset in CML patients suggests a chronic pathological mechanism with an insidious onset rather than an acute inflammatory or cardiac aetiology. Dasatinib has a broader effect than other TKIs; the major known difference between dasatinib and other TKIs is the additional inhibition of Src family kinases. Therefore, Src inhibition was thought to play a role in the development of dasatinib-induced PAH. However, recently, it was also speculated that chronic dasatinib therapy may cause pulmonary endothelial damage, attenuate hypoxic pulmonary vasoconstriction responses and increase susceptibility to PAH independently of the Src family kinase-induced mechanism. Dasatinib-induced PAH usually seems to be reversible with the cessation of the drug, and sometimes with PAH-specific treatment strategies. Transthoracic echocardiography can be recommended as a routine screening prior to dasatinib initiation, and this non-invasive procedure can be utilized in patients having signs and symptoms attributable to PAH during dasatinib treatment.
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Affiliation(s)
- Nurgül Özgür Yurttaş
- Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of MedicineIstanbul UniversityIstanbulTurkey
| | - Ahmet Emre Eşkazan
- Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of MedicineIstanbul UniversityIstanbulTurkey
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Li Y, Li L, Qian Z, Lin B, Chen J, Luo Y, Qu J, Raj JU, Gou D. Phosphatidylinositol 3-Kinase-DNA Methyltransferase 1-miR-1281-Histone Deacetylase 4 Regulatory Axis Mediates Platelet-Derived Growth Factor-Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells. J Am Heart Assoc 2018; 7:e007572. [PMID: 29514810 PMCID: PMC5907547 DOI: 10.1161/jaha.117.007572] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Platelet-derived growth factor BB, a potent mitogen of pulmonary artery smooth muscle cells (PASMCs), has been implicated in pulmonary arterial remodeling, which is a key pathogenic feature of pulmonary arterial hypertension. Previous microRNA profiling in platelet-derived growth factor BB-treated PASMCs found a significantly downregulated microRNA, miR-1281, but it has not been associated with any cellular function, and we investigated the possibility. METHODS AND RESULTS Real-time quantitative reverse transcription-polymerase chain reaction assay proved that downregulation of miR-1281 was a conserved phenomenon in human and rat PASMCs. Overexpression and inhibition of miR-1281 in PASMCs promoted and suppressed, respectively, the cell proliferation and migration. Bioinformatic prediction and 3'-untranslated region reporter assay identified histone deacetylase 4 to be a direct target of miR-1281. Supporting this, proliferation and migration assay demonstrated the cellular function of histone deacetylase 4 is inversely correlated with that of miR-1281. Mechanistically, it is found that platelet-derived growth factor BB activates the phosphatidylinositol 3-kinase pathway, which then induces the expression of DNA methyltransferase 1, leading to enhanced methylation of a flanking CpG island and repressed miR-1281 expression. Finally, a reduced miR-1281 level was consistently identified in hypoxic PASMCs in vitro, in pulmonary arteries of rats with monocrotaline-induced pulmonary arterial hypertension, and in serum of patients with coronary heart disease-pulmonary arterial hypertension. These data suggest that there may be a diagnostic and therapeutic use for miR-1281. CONCLUSIONS Herein, we report a novel regulatory axis, phosphatidylinositol 3-kinase-DNA methyltransferase 1-miR-1281-histone deacetylase 4, integrating multiple epigenetic regulators that participate in platelet-derived growth factor BB-stimulated PASMC proliferation and migration and pulmonary vascular remodeling.
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MESH Headings
- Animals
- Becaplermin/pharmacology
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- DNA (Cytosine-5-)-Methyltransferase 1/metabolism
- Disease Models, Animal
- HEK293 Cells
- Histone Deacetylases/genetics
- Histone Deacetylases/metabolism
- Humans
- Hypertension, Pulmonary/enzymology
- Hypertension, Pulmonary/genetics
- Hypertension, Pulmonary/pathology
- Male
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Monocrotaline
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/enzymology
- Myocytes, Smooth Muscle/pathology
- Phosphatidylinositol 3-Kinase/metabolism
- Pulmonary Artery/enzymology
- Pulmonary Artery/pathology
- Rats, Sprague-Dawley
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
- Signal Transduction/drug effects
- Vascular Remodeling/drug effects
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Affiliation(s)
- Yanjiao Li
- Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China
| | - Li Li
- Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
| | - Zhengjiang Qian
- Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
- The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Boya Lin
- Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
| | - Jidong Chen
- Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China
| | - Yixuan Luo
- Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
| | - Junle Qu
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China
| | - J Usha Raj
- Department of Pediatrics, University of Illinois at Chicago, IL
| | - Deming Gou
- Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong, China
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Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats. Vascul Pharmacol 2018; 100:41-50. [DOI: 10.1016/j.vph.2017.10.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 10/21/2017] [Accepted: 10/29/2017] [Indexed: 12/14/2022]
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Hemnes AR, Humbert M. Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled. Eur Respir Rev 2017; 26:26/146/170093. [DOI: 10.1183/16000617.0093-2017] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 12/08/2017] [Indexed: 01/09/2023] Open
Abstract
The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.
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10
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Halliday SJ, Hemnes AR. Identifying "super responders" in pulmonary arterial hypertension. Pulm Circ 2017; 7:300-311. [PMID: 28597766 PMCID: PMC5467924 DOI: 10.1177/2045893217697708] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/13/2017] [Indexed: 02/01/2023] Open
Abstract
Pharmacotherapeutic options for pulmonary arterial hypertension (PAH) have increased dramatically in the last two decades and along with this have been substantial improvements in survival. Despite these advances, however, PAH remains a progressive and ultimately fatal disease for most patients and only epoprostenol has been shown to improve survival in a randomized control trial. Clinical observations of the heterogeneity of treatment response to different classes of medications across the phenotypically diverse PAH population has led to the identification of patients who derive significantly more benefit from certain medications than the population mean, the so-called "super responders." This was first recognized among PAH patients with acute vasodilator response during invasive hemodynamic testing, a subset of whom have dramatically improved survival when treated with calcium channel blocker (CCB) therapy. Retrospective studies have now suggested a sex discrepancy in response to endothelin receptor antagonists (ERA) and phosphodiesterase inhibitors, and more recently a few studies have found genomic associations with response to CCBs and ERAs. With increasing availability of "omics" technologies, recognition of these "super responders," combined with careful clinical and molecular phenotyping, will lead to advances in pharmacogenomics, precision medicine, and continued improvements in survival among PAH patients.
