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Waligóra M, Kurzyna M, Mularek-Kubzdela T, Skoczylas I, Chrzanowski Ł, Błaszczak P, Jaguszewski M, Kuśmierczyk B, Ptaszyńska K, Grześk G, Mizia-Stec K, Malinowska E, Peregud-Pogorzelska M, Lewicka E, Tomaszewski M, Jacheć W, Florczyk M, Mroczek E, Gąsior Z, Pawlak A, Betkier-Lipińska K, Pruszczyk P, Widejko K, Zabłocka W, Kopeć G. Effects of β-Blockers on the Outcomes in Patients With Pulmonary Arterial Hypertension Stratified by the Presence of Comorbid Conditions: A Multicenter Prospective Cohort Study: The Database of Pulmonary Hypertension in the Polish Population (BNP-PL). Chest 2025; 167:1171-1181. [PMID: 39528108 DOI: 10.1016/j.chest.2024.10.051] [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: 07/16/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Current guidelines do not recommend β-blockers in pulmonary arterial hypertension (PAH) unless indicated by comorbidities. However, the evidence regarding the role of β-blockers in PAH is contradictory. RESEARCH QUESTION What are the effects of β-blockers on clinical outcomes in patients newly diagnosed with PAH, and how do these outcomes differ based on the presence of cardiovascular comorbidities that are standard indications for β-blocker use? STUDY DESIGN AND METHODS We analyzed data from 806 patients newly diagnosed with PAH enrolled prospectively in the Database of Pulmonary Hypertension in the Polish Population (BNP-PL). The end points were all-cause mortality and a composite of hospitalization due to right-sided heart failure, syncope, or death. Indications for β-blocker use included hypertension, significant arrhythmia, and coronary artery disease. Propensity score matching was used to form a control group based on age, PAH mortality risk variables, and initially introduced PAH-specific therapy. RESULTS Of the 806 patients, 469 (58.2%) received β-blockers at the time of PAH diagnosis. In propensity score matching, β-blocker treatment showed a higher incidence of the composite end point (hazard ratio, 1.44; 95% CI, 1.04-1.99; P = .03) and had a neutral impact on mortality (hazard ratio, 1.22; 95% CI, 0.87-1.72; P = .25). When stratified according to the presence of comorbidities, β-blockers showed adverse effects on the composite end point in patients without comorbidities and a neutral effect in patients with at least one comorbidity. INTERPRETATION Our results indicate that β-blockers pose significant risks in patients with PAH, especially in patients without coexisting systemic hypertension, coronary artery disease, or arrhythmia. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT03959748; URL: www. CLINICALTRIALS gov.
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Affiliation(s)
- Marcin Waligóra
- Department of Cardiac and Vascular Diseases, St. John Paul II Hospital, Krakow, Poland; Pulmonary Circulation Centre, Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland; Center for Innovative Medical Education, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Marcin Kurzyna
- Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, Fryderyk Chopin Hospital in European Health Centre, Otwock, Poland
| | | | - Ilona Skoczylas
- 3rd Department of Cardiology, Faculty of Medical Sciences in Zabrze, Katowice, Poland
| | | | - Piotr Błaszczak
- Department of Cardiology, Cardinal Wyszynski Hospital, Lublin, Poland
| | | | - Beata Kuśmierczyk
- Department of Congenital Heart Disease, Institute of Cardiology, Warsaw, Poland
| | | | - Grzegorz Grześk
- Department of Cardiology and Clinical Pharmacology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Katarzyna Mizia-Stec
- First Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Ewa Malinowska
- Pulmonary Department, University of Warmia and Mazury, Olsztyn, Poland
| | | | - Ewa Lewicka
- Department of Cardiology and Electrotherapy, Medical University of Gdansk, Gdansk, Poland
| | | | - Wojciech Jacheć
- 2nd Department of Cardiology, Faculty of Medical Sciences in Zabrze, Silesian Medical University in Katowice, Zabrze, Poland
| | - Michał Florczyk
- Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, Fryderyk Chopin Hospital in European Health Centre, Otwock, Poland
| | - Ewa Mroczek
- Department of Cardiology, Institute of Heart Diseases, Wroclaw Medical University, Poland
| | - Zbigniew Gąsior
- Department of Cardiology, School of Health Sciences, Medical University of Silesia in Katowice, Katowice, Poland
| | - Agnieszka Pawlak
- Department of Invasive Cardiology, Polish Academy of Sciences, Mossakowski Medical Research Centre, Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland
| | - Katarzyna Betkier-Lipińska
- Department of Cardiology and Internal Medicine, Military Institute of Medicine-National Research Institute, Warsaw, Poland
| | - Piotr Pruszczyk
- Department of Internal Medicine and Cardiology, Center for Diagnosis and Treatment of Venous Thromboembolism, Medical University of Warsaw, Warszawa, Poland
| | | | - Wiesława Zabłocka
- Department of Cardiology, Provincial Specialist Hospital, Szczecin, Poland
| | - Grzegorz Kopeć
- Department of Cardiac and Vascular Diseases, St. John Paul II Hospital, Krakow, Poland; Pulmonary Circulation Centre, Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland.
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Bogaard HJ, de Man FS. Beta-Blockers in Pulmonary Arterial Hypertension: Physiology Getting in Biology's Way. Chest 2025; 167:935-938. [PMID: 40210311 DOI: 10.1016/j.chest.2025.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 01/11/2025] [Indexed: 04/12/2025] Open
Affiliation(s)
- Harm Jan Bogaard
- Department of Pulmonary Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands.
| | - Frances S de Man
- Department of Pulmonary Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
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Dongdem JT, Etornam AE, Beletaa S, Alidu I, Kotey H, Wezena CA. The β 3-Adrenergic Receptor: Structure, Physiopathology of Disease, and Emerging Therapeutic Potential. Adv Pharmacol Pharm Sci 2024; 2024:2005589. [PMID: 39640497 PMCID: PMC11620816 DOI: 10.1155/2024/2005589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 10/24/2024] [Indexed: 12/07/2024] Open
Abstract
The discovery and characterization of the signal cascades of the β-adrenergic receptors have made it possible to effectively target the receptors for drug development. β-Adrenergic receptors are a class A rhodopsin type of G protein-coupled receptors (GPCRs) that are stimulated mainly by catecholamines and therefore mediate diverse effects of the parasympathetic nervous system in eliciting "fight or flight" type responses. They are detectable in several human tissues where they control a plethora of physiological processes and therefore contribute to the pathogenesis of several disease conditions. Given the relevance of the β-adrenergic receptor as a molecular target for many pathological conditions, this comprehensive review aims at providing an in-depth exploration of the recent advancements in β3-adrenergic receptor research. More importantly, we delve into the prospects of the β3-adrenergic receptor as a therapeutic target across a variety of clinical domains.
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Affiliation(s)
- Julius T. Dongdem
- Department of Chemical Pathology, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Axandrah E. Etornam
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Solomon Beletaa
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Issah Alidu
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Hassan Kotey
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Cletus A. Wezena
- Department of Microbiology, Faculty of Biosciences, University for Development Studies, Tamale, Northern Region, Ghana
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Lopes Soares L, Portes AMO, Costa SFF, Leite LB, Natali AJ. Autonomic Dysregulation in Pulmonary Hypertension: Role of Physical Exercise. Hypertension 2024; 81:2228-2236. [PMID: 39234679 DOI: 10.1161/hypertensionaha.124.23573] [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] [Indexed: 09/06/2024]
Abstract
Pulmonary hypertension (PH) is a rare and severe condition characterized by increased pressure in the pulmonary circulation, often resulting in right ventricular failure and death. The autonomic nervous system (ANS) plays a crucial role in the cardiovascular and pulmonary controls. Dysfunction of ANS has been implicated in the pathogenesis of cardiopulmonary diseases. Conversely, dysfunctions in ANS can arise from these diseases, impacting cardiac and pulmonary autonomic functions and contributing to disease progression. The complex interaction between ANS dysfunction and PH plays a crucial role in the disease progression, making it essential to explore interventions that modulate ANS, such as physical exercise, to improve the treatment and prognosis of patients with PH. This review addresses autonomic dysfunctions found in PH and their implications for the cardiopulmonary system. Furthermore, we discuss how physical exercise, a significant modulator of ANS, may contribute to the prognosis of PH. Drawing from evidence of aerobic and resistance exercise training in patients and experimental models of PH, potential cardiovascular benefits of exercise are presented. Finally, we highlight emerging therapeutic targets and perspectives to better cope with the complex condition. A comprehensive understanding of the interaction between ANS and PH, coupled with targeted physical exercise interventions, may pave the way for innovative therapeutic strategies and significantly improve the treatment and prognosis of vulnerable patients.
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Affiliation(s)
- Leôncio Lopes Soares
- Department of Physical Education, Federal University of Viçosa, Minas Gerais, Brazil (L.L.S., S.F.F.C., L.B.L., A.J.N.)
| | | | | | - Luciano Bernardes Leite
- Department of Physical Education, Federal University of Viçosa, Minas Gerais, Brazil (L.L.S., S.F.F.C., L.B.L., A.J.N.)
| | - Antônio José Natali
- Department of Physical Education, Federal University of Viçosa, Minas Gerais, Brazil (L.L.S., S.F.F.C., L.B.L., A.J.N.)
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Carlström M, Weitzberg E, Lundberg JO. Nitric Oxide Signaling and Regulation in the Cardiovascular System: Recent Advances. Pharmacol Rev 2024; 76:1038-1062. [PMID: 38866562 DOI: 10.1124/pharmrev.124.001060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/30/2024] [Accepted: 05/29/2024] [Indexed: 06/14/2024] Open
Abstract
Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. SIGNIFICANCE STATEMENT: After four decades of intensive research, questions persist about the transduction and control of nitric oxide (NO) synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Nonclassical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered.
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Affiliation(s)
- Mattias Carlström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.C., E.W., J.O.L.); and Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden (E.W.)
| | - Eddie Weitzberg
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.C., E.W., J.O.L.); and Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden (E.W.)
| | - Jon O Lundberg
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.C., E.W., J.O.L.); and Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden (E.W.)
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Tsai J, Malik S, Tjen-A-Looi SC. Pulmonary Hypertension: Pharmacological and Non-Pharmacological Therapies. Life (Basel) 2024; 14:1265. [PMID: 39459565 PMCID: PMC11509317 DOI: 10.3390/life14101265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/23/2024] [Accepted: 10/01/2024] [Indexed: 10/28/2024] Open
Abstract
Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling, often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here, we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including imbalances in vasoconstrictor-vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neurostimulation including acupuncture. Lastly, we also touch upon the disease's different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost.
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Affiliation(s)
- Jason Tsai
- Susan Samueli Integrative Health Institute, College of Health Sciences, University of California-Irvine, Irvine, CA 92617, USA;
| | | | - Stephanie C. Tjen-A-Looi
- Susan Samueli Integrative Health Institute, College of Health Sciences, University of California-Irvine, Irvine, CA 92617, USA;
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Liu X, Liu B, Luo X, Liu Z, Tan X, Zhu K, Ouyang F. Research progress on the role of p53 in pulmonary arterial hypertension. Respir Investig 2024; 62:541-550. [PMID: 38643536 DOI: 10.1016/j.resinv.2024.03.011] [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: 09/19/2023] [Revised: 03/13/2024] [Accepted: 03/28/2024] [Indexed: 04/23/2024]
Abstract
PURPOSE OF REVIEW Pulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary vascular resistance and pulmonary arterial pressure. At present, the definitive pathology of PAH has not been elucidated and its effective treatment remains lacking. Despite PAHs having multiple pathogeneses, the cancer-like characteristics of cells have been considered the main reason for PAH progression. RECENT FINDINGS p53 protein, an important tumor suppressor, regulates a multitude of gene expressions to maintain normal cellular functions and suppress the progression of malignant tumors. Recently, p53 has been found to exert multiple biological effects on cardiovascular diseases. Since PAH shares similar metabolic features with cancer cells, the regulatory roles of p53 in PAH are mainly the induction of cell cycle, inhibition of cell proliferation, and promotion of apoptosis. SUMMARY This paper summarized the advanced findings on the molecular mechanisms and regulatory functions of p53 in PAH, aiming to reveal the potential therapeutic targets for PAH.
