{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:32:28Z","timestamp":1778113948886,"version":"3.51.4"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T00:00:00Z","timestamp":1729296000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82304213"],"award-info":[{"award-number":["82304213"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2022J01706"],"award-info":[{"award-number":["2022J01706"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Accumulating studies reported that several phosphodiesterases (PDEs) inhibitors might have cardiovascular benefits.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>This study aimed to explore the relationship between genetically-predicted PDEs and ischaemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments. The outcomes included coronary heart disease (CHD) and myocardial infarction (MI). In the real-world study, a retrospective cohort was conducted to compare the incidence of outcomes between PDE5 inhibitors and alprostadil use by linking Swedish nationwide registers. MR analyses identified two types of PDEs, PDE5, and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD [odds ratio (OR)PDE5A\u00a0=\u00a01.22,95% confidence interval (CI)\u00a0=\u00a01.06\u20131.40; ORPDE8A\u00a0=\u00a01.26,95% CI\u00a0=\u00a01.07\u20131.49] and MI (ORPDE5A\u00a0=\u00a01.27,95% CI\u00a0=\u00a01.09\u20131.48; ORPDE8A\u00a0=\u00a01.24,95% CI\u00a0=\u00a01.04\u20131.48). Notably, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR\u00a0=\u00a01.17,95% CI\u00a0=\u00a01.05\u20131.32) and MI (OR\u00a0=\u00a01.15,95% CI\u00a0=\u00a01.02\u20131.30). Real-world study provided supportive evidence that as compared to alprostadil use, PDE5 inhibitors use significantly reduced the incidence of CHD (adjusted HR\u00a0=\u00a00.70,95% CI\u00a0=\u00a00.66\u20130.73) and MI (adjusted HR\u00a0=\u00a00.79,95% CI\u00a0=\u00a00.73\u20130.84).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This study provided observational and genetic evidence about the protective role of PDE5 inhibition against ischaemic heart disease, indicating the potential of these drugs to be repurposed for ischemia heart disease prevention and treatment.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ehjcvp\/pvae081","type":"journal-article","created":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T02:21:07Z","timestamp":1729304467000},"page":"75-83","source":"Crossref","is-referenced-by-count":4,"title":["Phosphodiesterase 5 and its inhibitors with ischaemic heart disease: a Mendelian randomization analysis and a real-world study"],"prefix":"10.1093","volume":"11","author":[{"given":"Jun","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery , Fujian Medical University, Union Hospital, Fuzhou, Fujian,","place":["China"]},{"name":"Heart Center of Fujian Medical University , Fuzhou, Fujian,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naiqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Primary Health Care Research , Department of Clinical Sciences Malm\u00f6, Lund University,","place":["Sweden"]},{"name":"Nutritional Epidemiology , Department of Clinical Sciences Malm\u00f6, Lund University, Malm\u00f6,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziting","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics , School of Public Health, Fujian Medical University, Fuzhou, Fujian,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajing","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics , School of Public Health, Fujian Medical University, Fuzhou, Fujian,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongye","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics , School of Public Health, Fujian Medical University, Fuzhou, Fujian,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyi","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics , School of Public Health, Fujian Medical University, Fuzhou, Fujian,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8031-279X","authenticated-orcid":false,"given":"Kristina","family":"Sundquist","sequence":"additional","affiliation":[{"name":"Center for Primary Health Care Research , Department of Clinical Sciences Malm\u00f6, Lund University,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7228-5015","authenticated-orcid":false,"given":"Jan","family":"Sundquist","sequence":"additional","affiliation":[{"name":"Center for Primary Health Care Research , Department of Clinical Sciences Malm\u00f6, Lund University,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianguang","family":"Ji","sequence":"additional","affiliation":[{"name":"Center for Primary Health Care Research , Department of Clinical Sciences Malm\u00f6, Lund University,","place":["Sweden"]},{"name":"Department of Public Health and Medicinal Administration , Faculty of Health Sciences, University of Macau, Macao, Macao SAR,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7616-8622","authenticated-orcid":false,"given":"Wuqing","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Health Statistics , School of Public Health, Fujian Medical University, Fuzhou, Fujian,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"key":"2025020804510870400_bib1","doi-asserted-by":"crossref","first-page":"S252","DOI":"10.1038\/sj.bjp.0706495","article-title":"Phosphodiesterase inhibitors","volume":"147","author":"Boswell-Smith","year":"2006","journal-title":"Br J Pharmacol"},{"key":"2025020804510870400_bib2","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nrd4228","article-title":"Advances in targeting cyclic nucleotide phosphodiesterases","volume":"13","author":"Maurice","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"2025020804510870400_bib3","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1053\/j.gastro.2019.05.012","article-title":"Use of phosphodiesterase 5 inhibitors is associated with lower risk of colorectal cancer