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Affiliation(s)
- Stephen J. Halliday
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Anna R. Hemnes
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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11
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Velayati A, Valerio MG, Shen M, Tariq S, Lanier GM, Aronow WS. Update on pulmonary arterial hypertension pharmacotherapy. Postgrad Med 2016; 128:460-473. [PMID: 27232660 DOI: 10.1080/00325481.2016.1188664] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 05/09/2016] [Indexed: 10/21/2022]
Abstract
Pulmonary artery hypertension (PAH) refers to several subgroups of disease in which the mean pulmonary artery pressure (mPAP) is elevated to more than 25 mm Hg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR) > 3 Wood units as confirmed by right heart catheterization. The prevalence and geographic distribution of PAH vary depending on the type and etiology of the disease. Despite enormous efforts in the research and development of therapeutic agents in the last twenty years, the disease remains relatively incurable and the overall prognosis remains guarded. Median survival for an untreated patient is 2.8 years. In the last three decades, there have been dramatic advances in understanding the molecular mechanisms and signaling pathways involved in the disease, resulting in emerging new treatment strategies. In the following pages, we will review currently approved treatments for PAH, as well as a new generation of investigational drugs.
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Affiliation(s)
- Arash Velayati
- a Department of Medicine, Division of Cardiology , Westchester Medical Center/New York Medical College , Valhalla , NY , USA
| | - Marcos G Valerio
- a Department of Medicine, Division of Cardiology , Westchester Medical Center/New York Medical College , Valhalla , NY , USA
| | - Michael Shen
- a Department of Medicine, Division of Cardiology , Westchester Medical Center/New York Medical College , Valhalla , NY , USA
| | - Sohaib Tariq
- a Department of Medicine, Division of Cardiology , Westchester Medical Center/New York Medical College , Valhalla , NY , USA
| | - Gregg M Lanier
- a Department of Medicine, Division of Cardiology , Westchester Medical Center/New York Medical College , Valhalla , NY , USA
| | - Wilbert S Aronow
- a Department of Medicine, Division of Cardiology , Westchester Medical Center/New York Medical College , Valhalla , NY , USA
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12
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Frost AE, Barst RJ, Hoeper MM, Chang HJ, Frantz RP, Fukumoto Y, Galié N, Hassoun PM, Klose H, Matsubara H, Morrell NW, Peacock AJ, Pfeifer M, Simonneau G, Tapson VF, Torres F, Dario Vizza C, Lawrence D, Yang W, Felser JM, Quinn DA, Ghofrani HA. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant 2015. [DOI: 10.1016/j.healun.2015.05.025] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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13
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Novel Therapeutic Strategies for Reducing Right Heart Failure Associated Mortality in Fibrotic Lung Diseases. BIOMED RESEARCH INTERNATIONAL 2015; 2015:929170. [PMID: 26583148 PMCID: PMC4637079 DOI: 10.1155/2015/929170] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Accepted: 08/26/2015] [Indexed: 11/21/2022]
Abstract
Fibrotic lung diseases carry a significant mortality burden worldwide. A large proportion of these deaths are due to right heart failure and pulmonary hypertension. Underlying contributory factors which appear to play a role in the mechanism of progression of right heart dysfunction include chronic hypoxia, defective calcium handling, hyperaldosteronism, pulmonary vascular alterations, cyclic strain of pressure and volume changes, elevation of circulating TGF-β, and elevated systemic NO levels. Specific therapies targeting pulmonary hypertension include calcium channel blockers, endothelin (ET-1) receptor antagonists, prostacyclin analogs, phosphodiesterase type 5 (PDE5) inhibitors, and rho-kinase (ROCK) inhibitors. Newer antifibrotic and anti-inflammatory agents may exert beneficial effects on heart failure in idiopathic pulmonary fibrosis. Furthermore, right ventricle-targeted therapies, aimed at mitigating the effects of functional right ventricular failure, include β-adrenoceptor (β-AR) blockers, angiotensin-converting enzyme (ACE) inhibitors, antioxidants, modulators of metabolism, and 5-hydroxytryptamine-2B (5-HT2B) receptor antagonists. Newer nonpharmacologic modalities for right ventricular support are increasingly being implemented. Early, effective, and individualized therapy may prevent overt right heart failure in fibrotic lung disease leading to improved outcomes and quality of life.
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14
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Hu J, Xu Q, McTiernan C, Lai YC, Osei-Hwedieh D, Gladwin M. Novel Targets of Drug Treatment for Pulmonary Hypertension. Am J Cardiovasc Drugs 2015; 15:225-34. [PMID: 26016608 DOI: 10.1007/s40256-015-0125-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Biomedical advances over the last decade have identified the central role of proliferative pulmonary arterial smooth muscle cells (PASMCs) in the development of pulmonary hypertension (PH). Furthermore, promoters of proliferation and apoptosis resistance in PASMCs and endothelial cells, such as aberrant signal pathways involving growth factors, G protein-coupled receptors, kinases, and microRNAs, have also been described. As a result of these discoveries, PH is currently divided into subgroups based on the underlying pathology, which allows focused and targeted treatment of the condition. The defining features of PH, which subsequently lead to vascular wall remodeling, are dysregulated proliferation of PASMCs, local inflammation, and apoptosis-resistant endothelial cells. Efforts to assess the relative contributions of these factors have generated several promising targets. This review discusses recent novel targets of therapies for PH that have been developed as a result of these advances, which are now in pre-clinical and clinical trials (e.g., imatinib [phase III]; nilotinib, AT-877ER, rituximab, tacrolimus, paroxetine, sertraline, fluoxetine, bardoxolone methyl [phase II]; and sorafenib, FK506, aviptadil, endothelial progenitor cells (EPCs) [phase I]). While substantial progress has been made in recent years in targeting key molecular pathways, PH still remains without a cure, and these novel therapies provide an important conceptual framework of categorizing patients on the basis of molecular phenotype(s) for effective treatment of the disease.