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Affiliation(s)
- Xiangyang Liu
- Department of Cardiovascular Medicine, Zhuzhou Central Hospital, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, No.116 Changjiangnan Road, Tianyuan District, Zhuzhou City, 412000, Hunan, China
| | - Biao Liu
- Department of Cardiovascular Medicine, Taojiang County People's Hospital, No.328 Taohuaxi Road, Taohuajiang Town, Taojiang County, Yiyang City, 413499, Hunan, China
| | - Xin Luo
- Department of Cardiovascular Medicine, Zhuzhou Central Hospital, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, No.116 Changjiangnan Road, Tianyuan District, Zhuzhou City, 412000, Hunan, China
| | - Zhenfang Liu
- Department of Cardiovascular Medicine, Zhuzhou Central Hospital, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, No.116 Changjiangnan Road, Tianyuan District, Zhuzhou City, 412000, Hunan, China
| | - Xiaoli Tan
- Department of Cardiovascular Medicine, Zhuzhou Central Hospital, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, No.116 Changjiangnan Road, Tianyuan District, Zhuzhou City, 412000, Hunan, China
| | - Ke Zhu
- Department of Cardiovascular Medicine, Zhuzhou Central Hospital, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, No.116 Changjiangnan Road, Tianyuan District, Zhuzhou City, 412000, Hunan, China.
| | - Fan Ouyang
- Department of Cardiovascular Medicine, Zhuzhou Central Hospital, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, No.116 Changjiangnan Road, Tianyuan District, Zhuzhou City, 412000, Hunan, China.
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Corbi G, Comegna M, Vinciguerra C, Capasso A, Onorato L, Salucci AM, Rapacciuolo A, Cannavo A. Age and sex mediated effects of estrogen and Β3-adrenergic receptor on cardiovascular pathophysiology. Exp Gerontol 2024; 190:112420. [PMID: 38588751 DOI: 10.1016/j.exger.2024.112420] [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: 02/06/2024] [Revised: 03/29/2024] [Accepted: 04/05/2024] [Indexed: 04/10/2024]
Abstract
Sex differences are consistently identified in determining the prevalence, manifestation, and response to therapies in several systemic disorders, including those affecting the cardiovascular (CV), skeletal muscle, and nervous system. Interestingly, such differences are often more noticeable as we age. For example, premenopausal women experience a lower risk of CV disease than men of the same age. While at an advanced age, with menopause, the risk of cardiovascular diseases and adverse outcomes increases exponentially in women, exceeding that of men. However, this effect appears to be reversed in diseases such as pulmonary hypertension, where women are up to seven times more likely than men to develop an idiopathic form of the disease with symptoms developing ten years earlier than their male counterparts. Explaining this is a complex question. However, several factors and mechanisms have been identified in recent decades, including a role for sex hormones, particularly estrogens and their related receptors. Furthermore, an emerging role in these sex differences has also been suggested for β-adrenergic receptors (βARs), which are essential regulators of mammalian physiology. It has in fact been shown that βARs interact with estrogen receptors (ER), providing further demonstration of their involvement in determining sexual differences. Based on these premises, this review article focused on the β3AR subtype, which shows important activities in adipose tissue but with new and interesting roles in regulating the function of cardiomyocytes and vascular cells. In detail, we examined how β3AR and ER signaling are intertwined and whether there would be sex- and age-dependent specific effects of these receptor systems.
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Affiliation(s)
- Graziamaria Corbi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Marika Comegna
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; CEINGE-Advanced Biotechnologies - Franco Salvatore, Naples, Italy
| | - Caterina Vinciguerra
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Alessio Capasso
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Luigi Onorato
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | | | - Antonio Rapacciuolo
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Alessandro Cannavo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
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Waddingham MT, Tsuchimochi H, Sonobe T, Sequeira V, Nayeem MJ, Shirai M, Pearson JT, Ogo T. The selective serotonin reuptake inhibitor paroxetine improves right ventricular systolic function in experimental pulmonary hypertension. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY PLUS 2024; 8:100072. [PMID: 39802918 PMCID: PMC11708357 DOI: 10.1016/j.jmccpl.2024.100072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/13/2024] [Accepted: 03/24/2024] [Indexed: 01/16/2025]
Abstract
Background Pulmonary hypertension (PH) often leads to right ventricle (RV) failure, a significant cause of morbidity and mortality. Despite advancements in PH management, progression to RV maladaptation and subsequent failure remain a clinical challenge. This study explored the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on RV function in a rat model of PH, hypothesizing that it improves RV function by inhibiting G protein-coupled receptor kinase 2 (GRK2) and altering myofilament protein phosphorylation. Methods The Su5416/hypoxia (SuHx) rat model was used to induce PH. Rats were treated with paroxetine and compared to vehicle-treated and control groups. Parameters measured included RV morphology, systolic and diastolic function, myofilament protein phosphorylation, GRK2 activity, and sympathetic nervous system (SNS) markers. Results Paroxetine treatment significantly improved RV systolic function, evidenced by increased stroke volume, cardiac output, and ejection fraction, without significantly affecting RV hypertrophy, myosin heavy chain/titin isoform switching, or fibrosis. Enhanced phosphorylation of titin and myosin light chain-2 was observed, correlating positively with improved systolic function. Contrary to the hypothesis, improvements occurred independently of GRK2 inhibition or SNS modulation, suggesting an alternate mechanism, potentially involving antioxidant properties of paroxetine. Conclusion Paroxetine improves RV systolic function in PH rats, likely through mechanisms beyond GRK2 inhibition, possibly related to its antioxidant effects. This highlights the potential of paroxetine in managing RV dysfunction in PH, warranting further investigation into its detailed mechanisms of action and clinical applicability.
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Affiliation(s)
- Mark T. Waddingham
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
| | - Hirotsugu Tsuchimochi
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
| | - Takashi Sonobe
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
- Department of Bioregulatory Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Vasco Sequeira
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
- DZHI, Department of Translational Science Universitätsklinikum, Würzburg, Germany
| | - Md Junayed Nayeem
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
| | - Mikiyasu Shirai
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
| | - James T. Pearson
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
- Department of Physiology, Victoria Heart Institute, Monash Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Takeshi Ogo
- Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
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Xueyuan L, Yanping X, Jiaoqiong G, Yuehui Y. Autonomic nervous modulation: early treatment for pulmonary artery hypertension. ESC Heart Fail 2024; 11:619-627. [PMID: 38108098 DOI: 10.1002/ehf2.14616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 11/09/2023] [Accepted: 11/17/2023] [Indexed: 12/19/2023] Open
Abstract
Pulmonary artery hypertension (PAH) is a chronic vascular disease defined by the elevation of pulmonary vascular resistance and mean pulmonary artery pressure, which arises due to pulmonary vascular remodelling. Prior research has already established a link between the autonomic nervous system (ANS) and PAH. Therefore, the rebalancing of the ANS offers a promising approach for the treatment of PAH. The process of rebalancing involves two key aspects: inhibiting an overactive sympathetic nervous system and fortifying the impaired parasympathetic nervous system through pharmacological or interventional procedures. However, the understanding of the precise mechanisms involved in neuromodulation, whether achieved through medication or intervention, remains insufficient. This limited understanding hinders our ability to determine the appropriate timing and scope of such treatment. This review aims to integrate the findings from clinical and mechanistic studies on ANS rebalancing as a treatment approach for PAH, with the ultimate goal of identifying a path to enhance the safety and efficacy of neuromodulation therapy and improve the prognosis of PAH.
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Affiliation(s)
- Liu Xueyuan
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xu Yanping
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guan Jiaoqiong
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yin Yuehui
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Wang J, Chen J, Shu L, Zhang R, Dai M, Fang X, Hu Z, Xiao L, Xi Z, Zhang J, Bao M. Carotid Baroreceptor Stimulation Improves Pulmonary Arterial Remodeling and Right Ventricular Dysfunction in Pulmonary Arterial Hypertension. JACC Basic Transl Sci 2024; 9:475-492. [PMID: 38680958 PMCID: PMC11055206 DOI: 10.1016/j.jacbts.2024.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 05/01/2024]
Abstract
Autonomic nervous system imbalance is intricately associated with the severity and prognosis of pulmonary arterial hypertension (PAH). Carotid baroreceptor stimulation (CBS) is a nonpharmaceutical intervention for autonomic neuromodulation. The effects of CBS on monocrotaline-induced PAH were investigated in this study, and its underlying mechanisms were elucidated. The results indicated that CBS improved pulmonary hemodynamic status and alleviated right ventricular dysfunction, improving pulmonary arterial remodeling and right ventricular remodeling, thus enhancing the survival rate of monocrotaline-induced PAH rats. The beneficial effects of CBS treatment on PAH might be mediated through the inhibition of sympathetic overactivation and inflammatory immune signaling pathways.
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Affiliation(s)
- Jing Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
- Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ling Shu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Ruoliu Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Mingyan Dai
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Xuesheng Fang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Zhiling Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Lingling Xiao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Zhaoqing Xi
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Junxia Zhang
- Department of Endocrinology, Taikang Tongji (Wuhan) Hospital, Wuhan, China
| | - Mingwei Bao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
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12
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Zhao H, Song J, Li X, Xia Z, Wang Q, Fu J, Miao Y, Wang D, Wang X. The role of immune cells and inflammation in pulmonary hypertension: mechanisms and implications. Front Immunol 2024; 15:1374506. [PMID: 38529271 PMCID: PMC10962924 DOI: 10.3389/fimmu.2024.1374506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 02/26/2024] [Indexed: 03/27/2024] Open
Abstract
Pulmonary hypertension (PH) is a malignant disease with progressive increase of pulmonary vascular pressure, which eventually leads to right heart failure. More and more evidences show that immune cells and inflammation play an important role in the occurrence and development of PH. In the context of pulmonary vascular diseases, immune cells migrate into the walls of the pulmonary vascular system. This leads to an increase in the levels of cytokines and chemokines in both the bloodstream and the surrounding tissues of the pulmonary vessels. As a result, new approaches such as immunotherapy and anti-inflammatory treatments are being considered as potential strategies to halt or potentially reverse the progression of PH. We reviewed the potential mechanisms of immune cells, cytokines and chemokines in PH development. The potential relationship of vascular cells or bone morphogenetic protein receptor 2 (BMPR2) in immune regulation was also expounded. The clinical application and future prospect of immunotherapy were further discussed.
