{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:13:18Z","timestamp":1792512798373,"version":"4.5.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T00:00:00Z","timestamp":1677801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Pulmonary hypertension has high disability and mortality rates. Among them, pulmonary hypertension caused by left heart disease (PH-LHD) is the most common type. According to the 2022 ESC\/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension, PH-LHD is classified as group 2 pulmonary hypertension. PH-LHD belongs to postcapillary pulmonary hypertension, which is distinguished from other types of pulmonary hypertension because of its elevated pulmonary artery wedge pressure. PH-LHD includes PH due to systolic or diastolic left ventricular dysfunction, mitral or aortic valve disease and congenital left heart disease. The primary strategy in managing PH-LHD is optimizing treatment of the underlying cardiac disease. Recent clinical studies have found that mechanical unloading of left ventricle by an implantable non-pulsatile left ventricular assist device with continuous flow properties can reverse pulmonary hypertension in patients with heart failure. However, the specific therapies for PH in LHD have not yet been identified. Treatments that specifically target PH in LHD could slow its progression and potentially improve disease severity, leading to far better clinical outcomes. Therefore, exploring the current research on the pathogenesis of PH-LHD is important. This paper summarizes and classifies the research articles on the pathogenesis of PH-LHD to provide references for the mechanism research and clinical treatment of PH-LHD, particularly molecular targeted therapy.<\/jats:p>","DOI":"10.3389\/fcvm.2023.1079142","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T04:37:51Z","timestamp":1677818271000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Pathogenesis of pulmonary hypertension caused by left heart disease"],"prefix":"10.3389","volume":"10","author":[{"given":"Mingzhu","family":"Xiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disheng","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caojin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"819145","DOI":"10.3389\/fphys.2022.819145","article-title":"Dysregulated immunity in pulmonary hypertension: from companion to composer","volume":"13","author":"Funk-Hilsdorf","year":"2022","journal-title":"Front Physiol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.cjca.2014.10.012","article-title":"Pathophysiology and clinical relevance of pulmonary remodelling in pulmonary hypertension due to left heart diseases","volume":"31","author":"Dupuis","year":"2015","journal-title":"Can J Cardiol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3618","DOI":"10.1093\/eurheartj\/ehac237","article-title":"ESC\/ERS guidelines for the diagnosis and treatment of pulmonary hypertension","volume":"43","author":"Humbert","year":"2022","journal-title":"Eur Heart J"},{"key":"ref4","first-page":"165","article-title":"Left heart disease-related pulmonary hypertension and medication advances","volume":"21","author":"Zhu Ge","year":"2016","journal-title":"Chin Cardiovasc J"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.3969\/j.issn.1009-6663.2019.08.039","article-title":"Advances in pulmonary hypertension owing to left heart diseas","volume":"24","author":"Jiang","year":"2019","journal-title":"J Clin Pulm Med"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"380","DOI":"10.16439\/j.issn.1673-7245.2021.04.014","article-title":"Research progress on hemodynamic characteristics and prognostic factors of pulmonary hypertension due to left heart disease","volume":"29","author":"Wang","year":"2021","journal-title":"Chin J Hypertens"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"174","DOI":"10.3389\/fmed.2018.00174","article-title":"Pathophysiology and diagnosis of pulmonary hypertension due to left heart disease","volume":"5","author":"Charalampopoulos","year":"2018","journal-title":"Front Med (Lausanne)"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1161\/CIRCHEARTFAILURE.113.000823","article-title":"Pulmonary hypertension in heart failure preserved ejection fraction: prevalence, pathophysiology, and clinical perspectives","volume":"7","author":"Guazzi","year":"2014","journal-title":"Circ Heart Fail"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1378\/chest.114.3.780","article-title":"Comparison of inhaled nitric oxide and inhaled aerosolized prostacyclin in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance","volume":"114","author":"Haraldsson","year":"1998","journal-title":"Chest"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1016\/j.ejheart.2004.10.021","article-title":"Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure","volume":"7","author":"Delgado","year":"2005","journal-title":"Eur