in men with benign colorectal neoplasms","volume":"157","author":"Huang","year":"2019","journal-title":"Gastroenterology"},{"key":"2025020804510870400_bib4","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1136\/heartjnl-2017-312865","article-title":"Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection?","volume":"104","author":"Hutchings","year":"2018","journal-title":"Heart"},{"key":"2025020804510870400_bib5","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1097\/01.crd.0000233904.77128.49","article-title":"Type 5 phosphodiesterase inhibitors in the treatment of erectile dysfunction and cardiovascular disease","volume":"15","author":"Ravipati","year":"2007","journal-title":"Cardiol Rev"},{"key":"2025020804510870400_bib6","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.pharmthera.2014.10.003","article-title":"PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer","volume":"147","author":"Das","year":"2015","journal-title":"Pharmacol Ther"},{"key":"2025020804510870400_bib7","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1161\/CIRCULATIONAHA.117.030490","article-title":"Acute enhancement of cardiac function by phosphodiesterase type 1 inhibition","volume":"138","author":"Hashimoto","year":"2018","journal-title":"Circulation"},{"key":"2025020804510870400_bib8","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1161\/CIRCHEARTFAILURE.114.001218","article-title":"Age-related differences in phosphodiesterase activity and effects of chronic phosphodiesterase inhibition in idiopathic dilated cardiomyopathy","volume":"8","author":"Nakano","year":"2015","journal-title":"Circ Heart Fail"},{"key":"2025020804510870400_bib9","first-page":"73","article-title":"Cardiovascular cyclic nucleotide phosphodiesterases and their role in regulating cardiovascular function","volume":"87","author":"Pagani","year":"1992","journal-title":"Basic Res Cardiol"},{"key":"2025020804510870400_bib10","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1161\/01.CIR.0000146906.42375.D3","article-title":"Cardiovascular effects of the 3 phosphodiesterase-5 inhibitors approved for the treatment of erectile dysfunction","volume":"110","author":"Kloner","year":"2004","journal-title":"Circulation"},{"key":"2025020804510870400_bib11","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22168414","article-title":"Dual activation of phosphodiesterase 3 and 4 regulates basal cardiac pacemaker function and beyond","volume":"22","author":"Vinogradova","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2025020804510870400_bib12","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1161\/CIRCULATIONAHA.118.036325","article-title":"Inhibit a phosphodiesterase to treat heart failure?","volume":"138","author":"Leroy","year":"2018","journal-title":"Circulation"},{"key":"2025020804510870400_bib13","doi-asserted-by":"crossref","first-page":"110251","DOI":"10.1016\/j.cellsig.2022.110251","article-title":"Phosphodiesterase-1 in the cardiovascular system","volume":"92","author":"Roks","year":"2022","journal-title":"Cell. Signal."},{"key":"2025020804510870400_bib14","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1161\/01.STR.0000162713.06519.41","article-title":"Phosphodiesterase 4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis","volume":"36","author":"Bevan","year":"2005","journal-title":"Stroke"},{"key":"2025020804510870400_bib15","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/nature14332","article-title":"Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease","volume":"519","author":"Lee","year":"2015","journal-title":"Nature"},{"key":"2025020804510870400_bib16","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1161\/CIRCULATIONAHA.119.042178","article-title":"A novel role of cyclic nucleotide phosphodiesterase 10A in pathological cardiac remodeling and dysfunction","volume":"141","author":"Chen","year":"2020","journal-title":"Circulation"},{"key":"2025020804510870400_bib17","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s43657-021-00022-1","article-title":"Phenotypes of cardiovascular diseases: current status and future perspectives","volume":"1","author":"Zhang","year":"2021","journal-title":"Phenomics"},{"key":"2025020804510870400_bib18","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1538-7836.2011.04576.x","article-title":"Novel roles of cAMP\/cGMP-dependent signaling in platelets","volume":"10","author":"Smolenski","year":"2012","journal-title":"J Thromb Haemost"},{"key":"2025020804510870400_bib19","doi-asserted-by":"crossref","first-page":"107475","DOI":"10.1016\/j.pharmthera.2020.107475","article-title":"Cyclic nucleotide phosphodiesterases: new targets in the metabolic syndrome?","volume":"208","author":"Lugnier","year":"2020","journal-title":"Pharmacol Ther"},{"key":"2025020804510870400_bib20","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1093\/eurheartj\/ehac394","article-title":"From the garden to the clinic: how Mendelian randomization is shaping up atherosclerotic cardiovascular disease prevention strategies","volume":"43","author":"Arsenault","year":"2022","journal-title":"Eur Heart J"},{"key":"2025020804510870400_bib21","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1093\/eurheartj\/ehx462","article-title":"How to use Mendelian randomization to anticipate the results of randomized trials","volume":"39","author":"Ference","year":"2018","journal-title":"Eur Heart J"},{"key":"2025020804510870400_bib22","doi-asserted-by":"crossref","first-page":"4913","DOI":"10.1093\/eurheartj\/ehad736","article-title":"Mendelian randomization for cardiovascular diseases: principles and applications","volume":"44","author":"Larsson","year":"2023","journal-title":"Eur Heart J"},{"key":"2025020804510870400_bib23","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/s41591-021-01310-z","article-title":"Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19","volume":"27","author":"Gaziano","year":"2021","journal-title":"Nat