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Affiliation(s)
- Hui Zhao
- School of Materials and Chemistry, Institute of Bismuth and Rhenium, University of Shanghai for Science and Technology, Shanghai, China
| | - Jialin Song
- Department of Limb Trauma, Wendeng Orthopaedic Hospital of Shandong Province, Weihai, Shandong, China
| | - Xiujun Li
- Department of Medicine, Chifeng University, Chifeng, China
| | - Zhaoyi Xia
- Department of Library, Children's Hospital Affiliated to Shandong University, Jinan, Shandong, China
- Department of Library, Jinan Children's Hospital, Shandong, Jinan, Shandong, China
| | - Qian Wang
- School of Materials and Chemistry, Institute of Bismuth and Rhenium, University of Shanghai for Science and Technology, Shanghai, China
| | - Jiaqi Fu
- School of Materials and Chemistry, Institute of Bismuth and Rhenium, University of Shanghai for Science and Technology, Shanghai, China
| | - Yuqing Miao
- School of Materials and Chemistry, Institute of Bismuth and Rhenium, University of Shanghai for Science and Technology, Shanghai, China
| | - Dapeng Wang
- Department of Intensive Medicine, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Xuguang Wang
- Department of Limb Trauma, Wendeng Orthopaedic Hospital of Shandong Province, Weihai, Shandong, China
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13
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Gul R, Okla M, Mahmood A, Nawaz S, Fallata A, Bazighifan A, Alfayez M, Alfadda AA. Comparison of the Protective Effects of Nebivolol and Metoprolol against LPS-Induced Injury in H9c2 Cardiomyoblasts. Curr Issues Mol Biol 2023; 45:9316-9327. [PMID: 37998760 PMCID: PMC10670410 DOI: 10.3390/cimb45110583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/31/2023] [Accepted: 11/03/2023] [Indexed: 11/25/2023] Open
Abstract
Here, we, for the first time, compared the cardioprotective effects of third-generation vasodilating beta-blocker nebivolol (Neb) and conventional beta-blocker metoprolol (Met) on LPS-induced injury in H9c2 cardiomyoblasts. Our findings denoted that Neb and Met pretreatment diminish LPS-mediated cytotoxicity and oxidative stress. Concomitantly, LPS-triggered inflammatory cytokines activation was significantly suppressed by Neb but not by Met. Pretreatment with either Neb or Met alleviated LPS-mediated mitochondrial impairment by enhancing the expression of genes related to its biogenesis such as PGC-1α, NRF1, and TFAM. On the contrary, Neb but not Met-upregulated mitochondrial fusion-related genes such as OPA, and MFN2. In summary, our findings suggest that Neb and Met treatment significantly ameliorated the LPS-induced cytotoxicity and oxidative stress. Additionally, these findings suggest that Neb but not Met significantly down-regulates LPS-induced proinflammatory factors, probably by enhancing mitochondrial biogenesis and fusion.
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Affiliation(s)
- Rukhsana Gul
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia; (S.N.); (A.B.); (A.A.A.)
| | - Meshail Okla
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia
| | - Amer Mahmood
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia
| | - Shahid Nawaz
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia; (S.N.); (A.B.); (A.A.A.)
| | - Amina Fallata
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia; (S.N.); (A.B.); (A.A.A.)
| | - Arwa Bazighifan
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia; (S.N.); (A.B.); (A.A.A.)
| | - Musaad Alfayez
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia
| | - Assim A. Alfadda
- Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia; (S.N.); (A.B.); (A.A.A.)
- Department of Medicine, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia
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Saint-Martin Willer A, Santos-Gomes J, Adão R, Brás-Silva C, Eyries M, Pérez-Vizcaino F, Capuano V, Montani D, Antigny F. Physiological and pathophysiological roles of the KCNK3 potassium channel in the pulmonary circulation and the heart. J Physiol 2023; 601:3717-3737. [PMID: 37477289 DOI: 10.1113/jp284936] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 07/04/2023] [Indexed: 07/22/2023] Open
Abstract
Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two-pore domain potassium channel family, constitutively active at resting membrane potentials in excitable cells, including smooth muscle and cardiac cells. Several physiological and pharmacological mediators, such as intracellular signalling pathways, extracellular pH, hypoxia and anaesthetics, regulate KCNK3 channel function. Recent studies show that modulation of KCNK3 channel expression and function strongly influences pulmonary vascular cell and cardiomyocyte function. The altered activity of KCNK3 in pathological situations such as atrial fibrillation, pulmonary arterial hypertension and right ventricular dysfunction demonstrates the crucial role of KCNK3 in cardiovascular homeostasis. Furthermore, loss of function variants of KCNK3 have been identified in patients suffering from pulmonary arterial hypertension and atrial fibrillation. This review focuses on current knowledge of the role of the KCNK3 channel in pulmonary circulation and the heart, in healthy and pathological conditions.
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Affiliation(s)
- Anaïs Saint-Martin Willer
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999 'Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique', Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Joana Santos-Gomes
- Cardiovascular R&D Centre-UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Rui Adão
- Cardiovascular R&D Centre-UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
- CIBER Enfermedades Respiratorias (Ciberes), Madrid, Spain
| | - Carmen Brás-Silva
- Cardiovascular R&D Centre-UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Mélanie Eyries
- Département de génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France
- INSERM UMRS1166, ICAN - Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France
| | - Francisco Pérez-Vizcaino
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
- CIBER Enfermedades Respiratorias (Ciberes), Madrid, Spain
| | - Véronique Capuano
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999 'Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique', Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - David Montani
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999 'Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique', Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Fabrice Antigny
- Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999 'Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique', Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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15
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New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci 2023; 24:ijms24065850. [PMID: 36982922 PMCID: PMC10058689 DOI: 10.3390/ijms24065850] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/12/2023] [Accepted: 03/14/2023] [Indexed: 03/22/2023] Open
Abstract
Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH.
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Karimi Galougahi K, Zhang Y, Kienzle V, Liu C, Quek L, Patel S, Lau E, Cordina R, Figtree GA, Celermajer DS. β3 adrenergic agonism: A novel pathway which improves right ventricular-pulmonary arterial hemodynamics in pulmonary arterial hypertension. Physiol Rep 2023; 11:e15549. [PMID: 36597221 PMCID: PMC9810839 DOI: 10.14814/phy2.15549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/29/2022] [Accepted: 12/01/2022] [Indexed: 06/17/2023] Open
Abstract
Efficacy of therapies that target the downstream nitric oxide (NO) pathway in pulmonary arterial hypertension (PAH) depends on the bioavailability of NO. Reduced NO level in PAH is secondary to "uncoupling" of endothelial nitric oxide synthase (eNOS). Stimulation of β3 adrenergic receptors (β3 ARs) may lead to the recoupling of NOS and therefore be beneficial in PAH. We aimed to examine the efficacy of β3 AR agonism as a novel pathway in experimental PAH. In hypoxia (5 weeks) and Sugen hypoxia (hypoxia for 5 weeks + SU5416 injection) models of PAH, we examined the effects of the selective β3 AR agonist CL316243. We measured echocardiographic indices and invasive right ventricular (RV)-pulmonary arterial (PA) hemodynamics and compared CL316243 with riociguat and sildenafil. We assessed treatment effects on RV-PA remodeling, oxidative stress, and eNOS glutathionylation, an oxidative modification that uncouples eNOS. Compared with normoxic mice, RV systolic pressure was increased in the control hypoxic mice (p < 0.0001) and Sugen hypoxic mice (p < 0.0001). CL316243 reduced RV systolic pressure, to a similar degree to riociguat and sildenafil, in both hypoxia (p < 0.0001) and Sugen hypoxia models (p < 0.03). CL316243 reversed pulmonary vascular remodeling, decreased RV afterload, improved RV-PA coupling efficiency and reduced RV stiffness, hypertrophy, and fibrosis. Although all treatments decreased oxidative stress, CL316243 significantly reduced eNOS glutathionylation. β3 AR stimulation improved RV hemodynamics and led to beneficial RV-PA remodeling in experimental models of PAH. β3 AR agonists may be effective therapies in PAH.
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Affiliation(s)
- Keyvan Karimi Galougahi
- Heart Research InstituteSydneyAustralia
- Royal Prince Alfred HospitalSydneyAustralia
- Sydney Medical SchoolFaculty of Medicine and HealthUniversity of SydneySydneyAustralia
| | | | | | - Chia‐Chi Liu
- Heart Research InstituteSydneyAustralia
- Sydney Medical SchoolFaculty of Medicine and HealthUniversity of SydneySydneyAustralia
- Kolling Institute for Medical ResearchSydneyAustralia
| | - Lake‐Ee Quek
- Charles Perkins CenterUniversity of SydneySydneyAustralia
| | - Sanjay Patel
- Heart Research InstituteSydneyAustralia
- Royal Prince Alfred HospitalSydneyAustralia
- Sydney Medical SchoolFaculty of Medicine and HealthUniversity of SydneySydneyAustralia
| | - Edmund Lau
- Sydney Medical SchoolFaculty of Medicine and HealthUniversity of SydneySydneyAustralia
- Department of Respiratory MedicineRoyal Prince Alfred HospitalSydneyAustralia
| | - Rachael L. Cordina
- Royal Prince Alfred HospitalSydneyAustralia
- Sydney Medical SchoolFaculty of Medicine and HealthUniversity of SydneySydneyAustralia
| | - Gemma A. Figtree
- Sydney Medical SchoolFaculty of Medicine and HealthUniversity of SydneySydneyAustralia
- Kolling Institute for Medical ResearchSydneyAustralia
- Department of CardiologyRoyal North Shore HospitalSydneyAustralia
| | - David S. Celermajer
- Heart Research InstituteSydneyAustralia
- Royal Prince Alfred HospitalSydneyAustralia
- Sydney Medical SchoolFaculty of Medicine and HealthUniversity of SydneySydneyAustralia
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17
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Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV, Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV. Endothelial dysfunction: developmental mechanisms and therapeutic strategies. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.80376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious.
The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability.
Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction.
Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction.
Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology.
Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described.
Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect.
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18
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Rai N, Sydykov A, Kojonazarov B, Wilhelm J, Manaud G, Veeroju S, Ruppert C, Perros F, Ghofrani HA, Weissmann N, Seeger W, Schermuly RT, Novoyatleva T. Targeting peptidyl-prolyl isomerase 1 in experimental pulmonary arterial hypertension. Eur Respir J 2022; 60:2101698. [PMID: 35058248 PMCID: PMC9403440 DOI: 10.1183/13993003.01698-2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 12/29/2021] [Indexed: 11/05/2022]
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive disease characterised by pro-proliferative and anti-apoptotic phenotype in vascular cells, leading to pulmonary vascular remodelling and right heart failure. Peptidyl-prolyl cis/trans isomerase, NIMA interacting 1 (Pin1), a highly conserved enzyme, which binds to and catalyses the isomerisation of specific phosphorylated Ser/Thr-Pro motifs, acts as a molecular switch in multiple coordinated cellular processes. We hypothesised that Pin1 plays a substantial role in PAH, and its inhibition with a natural organic compound, Juglone, would reverse experimental pulmonary hypertension. RESULTS We demonstrated that the expression of Pin1 was markedly elevated in experimental pulmonary hypertension (i.e. hypoxia-induced mouse and Sugen/hypoxia-induced rat models) and pulmonary arterial smooth muscle cells of patients with clinical PAH. In vitro Pin1 inhibition by either Juglone treatment or short interfering RNA knockdown resulted in an induction of apoptosis and decrease in proliferation of human pulmonary vascular cells. Stimulation with growth factors induced Pin1 expression, while its inhibition reduced the activity of numerous PAH-related transcription factors, such as hypoxia-inducible factor (HIF)-α and signal transducer and activator of transcription (STAT). Juglone administration lowered pulmonary vascular resistance, enhanced right ventribular function, improved pulmonary vascular and cardiac remodelling in the Sugen/hypoxia rat model of PAH and the chronic hypoxia-induced pulmonary hypertension model in mice. CONCLUSION Our study demonstrates that targeting of Pin1 with small molecule inhibitor, Juglone, might be an attractive future therapeutic strategy for PAH and right heart disease secondary to PAH.