J Heart Fail"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1161\/01.cir.102.14.1718","article-title":"Secondary pulmonary hyper-tension in chronic heart failure: the role of the endothelium in pathophysiology and management","volume":"102","author":"Moraes","year":"2000","journal-title":"Circulation"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.hlc.2017.09.015","article-title":"Left heart disease and pulmonary hypertension: are we seeing the full picture?","volume":"27","author":"Chung","year":"2018","journal-title":"Heart Lung Circ"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1016\/j.cjca.2019.04.027","article-title":"The complex relationship that is RV-PA coupling and its relevance to managing congenital heart disease","volume":"35","author":"Sathananthan","year":"2019","journal-title":"Can J Cardiol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1378\/chest.12-1653","article-title":"Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in \"out-of-proportion\" pulmonary hypertension","volume":"143","author":"Gerges","year":"2013","journal-title":"Chest"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e020633","DOI":"10.1161\/JAHA.120.020633","article-title":"Therapeutic challenges and emerging treatment targets for pulmonary hypertension in left heart disease","volume":"10","author":"Lteif","year":"2021","journal-title":"J Am Heart Assoc"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1161\/HYPERTENSIONAHA.111.186072","article-title":"Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung disease","volume":"59","author":"Chen","year":"2012","journal-title":"Hypertension"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"2525","DOI":"10.1016\/j.jacc.2016.09.942","article-title":"Clinical and biological insights into combined post- and pre-capillary pulmonary hypertension","volume":"68","author":"Assad","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1164\/rccm.201503-0529OC","article-title":"Pulmonary hypertension in heart failure. Epidemiology, right ventricular function, and survival","volume":"192","author":"Gerges","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"147","DOI":"10.36628\/ijhf.2020.0053","article-title":"Pulmonary hypertension in heart failure","volume":"3","author":"Jang","year":"2021","journal-title":"Int J Heart Fail"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1800067","DOI":"10.1183\/13993003.00067-2018","article-title":"In-depth haemodynamic phenotyping of pulmonary hypertension due to left heart disease","volume":"51","author":"Gerges","year":"2018","journal-title":"Eur Respir J"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"5884","DOI":"10.3390\/ijms20235884","article-title":"The biological bases of group 2 pulmonary hypertension","volume":"20","author":"Fern\u00e1ndez","year":"2019","journal-title":"Int J Mol Sci"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1086\/688516","article-title":"Hemodynamic evidence of vascular remodeling in combined post- and precapil-lary pulmonary hypertension","volume":"6","author":"Assad","year":"2016","journal-title":"Pulm Circ"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"394","DOI":"10.7507\/1007-4848.201805072","article-title":"Research progress of pulmonary hypertension due to left heart disease","volume":"26","author":"Qian","year":"2019","journal-title":"Chin J Clin Thorac Cardiovascul Surg"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"57","DOI":"10.3390\/biomedicines9010057","article-title":"Endothelial dysfunction in pulmonary hypertension: cause or consequence?","volume":"9","author":"Kurakula","year":"2021","journal-title":"Biomedicine"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/s0008-6363(99)00230-8","article-title":"Role of endothelial and smooth muscle cells in the physiopathology and treatment management of pulmonary hypertension","volume":"44","author":"Veyssier-Belot","year":"1999","journal-title":"Cardiovasc Res"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"29","DOI":"10.5339\/gcsp.2014.29","article-title":"The role of endothelin-1 in pulmonary arterial hypertension","volume":"2014","author":"Chester","year":"2014","journal-title":"Glob Cardiol Sci Pract"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"986","DOI":"10.3390\/life11090986","article-title":"The causal relationship between Endothelin-1 and hypertension: focusing on endothelial dysfunction, arterial stiffness, vascular remodeling, and Blood pressure regulation","volume":"11","author":"Kostov","year":"2021","journal-title":"Life (Basel)"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1080\/01902148.2019.1605426","article-title":"Opposite alterations of endothelin-1 in lung and pulmonary artery mirror gene expression of bone