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15
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Prada LFL, Gavilanes F, Souza R. Incidence of spontaneous subdural hematoma in incident cases of pulmonary arterial hypertension: a registry of cases occurring over a five-year period. J Bras Pneumol 2015; 41:101-2. [PMID: 25750681 PMCID: PMC4350832 DOI: 10.1590/s1806-37132015000100014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 06/30/2014] [Indexed: 11/22/2022] Open
Affiliation(s)
- Luis Felipe Lopes Prada
- University of São Paulo, School of Medicine, Hospital das Clínicas, São Paulo, Brazil, Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil
| | - Francisca Gavilanes
- University of São Paulo, School of Medicine, Hospital das Clínicas, São Paulo, Brazil, Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil
| | - Rogério Souza
- University of São Paulo, School of Medicine, São Paulo, Brazil, University of São Paulo School of Medicine, São Paulo, Brazil
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16
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Abstract
Pulmonary arterial hypertension (PAH) includes a heterogeneous group of diseases characterized by pulmonary vasoconstriction and remodeling of the lung circulation. Although PAH is a disease of the lungs, patients with PAH frequently die of right heart failure. Indeed, survival of patients with PAH depends on the adaptive response of the right ventricle (RV) to the changes in the lung circulation. PAH-specific drugs affect the function of the RV through afterload reduction and perhaps also through direct effects on the myocardium. Prostacyclins, type 5 phosphodiesterase inhibitors, and guanylyl cyclase stimulators may directly enhance myocardial contractility through increased cyclic adenosine and guanosine monophosphate availability. Although this may initially improve cardiac performance, the long-term effects on myocardial oxygen consumption and function are unclear. Cardiac effects of endothelin receptor antagonists may be opposite, as endothelin-1 is known to suppress cardiac contractility. Because PAH is increasingly considered as a disease with quasimalignant growth of cells in the pulmonary vascular wall, therapies are being developed that inhibit hypertrophy and angiogenesis, and promote apoptosis. The inherent danger of these therapies is a further compromise to the already ischemic, fibrotic, and dysfunctional RV. More recently, the right heart has been identified as a direct treatment target in PAH. The effects of well established therapies for left heart failure, such as β-adrenergic receptor blockers, inhibitors of the renin-angiotensin system, exercise training, and assist devices, are currently being investigated in PAH. Future treatment of patients with PAH will likely consist of a multifaceted approaches aiming to reduce the pressure in the lung circulation and improving right heart adaptation simultaneously.
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Speich R, Ulrich S, Domenighetti G, Huber LC, Fischler M, Treder U, Breitenstein A. Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension. Respiration 2015; 89:515-24. [DOI: 10.1159/000381923] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 03/26/2015] [Indexed: 11/19/2022] Open
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Vaidya B, Gupta V. Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery. J Control Release 2015; 211:118-33. [PMID: 26036906 DOI: 10.1016/j.jconrel.2015.05.287] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 05/26/2015] [Accepted: 05/28/2015] [Indexed: 01/07/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a cardiopulmonary disorder characterized by increased blood pressure in the small arterioles supplying blood to lungs for oxygenation. Advances in understanding of molecular and cellular biology techniques have led to the findings that PAH is indeed a cascade of diseases exploiting multi-faceted complex pathophysiology, with cellular proliferation and vascular remodeling being the key pathogenic events along with several cellular pathways involved. While current therapies for PAH do provide for amelioration of disease symptoms and acute survival benefits, their full therapeutic potential is hindered by patient incompliance and off-target side effects. To overcome the issues related with current therapy and to devise a more selective therapy, various novel pathways are being investigated for PAH treatment. In addition, inability to deliver anti-PAH drugs to the disease site i.e., distal pulmonary arterioles has been one of the major challenges in achieving improved patient outcomes and improved therapeutic efficacy. Several novel carriers have been explored to increase the selectivity of currently approved anti-PAH drugs and to act as suitable carriers for the delivery of investigational drugs. In the present review, we have discussed potential of various novel molecular pathways/targets including RhoA/Rho kinase, tyrosine kinase, endothelial progenitor cells, vasoactive intestinal peptide, and miRNA in PAH therapeutics. We have also discussed various techniques for site-specific drug delivery of anti-PAH therapeutics so as to improve the efficacy of approved and investigational drugs. This review will provide gainful insights into current advances in PAH therapeutics with an emphasis on site-specific drug payload delivery.
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Affiliation(s)
- Bhuvaneshwar Vaidya
- School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, United States
| | - Vivek Gupta
- School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, United States.
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Akagi S, Nakamura K, Miura D, Saito Y, Matsubara H, Ogawa A, Matoba T, Egashira K, Ito H. Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension. Int Heart J 2015; 56:354-9. [PMID: 25902888 DOI: 10.1536/ihj.14-338] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Platelet-derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by (3)H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PAS-MCs.
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Affiliation(s)
- Satoshi Akagi
- Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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Sharma M, Pinnamaneni S, Aronow WS, Jozwik B, Frishman WH. Existing drugs and agents under investigation for pulmonary arterial hypertension. Cardiol Rev 2014; 22:297-305. [PMID: 25098201 DOI: 10.1097/crd.0000000000000035] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Pulmonary arterial hypertension is a progressive and debilitating disorder with an associated high morbidity and mortality rate. Significant advances in our understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary hypertension have occurred over the past several decades. This has allowed the development of new therapeutic options in this disease. Today, our selection of therapeutic modalities is broader, including calcium channel blockers, prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators, but the disease remains fatal. This underscores the need for a continued search for novel therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include rho-kinase inhibitors, long-acting nonprostanoid prostacyclin receptor agonists, tyrosine protein kinase inhibitors, endothelial nitric oxide synthase couplers, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.
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Affiliation(s)
- Mala Sharma
- From the *Department of Medicine, Division of Cardiology, New York Medical College, Westchester Medical Center, Valhalla, NY; and †Department of Medicine, Yale School of Medicine/Norwalk Hospital, Norwalk, CT
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Pitsiou G, Zarogoulidis P, Petridis D, Kioumis I, Lampaki S, Organtzis J, Porpodis K, Papaiwannou A, Tsiouda T, Hohenforst-Schmidt W, Kakolyris S, Syrigos K, Huang H, Li Q, Turner JF, Zarogoulidis K. Inhaled tyrosine kinase inhibitors for pulmonary hypertension: a possible future treatment. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 8:1753-63. [PMID: 25336919 PMCID: PMC4199972 DOI: 10.2147/dddt.s70277] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Pulmonary hypertension is a disease with severe consequences for the human body. There are several diseases and situations that induce pulmonary hypertension and are usually underdiagnosed. Treatments include conventional medical therapies and oral, inhaled, intravenous, and subcutaneous options. Depending on its severity, heart or lung transplant may also be an option. A possible novel treatment could be tyrosine kinase inhibitors. We conducted experiments with three jet nebulizers and three ultrasound nebulizers with erlotinib, gefitinib, and imatinib. Different residual cup designs and residual cup loadings were used in order to identify the best combination to produce droplets of less than 5 μm in mass median aerodynamic diameter. We found that gefitinib could not be transformed into a powder, so conversion to an aerosol form was not possible. Our experiments indicated that imatinib is superior to erlotinib with regard to small droplet size formation using both inhaled technologies (1.37 μm <2.23 μm and 1.92 μm <3.11 μm, jet and ultrasound, respectively) and, at jet devices (1.37 μm <1.92 μm). Cup designs C and G contribute best to small droplet creation uniquely supporting and equally well the activity of both drugs. The disadvantage of the large droplets formed for erlotinib was offset when combined with residual cup C (1.37 μm instead of 2.23 μm). At a 2 mL dose, the facemask and cone mouthpieces performed best and evenly; the facemask and low dose were the best choice (2.08 μm and 2.12 μm, respectively). Erlotinib and imatinib can be administered as an aerosols, and further in vivo experimentation is necessary to investigate the positive effects of these drugs in the treatment of pulmonary hypertension.