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Affiliation(s)
- Nabham Rai
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Akylbek Sydykov
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Baktybek Kojonazarov
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
- Institute for Lung Health, Giessen, Germany
| | - Jochen Wilhelm
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
- Institute for Lung Health, Giessen, Germany
| | - Grégoire Manaud
- Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
| | - Swathi Veeroju
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Clemens Ruppert
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
- Institute for Lung Health, Giessen, Germany
| | - Frédéric Perros
- Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
| | - Hossein Ardeschir Ghofrani
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Norbert Weissmann
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
| | - Werner Seeger
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
- Institute for Lung Health, Giessen, Germany
- Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Ralph T Schermuly
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
- These co-senior authors contributed equally to this work
| | - Tatyana Novoyatleva
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany
- These co-senior authors contributed equally to this work
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Badagliacca R, Mercurio V, Romeo E, Correale M, Masarone D, Papa S, Tocchetti C, Agostoni P. Beta-blockers in pulmonary arterial hypertension: Time for a second thought? Vascul Pharmacol 2022; 144:106974. [DOI: 10.1016/j.vph.2022.106974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/19/2022] [Accepted: 02/26/2022] [Indexed: 11/29/2022]
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20
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Wongngam W, Roytrakul S, Mitani T, Katayama S, Nakamura S, Yongsawatdigul J. Isolation, identification, and in vivo evaluation of the novel antihypertensive peptide, VSKRLNGDA, derived from chicken blood cells. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.02.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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21
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Cell-to-Cell Crosstalk: A New Insight into Pulmonary Hypertension. Rev Physiol Biochem Pharmacol 2022; 184:159-179. [PMID: 35380274 DOI: 10.1007/112_2022_70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Pulmonary hypertension (PH) is a disease with high pulmonary arterial pressure, pulmonary vasoconstriction, pulmonary vascular remodeling, and microthrombosis in complex plexiform lesions, but it has been unclear of the exact mechanism of PH. A new understanding of the pathogenesis of PH is occurred and focused on the role of crosstalk between the cells on pulmonary vessels and pulmonary alveoli. It was found that the crosstalks among the endothelial cells, smooth muscle cells, fibroblasts, pericytes, alveolar epithelial cells, and macrophages play important roles in cell proliferation, migration, inflammation, and so on. Therefore, the heterogeneity of multiple pulmonary blood vessels and alveolar cells and tracking the transmitters of cell communication could be conducive to the further insights into the pathogenesis of PH to discover the potential therapeutic targets for PH.
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22
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Zolty R. Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension. J Exp Pharmacol 2021; 13:817-857. [PMID: 34429666 PMCID: PMC8380049 DOI: 10.2147/jep.s236743] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 07/07/2021] [Indexed: 12/18/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary artery vasoconstriction and vascular remodeling leading to vascular rarefaction with elevation of pulmonary arterial pressures and pulmonary vascular resistance. Often PAH will cause death from right heart failure. Current PAH-targeted therapies improve functional capacity, pulmonary hemodynamics and reduce hospitalization. Nevertheless, today PAH still remains incurable and is often refractory to medical therapy, underscoring the need for further research. Over the last three decades, PAH has evolved from a disease of unknown pathogenesis devoid of effective therapy to a condition whose cellular, genetic and molecular underpinnings are unfolding. This article provides an update on current knowledge and summarizes the progression in recent advances in pharmacological therapy in PAH.
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Affiliation(s)
- Ronald Zolty
- Pulmonary Hypertension Program, University of Nebraska Medical Center, Lied Transplant Center, Omaha, NE, USA
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Becker RC. Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor's page series. J Thromb Thrombolysis 2021; 52:692-707. [PMID: 34403043 PMCID: PMC8367772 DOI: 10.1007/s11239-021-02549-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 12/13/2022]
Abstract
Abstract The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives. Graphic abstract The autonomic nervous system is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common collection of signs and symptoms among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Abnormalities in the autonomic nervous system (ANS) can contribute to each of these identifiers, potentially offering a unifying pathobiology for acute, subacute and the long-term sequelae of SARS-CoV-2 infection (PASC) and a target for intervention.
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Affiliation(s)
- Richard C Becker
- Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.
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24
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Sumransub N, El Jurdi N, Chiraphapphaiboon W, Maakaron JE. Putting function back in dysfunction: Endothelial diseases and current therapies in hematopoietic stem cell transplantation and cellular therapies. Blood Rev 2021; 51:100883. [PMID: 34429234 DOI: 10.1016/j.blre.2021.100883] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/16/2021] [Accepted: 08/12/2021] [Indexed: 01/28/2023]
Abstract
Endothelial dysfunction is characterized by altered vascular permeability and prothrombotic, pro-inflammatory phenotypes. Endothelial dysfunction results in end-organ damage and has been associated with diverse disease pathologies. Complications observed after hematopoietic stem cell transplantation (HCT) and chimeric antigen receptor-T cell (CAR-T) therapy for hematologic and neoplastic disorders share overlapping clinical manifestations and there is increasing evidence linking these complications to endothelial dysfunction. Despite advances in supportive care and treatments, end-organ toxicity remains the leading cause of mortality. A new strategy to mitigate endothelial dysfunction could lead to improvement of clinical outcomes for patients. Statins have demonstrated pleiotropic effects of immunomodulatory and endothelial protection by various molecular mechanisms. Recent applications in immune-mediated diseases such as autoimmune disorders, chronic inflammatory conditions, and graft-versus-host disease (GVHD) have shown promising results. In this review, we cover the mechanisms underlying endothelial dysfunction in GVHD and CAR-T cell-related toxicities. We summarize the current knowledge about statins and other agents used as endothelial protectants. We propose further studies using statins for prophylaxis and prevention of end-organ damage related to extensive endothelial dysfunction in HCT and CAR-T.
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Affiliation(s)
- Nuttavut Sumransub
- Department of Medicine, University of Minnesota, 420 Delaware St. SE MMC 480, Minneapolis, MN 55455, United States of America
| | - Najla El Jurdi
- Department of Medicine, University of Minnesota, 420 Delaware St. SE MMC 480, Minneapolis, MN 55455, United States of America
| | - Wannasiri Chiraphapphaiboon
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Rd, Bangkok-Noi, Bangkok 10700, Thailand
| | - Joseph E Maakaron
- Department of Medicine, University of Minnesota, 420 Delaware St. SE MMC 480, Minneapolis, MN 55455, United States of America.
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25
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Peters EL, Bogaard HJ, Vonk Noordegraaf A, de Man FS. Neurohormonal modulation in pulmonary arterial hypertension. Eur Respir J 2021; 58:13993003.04633-2020. [PMID: 33766951 PMCID: PMC8551560 DOI: 10.1183/13993003.04633-2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/13/2021] [Indexed: 12/15/2022]
Abstract
Pulmonary hypertension is a fatal condition of elevated pulmonary pressures, complicated by right heart failure. Pulmonary hypertension appears in various forms; one of those is pulmonary arterial hypertension (PAH) and is particularly characterised by progressive remodelling and obstruction of the smaller pulmonary vessels. Neurohormonal imbalance in PAH patients is associated with worse prognosis and survival. In this back-to-basics article on neurohormonal modulation in PAH, we provide an overview of the pharmacological and nonpharmacological strategies that have been tested pre-clinically and clinically. The benefit of neurohormonal modulation strategies in PAH patients has been limited by lack of insight into how the neurohormonal system is changed throughout the disease and difficulties in translation from animal models to human trials. We propose that longitudinal and individual assessments of neurohormonal status are required to improve the timing and specificity of neurohormonal modulation strategies. Ongoing developments in imaging techniques such as positron emission tomography may become helpful to determine neurohormonal status in PAH patients in different disease stages and optimise individual treatment responses.
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Affiliation(s)
- Eva L Peters
- Dept of Pulmonology, Amsterdam UMC, Amsterdam, The Netherlands.,Dept of Physiology, Amsterdam UMC, Amsterdam, The Netherlands
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26
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Kim CW, Aronow WS, Dutta T, Spevack DM, Frishman WH. Pulmonary Artery Denervation as an Innovative Treatment for Pulmonary Hypertension With and Without Heart Failure. Cardiol Rev 2021; 29:89-95. [PMID: 32032132 DOI: 10.1097/crd.0000000000000299] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Pulmonary hypertension (PH) is categorized into 5 groups based on etiology. The 2 most prevalent forms are pulmonary arterial hypertension (PAH) and PH due to left heart disease (PH-LHD). Therapeutic options do exist for PAH to decrease symptoms and improve functional capacity; however, the mortality rate remains high and clinical improvements are limited. PH-LHD is the most common cause of PH; however, no treatment exists and the use of PAH-therapies is discouraged. Pulmonary artery denervation (PADN) is an innovative catheter-based ablation technique targeting the afferent and efferent fibers of a baroreceptor reflex in the main pulmonary artery (PA) trunk and its bifurcation. This reflex is involved in the elevation of the PA pressure seen in PH. Since 2013, both animal trials and human trials have shown the efficacy of PADN in improving PAH, including improved hemodynamic parameters, increased functional capacity, decreased PA remodeling, and much more. PADN has been shown to decrease the rate of rehospitalization, PH-related complications, and death, and is an overall safe procedure. PADN has also been shown to be effective for PH-LHD. Additional therapeutic mechanisms and benefits of PADN are discussed along with new PADN techniques. PADN has shown efficacy and safety as a potential treatment option for PH.
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Affiliation(s)
- Chan W Kim
- From the Department of Medicine, Cardiology Division, Westchester Medical Center and New York Medical College, Valhalla, NY
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27
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Santiago-Vacas E, García-Lunar I, Solanes N, Dantas AP, Ascaso M, Jimenez-Trinidad FR, Ramirez J, Fernández-Friera L, Galán C, Sánchez J, Sabaté M, Pérez-Villa F, Rigol M, Pereda D, Ibañez B, García-Álvarez A. Effect of sildenafil on right ventricular performance in an experimental large-animal model of postcapillary pulmonary hypertension. Transl Res 2021; 228:64-75. [PMID: 32835905 DOI: 10.1016/j.trsl.2020.08.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/29/2020] [Accepted: 08/17/2020] [Indexed: 12/21/2022]
Abstract
Right ventricle (RV) dysfunction is a main determinant of morbidity and mortality in postcapillary pulmonary hypertension (PH). However, currently there are not available therapies. Since reduced nitric oxide (NO) availability and cyclic guanylate monophosphate (cGMP) levels are central in this disease, therapies targeting the NO pathway might have a beneficial effect on RV performance. In this regard, sildenafil has shown contradictory results. Our objective was to evaluate the effect of sildenafil on RV performance in an experimental pig model of postcapillary PH induced by a fixed banding of the venous pulmonary confluent. Animals were evaluated by right heart catheterization and cardiac magnetic resonance before randomization and after 8 weeks on sildenafil (n = 8) or placebo (n = 8), and myocardial tissues were analyzed with histology and molecular biology. At the end of the study, animals receiving sildenafil showed better RV performance as compared with those on placebo (improvement in RV ejection fraction of 7.3% ± 5.8% versus -0.6% ± 5.0%, P= 0.021) associated with less apoptotic cells and gene expression related with reduced oxidative stress and increased anti-inflammatory activity in the myocardium. No differences were observed in pulmonary hemodynamics. In conclusion, in a translational large animal model of chronic postcapillary PH, sildenafil improved RV systolic function independently of afterload. Further research with pharmacological approaches able to manipulate the NO-cGMP axis are needed to confirm this potential cardioprotective effect.