morphogenetic protein receptor 2 in experimental pulmonary hypertension","volume":"45","author":"Veteskova","year":"2019","journal-title":"Exp Lung Res"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1254\/jphs.08069fp","article-title":"Sildenafil inhibits human pulmonary artery smooth muscle cell proliferation by decreasing capacitative Ca2+ entry","volume":"108","author":"Wang","year":"2008","journal-title":"J Pharmacol Sci"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"E2677","DOI":"10.1073\/pnas.1424774112","article-title":"Interleukin-6\/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension","volume":"112","author":"Hashimoto-Kataoka","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"21176","DOI":"10.1038\/srep21176","article-title":"Effect of TGF-\u03b21 on the migration and recruitment of Mesenchymal stem cells after vascular balloon injury: involvement of matrix metalloproteinase-14","volume":"6","author":"Zhao","year":"2016","journal-title":"Sci Rep"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"844","DOI":"10.16806\/j.cnki.issn.1004-3934.2020.08.015","article-title":"Molecular mechanism of hypoxia-inducible Factor-1 activation induced by reactive oxygen species in vascular remodeling of pulmonary","volume":"41","author":"Xue","year":"2020","journal-title":"Ther Adv Cardiovasc Dis"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"5467","DOI":"10.1111\/bph.14920","article-title":"Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease","volume":"177","author":"Tzoumas","year":"2020","journal-title":"Br J Pharmacol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1080\/13543784.2019.1571582","article-title":"Experimental and investigational phosphodiesterase inhibitors in development for asthma","volume":"28","author":"Ntontsi","year":"2019","journal-title":"Expert Opin Investig Drugs"},{"key":"ref35","first-page":"721","article-title":"Effects of tadalafil (PDE5 inhibitor) and roflumilast (PDE4 inhibitor) on airway reactivity and markers of inflammation in ovalbumin-induced airway hyperresponsiveness in Guinea pigs","volume":"68","author":"Mokry","year":"2017","journal-title":"J Physiol Pharmacol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"111128","DOI":"10.1016\/j.biopha.2020.111128","article-title":"Phosphodiesterase 5 (PDE5): structure-function regulation and therapeutic applications of inhibitors","volume":"134","author":"Ahmed","year":"2021","journal-title":"Biomed Pharmacother"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.pcad.2016.05.002","article-title":"Lung capillary stress failure and arteriolar remodelling in pulmonary hypertension associated with left heart disease (group 2 PH)","volume":"59","author":"Dayeh","year":"2016","journal-title":"Prog Cardiovasc Dis"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1164\/rccm.201304-0686PP","article-title":"Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension","volume":"188","author":"Klinger","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1161\/CIRCRESAHA.116.306531","article-title":"Thirty years of saying NO: sources, fate, actions, and misfortunes of the endothelium-derived vasodilator mediator","volume":"119","author":"Vanhoutte","year":"2016","journal-title":"Circ Res"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1177\/10742484211006531","article-title":"Combination therapy in pulmonary arterial hypertension-targeting the nitric oxide and prostacyclin pathways","volume":"26","author":"Mandras","year":"2021","journal-title":"J Cardiovasc Pharmacol Ther"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.arcmed.2019.05.004","article-title":"Vitamin C for type 2 diabetes mellitus and hypertension","volume":"50","author":"Das","year":"2019","journal-title":"Arch Med Res"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/263663a0","article-title":"An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation","volume":"263","author":"Moncada","year":"1976","journal-title":"Nature"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.tips.2017.03.003","article-title":"Targeting the prostacyclin pathway: beyond pulmonary arterial hypertension","volume":"38","author":"Pluchart","year":"2017","journal-title":"Trends Pharmacol Sci"},{"key":"ref44","article-title":"Physiology, thromboxane A2","volume-title":"Stat Pearls","author":"Rucker","year":"2022"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"e21877","DOI":"10.1096\/fj.202101077R","article-title":"Endothelium-dependent contraction: the non-classical action of endothelial prostacyclin, its underlying mechanisms, and implications","volume":"35","author":"Liu","year":"2021","journal-title":"FASEB J"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"4103","DOI":"10.1002\/cphy.c220004","article-title":"Serotonin and pulmonary hypertension; sex and drugs