Med"},{"key":"2025020804510870400_bib24","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.73873","article-title":"Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study","volume":"10","author":"Huang","year":"2021","journal-title":"eLife"},{"key":"2025020804510870400_bib25","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"V\u00f5sa","year":"2021","journal-title":"Nat Genet"},{"key":"2025020804510870400_bib26","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx Consortium atlas of genetic regulatory effects across human tissues","volume":"369","author":"Aguet","year":"2020","journal-title":"Science"},{"key":"2025020804510870400_bib27","doi-asserted-by":"crossref","first-page":"17605","DOI":"10.1038\/s41598-018-35871-w","article-title":"Identification of 55\u00a0000 replicated DNA Methylation QTL","volume":"8","author":"Mcrae","year":"2018","journal-title":"Sci Rep"},{"key":"2025020804510870400_bib28","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/ng.3396","article-title":"A comprehensive 1\u00a0000 genomes-based genome-wide association meta-analysis of coronary artery disease","volume":"47","author":"Nikpay","year":"2015","journal-title":"Nat Genet"},{"key":"2025020804510870400_bib29","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat Genet"},{"key":"2025020804510870400_bib30","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1093\/ije\/dyr036","article-title":"Avoiding bias from weak instruments in Mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int J Epidemiol"},{"key":"2025020804510870400_bib31","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s10654-021-00757-1","article-title":"Mendelian randomisation for mediation analysis: current methods and challenges for implementation","volume":"36","author":"Carter","year":"2021","journal-title":"Eur J Epidemiol"},{"key":"2025020804510870400_bib32","doi-asserted-by":"crossref","first-page":"113123","DOI":"10.1016\/j.ejmech.2020.113123","article-title":"The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure","volume":"212","author":"Nadur","year":"2021","journal-title":"Eur J Med Chem"},{"key":"2025020804510870400_bib33","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1016\/j.jacc.2021.01.045","article-title":"Association of phosphodiesterase-5 inhibitors versus alprostadil with survival in men with coronary artery disease","volume":"77","author":"Andersson","year":"2021","journal-title":"J Am Coll Cardiol"},{"key":"2025020804510870400_bib34","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1016\/j.jacc.2007.10.069","article-title":"Erectile dysfunction as a predictor of cardiovascular events and death in diabetic patients with angiographically proven asymptomatic coronary artery disease: a potential protective role for statins and 5-phosphodiesterase inhibitors","volume":"51","author":"Gazzaruso","year":"2008","journal-title":"J Am Coll Cardiol"},{"key":"2025020804510870400_bib35","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1177\/2047487317718082","article-title":"Relationship between treatment of erectile dysfunction and future risk of cardiovascular disease: a nationwide cohort study","volume":"24","author":"Vestergaard","year":"2017","journal-title":"Eur J Prev Cardiol"},{"key":"2025020804510870400_bib36","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1093\/eurheartj\/ehl142","article-title":"Association between erectile dysfunction and coronary artery disease. Role of coronary clinical presentation and extent of coronary vessels involvement: the COBRA trial","volume":"27","author":"Montorsi","year":"2006","journal-title":"Eur Heart J"},{"key":"2025020804510870400_bib37","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.1093\/eurheartj\/ehad191","article-title":"2023 ESC Guidelines for the management of acute coronary syndromes","volume":"44","author":"Byrne","year":"2023","journal-title":"Eur Heart J"},{"key":"2025020804510870400_bib38","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1093\/eurheartj\/ehz425","article-title":"2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes","volume":"41","author":"Knuuti","year":"2020","journal-title":"Eur Heart J"},{"key":"2025020804510870400_bib39","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1165\/rcmb.2017-0294OC","article-title":"PDE8 is expressed in human airway smooth muscle and selectively regulates cAMP signaling by beta(2)-adrenergic receptors and adenylyl cyclase 6","volume":"58","author":"Johnstone","year":"2018","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2025020804510870400_bib40","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1016\/j.apsb.2022.02.012","article-title":"Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia","volume":"12","author":"Wu","year":"2022","journal-title":"Acta Pharm Sin B"}],"container-title":["European Heart Journal - Cardiovascular Pharmacotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ehjcvp\/advance-article-pdf\/doi\/10.1093\/ehjcvp\/pvae081\/60431863\/pvae081.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ehjcvp\/article-pdf\/11\/1\/75\/60431863\/pvae081.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ehjcvp\/article-pdf\/11\/1\/75\/60431863\/pvae081.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T04:53:16Z","timestamp":1738990396000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ehjcvp\/article\/11\/1\/75\/7826774"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,18]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,10,18]]},"published-print":{"date-parts":[[2025,2,8]]}},"URL":"https:\/\/doi.org\/10.1093\/ehjcvp\/pvae081","relation":{},"ISSN":["2055-6837","2055-6845"],"issn-type":[{"value":"2055-6837","type":"print"},{"value":"2055-6845","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,1]]},"published":{"date-parts":[[2024,10,18]]}}}