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Affiliation(s)
- Evelyn Santiago-Vacas
- IDIBAPS, Hospital Clínic, Barcelona, Spain; Departament of Medicine, Universitat de Barcelona, Barcelona, Spain; Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Inés García-Lunar
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Hospital Universitario Quirónsalud Madrid, UEM, Madrid, Spain
| | | | | | | | | | | | - Leticia Fernández-Friera
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM-CIEC, Madrid, Spain
| | - Carlos Galán
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | | | | | | | - Montserrat Rigol
- IDIBAPS, Hospital Clínic, Barcelona, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Daniel Pereda
- IDIBAPS, Hospital Clínic, Barcelona, Spain; Departament of Medicine, Universitat de Barcelona, Barcelona, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Borja Ibañez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; IIS- Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Ana García-Álvarez
- IDIBAPS, Hospital Clínic, Barcelona, Spain; Departament of Medicine, Universitat de Barcelona, Barcelona, Spain; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
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28
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Kearney K, Kotlyar E, Lau EMT. Pulmonary Vascular Disease as a Systemic and Multisystem Disease. Clin Chest Med 2021; 42:167-177. [PMID: 33541610 DOI: 10.1016/j.ccm.2020.11.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a disease of progressive pulmonary vascular remodeling due to abnormal proliferation of pulmonary vascular endothelial and smooth muscle cells and endothelial dysfunction. PAH is a multisystem disease with systemic manifestations and complications. This article covers the chronic heart failure syndrome, including the systemic consequences of right ventricle-pulmonary artery uncoupling and neurohormonal activation, skeletal and respiratory muscle effects, systemic endothelial dysfunction and coronary artery disease, systemic inflammation and infection, endocrine and metabolic changes, the liver and gut axis, sleep, neurologic complications, and skin and iron metabolic changes.
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Affiliation(s)
- Katherine Kearney
- Cardiology Department, St Vincent's Hospital, 394 Victoria Street, Darlinghurst, New South Wales 2010, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| | - Eugene Kotlyar
- St Vincent's Clinical School, University of New South Wales, Sydney, Australia; Heart Transplant Unit, St Vincent's Hospital, 394 Victoria Street, Darlinghurst, New South Wales 2010, Australia
| | - Edmund M T Lau
- Department of Respiratory Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia; Sydney Medical School, University of Sydney, Camperdown, Australia.
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29
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Klouda T, Yuan K. Inflammation in Pulmonary Arterial Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:351-372. [PMID: 33788202 DOI: 10.1007/978-3-030-63046-1_19] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Pulmonary artery hypertension (PAH) is a devastating cardiopulmonary disease characterized by vascular remodeling and obliteration of the precapillary pulmonary arterioles. Alterations in the structure and function of pulmonary vessels result in the resistance of blood flow and can progress to right-sided heart failure, causing significant morbidity and mortality. There are several types of PAH, and the disease can be familial or secondary to an underlying medical condition such as a connective tissue disorder or infection. Regardless of the cause, the exact pathophysiology and cellular interactions responsible for disease development and progression are largely unknown.There is significant evidence to suggest altered immune and vascular cells directly participate in disease progression. Inflammation has long been hypothesized to play a vital role in the development of PAH, as an altered or skewed immune response favoring a proinflammatory environment that can lead to the infiltration of cells such as lymphocytes, macrophages, and neutrophils. Current treatment strategies focus on the dilation of partially occluded vessels; however, such techniques have not resulted in an effective strategy to reverse or prevent vascular remodeling. Therefore, current studies in human and animal models have attempted to understand the underlying pathophysiology of pulmonary hypertension (PH), specifically focusing on the inflammatory cascade predisposing patients to disease so that better therapeutic targets can be developed to potentially reverse or prevent disease progression.The purpose of this chapter is to provide a comprehensive review of the expanding literature on the inflammatory process that participates in PH development while highlighting important and current studies in both animal and human models. While our primary focus will be on cells found in the adaptive and innate immune system, we will review all potential causes of PAH, including cells of the endothelium, pulmonary lymphatics, and genetic mutations predisposing patients. In addition, we will discuss current therapeutic options while highlighting potential future treatments and the questions that still remain unanswered.
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Affiliation(s)
- Timothy Klouda
- Divisions of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ke Yuan
- Divisions of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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30
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Lyu Q, Bai Y, Cheng J, Liu H, Li S, Yang J, Wang Z, Ma Y, Jiang M, Dong D, Yan Y, Shi Q, Ren X, Ma J. Intermittent short-duration reoxygenation protects against simulated high altitude-induced pulmonary hypertension in rats. FASEB J 2020; 35:e21212. [PMID: 33230951 DOI: 10.1096/fj.202000533rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 12/17/2022]
Abstract
High-altitude pulmonary hypertension (HAPH) is a severe and progressive disease caused by chronic hypoxia and subsequent pulmonary vascular remodeling. No cure is currently available owing to an incomplete understanding about vascular remodeling. It is believed that hypoxia-induced diseases can be prevented by treating hypoxia. Thus, this study aimed to determine whether daily short-duration reoxygenation at sea level attenuates pulmonary hypertension under high-altitude hypoxia. To this end, a simulated 5000-m hypoxia rat model and hypoxic cultured human pulmonary artery smooth muscle cells were used to evaluate the effect of short-duration reoxygenation. Results show that intermittent, not continuous, short-duration reoxygenation effectively attenuates hypoxia-induced pulmonary hypertension. The mechanisms underlining the protective effects involved that intermittent, short-duration reoxygenation prevented functional and structural remodeling of pulmonary arteries and proliferation, migration, and phenotypic conversion of pulmonary artery smooth muscle cells under hypoxia. The specific genes or potential molecular pathways responsible for mediating the protective effects were also characterised by RNA sequencing. Further, the frequency and the total time of intermittent reoxygenation affected its preventive effect of HAPH, which was likely attributable to augmented oxidative stress. Hence, daily intermittent, not continuous, short-duration reoxygenation partially prevented pulmonary hypertension induced by 5000-m hypoxia in rats. This study is novel in revealing a new potential method in preventing HAPH. It gives insights into the selection and optimisation of oxygen supply schemes in high-altitude areas.
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Affiliation(s)
- Qiang Lyu
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Yungang Bai
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Jiuhua Cheng
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Huan Liu
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Shaohua Li
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Jing Yang
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Zhongchao Wang
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Yan Ma
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Min Jiang
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Dong Dong
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Yiquan Yan
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Qixin Shi
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
| | - Xinling Ren
- Department of Respiratory Diseases, Xi'an, China
| | - Jin Ma
- Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, China
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31
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Neurohormonal Modulation as a Therapeutic Target in Pulmonary Hypertension. Cells 2020; 9:cells9112521. [PMID: 33266371 PMCID: PMC7700466 DOI: 10.3390/cells9112521] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
The autonomic nervous system (ANS) and renin-angiotensin-aldosterone system (RAAS) are involved in many cardiovascular disorders, including pulmonary hypertension (PH). The current review focuses on the role of the ANS and RAAS activation in PH and updated evidence of potential therapies targeting both systems in this condition, particularly in Groups 1 and 2. State of the art knowledge in preclinical and clinical use of pharmacologic drugs (beta-blockers, beta-three adrenoceptor agonists, or renin-angiotensin-aldosterone signaling drugs) and invasive procedures, such as pulmonary artery denervation, is provided.
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32
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Role of β 3-Adrenoceptor Activation in Changes of Pulmonary Microhemodynamics after Experimental Pulmonary Thromboembolism. Bull Exp Biol Med 2020; 169:751-754. [PMID: 33119807 DOI: 10.1007/s10517-020-04971-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Indexed: 10/23/2022]
Abstract
Changes in pulmonary microhemodynamics during modelling of pulmonary thromboembolism against the background of nebivolol and mirabegron pretreatment were studied in isolated perfused rabbit lungs. In both cases, the pulmonary artery pressure and precapillary and pulmonary vascular resistance increased to a greater extent than in control animals, but the increase in capillary hydrostatic pressure was less pronounced. The postcapillary resistance did not change in pulmonary embolism against the background of nebivolol administration and increased in case of mirabegron pretreatment; capillary filtration coefficient after nebivolol pretreatment increased less markedly than after mirabegron administration. The increase in capillary filtration coefficient after activation of β3-adrenoceptors with the specified drugs depended on the ratio of constriction of pulmonary veins, capillary hydrostatic pressure, and endothelial permeability.
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33
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Wang SJ, Sander GE. Nebivolol/valsartan combination for the treatment of hypertension: a review. Future Cardiol 2020; 17:573-583. [PMID: 33064027 DOI: 10.2217/fca-2020-0079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Nebivolol (N) is a β1-adrenoreceptor antagonist that is approved for treatment of hypertension in the USA. Effective treatment of hypertension is becoming an increasingly difficult process that often requires multiple drug combinations to meet target guidelines. This has resulted in the increasing introduction of multidrug single-pill combinations (SPCs) to facilitate cost and compliance issues. Some of the SPCs have added valsartan (V), an angiotensin receptor blocker, which is an increasingly advocated antihypertensive class. Pharmacological profiles of N and V, alone and combined, are well characterized. In 2007, the SPC of N and V, 5 and 80 mg, respectively, was approved by the US FDA for treatment of hypertension. This paper will summarize and update key issues in pharmacology, clinical use and benefit.
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Affiliation(s)
- Sarah J Wang
- Department of Medicine, Heart & Vascular Institute, Section of Cardiology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Gary E Sander
- Department of Medicine, Heart & Vascular Institute, Section of Cardiology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA
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34
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Le Ribeuz H, Dumont F, Ruellou G, Lambert M, Balliau T, Quatredeniers M, Girerd B, Cohen-Kaminsky S, Mercier O, Yen-Nicolaÿ S, Humbert M, Montani D, Capuano V, Antigny F. Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells. Int J Mol Sci 2020; 21:E7400. [PMID: 33036472 PMCID: PMC7582549 DOI: 10.3390/ijms21197400] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/02/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 function/expression is a hallmark of PAH. However, the molecular mechanisms involved in KCNK3 dysfunction are mostly unknown. To identify the pathological molecular mechanisms downstream of KCNK3 in human PASMCs (hPASMCs) and human PAECs (hPAECs), we used a Liquid Chromatography-Tandem Mass Spectrometry-based proteomic approach to identify the molecular pathways regulated by KCNK3. KCNK3 loss of expression was induced in control hPASMCs or hPAECs by specific siRNA targeting KCNK3. We found that the loss of KCNK3 expression in hPAECs and hPASMCs leads to 326 and 222 proteins differentially expressed, respectively. Among them, 53 proteins were common to hPAECs and hPASMCs. The specific proteome remodeling in hPAECs in absence of KCNK3 was mostly related to the activation of glycolysis, the superpathway of methionine degradation, and the mTOR signaling pathways, and to a reduction in EIF2 signaling pathways. In hPASMCs, we found an activation of the PI3K/AKT signaling pathways and a reduction in EIF2 signaling and the Purine Nucleotides De Novo Biosynthesis II and IL-8 signaling pathways. Common to hPAECs and hPASMCs, we found that the loss of KCNK3 expression leads to the activation of the NRF2-mediated oxidative stress response and a reduction in the interferon pathway. In the hPAECs and hPASMCs, we found an increased expression of HO-1 (heme oxygenase-1) and a decreased IFIT3 (interferon-induced proteins with tetratricopeptide repeats 3) (confirmed by Western blotting), allowing us to identify these axes to understand the consequences of KCNK3 dysfunction. Our experiments, based on the loss of KCNK3 expression by a specific siRNA strategy in control hPAECs and hPASMCs, allow us to identify differences in the activation of several signaling pathways, indicating the key role played by KCNK3 dysfunction in the development of PAH. Altogether, these results allow us to better understand the consequences of KCNK3 dysfunction and suggest that KCNK3 loss of expression acts in favor of the proliferation and migration of hPASMCs and promotes the metabolic shift and apoptosis resistance of hPAECs.