and ROCK and rho","volume":"12","author":"Mac Lean","year":"2022","journal-title":"Compr Physiol"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1089\/ham.2010.1076","article-title":"Preservation of serotonin-mediated contractility in adult sheep pulmonary arteries following long-term high-altitude hypoxia","volume":"12","author":"Papamatheakis","year":"2011","journal-title":"High Alt Med Biol"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1164\/rccm.200805-691OC","article-title":"Rho a and rho kinase activation in human pulmonary hypertension role of 5-HT signaling","volume":"179","author":"Guilluy","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"L846","DOI":"10.1152\/ajplung.00050.2016","article-title":"Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension","volume":"310","author":"Tang","year":"2016","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"L924","DOI":"10.1152\/ajplung.00146.2015","article-title":"The pathophysiology of pulmonary hypertension in left heart disease","volume":"309","author":"Breitling","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"751008","DOI":"10.3389\/fphys.2021.751008","article-title":"Calcium-activated chloride channels in Myometrial and vascular smooth muscle","volume":"12","author":"Wray","year":"2021","journal-title":"Front Physiol"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.3760\/cma.j.issn.2095-428X.2013.18.018","article-title":"Study of electrophysiology of Ca+-activated cl\u2212 channels in pulmonary arterial smooth muscle cells of pulmonary hypertension induced by high pulmonary blood flow in rats","volume":"28","author":"Zeng","year":"2013","journal-title":"Chin J Appl Clin Pediatr"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1016\/j.jacc.2015.03.540","article-title":"Management of pulmonary arterial hypertension","volume":"65","author":"McLaughlin","year":"2015","journal-title":"J Am Coll Cardiol"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"933","DOI":"10.3760\/cma.j.cn112137-20201008-02778","article-title":"Chinese guidelines for diagnosis and treatment of pulmonary hypertension","volume":"46","year":"2021","journal-title":"Zhonghua Xin Xue Guan Bing Za Zhi"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"308","DOI":"10.5483\/bmbrep.2017.50.6.059","article-title":"Clinical significance linked to functional defects in bone morphogenetic protein type 2 receptor, BMPR2","volume":"50","author":"Kim","year":"2017","journal-title":"BMB Rep"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1055\/s-0034-1365456","article-title":"Pulmonary hypertension: micro RNAs in pathogenesis, diagnosis and therapy","volume":"68","author":"Huber","year":"2014","journal-title":"Pneumologie"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/1465-9921-12-84","article-title":"Physiologic and molecular consequences of endothelial Bmpr 2 mutation","volume":"12","author":"Majka","year":"2011","journal-title":"Respir Res"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1586\/17476348.2014.909731","article-title":"KCNK3: new gene target for pulmonary hypertension?","volume":"8","author":"Girerd","year":"2014","journal-title":"Expert Rev Respir Med"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1093\/cvr\/cvy016","article-title":"Loss of KCNK3 is ahallmark of RV hypertrophy\/dysfunction associated with pulmonary hypertension","volume":"114","author":"Lambert","year":"2018","journal-title":"Cardiovasc Res"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"2474","DOI":"10.1093\/cvr\/cvab016","article-title":"Kcnk 3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload","volume":"117","author":"Lambert","year":"2021","journal-title":"Cardiovasc Res"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"L841","DOI":"10.1152\/ajplung.00158.2005","article-title":"BMP signaling controls PASMC KV channel expression in vitro and in vivo","volume":"290","author":"Young","year":"2006","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"2045894018773049","DOI":"10.1177\/2045894018773049","article-title":"Endothelial nitric oxide synthase genotype is associated with pulmonary hypertension severity in left heart failure patients","volume":"8","author":"Duarte","year":"2018","journal-title":"Pulm Circ."