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Affiliation(s)
- Georgia Pitsiou
- Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paul Zarogoulidis
- Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitris Petridis
- Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, Thessaloniki, Greece
| | - Ioannis Kioumis
- Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Sofia Lampaki
- Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - John Organtzis
- Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Porpodis
- Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Papaiwannou
- Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theodora Tsiouda
- Internal Medicine Department, Thegenio Anticancer Hospital, Thessaloniki, Greece
| | | | - Stylianos Kakolyris
- Oncology Department, Sotiria Hospital of Chest Diseases, University of Athens, Athens, Greece
| | - Konstantinos Syrigos
- Oncology Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Haidong Huang
- Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People's Republic of China
| | - Qiang Li
- Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People's Republic of China
| | - J Francis Turner
- Division of Interventional Pulmonology and Medical Oncology, Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, AZ, USA
| | - Konstantinos Zarogoulidis
- Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Kazama K, Okada M, Yamawaki H. A novel adipocytokine, omentin, inhibits monocrotaline-induced pulmonary arterial hypertension in rats. Biochem Biophys Res Commun 2014; 452:142-6. [DOI: 10.1016/j.bbrc.2014.08.070] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 08/14/2014] [Indexed: 02/06/2023]
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Nayyar D, Muthiah K, Kumarasinghe G, Hettiarachchi R, Celermajer D, Kotlyar E, Keogh A. Imatinib for the treatment of pulmonary arterial hypertension and pulmonary capillary hemangiomatosis. Pulm Circ 2014; 4:342-5. [PMID: 25006453 DOI: 10.1086/675996] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 02/17/2014] [Indexed: 11/04/2022] Open
Abstract
Despite currently available treatments, the prognoses of pulmonary arterial hypertension (PAH) and pulmonary capillary hemangiomatosis (PCH) remain poor. Platelet-derived growth factor and its receptor (PDGFR) have been implicated in the pathogenesis of pulmonary hypertension in PAH and PCH. Imatinib, a PDGFR antagonist, may be beneficial in the treatment of both conditions because of its potent antiproliferative effect. We report two cases that demonstrate the potential for safe and efficacious use of imatinib in PAH and PCH.
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Affiliation(s)
- Dhruv Nayyar
- St. Vincent's Hospital, Sydney, Australia ; University of New South Wales, Kensington, Australia
| | | | | | - Ravin Hettiarachchi
- St. Vincent's Hospital, Sydney, Australia ; University of New South Wales, Kensington, Australia
| | | | | | - Anne Keogh
- St. Vincent's Hospital, Sydney, Australia
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Targeted therapies in pulmonary arterial hypertension. Pharmacol Ther 2014; 141:172-91. [DOI: 10.1016/j.pharmthera.2013.10.002] [Citation(s) in RCA: 138] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 08/21/2013] [Indexed: 12/21/2022]
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Hassoun PM. Therapies for scleroderma-related pulmonary arterial hypertension. Expert Rev Respir Med 2014; 3:187-196. [PMID: 19885388 DOI: 10.1586/ers.09.5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pulmonary arterial hypertension (PAH), a common complication of systemic sclerosis, carries a very severe prognosis and is one of the leading causes of death in patients who suffer from it. Indeed, response to modern medical therapy has been disappointing in scleroderma-related PAH compared with other forms of PAH from the WHO group 1 classification of diseases, despite similar histological changes involving the pulmonary vasculature. This review discusses specific features of scleroderma-related PAH, currently available and US FDA-approved therapy for this syndrome, as well as potential future therapeutic developments based on newly acquired knowledge of this disorder.
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Affiliation(s)
- Paul M Hassoun
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21224, USA, Tel.: +1 410 614 5158, ,
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Speich R, Treder U, Domenighetti G, Huber LC, Ulrich S. Weaning from intravenous prostanoids and normalization of hemodynamics by long-term imatinib therapy in severe idiopathic pulmonary arterial hypertension. Int J Clin Pharm 2013; 36:256-60. [PMID: 24287663 PMCID: PMC3984669 DOI: 10.1007/s11096-013-9881-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 11/07/2013] [Indexed: 11/30/2022]
Abstract
Introduction Despite new treatment options targeted at its three main pathogenic pathways, prognosis of idiopathic pulmonary arterial hypertension has remained dismal, with 3-year survival rates around 70 %. Antiproliferative agents have emerged as a new therapeutic concept. However, they may exert their effects only after a prolonged period of time. Case description Herein we present a patient who, despite being on a triple targeted drug therapy including high-dose intravenous prostanoids, still had severe pulmonary hypertension. After 4 years treatment with the tyrosine kinase inhibitor imatinib, the patient could be weaned from intravenous prostanoids and attained a persistent hemodynamic normalization. Conclusions Antiproliferative agents might be a promising new class of drugs in pulmonary arterial hypertension. However, the occurrence of unexpected side effects like the increased incidence of subdural hematomas, has led to the recommendation that at present such an off-label use is strongly discouraged, and that further studies elucidating the risk/benefit ratio of tyrosine kinase inhibitors are clearly needed.
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Affiliation(s)
- Rudolf Speich
- University Hospital, Rämistrasse 100, Room HOER C 11, 8091, Zurich, Switzerland,
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27
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Izikki M, Mercier O, Lecerf F, Lubert Guin L, Hoang E, Dorfmüller P, Perros F, Humbert M, Simonneau G, Dartevelle P, Fadel E, Eddahibi S. The beneficial effect of suramin on monocrotaline-induced pulmonary hypertension in rats. PLoS One 2013; 8:e77073. [PMID: 24143201 PMCID: PMC3797142 DOI: 10.1371/journal.pone.0077073] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 09/06/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Pulmonary hypertension (PH) is a progressive disorder characterized by an increase in pulmonary artery pressure and structural changes in the pulmonary vasculature. Several observations indicate that growth factors play a key role in PH by modulating pulmonary artery smooth muscle cell (PA-SMC) function. In rats, established monocrotaline-induced PH (MCT-PH) can be reversed by blocking platelet-derived growth factor receptors (PDGF-R), epidermal growth factor receptors (EGF-R), or fibroblast growth factor receptors (FGF-R). All these receptors belong to the receptor tyrosine kinase (RTK) family. METHODS AND RESULTS We evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth-factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen. CONCLUSIONS RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension.