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Affiliation(s)
- Hélène Le Ribeuz
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Florent Dumont
- UMS Ingénierie et Plateformes au Service de l’Innovation Thérapeutique, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (F.D.); (G.R.); (S.Y.-N.)
| | - Guillaume Ruellou
- UMS Ingénierie et Plateformes au Service de l’Innovation Thérapeutique, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (F.D.); (G.R.); (S.Y.-N.)
| | - Mélanie Lambert
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Thierry Balliau
- PAPPSO-GQE-Le Moulon, INRAE, CNRS, AgroParisTech, Université Paris-Saclay, 91190 Gif-sur-Yvette, France;
| | - Marceau Quatredeniers
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Barbara Girerd
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Sylvia Cohen-Kaminsky
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Olaf Mercier
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Stéphanie Yen-Nicolaÿ
- UMS Ingénierie et Plateformes au Service de l’Innovation Thérapeutique, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (F.D.); (G.R.); (S.Y.-N.)
| | - Marc Humbert
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - David Montani
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Véronique Capuano
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Fabrice Antigny
- Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France; (H.L.R.); (M.L.); (M.Q.); (B.G.); (S.C.-K.); (O.M.); (M.H.); (D.M.); (V.C.)
- INSERM UMR_S 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France
- Assistance Publique - Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
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Toshner M, Spiekerkoetter E, Bogaard H, Hansmann G, Nikkho S, Prins KW. Repurposing of medications for pulmonary arterial hypertension. Pulm Circ 2020; 10:2045894020941494. [PMID: 33282182 PMCID: PMC7682234 DOI: 10.1177/2045894020941494] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 06/20/2020] [Indexed: 12/18/2022] Open
Abstract
This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.
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Affiliation(s)
- Mark Toshner
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Edda Spiekerkoetter
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Harm Bogaard
- Department of Pulmonary Medicine, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Georg Hansmann
- Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover, Germany
| | - Sylvia Nikkho
- Bayer Pharmaceuticals, Clinical Development Pulmonology, Berlin, Germany
| | - Kurt W. Prins
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA
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36
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Klinke A, Schubert T, Müller M, Legchenko E, Zelt JGE, Shimauchi T, Napp LC, Rothman AMK, Bonnet S, Stewart DJ, Hansmann G, Rudolph V. Emerging therapies for right ventricular dysfunction and failure. Cardiovasc Diagn Ther 2020; 10:1735-1767. [PMID: 33224787 PMCID: PMC7666928 DOI: 10.21037/cdt-20-592] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/27/2020] [Indexed: 12/17/2022]
Abstract
Therapeutic options for right ventricular (RV) dysfunction and failure are strongly limited. Right heart failure (RHF) has been mostly addressed in the context of pulmonary arterial hypertension (PAH), where it is not possible to discern pulmonary vascular- and RV-directed effects of therapeutic approaches. In part, opposing pathomechanisms in RV and pulmonary vasculature, i.e., regarding apoptosis, angiogenesis and proliferation, complicate addressing RHF in PAH. Therapy effective for left heart failure is not applicable to RHF, e.g., inhibition of adrenoceptor signaling and of the renin-angiotensin system had no or only limited success. A number of experimental studies employing animal models for PAH or RV dysfunction or failure have identified beneficial effects of novel pharmacological agents, with most promising results obtained with modulators of metabolism and reactive oxygen species or inflammation, respectively. In addition, established PAH agents, in particular phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, may directly address RV integrity. Promising results are furthermore derived with microRNA (miRNA) and long non-coding RNA (lncRNA) blocking or mimetic strategies, which can target microvascular rarefaction, inflammation, metabolism or fibrotic and hypertrophic remodeling in the dysfunctional RV. Likewise, pre-clinical data demonstrate that cell-based therapies using stem or progenitor cells have beneficial effects on the RV, mainly by improving the microvascular system, however clinical success will largely depend on delivery routes. A particular option for PAH is targeted denervation of the pulmonary vasculature, given the sympathetic overdrive in PAH patients. Finally, acute and durable mechanical circulatory support are available for the right heart, which however has been tested mostly in RHF with concomitant left heart disease. Here, we aim to review current pharmacological, RNA- and cell-based therapeutic options and their potential to directly target the RV and to review available data for pulmonary artery denervation and mechanical circulatory support.
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Affiliation(s)
- Anna Klinke
- Clinic for General and Interventional Cardiology/Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany
| | - Torben Schubert
- Clinic for General and Interventional Cardiology/Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany
| | - Marion Müller
- Clinic for General and Interventional Cardiology/Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany
| | - Ekaterina Legchenko
- Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover, Germany
| | - Jason G. E. Zelt
- Division of Cardiology, University of Ottawa Heart Institute and the Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
| | - Tsukasa Shimauchi
- Pulmonary Hypertension Research Group, Centre de recherche de IUCPQ/Laval University, Quebec, Canada
| | - L. Christian Napp
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | | | - Sébastien Bonnet
- Pulmonary Hypertension Research Group, Centre de recherche de IUCPQ/Laval University, Quebec, Canada
| | - Duncan J. Stewart
- Division of Cardiology, University of Ottawa Heart Institute and the Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
| | - Georg Hansmann
- Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover, Germany
| | - Volker Rudolph
- Clinic for General and Interventional Cardiology/Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany
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Spaczyńska M, Rocha SF, Oliver E. Pharmacology of Pulmonary Arterial Hypertension: An Overview of Current and Emerging Therapies. ACS Pharmacol Transl Sci 2020; 3:598-612. [PMID: 32832865 DOI: 10.1021/acsptsci.0c00048] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Indexed: 12/21/2022]
Abstract
Pulmonary arterial hypertension is a rare and devastating disease characterized by an abnormal chronic increase in pulmonary arterial pressure above 20 mmHg at rest, with a poor prognosis if not treated. Currently, there is not a single fully effective therapy, even though a dozen of drugs have been developed in the last decades. Pulmonary arterial hypertension is a multifactorial disease, meaning that several molecular mechanisms are implicated in its pathology. The main molecular pathways regulating the pulmonary vasomotor tone-endothelin, nitric oxide, and prostacyclin-are the most biologically and therapeutically explored to date. However, drugs targeting these pathways have already found their limitations. In the last years, translational research and clinical trials have made a strong effort in suggesting and testing novel therapeutic strategies for this disease. These approaches involve targeting the main molecular pathways with novel drugs, drug repurposing for novel targets, and also using combinatorial therapies. In this review, we summarize current strategies and drugs targeting the endothelin, nitric oxide, and prostacyclin pathways, as well as, the emerging new drugs proposed to cope with vascular remodelling, metabolic switch, perivascular inflammation, epigenetic modifications, estrogen deregulation, serotonin, and other neurohumoral mechanisms characteristic of this disease. Nowadays, pulmonary arterial hypertension remains an incurable disease; however, the incoming new knowledge makes us believe that new promising therapies are coming to the clinical arena soon.
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Affiliation(s)
- Monika Spaczyńska
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain
| | - Susana F Rocha
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain
| | - Eduardo Oliver
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain.,Centro de Investigaciones Biomédicas en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, 28029, Spain
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Rothman AMK, Vachiery JL, Howard LS, Mikhail GW, Lang IM, Jonas M, Kiely DG, Shav D, Shabtay O, Avriel A, Lewis GD, Rosenzweig EB, Kirtane AJ, Kim NH, Mahmud E, McLaughlain VV, Chetcuti S, Leon MB, Ben-Yehuda O, Rubin LJ. Intravascular Ultrasound Pulmonary Artery Denervation to Treat Pulmonary Arterial Hypertension (TROPHY1): Multicenter, Early Feasibility Study. JACC Cardiovasc Interv 2020; 13:989-999. [PMID: 32327095 DOI: 10.1016/j.jcin.2019.12.027] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 11/25/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The aim of this study was to investigate whether therapeutic intravascular ultrasound pulmonary artery denervation (PDN) is safe and reduces pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) on a minimum of dual oral therapy. BACKGROUND Early studies have suggested that PDN can reduce PVR in patients with PAH. METHODS TROPHY1 (Treatment of Pulmonary Hypertension 1) was a multicenter, international, open-label trial undertaken at 8 specialist centers. Patients 18 to 75 years of age with PAH were eligible if taking dual oral or triple nonparenteral therapy and not responsive to acute vasodilator testing. Eligible patients underwent PDN (TIVUS System). The primary safety endpoint was procedure-related adverse events at 30 days. Secondary endpoints included procedure-related adverse events, disease worsening and death to 12 months, and efficacy endpoints that included change in pulmonary hemodynamic status, 6-min walk distance, and quality of life from baseline to 4 or 6 months. Patients were to remain on disease-specific medication for the duration of the study. RESULTS Twenty-three patients underwent PDN, with no procedure-related serious adverse events reported. The reduction in PVR at 4- or 6-month follow-up was 94 ± 151 dyn·s·cm-5 (p = 0.001) or 17.8%, which was associated with a 42 ± 63 m (p = 0.02) increase in 6-min walk distance and a 671 ± 1,555 step (p = 0.04) increase in daily activity. CONCLUSIONS In this multicenter early feasibility study, PDN with an intravascular ultrasound catheter was performed without procedure-related adverse events and was associated with a reduction in PVR and increases in 6-min walk distance and daily activity in patients with PAH on background dual or triple therapy.
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Affiliation(s)
- Alexander M K Rothman
- University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.
| | - Jean-Luc Vachiery
- Cliniques Universitaires de Bruxelles, Erasme Hospital, Brussels, Belgium
| | - Luke S Howard
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Ghada W Mikhail
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | | | | | - David G Kiely
- University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | | | | | | | | | - Erika B Rosenzweig
- University of Columbia Medical Center, NewYork-Presbyterian Hospital, New York, New York
| | - Ajay J Kirtane
- University of Columbia Medical Center, NewYork-Presbyterian Hospital, New York, New York; Cardiovascular Research Foundation, New York, New York
| | - Nick H Kim
- University of California, San Diego, San Diego, California
| | | | | | | | - Martin B Leon
- University of Columbia Medical Center, NewYork-Presbyterian Hospital, New York, New York; Cardiovascular Research Foundation, New York, New York
| | | | - Lewis J Rubin
- University of California, San Diego, San Diego, California
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Rijnierse MT, Groeneveldt JA, van Campen JSJA, de Boer K, van der Bruggen CEE, Harms HJ, Raijmakers PG, Lammertsma AA, Knaapen P, Bogaard HJ, Westerhof BE, Vonk Noordegraaf A, Allaart CP, de Man FS. Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients. Pulm Circ 2020; 10:2045894019873548. [PMID: 32363028 PMCID: PMC7187746 DOI: 10.1177/2045894019873548] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 07/29/2019] [Indexed: 11/27/2022] Open
Abstract
Right ventricular (RV) function and autonomic dysfunction are important
determinants of morbidity and mortality in patients with pulmonary arterial
hypertension (PAH). Although successful in animal studies, effects of
beta-blocker therapy on RV function in clinical trials were disappointing. To
understand this discrepancy, we studied whether beta-blocker therapy changes RV
sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker
therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic
resonance imaging, right heart catheterization, and a
[11C]-hydroxyephedrine positron emission tomography
([11C]HED PET) scan at baseline to determine, respectively, RV
ejection fraction (RVEF), RV pressures, and sympathetic activity.