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1161\/CIRCULATIONAHA.115.016382","article-title":"Downregulation of micro RNA-126 contributes to the failing right ventricle in pulmonary arterial hypertension","volume":"132","author":"Potus","year":"2015","journal-title":"Circulation"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1080\/15592294.2019.1638701","article-title":"DNA hypermethylation in disease: mechanisms and clinical relevance","volume":"14","author":"Ehrlich","year":"2019","journal-title":"Epigenetics"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nrg3354","article-title":"DNA methylation: roles in mammalian development","volume":"14","author":"Smith","year":"2013","journal-title":"Nat Rev Genet"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"5039","DOI":"10.1182\/blood.v118.21.5039.5039","article-title":"Pulmonary hypertension may be a relevant comorbidity in patients with Myelodysplastic syndromes","volume":"118","author":"Kqiku","year":"2011","journal-title":"Blood"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1038\/ng.3610","article-title":"DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells","volume":"48","author":"Zhang","year":"2016","journal-title":"Nat Genet"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1161\/CIRCRESAHA.118.313225","article-title":"CRISPR-mediated gene editing to assess the roles of Tet 2 and Dnmt 3a in clonal hematopoiesis and cardiovascular disease","volume":"123","author":"Sano","year":"2018","journal-title":"Circ Res"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1161\/CIRCRESAHA.118.313650","article-title":"Medical therapy for heart failure associated with pulmonary hypertension","volume":"124","author":"Zelt","year":"2019","journal-title":"Circ Res"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"42","DOI":"10.13865\/j.cnki.cjbmb.2021.04.1661","article-title":"The role of mast cells on tumor occurrence and development","volume":"38","author":"Zhang","year":"2022","journal-title":"Chin J Biochem Molecul Biol"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"2003957","DOI":"10.1183\/13993003.03957-2020","article-title":"Endothelial cells in the pathogenesis of pulmonary arterial hypertension","volume":"58","author":"Evans","year":"2021","journal-title":"Eur Respir J"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"641734","DOI":"10.3389\/fmolb.2021.641734","article-title":"Role of Interleukin-6 in vascular health and disease","volume":"8","author":"Villar-Fincheira","year":"2021","journal-title":"Front Mol Biosci"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1161\/CIRCRESAHA.118.314555","article-title":"Metabolic syndrome exacerbates pulmonary hypertension due to left heart disease","volume":"125","author":"Ranchoux","year":"2019","journal-title":"Circ Res"},{"key":"ref74","doi-asserted-by":"publisher","DOI":"10.27691\/d.cnki.gcdyx.2021.000293","article-title":"Changes and significance of serum IL-6 and IMA levels in patients with pulmonary hypertension associated with left heart disease","author":"Yang","year":"2021","journal-title":"Chengde Medical College Hebei Province"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"28067","DOI":"10.1074\/jbc.M112.379487","article-title":"Bone morphogenetic protein signaling in vascular disease: anti-inflammatory action through myocardin-related transcription factor a","volume":"287","author":"Wang","year":"2012","journal-title":"J Biol Chem"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1146\/annurev-physiol-031620-123956","article-title":"Metabolism in pulmonary hypertension","volume":"83","author":"Xu","year":"2021","journal-title":"Annu Rev Physiol"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"j5492","DOI":"10.1136\/bmj.j5492","article-title":"Pulmonary arterial hypertension: pathogenesis and clinical management","volume":"360","author":"Thenappan","year":"2018","journal-title":"BMJ"},{"key":"ref78","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.biocel.2014.08.012","article-title":"Mitochondria: roles in pulmonary hypertension","volume":"55","author":"Freund-Michel","year":"2014","journal-title":"Int J Biochem Cell Biol"},{"key":"ref79","doi-asserted-by":"publisher","first-page":"761","DOI":"10.3390\/ijms17050761","article-title":"Molecular mechanisms of pulmonary vascular remodeling in pulmonary arterial hypertension","volume":"17","author":"Leopold","year":"2016","journal-title":"Int J Mol Sci"},{"key":"ref80","doi-asserted-by":"publisher","first-page":"eabl5471","DOI":"10.1126\/scitranslmed.abl5471","article-title":"JAGGED-NOTCH3 signaling in vascular remodeling in pulmonary arterial hypertension","volume":"14","author":"Zhang","year":"2022","journal-title":"Sci Transl Med"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"2481","DOI":"10.1042\/CS20190835","article-title":"Notch 3 signalling and vascular remodelling in pulmonary arterial hypertension","volume":"133","author":"Morris","year":"2019","journal-title":"Clin Sci (Lond)"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/nm.2021","article-title":"Notch 3 signaling promotes the development of pulmonary arterial hypertension","volume":"15","author":"Li","year":"2009","journal-title":"Nat Med"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.pcad.2014.11.002","article-title":"Impact of pharmacologic interventions--treating endothelial dysfunction and group 2 