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Affiliation(s)
| | - Olaf Mercier
- Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
| | - Florence Lecerf
- INSERM U999, Le Plessis-Robinson, France
- Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
| | | | - Eric Hoang
- INSERM U999, Le Plessis-Robinson, France
| | - Peter Dorfmüller
- INSERM U999, Le Plessis-Robinson, France
- Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
| | | | | | | | | | - Elie Fadel
- INSERM U999, Le Plessis-Robinson, France
- Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
| | - Saadia Eddahibi
- INSERM U999, Le Plessis-Robinson, France
- Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France
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Analysis of erectile responses to imatinib in the rat. Urology 2013; 82:253.e17-24. [PMID: 23806406 DOI: 10.1016/j.urology.2013.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 03/12/2013] [Accepted: 04/03/2013] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To investigate the erectile and cardiovascular responses to the tyrosine kinase inhibitor imatinib in the rat. MATERIALS AND METHODS The effect of intracavernosal injection of imatinib on the intracavernosal pressure (ICP), ICP/mean arterial pressure (MAP) ratio, area under the curve, and duration of the increase in ICP and the effect of intravenous injection of imatinib on the MAP, cardiac output, and total peripheral resistance were investigated. The effect of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on the responses to imatinib was investigated. RESULTS Intracavernosal injection of imatinib produced significant dose-related increases in the ICP, ICP/MAP ratio, area under the curve, and duration of the increase in ICP and decreases in the MAP. The erectile responses to imatinib were rapid in onset and short in duration. The erectile responses to imatinib were not significantly altered by NG-nitro-L-arginine methyl ester or cavernosal nerve crush injury, and imatinib was significantly less potent than the nitric oxide donor sodium nitroprusside in inducing erection. Intravenous injection of imatinib produced significant dose-related decreases in the MAP without significantly changing the cardiac output, and imatinib was significantly less potent than sodium nitroprusside in decreasing the MAP. Systemic vascular resistance was decreased in a significant dose-related manner, and the vasodilator responses to imatinib were not altered by NG-nitro-L-arginine methyl ester. CONCLUSION The present results have indicated that imatinib has significant erectile and systemic vasodilator activity in the rat that is not dependent on nitric oxide release. Another tyrosine kinase inhibitor, nilotinib, also increased the ICP and decreased the MAP in the rat. These data suggest that tyrosine kinases might play a constitutive role in maintaining penile tumescence and the baseline vasoconstrictor tone in the peripheral vascular bed.
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Heldin CH. Targeting the PDGF signaling pathway in the treatment of non-malignant diseases. J Neuroimmune Pharmacol 2013; 9:69-79. [PMID: 23793451 DOI: 10.1007/s11481-013-9484-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 06/05/2013] [Indexed: 12/13/2022]
Abstract
Platelet-derived growth factor (PDGF) is a family of mesenchymal mitogens with important functions during the embryonal development and in the control of tissue homeostasis in the adult. The PDGF isoforms exert their effects by binding to α-and β-tyrosine kinase receptors. Overactivity of PDGF signaling has been linked to the development of certain malignant and non-malignant diseases, including atherosclerosis and various fibrotic diseases. Different types of PDGF antagonists have been developed, including inhibitory monoclonal antibodies and DNA aptamers against PDGF isoforms and receptors, and receptor tyrosine kinase inhibitors. Beneficial effects have been recorded using such inhibitors in preclinical models and in patients with certain malignant as well as non-malignant diseases. The present communication summarizes the use of PDGF antagonists in the treatment of non-malignant diseases.
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Affiliation(s)
- Carl-Henrik Heldin
- Ludwig Institute for Cancer Research Ltd, Science for Life Laboratory, Uppsala University, Box 595, SE-75124, Uppsala, Sweden,
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Ormiston ML, Deng Y, Rundle N, Bendjelloul F, Tsoporis JN, Parker TG, Stewart DJ, Courtman DW. A Lymphocyte-Dependent Mode of Action for Imatinib Mesylate in Experimental Pulmonary Hypertension. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:1541-51. [DOI: 10.1016/j.ajpath.2013.01.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 12/24/2012] [Accepted: 01/17/2013] [Indexed: 12/22/2022]
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Arita S, Arita N, Hikasa Y. Therapeutic effect of low-dose imatinib on pulmonary arterial hypertension in dogs. THE CANADIAN VETERINARY JOURNAL = LA REVUE VETERINAIRE CANADIENNE 2013; 54:255-261. [PMID: 23997262 PMCID: PMC3573631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
This was a pilot study to determine the effectiveness of low-dose imatinib therapy for hemodynamic disturbances, including pulmonary arterial hypertension (PAH), and clinical manifestations caused by chronic heart failure in dogs. Six client-owned dogs with PAH were administered imatinib mesylate orally, 3 mg/kg body weight q24h, for 30 d. Physical examination, blood biochemical tests, radiography, and Doppler echocardiography were performed prior to imatinib administration and again 30 days after administration. Clinical scores were significantly reduced after imatinib treatment. Systolic pulmonary arterial pressure, heart rate, maximum tricuspid regurgitation velocity, left atrium/aorta ratio, right and left ventricular Tei indexes, early diastolic transmitral flow wave/mitral annulus velocity ratio, and plasma atrial natriuretic peptide concentration decreased significantly after therapy. Diastolic blood pressure, stroke volume, cardiac output, and left ventricular fractional shortening increased significantly after therapy. These results indicate that low-dose imatinib therapy was effective for heart failure in dogs with PAH.
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Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galié N, Gómez-Sánchez MA, Grimminger F, Grünig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, Ghofrani HA. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013; 127:1128-38. [PMID: 23403476 DOI: 10.1161/circulationaha.112.000765] [Citation(s) in RCA: 417] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥ 800 dyne·s·cm(-5) symptomatic on ≥ 2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm(-5) (95% confidence interval, -502 to - 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. CONCLUSIONS Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).
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Affiliation(s)
- Marius M Hoeper
- Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany.
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Abstract
Genetically modified mouse models have unparalleled power to determine the mechanisms behind different processes involved in the molecular and physiologic etiology of various classes of human pulmonary hypertension (PH). Processes known to be involved in PH for which there are extensive mouse models available include the following: (1) Regulation of vascular tone through secreted vasoactive factors; (2) regulation of vascular tone through potassium and calcium channels; (3) regulation of vascular remodeling through alteration in metabolic processes, either through alteration in substrate usage or through circulating factors; (4) spontaneous vascular remodeling either before or after development of elevated pulmonary pressures; and (5) models in which changes in tone and remodeling are primarily driven by inflammation. PH development in mice is of necessity faster and with different physiologic ramifications than found in human disease, and so mice make poor models of natural history of PH. However, transgenic mouse models are a perfect tool for studying the processes involved in pulmonary vascular function and disease, and can effectively be used to test interventions designed against particular molecular pathways and processes involved in disease.