[11C]HED, a norepinephrine analogue, allows determination of
sympathetic innervation of the RV. [11C]HED retention index reflects
norepinephrine transporter activity. As a consequence of excessive catecholamine
levels in the synaptic cleft, this transporter may be downregulated. Therefore,
low [11C]HED retention index indicates high sympathetic activity. 13
IPAH patients underwent [11C]HED PET scans at baseline and after
bisoprolol treatment. Although heart rate was reduced, systemic modulation of
autonomic activity by bisoprolol did not affect local RV sympathetic nerve
activity, RV function, or RV wall tension. In PAH patients, RV
[11C]HED retention index was lower compared to LV tracer uptake
(p<0.01) and was related to systolic wall tension (R2 = 0.4731,
p<0.01) and RV function (R2 = 0.44, p = 0.01). In RV failure, the
tolerated dosage of bisoprolol did not result in an improvement of RV function
nor in a reduction in RV sympathetic activity.
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Affiliation(s)
- Mischa T Rijnierse
- Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Joanne A Groeneveldt
- Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Jasmijn S J A van Campen
- Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Karin de Boer
- Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Cathelijne E E van der Bruggen
- Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Hendrik J Harms
- Radiology and Nuclear Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Pieter G Raijmakers
- Radiology and Nuclear Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Adriaan A Lammertsma
- Radiology and Nuclear Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Paul Knaapen
- Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Harm Jan Bogaard
- Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Berend E Westerhof
- Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.,Medical Biology, Section of Systems Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Anton Vonk Noordegraaf
- Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Cornelis P Allaart
- Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Frances S de Man
- Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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40
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Rosenkranz S, Howard LS, Gomberg-Maitland M, Hoeper MM. Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure. Circulation 2020; 141:678-693. [PMID: 32091921 DOI: 10.1161/circulationaha.116.022362] [Citation(s) in RCA: 172] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pulmonary hypertension (PH) is a feature of a variety of diseases and continues to harbor high morbidity and mortality. The main consequence of PH is right-sided heart failure which causes a complex clinical syndrome affecting multiple organ systems including left heart, brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as the endocrine, immune, and autonomic systems. Interorgan crosstalk and interdependent mechanisms include hemodynamic consequences such as reduced organ perfusion and congestion as well as maladaptive neurohormonal activation, oxidative stress, hormonal imbalance, and abnormal immune cell signaling. These mechanisms, which may occur in acute, chronic, or acute-on-chronic settings, are common and precipitate adverse functional and structural changes in multiple organs which contribute to increased morbidity and mortality. While the systemic character of PH and right-sided heart failure is often neglected or underestimated, such consequences place additional burden on patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the current state-of-the-art understanding of the systemic consequences of PH and right-sided heart failure on multiple organ systems, focusing on self-perpetuating pathophysiological mechanisms, aspects of increased susceptibility of organ damage, and their reciprocal impact on the course of the disease.
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Affiliation(s)
- Stephan Rosenkranz
- Clinic III for Internal Medicine (Cardiology) and Cologne Cardiovascular Research Center (CCRC), Heart Center at the University of Cologne, Germany (S.R.).,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany (S.R.)
| | - Luke S Howard
- National Pulmonary Hypertension Service, Imperial College Healthcare NHS Trust, London, United Kingdom (L.S.H.)
| | | | - Marius M Hoeper
- Department of Respiratory Medicine, Hannover Medical School, Germany (M.M.H.).,German Center for Lung Research (DZL), Hannover, Germany (M.M.H.)
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41
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Maron BA, Leopold JA, Hemnes AR. Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension. Br J Pharmacol 2020; 177:1457-1471. [PMID: 31881099 DOI: 10.1111/bph.14968] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 12/03/2019] [Accepted: 12/09/2019] [Indexed: 12/11/2022] Open
Abstract
Pulmonary vascular disease, including pulmonary arterial hypertension (PAH), is increasingly recognized to be affected by systemic alterations including up-regulation of the renin-angiotensin-aldosterone system and perturbations to metabolic pathways, particularly glucose and fat metabolism. There is increasing preclinical and clinical data that each of these pathways can promote pulmonary vascular disease and right heart failure and are not simply disease markers. More recently, trials of therapeutics aimed at neurohormonal activation or metabolic dysfunction are beginning to shed light on how interventions in these pathways may affect patients with PAH. This review will focus on underlying mechanistic data that supports neurohormonal activation and metabolic dysfunction in the pathogenesis of PAH and right heart failure as well as discussing early translational data in patients with PAH.
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Affiliation(s)
- Bradley A Maron
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jane A Leopold
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Anna R Hemnes
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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42
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Tello K, Seeger W, Naeije R, Vanderpool R, Ghofrani HA, Richter M, Tedford RJ, Bogaard HJ. Right heart failure in pulmonary hypertension: Diagnosis and new perspectives on vascular and direct right ventricular treatment. Br J Pharmacol 2019; 178:90-107. [PMID: 31517994 DOI: 10.1111/bph.14866] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 07/15/2019] [Accepted: 09/04/2019] [Indexed: 12/18/2022] Open
Abstract
Adaptation of right ventricular (RV) function to increased afterload-known as RV-arterial coupling-is a key determinant of prognosis in pulmonary hypertension. However, measurement of RV-arterial coupling is a complex, invasive process involving analysis of the RV pressure-volume relationship during preload reduction over multiple cardiac cycles. Simplified methods have therefore been proposed, including echocardiographic and cardiac MRI approaches. This review describes the available methods for assessment of RV function and RV-arterial coupling and the effects of pharmacotherapy on these variables. Overall, pharmacotherapies for pulmonary hypertension have shown beneficial effects on various measures of RV function, but it is often unclear if these are direct RV effects or indirect results of afterload reduction. Studies of the effects of pharmacotherapies on RV-arterial coupling are limited and mostly restricted to experimental models. Simplified methods to assess RV-arterial coupling should be validated and incorporated into routine clinical follow-up and future clinical trials. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.
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Affiliation(s)
- Khodr Tello
- Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany
| | - Werner Seeger
- Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany
| | - Robert Naeije
- Physiology, Erasme University Hospital, Brussels, Belgium
| | | | - 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
| | - Manuel Richter
- Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany
| | - Ryan J Tedford
- Division of Cardiology, Department of Medicine, Medical University of South Carolina (MUSC), Charleston, SC, USA
| | - Harm J Bogaard
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Sun J, Cheng J, Ding X, Chi J, Yang J, Li W. β3 adrenergic receptor antagonist SR59230A exerts beneficial effects on right ventricular performance in monocrotaline-induced pulmonary arterial hypertension. Exp Ther Med 2019; 19:489-498. [PMID: 31853320 PMCID: PMC6909721 DOI: 10.3892/etm.2019.8236] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 10/15/2019] [Indexed: 02/07/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease with a high mortality rate. Previous studies have revealed the important function of the β3 adrenergic receptor (β3-AR) in cardiovascular diseases, and the potential beneficial effects of numerous β3-AR agonists on pulmonary vasodilation. Conversely, a number of studies have proposed that the antagonism of β3-AR may prevent heart failure. The present study aimed to investigate the functional involvement of β3-AR and the effects of the β3-AR antagonist, SR59230A, in PAH and subsequent heart failure. A rat PAH model was established by the subcutaneous injection of monocrotaline (MCT), and the rats were randomly assigned to groups receiving four weeks of SR59230A treatment or the vehicle control. SR59230A treatment significantly improved right ventricular function in PAH in vivo compared with the vehicle control (P<0.001). Additionally, the expression level of β3-AR was significantly upregulated in the lung and heart tissues of PAH rats compared with the sham group (P<0.01), and SR59230A treatment inhibited this increase in the lung (P<0.05), but not the heart. Specifically, SR59230A suppressed the elevated expression of endothelial nitric oxide and alleviated inflammatory infiltration to the lung under PAH conditions. These results are, to the best of our knowledge, the first to reveal that SR59230A exerts beneficial effects on right ventricular performance in rats with MCT-induced PAH. Furthermore, blocking β3-AR with SR59230A may alleviate the structural changes and inflammatory infiltration to the lung as a result of reduced oxidative stress.
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Affiliation(s)
- Jiantao Sun
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jiali Cheng
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xue Ding
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jing Chi
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jiemei Yang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Weimin Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.,Department of Cardiovascular Medicine, The First Hospital of Harbin City, Harbin, Heilongjiang 150000, P.R. China
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Ntiloudi D, Qanud K, Tomaio JN, Giannakoulas G, Al-Abed Y, Zanos S. Pulmonary arterial hypertension: the case for a bioelectronic treatment. Bioelectron Med 2019; 5:20. [PMID: 32232109 PMCID: PMC7098229 DOI: 10.1186/s42234-019-0036-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/08/2019] [Indexed: 12/16/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease of unknown etiology that progresses to right ventricular failure. It has a complex pathophysiology, which involves an imbalance between vasoconstrictive and vasodilative processes in the pulmonary circulation, pulmonary vasoconstriction, vascular and right ventricular remodeling, systemic inflammation, and autonomic imbalance, with a reduced parasympathetic and increased sympathetic tone. Current pharmacological treatments for PAH include several classes of drugs that target signaling pathways in vascular biology and cardiovascular physiology, but they can have severe unwanted effects and they do not typically stop the progression of the disease. Pulmonary artery denervation has been tested clinically as a method to suppress sympathetic overactivation, however it is a nonspecific and irreversible intervention. Bioelectronic medicine, in particular vagus nerve stimulation (VNS), has been used in cardiovascular disorders like arrhythmias, heart failure and arterial hypertension and could, in principle, be tested as a treatment in PAH. VNS can produce pulmonary vasodilation and renormalize right ventricular function, via activation of pulmonary and cardiac vagal fibers. It can suppress systemic inflammation, via activation of fibers that innervate the spleen. Finally, VNS can gradually restore the balance between parasympathetic and sympathetic tone by regulating autonomic reflexes. Preclinical studies support the feasibility of using VNS in PAH. However, there are challenges with such an approach, arising from the need to affect a relatively small number of relevant vagal fibers, and the potential for unwanted cardiac and noncardiac effects of VNS in this sensitive patient population.