pulmonary hypertension","volume":"57","author":"Guazzi","year":"2015","journal-title":"Prog Cardiovasc Dis"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"107835","DOI":"10.1016\/j.pharmthera.2021.107835","article-title":"Potassium (K+) channels in the pulmonary vasculature: implications in pulmonary hypertension physiological, pathophysiological and pharmacological regulation","volume":"225","author":"Mond\u00e9jar-Parre\u00f1o","year":"2021","journal-title":"Pharmacol Ther"},{"key":"ref85","doi-asserted-by":"publisher","first-page":"114734","DOI":"10.1016\/j.jep.2021.114734","article-title":"Pretreatment with the active fraction of Rhodiola tangutica (maxim.) S.H. Fu rescues hypoxia-induced potassium channel inhibition in rat pulmonary artery smooth muscle cells","volume":"283","author":"Zhang","year":"2022","journal-title":"J Ethnopharmacol"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1159\/000475569","article-title":"The circulating micro RNA-206 level predicts the severity of pulmonary hypertension in patients with left heart diseases","volume":"41","author":"Jin","year":"2017","journal-title":"Cell Physiol Biochem"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s00392-014-0765-4","article-title":"Pulmonary hypertension 2015: current definitions, terminology, and novel treatment options","volume":"104","author":"Rosenkranz","year":"2015","journal-title":"Clin Res Cardiol"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"D60","DOI":"10.1016\/j.jacc.2013.10.031","article-title":"Updated treatment algorithm of pulmonary arterial hypertension","volume":"62","author":"Galie","year":"2013","journal-title":"J Am Coll Cardiol"},{"key":"ref89","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/S0140-6736(04)16723-8","article-title":"EARTH investigator. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin a receptor antagonist trial in heart failure (EARTH): randomised, double-blind, placebo-controlled trial","volume":"364","author":"Anand","year":"2004","journal-title":"Lancet"},{"key":"ref90","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/s0167-5273(02)00182-1","article-title":"Do results of the ENABLE Endothelin antagonist Bosentan for lowering cardiac events in heart failure study spell the end for non-selective endothelin antagonism in heart failure?","volume":"85","author":"Kalra","year":"2002","journal-title":"Int J Cardiol"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.cardfail.2004.05.006","article-title":"Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study","volume":"11","author":"Packer","year":"2005","journal-title":"Card Faill"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1093\/eurjhf\/hfs152","article-title":"Sildenafil in heart failure (Sil HF). An investigator-initiated multinational randomized controlled clinical trial: rationale and design","volume":"15","author":"Cooper","year":"2013","journal-title":"Eur J Heart Fail"},{"key":"ref93","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1378\/chest.127.5.1647","article-title":"Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide","volume":"127","author":"Lepore","year":"2005","journal-title":"Chest"},{"key":"ref94","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1161\/CIRCULATIONAHA.113.001458","article-title":"Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, doseranging hemodynamic study","volume":"128","author":"Bonderman","year":"2013","journal-title":"Circulation"},{"key":"ref95","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1378\/chest.14-0106","article-title":"Acute hemodynamic effects of Riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study","volume":"146","author":"Bonderman","year":"2014","journal-title":"Chest"},{"key":"ref96","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/s0002-8703(97)70105-4","article-title":"A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan international randomized survival trial (FIRST)","volume":"134","author":"Califf","year":"1997","journal-title":"Am Heart J"},{"key":"ref97","doi-asserted-by":"publisher","first-page":"2869","DOI":"10.1093\/eurheartj\/ehw597","article-title":"Pulmonary hypertension in heart failure with preserved ejection fraction: a plea for proper phenotyping and further research","volume":"38","author":"Hoeper","year":"2017","journal-title":"Eur Heart J"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1079142\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T04:38:05Z","timestamp":1677818285000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1079142\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,3]]},"references-count":97,"alternative-id":["10.3389\/fcvm.2023.1079142"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2023.1079142","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,3]]},"article-number":"1079142"}}