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Affiliation(s)
- Mita Das
- Department of Internal Medicine, University of Arkansas Medical Sciences, Little Rock, Arkansas, USA
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Xing AP, Hu XY, Shi YW, Du YC. Implication of PDGF signaling in cigarette smoke-induced pulmonary arterial hypertension in rat. Inhal Toxicol 2012; 24:468-75. [PMID: 22746397 DOI: 10.3109/08958378.2012.688885] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Pulmonary artery hypertension (PAH) is a severe disease characterized with progressive increase of pulmonary vascular resistance that finally causes right ventricular failure and premature death. Cigarette smoke (CS) is a major factor of Chronic Obstructive Pulmonary Disease (COPD) that can lead to PAH. However, the mechanism of CS-induced PAH is poorly understood. Mounting evidence supports that pulmonary vascular remodeling play an important role in the development of PAH. PDGF signaling has been demonstrated to be a major mediator of vascular remodeling implicated in PAH. However, the association of PDGF signaling with CS-induced PAH has not been documented. In this study, we investigated CS-induced PAH in rats and the expression of platelet derived growth factor (PDGF) and PDGF receptor (PDGFR) in pulmonary artery. Forty male rats were randomly divided into control group and three experimental groups that were exposed to CS for 1, 2, and 3 months, respectively. CS significantly increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI). Histology staining demonstrated that CS significantly increased the thickness of pulmonary artery wall and collagen deposition. The expression of PDGF isoform B (PDGF-B) and PDGF receptor beta (PDGFRβ) were significantly increased at both protein and mRNA levels in pulmonary artery of rats with CS exposure. Furthermore, Cigarette smoke extract (CSE) significantly increased rat pulmonary artery smooth muscle cell (PASMC) proliferation, which was inhibited by PDGFR inhibitor Imatinib. Thus, our data suggest PDGF signaling is implicated in CS-induced PAH.
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Abstract
Major advances have been made in the treatment of World Health Organization Group 1 pulmonary arterial hypertension (PAH). Since the mid-1990s, nine medications have become available in the United States to target three key pathophysiologic derangements in PAH - the prostacyclin, endothelin, and nitric oxide pathways. As a group, these agents have led to improvements in functional capacity, symptoms, hemodynamics, and survival. Most patients with mild to moderate PAH are started on orally active agents such as endothelin receptor antagonists or phosphodiesterase inhibitors. Patients with more severe disease, particularly those with evidence of right heart failure, should be treated with continuous prostacyclin infusion or a combination of a prostacyclin and oral therapy. Each medication has unique properties and clinical considerations, and the selection of an appropriate therapy must be tailored to the individual patient. None of the currently available WHO Group 1 PAH therapies are curative, however, and it is the hope that new therapies in development may halt or reverse disease progression. This review will discuss the major therapeutic classes of presently available medications and their role in managing the patient with PAH. We will also review data supporting the use of combination therapy, adjuvant background therapy, and new agents currently under investigation.
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[Non oncologic applications of molecular targeted therapies]. Bull Cancer 2012; 99:953-62. [PMID: 23092598 DOI: 10.1684/bdc.2012.1641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Significant improvements in the knowledge of cancer biology have permitted the development of new molecular targeted therapies. Meanwhile, a better understanding of the physiology of various non-cancerous diseases has allowed developing these agents in other areas. This review intends to illustrate these perspectives through examples corresponding to different strategies of molecular-targeted therapies : use of a monoclonal antibody binding a receptor (rituximab and rheumatoid arthritis) or a ligand (bevacizumab and age-related macular degeneration), tyrosine kinase inhibitor (imatinib and systemic sclerosis) or inhibitor of cytoplasmic signal transduction pathways (immunosuppressive and antiproliferative effects of mammalian target of rapamycin [mTOR] inhibitors). Clinical results can draw today what could become molecular medicine of tomorrow.
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Vera-Lastra O, Porres-Aguilar M. Pulmonary arterial hypertension associated with systemic sclerosis: Current diagnostic approach and therapeutic strategies. World J Rheumatol 2012; 2:12-20. [DOI: 10.5499/wjr.v2.i2.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) represents a devastating vascular complication of systemic sclerosis (SSc) and is found in 10%-15% of cases carrying a severe prognosis. PAH has a dramatic impact on the clinical course and overall survival, being the single most common cause of death in patients with this entity. The clinical course and aggressive progression of PAH has led clinicians to perform annual screening for it, since early detection and diagnosis are the cornerstone of a prompt therapeutic intervention. The diagnosis of PAH can be challenging to clinicians, particularly in its early stages, since in the context of SSc, the multiple causes of dyspnea need to be assessed. Doppler echocardiography represents the best initial screening tool, however, right heart catheterization remains the gold standard and definitive diagnostic means. Remarkable advances have been achieved in elucidating the pathogenesis of PAH in the past two decades, leading to the development of disease-specific targeted therapies: prostacyclin analogues, endothelin receptor antagonists and inhibitors of five phosphodiesterase pathways. However, the clinical response to these therapies in SSc-associated PAH has not been as great as the one seen with idiopathic PAH. This review also focuses on the diagnosis and novel therapies that are currently available for PAH, as well as potential future therapeutic developments based on newly acquired knowledge of diverse pathogenic mechanisms.
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Maurer B, Reich N, Juengel A, Kriegsmann J, Gay RE, Schett G, Michel BA, Gay S, Distler JHW, Distler O. Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Ann Rheum Dis 2012; 71:1382-7. [PMID: 22523431 DOI: 10.1136/annrheumdis-2011-200940] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Systemic sclerosis-associated pulmonary arterial hypertension differs from idiopathic pulmonary arterial hypertension with respect to histopathology, treatment responses and survival. Medical progress on PAH is hampered by the lack of human biosamples and suitable animal models. In this study, the authors evaluated fos-related antigen 2 (Fra-2) transgenic mice as a novel model for systemic sclerosis-associated pulmonary arterial hypertension. METHODS Lung sections of Fra-2 transgenic (n=12) and wild-type mice (n=6) were analysed at 16 weeks by histology using Dana Point criteria. Cellular and molecular key players were assessed by immunohistochemistry. To test the model's sensitivity to change over treatment, a subgroup of Fra-2 transgenic mice (n=6) was treated with the tyrosine kinase inhibitor nilotinib twice daily 37.5 mg orally from 8 weeks of age. RESULTS Fra-2 transgenic mice developed severe vascular remodelling of pulmonary arteries and non-specific interstitial pneumonia-like interstitial lung disease resembling human systemic sclerosis-associated pulmonary hypertension. Histological features typical for systemic sclerosis-associated pulmonary arterial hypertension, such as intimal thickening with concentric laminar lesions, medial hypertrophy, perivascular inflammatory infiltrates, adventitial fibrosis, but not pulmonary occlusive venopathy were frequently detected. Platelet-derived growth factor signalling pathways were activated in pulmonary vessels of Fra-2 transgenic compared with wild-type mice. Since treatment with nilotinib strongly prevented the development of proliferative vasculopathy and lung fibrosis, the model proved to be sensitive to treatment. CONCLUSIONS This study suggests that Fra-2 transgenic mice as an animal model of systemic sclerosis-associated pulmonary arterial hypertension display main characteristic features of the human disease. It therefore allows studying pathophysiological aspects and might serve as a preclinical model for interventional proof-of-concept studies.