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Affiliation(s)
- Despοina Ntiloudi
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA.,2Department of Cardiology, AHEPA University Hospital, Thessaloniki, Greece
| | - Khaled Qanud
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA
| | - Jacquelyn-Nicole Tomaio
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA
| | | | - Yousef Al-Abed
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA
| | - Stavros Zanos
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA
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Affiliation(s)
- Haihua Qiu
- Department of Cardiovascular Medicine The Affiliated Zhuzhou Hospital Xiangya Medical College Central South University Zhuzhou Hunan China
| | - Yi He
- Department of Cardiovascular Medicine The Affiliated Zhuzhou Hospital Xiangya Medical College Central South University Zhuzhou Hunan China
| | - Fan Ouyang
- Department of Cardiovascular Medicine The Affiliated Zhuzhou Hospital Xiangya Medical College Central South University Zhuzhou Hunan China
| | - Ping Jiang
- Department of Cardiovascular Medicine The Affiliated Zhuzhou Hospital Xiangya Medical College Central South University Zhuzhou Hunan China
| | - Shuhong Guo
- Department of Cardiovascular Medicine The Affiliated Zhuzhou Hospital Xiangya Medical College Central South University Zhuzhou Hunan China
| | - Yuan Guo
- Department of Cardiovascular Medicine The Affiliated Zhuzhou Hospital Xiangya Medical College Central South University Zhuzhou Hunan China
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Zhao H, Wang Y, Zhang X, Guo Y, Wang X. miR-181b-5p inhibits endothelial-mesenchymal transition in monocrotaline-induced pulmonary arterial hypertension by targeting endocan and TGFBR1. Toxicol Appl Pharmacol 2019; 386:114827. [PMID: 31734320 DOI: 10.1016/j.taap.2019.114827] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 10/08/2019] [Accepted: 11/13/2019] [Indexed: 12/26/2022]
Abstract
Endothelial-mesenchymal transition (EndMT) is a frequent event in endothelial dysfunction, which is associated with pulmonary arterial hypertension (PAH). MiR-181 family members exert diverse effects in multiple biological processes. However, the relationships between miR-181b-5p (miR-181b) and EndMT in PAH are not well understood. In this study, Sprague-Dawley (SD) rats were injected with monocrotaline (MCT) to establish PAH model, and primary rat pulmonary arterial endothelial cells (rPAECs) were treated with TNF-α, TGFβ1 and IL-1β in combination to induce EndMT (I-EndMT). Then we explored miR-181b expression and examined its functional role in PAH. Our data showed that miR-181b was down-expressed in PAH, and its overexpression attenuated the hemodynamics, pulmonary vascular hypertrophy, right ventricular remodeling and EndMT process in MCT-induced PAH rats. In I-EndMT rPAECs, we observed that inducing miR-181b reversed the decrease of endothelial markers and increase of mesenchymal markers. However, knockdown of miR-181b induced similar effects to EndMT. In addition, endocan and TGFBR1 levels were also increased in EndMT, which were negatively regulated by miR-181b. Luciferase activity results indicated that endocan and TGFBR1 were direct target genes of miR-181b. In summary, our findings firstly demonstrate that the beneficial effect of miR-181b on PAH may be associated with endocan/TGFBR1-mediated EndMT, providing a new insight into the diagnosis and treatment of PAH.
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Affiliation(s)
- Haiyan Zhao
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Yang Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, People's Republic of China
| | - Xiaoli Zhang
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Yingying Guo
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Xiaofei Wang
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
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Zhao H, Guo Y, Sun Y, Zhang N, Wang X. miR-181a/b-5p ameliorates inflammatory response in monocrotaline-induced pulmonary arterial hypertension by targeting endocan. J Cell Physiol 2019; 235:4422-4433. [PMID: 31637717 DOI: 10.1002/jcp.29318] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by vascular remodeling, endothelial cell (EC) dysfunction, and inflammation. The roles of microRNAs have received much critical attention. Thus, this study was attempted to show the biological function of miR-181a/b-5p (miR-181a/b) in monocrotaline (MCT)-induced PAH. Here, rats injected with MCT were used as PAH models. The expression of miR-181a/b and its effect on PAH pathologies were examined using miR-181a/b overexpression lentivirus. A luciferase reporter analysis was performed to measure the relationships between miR-181a/b and endocan. Additionally, primary rat pulmonary arterial endothelial cells (rPAECs) treated with tumor necrosis factor-α (TNF-α) were employed to further validate the regulatory mechanism of miR-181a/b in vitro. Our results showed that miR-181a/b expression was reduced in PAH, and its upregulation significantly attenuated the short survival period, right ventricular systolic pressure and mean pulmonary artery pressure increments, right ventricular remodeling, and lung injury. Furthermore, the increase of intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) in PAH rats was inhibited by miR-181a/b overexpression. Similarly, our in vitro results showed that inducing miR-181a/b suppressed TNF-α-stimulated increase of ICAM1 and VCAM1 in rPAECs. Importantly, the increased expression of endocan in PAH model or TNF-α-treated rPAECs was restored by miR-181a/b upregulation. Further analysis validated the direct targeting relationships between miR-181a/b and endocan. Collectively, this study suggests that miR-181a/b targets endocan to ameliorate PAH symptoms by inhibiting inflammatory states, shedding new lights on the prevention and treatment of PAH.
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Affiliation(s)
- Haiyan Zhao
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yun Guo
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yue Sun
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Na Zhang
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaofei Wang
- Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang, China
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Rothman A, Jonas M, Castel D, Tzafriri AR, Traxler H, Shav D, Leon MB, Ben-Yehuda O, Rubin L. Pulmonary artery denervation using catheter-based ultrasonic energy. EUROINTERVENTION 2019; 15:722-730. [PMID: 31062694 DOI: 10.4244/eij-d-18-01082] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
AIMS Pulmonary arterial hypertension is a devastating disease characterised by pulmonary vascular remodelling and right heart failure. Radio-frequency pulmonary artery denervation (PDN) has improved pulmonary haemodynamics in preclinical and early clinical studies; however, denervation depth is limited. High-frequency non-focused ultrasound can deliver energy to the vessel adventitia, sparing the intima and media. We therefore aimed to investigate the feasibility, safety and efficacy of ultrasound PDN. METHODS AND RESULTS Histological examination demonstrated that innervation of human pulmonary arteries is predominantly sympathetic (71%), with >40% of nerves at a depth of >4 mm. Finite element analysis of ultrasound energy distribution and ex vivo studies demonstrated generation of temperatures >47ºC to a depth of 10 mm. In domestic swine, PDN reduced mean pulmonary artery pressure induced by thromboxane A2 in comparison to sham. No adverse events were observed up to 95 days. Histological examination identified structural and immunohistological changes of nerves in PDN-treated animals, with sparing of the intima and media and reduced tyrosine hydroxylase staining 95 days post procedure, indicating persistent alteration of the structure of sympathetic nerves. CONCLUSIONS Ultrasound PDN is safe and effective in the preclinical setting, with energy delivery to a depth that would permit targeting sympathetic nerves in humans.
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Affiliation(s)
- Alex Rothman
- Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
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Abstract
PURPOSE OF REVIEW Right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although substantial progress has been made in understanding the development of RV failure in the last decennia, this has not yet resulted in the development of RV selective therapies. In this review, we will discuss the current status on the treatment of RV failure and potential novel therapeutic strategies that are currently being investigated in clinical trials. RECENT FINDINGS Increased afterload results in elevated wall tension. Consequences of increased wall tension include autonomic disbalance, metabolic shift and inflammation, negatively affecting RV contractility. Compromised RV systolic function and low cardiac output activate renin-angiotensin aldosterone system, which leads to fluid retention and further increase in RV wall tension. This vicious circle can be interrupted by directly targeting the determinants of RV wall tension; preload and afterload by PAH-medications and diuretics, but is also possibly by restoring neurohormonal and metabolic disbalance, and inhibiting maladaptive inflammation. A variety of RV selective drugs are currently being studied in clinical trials. SUMMARY Nowadays, afterload reduction is still the cornerstone in treatment of PAH. New treatments targeting important pathobiological determinants of RV failure directly are emerging.
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Affiliation(s)
- Joanne A. Groeneveldt
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam
| | - Frances S. de Man
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam
| | - Berend E. Westerhof
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam
- Section of Systems Physiology, Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Mercurio V, Pellegrino T, Bosso G, Campi G, Parrella P, Piscopo V, Tocchetti CG, Hassoun PM, Petretta M, Cuocolo A, Bonaduce D. EXPRESS: Cardiac Sympathetic Dysfunction in Pulmonary Arterial Hypertension: Lesson from Left-sided Heart Failure. Pulm Circ 2019; 9:2045894019868620. [PMID: 31328636 PMCID: PMC6689920 DOI: 10.1177/2045894019868620] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 07/18/2019] [Indexed: 12/22/2022] Open
Abstract
Sympathetic nervous system hyperactivity has a well-recognized role in the pathophysiology of heart failure with reduced left ventricular ejection fraction. Alterations in sympathetic nervous system have been related to the pathophysiology of pulmonary arterial hypertension, but it is unclear whether cardiac sympathetic nervous system is impaired and how sympathetic dysfunction correlates with hemodynamics and clinical status in pulmonary arterial hypertension patients. The aim of this study was to evaluate the cardiac sympathetic nervous system activity by means of 123Iodine-metaiodobenzylguanidine nuclear imaging in pulmonary arterial hypertension patients and to explore its possible correlation with markers of disease severity. Twelve consecutive pulmonary arterial hypertension patients (nine women, median age 56.5 (17.8), eight idiopathic and four connective tissue-associated pulmonary arterial hypertension) underwent cardiac 123Iodine-metaiodobenzylguanidine scintigraphy. The results were compared with those of 12 subjects with a negative history of cardiovascular or pulmonary disease who underwent the same nuclear imaging test because of a suspected paraganglioma or pheochromocytoma, with a negative result (controls), and 12 patients with heart failure with reduced left ventricular ejection fraction. Hemodynamics, echocardiography, six-minute walking distance, cardiopulmonary exercise testing, and N-terminal pro brain natriuretic peptide were collected in pulmonary arterial hypertension patients within one week from 123Iodine-metaiodobenzylguanidine scintigraphy. Cardiac 123Iodine-metaiodobenzylguanidine uptake, assessed as early and late heart-to-mediastinum ratio, was significantly lower in pulmonary arterial hypertension compared to controls (p = 0.001), but similar to heart failure with reduced left ventricular ejection fraction. Myocardial 123Iodine-metaiodobenzylguanidine turnover, expressed as washout rate, was similar in pulmonary arterial hypertension and heart failure with reduced left ventricular ejection fraction and significantly higher compared to controls (p = 0.016). In the pulmonary arterial hypertension group, both early and late heart-to-mediastinum ratios and washout rate correlated with parameters of pulmonary arterial hypertension severity including pulmonary vascular resistance, right atrial pressure, tricuspid annular plane systolic excursion, N-terminal pro brain natriuretic peptide, and peak VO2. Although we evaluated a small number of subjects, our study showed a significant impairment in cardiac sympathetic nervous system in pulmonary arterial hypertension, similarly to that observed in heart failure with reduced left ventricular ejection fraction. This impairment correlated with indices of pulmonary arterial hypertension severity. Cardiac sympathetic dysfunction may be a contributing factor to the development of right-sided heart failure in pulmonary arterial hypertension.
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Affiliation(s)
- Valentina Mercurio
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, USA
| | - Teresa Pellegrino
- Referral Cancer Center of Basilicata, Scientific Institute for Hospitalization and Care, Rionero in Vulture, Italy
| | - Giorgio Bosso
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Giacomo Campi
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Paolo Parrella
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Valentina Piscopo
- Department of Advanced Biomedical Science, Federico II University, Naples, Italy
| | - Carlo G. Tocchetti
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Paul M. Hassoun
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, USA
| | - Mario Petretta
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Alberto Cuocolo
- Department of Advanced Biomedical Science, Federico II University, Naples, Italy
| | - Domenico Bonaduce
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
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