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MESH Headings
- Animals
- Disease Models, Animal
- Enzyme Inhibitors/pharmacology
- Fos-Related Antigen-2/genetics
- Fos-Related Antigen-2/metabolism
- Hypertension, Pulmonary/etiology
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/pathology
- Lung/metabolism
- Lung/pathology
- Lung Diseases, Interstitial/complications
- Lung Diseases, Interstitial/drug therapy
- Lung Diseases, Interstitial/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Peripheral Vascular Diseases/drug therapy
- Peripheral Vascular Diseases/etiology
- Peripheral Vascular Diseases/pathology
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Pulmonary Artery/drug effects
- Pulmonary Artery/pathology
- Pulmonary Circulation/drug effects
- Pulmonary Fibrosis/drug therapy
- Pulmonary Fibrosis/etiology
- Pulmonary Fibrosis/pathology
- Pyrimidines/pharmacology
- Scleroderma, Systemic/complications
- Scleroderma, Systemic/metabolism
- Scleroderma, Systemic/pathology
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Affiliation(s)
- Britta Maurer
- Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland
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Bournia VK, Evangelou K, Sfikakis PP. Therapeutic inhibition of tyrosine kinases in systemic sclerosis: a review of published experience on the first 108 patients treated with imatinib. Semin Arthritis Rheum 2012; 42:377-90. [PMID: 22789835 DOI: 10.1016/j.semarthrit.2012.06.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2012] [Revised: 05/27/2012] [Accepted: 06/03/2012] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Experimental and clinical evidence suggest a therapeutic role for the tyrosine kinase inhibitor imatinib in fibrosing conditions. We evaluated published data on the safety and efficacy of imatinib for patients with systemic sclerosis (SSc), a severe autoimmune disease with significant morbidity and mortality. METHODS A careful search for all original articles and abstracts on the use of imatinib in SSc published in English from 2008 through February 2012 was performed. Two additional patients from our center are also described. RESULTS Five small observational clinical trials on the use of imatinib in severe SSc have been conducted and case reports and small series of refractory to current approaches patients have been reported, adding to a total of 108 patients having received this drug to date. In most of these patients imatinib was given for skin or pulmonary fibrosis. Encouraging results were reported in 3 of 4 studies, whereas the fifth study was prematurely terminated for safety reasons. Overall, clinical results are highly variable, ranging from ineffective or toxic responses to extremely encouraging clinical improvements in some severely ill patients. These discrepancies could partly reflect imatinib-related safety issues, in particular, SSc patients or idiosyncratic resistance to imatinib, as happens in chronic myelogenous leukemia and gastrointestinal stromal tumors, the drug's approved indications. CONCLUSIONS The limited available experience suggests that imatinib could be considered as an individualized treatment approach in severe SSc and underscores the need to identify markers for selecting particular patients, who will safely respond to therapeutic inhibition of tyrosine kinases.
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Abstract
Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease of various origins characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. The most common symptom at presentation is breathlessness, with impaired exercise capacity as a hallmark of the disease. Advances in understanding the pathobiology over the last 2 decades have led to therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins or analogs) initially directed at reversing the pulmonary vasoconstriction and more recently directed toward reversing endothelial cell dysfunction and smooth muscle cell proliferation. Despite these advances, disease progression is common even with use of combination regimens targeting multiple mechanistic pathways. Overall 5-year survival for PAH has increased significantly from approximately 30% in the 1980s to approximately 60% at present, yet remains abysmal. This review summarizes the mechanisms of action, clinical data, and regulatory histories of approved PAH therapies and describes the latest agents in late-stage clinical development.
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Zanjani KS. Platelets in pulmonary hypertension: a causative role or a simple association? IRANIAN JOURNAL OF PEDIATRICS 2012; 22:145-57. [PMID: 23056879 PMCID: PMC3446075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Revised: 01/13/2012] [Accepted: 02/11/2012] [Indexed: 11/30/2022]
Abstract
PATHOPHYSIOLOGY OF PULMONARY ARTERIAL HYPERTENSION IS BASED ON THREE BASIC MECHANISMS: thrombotic pulmonary vascular lesions, vasoconstriction and vascular remodeling. Platelets are related to all of these mechanisms by their aggregation, production, storage and release of several mediators. The role of platelets is more prominent in some types of pulmonary arterial hypertension, including those which are secondary to inflammatory and infectious diseases, hemoglobinopathies, essential thrombocythemia, drugs, thromboembolism, and cardiac surgery. Most pulmonary antihypertensive drugs have a negative effect on platelets. In this review, the mechanisms of platelets association with pulmonary arterial hypertension, those types of pulmonary arterial hypertension with greatest platelet contribution to their pathophysiology, and the effects of pulmonary antihypertensive drugs on platelets are summarized.
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Affiliation(s)
- Keyhan Sayadpour Zanjani
- Corresponding Author:Address: Children's Medical Center, No 62, Dr Gharib St, 14194 Tehran, Iran. E-mail:
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Montani D, Bergot E, Günther S, Savale L, Bergeron A, Bourdin A, Bouvaist H, Canuet M, Pison C, Macro M, Poubeau P, Girerd B, Natali D, Guignabert C, Perros F, O'Callaghan DS, Jaïs X, Tubert-Bitter P, Zalcman G, Sitbon O, Simonneau G, Humbert M. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125:2128-37. [PMID: 22451584 DOI: 10.1161/circulationaha.111.079921] [Citation(s) in RCA: 426] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. METHODS AND RESULTS This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. CONCLUSIONS Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
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Affiliation(s)
- David Montani
- Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France
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Sano M, Saotome M, Urushida T, Katoh H, Satoh H, Ohnishi K, Hayashi H. Pulmonary arterial hypertension caused by treatment with dasatinib for chronic myeloid leukemia -critical alert-. Intern Med 2012; 51:2337-40. [PMID: 22975544 DOI: 10.2169/internalmedicine.51.7472] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
We present a case of pulmonary arterial hypertension (PAH), which is potentially related to treatment with dasatinib (Sprycel(®)). A 61-year-old woman, who had been treated with dasatinib for 27 months for chronic myeloid leukemia (CML), visited our hospital complaining of dyspnea. In right heart catheterization, her mean pulmonary arterial pressure was 35 mmHg. After other possible etiologies to cause PAH were excluded, the patient was diagnosed as a dasatinib-related PAH. As notified by U.S. Food and Drug Administration (FDA) in October 2011, we recommend routine cardiopulmonary evaluation before and during treatment with dasatinib in CML patients in terms of the adverse effects of PAH.
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Affiliation(s)
- Makoto Sano
- Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine, Japan
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Ratcliffe AJ. The Drug Discovery and Development of Kinase Inhibitors Outside of Oncology. KINASE DRUG DISCOVERY 2011. [DOI: 10.1039/9781849733557-00218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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ten Freyhaus H, Dumitrescu D, Berghausen E, Vantler M, Caglayan E, Rosenkranz S. Imatinib mesylate for the treatment of pulmonary arterial hypertension. Expert Opin Investig Drugs 2011; 21:119-34. [PMID: 22074410 DOI: 10.1517/13543784.2012.632408] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Despite recent advances, pulmonary arterial hypertension (PAH) remains a devastating disease which harbors a poor prognosis. Novel therapeutic approaches directly targeting pulmonary vascular remodeling are warranted. AREAS COVERED This review delineates the current limitations in the management of PAH and focuses on a novel, anti-proliferative therapeutic concept. It will help readers understand the mechanisms of receptor tyrosine kinase signaling, with a special focus on platelet-derived growth factor (PDGF) receptors and their role in the pathobiology of PAH. Furthermore, it provides a comprehensive summary regarding the rationale, efficacy and safety of the tyrosine kinase inhibitor imatinib mesylate , which potently inhibits the PDGF receptor, as an additional treatment option in PAH. EXPERT OPINION PDGF is a potent mitogen for pulmonary vascular smooth muscle cells and represents an important mediator of pulmonary vascular remodeling. Imatinib mesylate, a compound that inhibits the Bcr-Abl kinase and was developed for the treatment of chronic myeloid leukemia, also targets PDGF receptors. Both experimental and clinical data indicate that it reverses the vascular remodeling process even when it is fully established. Results from Phase II and III clinical trials suggest potent and prolonged efficacy in patients with severe PAH (i.e., pulmonary vascular resistance > 800 dynes*s*cm(-5)). Future studies should evaluate the long-term clinical efficacy and safety of imatinib, including patients with less impaired hemodynamics. Based on the current knowledge, this compound is likely to become an additional treatment option for patients with PAH and has the potential to at least partially correct the pathology of the disease.
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Affiliation(s)
- Henrik ten Freyhaus
- Klinik III für Innere Medizin, Center for Molecular Medicine Cologne, Universität zu Köln, Kerpener Str. 62, 50924 Köln, Germany
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Raja SG, Raja SM. Treating pulmonary arterial hypertension: current treatments and future prospects. Ther Adv Chronic Dis 2011; 2:359-370. [PMID: 23251761 PMCID: PMC3513893 DOI: 10.1177/2040622311420773] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) consists of a group of heterogeneous but distinct disorders characterized by complex proliferation of the pulmonary vascular endothelium and progressive pulmonary vascular remodeling that leads to right ventricular failure and death. Over the past two decades, significant advances in our understanding of the pathobiology of PAH have led to the development of several therapeutic targets in this disease. Besides conservative therapeutic strategies such as anticoagulation and diuretics, the current treatment paradigm for PAH targets the mediators of the three main biologic pathways that are critical for its pathogenesis and progression: endothelin receptor antagonists inhibit the upregulated endothelin pathway by blocking the biologic activity of endothelin-1; phosphodiesterase-5 inhibitors prevent breakdown and increase the endogenous availability of cyclic guanosine monophosphate, which signals the vasorelaxing effects of the downregulated mediator nitric oxide; and prostacyclin derivatives provide an exogenous supply of the deficient mediator prostacyclin. In addition to these established current therapeutic options, a large number of potential therapeutic targets are being investigated. These novel therapeutic targets include soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-hydroxytryptamine (serotonin) receptor 2B, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. This review provides an overview of the current therapeutic options and potential therapeutic targets for PAH.
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Mermis J, Gu H, Xue B, Li F, Tawfik O, Buch S, Bartolome S, O'Brien-Ladner A, Dhillon NK. Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling. Respir Res 2011; 12:103. [PMID: 21819559 PMCID: PMC3163194 DOI: 10.1186/1465-9921-12-103] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 08/05/2011] [Indexed: 12/29/2022] Open
Abstract
Background Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1α and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH. Methods The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB. Results HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120CM mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1α plays critical role in gp120 mediated up-regulation of PDGF-BB. Conclusion In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH.
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Affiliation(s)
- Joel Mermis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Kansas Medical Center, Kansas City, USA
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O'Callaghan DS, Savale L, Montani D, Jaïs X, Sitbon O, Simonneau G, Humbert M. Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol 2011; 8:526-38. [PMID: 21769113 DOI: 10.1038/nrcardio.2011.104] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature that results in elevated pulmonary vascular resistance and premature death. Although no cure exists for PAH, improved understanding of the pathobiological mechanisms of this disease has resulted in the development of effective therapies that target specific aberrant pathways. Agents that modulate abnormalities in the prostacyclin, endothelin, and nitric oxide pathways have been shown in randomized, controlled studies to confer improvements in functional status, pulmonary hemodynamics, and possibly even slow disease progression. Several additional pathways believed to play an important role in the pathogenesis of PAH have been identified as potentially useful therapeutic targets and a number of investigative approaches focusing on these targets are in active development. In this Review, we highlight the pharmacological agents currently available for the treatment of PAH and discuss potential novel strategies.
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Montani D, Perros F, Gambaryan N, Girerd B, Dorfmuller P, Price LC, Huertas A, Hammad H, Lambrecht B, Simonneau G, Launay JM, Cohen-Kaminsky S, Humbert M. C-Kit–Positive Cells Accumulate in Remodeled Vessels of Idiopathic Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2011; 184:116-23. [DOI: 10.1164/rccm.201006-0905oc] [Citation(s) in RCA: 149] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
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