{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:13:09Z","timestamp":1781194389176,"version":"3.54.1"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"CVIE Therapeutics, Taipei, Taiwan Windtree Therapeutics, Warrington, PA, USA"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharmacogenomics J"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant \u03b1-adducin and of the ouabain-activated Na-K pump at 10<jats:sup>\u201311<\/jats:sup>\u2009M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (<jats:italic>LSS<\/jats:italic> and <jats:italic>HSD3B1<\/jats:italic>), EO transport (<jats:italic>MDR1\/ABCB1<\/jats:italic>), adducin (<jats:italic>ADD1<\/jats:italic> and <jats:italic>ADD3<\/jats:italic>); P3, variants of the <jats:italic>LSS<\/jats:italic> gene only. In Caucasians, the group differences (rostafuroxin 50\u2009\u03bcg minus losartan 50\u2009mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 <jats:italic>LSS<\/jats:italic> rs2254524 AA [9.8 (0.6\u201319.0), <jats:italic>P<\/jats:italic>\u2009=\u20090.038 and 13.4 (25.4\u20132.5), <jats:italic>P<\/jats:italic>\u2009=\u20090.031, respectively]. In human H295R cells transfected with <jats:italic>LSS<\/jats:italic> A and <jats:italic>LSS<\/jats:italic> C variants, the EO production was greater in the former (<jats:italic>P<\/jats:italic>\u2009=\u20090.038); this difference was abolished by rostafuroxin at 10<jats:sup>\u201311<\/jats:sup>\u2009M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.<\/jats:p>","DOI":"10.1038\/s41397-021-00214-y","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T13:03:51Z","timestamp":1614603831000},"page":"346-358","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Antihypertensive treatment guided by genetics: PEARL-HT, the randomized proof-of-concept trial comparing rostafuroxin with losartan"],"prefix":"10.1038","volume":"21","author":[{"given":"Lorena","family":"Citterio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-3618","authenticated-orcid":false,"given":"Giuseppe","family":"Bianchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe A.","family":"Scioli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Glorioso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Bigazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Cusi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan A.","family":"Staessen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio","family":"Cavuto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Ferrandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Lanzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lit-Fui","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chern-En","family":"Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzung-Dau","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang-Ling","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3976-9696","authenticated-orcid":false,"given":"Paolo","family":"Manunta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,1]]},"reference":[{"key":"214_CR1","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1097\/00004872-199405000-00008","volume":"12","author":"P Manunta","year":"1994","unstructured":"Manunta P, Rogowski AC, Hamilton BP, Hamlyn JM. Ouabain-induced hypertension in the rat: relationships among plasma and tissue ouabain and blood pressure. J Hypertens. 1994;12:549\u201360.","journal-title":"J Hypertens"},{"key":"214_CR2","doi-asserted-by":"publisher","first-page":"33306","DOI":"10.1074\/jbc.M402187200","volume":"279","author":"M Ferrandi","year":"2004","unstructured":"Ferrandi M, Molinari I, Barassi P, Minotti E, Bianchi G, Ferrari P. Organ hypertrophic signaling within caveolae membrane subdomains triggered by ouabain and antagonized by PST 2238. J Biol Chem. 2004;279:33306\u201314.","journal-title":"J Biol Chem"},{"key":"214_CR3","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1161\/01.HYP.30.4.886","volume":"30","author":"M Ferrandi","year":"1997","unstructured":"Ferrandi M, Manunta P, Balzan S, Hamlyn JM, Bianchi G, Ferrari P. Ouabain-like factor quantification in mammalian tissues and plasma: comparison of two independent assays. Hypertension. 1997;30:886\u201396.","journal-title":"Hypertension"},{"key":"214_CR4","doi-asserted-by":"publisher","first-page":"R529","DOI":"10.1152\/ajpregu.00518.2005","volume":"290","author":"P Ferrari","year":"2006","unstructured":"Ferrari P, Ferrandi M, Valentini G, Bianchi G. Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na +-K +- ATPase alterations in ouabain and adducin-dependent hypertension. A J P Regul Integr Comp Physiol. 2006;290:R529\u201335.","journal-title":"A J P Regul Integr Comp Physiol"},{"key":"214_CR5","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1016\/j.bbadis.2010.01.009","volume":"1802","author":"P Ferrari","year":"2010","unstructured":"Ferrari P. Rostafuroxin: an ouabain-inhibitor counteracting specific forms of hypertension. Biochim Biophys Acta (BBA)\u2014Molecular Basis of Disease. 2010;1802:1254\u20138.","journal-title":"Biochim Biophys Acta (BBA)\u2014Molecular Basis of Disease"},{"key":"214_CR6","doi-asserted-by":"publisher","first-page":"3999","DOI":"10.1073\/pnas.91.9.3999","volume":"91","author":"G Bianchi","year":"1994","unstructured":"Bianchi G, Tripodi G, Casari G, Salardi S, Barber BR, Garcia R, et al. Two point mutations within the adducin genes are involved in blood pressure variation. Proc Natl Acad Sci U.S.A. 1994;91:3999\u20134003.","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"214_CR7","doi-asserted-by":"publisher","first-page":"2815","DOI":"10.1172\/JCI118737","volume":"97","author":"G Tripodi","year":"1996","unstructured":"Tripodi G, Valtorta F, Torielli L, Chieregatti E, Salardi S, Trusolino L, et al. Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest. 1996;97:2815\u201322.","journal-title":"J Clin Invest"},{"key":"214_CR8","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1016\/S0140-6736(97)01029-5","volume":"349","author":"D Cusi","year":"1997","unstructured":"Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M, et al. Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet. 1997;349:1353\u201357.","journal-title":"Lancet"},{"key":"214_CR9","doi-asserted-by":"publisher","first-page":"R1536","DOI":"10.1152\/ajpregu.00441.2005","volume":"289","author":"G Bianchi","year":"2005","unstructured":"Bianchi G. Genetic variations of tubular sodium reabsorption leading to \u2018primary\u2019 hypertension: from gene polymorphism to clinical symptoms. Am J Physiol Regul Integr Comp Physiol. 2005;289:R1536\u201349.","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"214_CR10","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1097\/HJH.0b013e3282f5315f","volume":"26","author":"P Manunta","year":"2008","unstructured":"Manunta P, Maillard M, Tantardini C, Simonini M, Lanzani C, Citterio L, et al. Relationships among endogenous ouabain, alpha-adducin polymorphisms and renal sodium handling in primary hypertension. J Hypertens. 2008;26:914\u201320.","journal-title":"J Hypertens"},{"key":"214_CR11","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1016\/j.bbadis.2010.03.014","volume":"1802","author":"L Citterio","year":"2010","unstructured":"Citterio L, Lanzani C, Manunta P, Bianchi G. Genetics of primary hypertension: the clinical impact of adducin polymorphisms. Biochim Biophys Acta (BBA)\u2014Molecular Basis of Disease. 2010;1802:1285\u201398.","journal-title":"Biochim Biophys Acta (BBA)\u2014Molecular Basis of Disease"},{"key":"214_CR12","doi-asserted-by":"publisher","first-page":"59ra86","DOI":"10.1126\/scitranslmed.3001815","volume":"2","author":"M Ferrandi","year":"2010","unstructured":"Ferrandi M, Molinari I, Torielli L, Padoani G, Salardi S, Rastaldi MP, et al. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 1: experimental studies. Sci Transl Med. 2010;2:59ra86\u20136.","journal-title":"Sci Transl Med"},{"key":"214_CR13","doi-asserted-by":"publisher","first-page":"59ra87","DOI":"10.1126\/scitranslmed.3001814","volume":"2","author":"C Lanzani","year":"2010","unstructured":"Lanzani C, Citterio L, Glorioso N, Manunta P, Tripodi G, Salvi E, et al. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 2: clinical studies. Sci Transl Med. 2010;2:59ra87\u20137.","journal-title":"Sci Transl Med"},{"key":"214_CR14","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/nchembio.296","volume":"6","author":"SV Frye","year":"2010","unstructured":"Frye SV. The art of the chemical probe. Nat Chem Biol. 2010;6:159\u201361.","journal-title":"Nat Chem Biol"},{"key":"214_CR15","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1007\/s11906-016-0632-y","volume":"18","author":"P Manunta","year":"2016","unstructured":"Manunta P, Ferrandi M, Cusi D, Staessen J, Bianchi G. Personalized therapy of hypertension: the past and the future. Curr Hypertens Rep. 2016;18:24\u201311.","journal-title":"Curr Hypertens Rep"},{"key":"214_CR16","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1161\/01.RES.0000149570.20845.89","volume":"95","author":"R Efendiev","year":"2004","unstructured":"Efendiev R, Krmar RT, Ogimoto G, Zwiller J, Tripodi G, Katz AI, et al. Hypertension- linked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na+,K+-ATPase trafficking in response to GPCR signals and intracellular sodium. Circ Res. 2004;95:1100\u20138.","journal-title":"Circ Res"},{"key":"214_CR17","doi-asserted-by":"publisher","first-page":"F478","DOI":"10.1152\/ajprenal.90226.2008","volume":"295","author":"L Torielli","year":"2008","unstructured":"Torielli L, Tivodar S, Montella RC, Iacone R, Padoani G, Tarsini P, et al. alpha-Adducin mutations increase Na\/K pump activity in renal cells by affecting constitutive endocytosis: implications for tubular Na reabsorption. Am J Physiol Renal Physiol. 2008;295:F478\u201387.","journal-title":"Am J Physiol Renal Physiol"},{"key":"214_CR18","doi-asserted-by":"publisher","first-page":"H919","DOI":"10.1152\/ajpheart.00131.2017","volume":"313","author":"MP Blaustein","year":"2017","unstructured":"Blaustein MP. How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+ pumps are crucial. Am J Physiol Heart Circ Physiol. 2017;313:H919\u201330.","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"214_CR19","first-page":"pii:204","volume":"6","author":"X Fan","year":"2017","unstructured":"Fan X, Xie J, Tian J. Reducing cardiac fibrosis: Na\/K-ATPase signaling complex as a novel target. Cardiovasc Pharm Open Access. 2017;6:pii:204.","journal-title":"Cardiovasc Pharm Open Access"},{"key":"214_CR20","doi-asserted-by":"publisher","first-page":"e0197688","DOI":"10.1371\/journal.pone.0197688","volume":"13","author":"CA Drummond","year":"2018","unstructured":"Drummond CA, Fan X, Haller ST, Kennedy DJ, Liu J, Tian J. Na\/K-ATPase signaling mediates miR-29b-3p regulation and cardiac fibrosis formation in mice with chronic kidney disease. PLoS ONE. 2018;13:e0197688.","journal-title":"PLoS ONE"},{"key":"214_CR21","doi-asserted-by":"publisher","first-page":"R151","DOI":"10.1093\/hmg\/ddz197","volume":"28","author":"CP Cabrera","year":"2019","unstructured":"Cabrera CP, Ng FL, Nicholls HL, Gupta A, Barnes MR, Munroe PB, et al. Over 1,000 genetic loci influencing blood pressure with multiple systems and tissues implicated. Hum Mol Genet. 2019;28:R151\u201361.","journal-title":"Hum Mol Genet"},{"key":"214_CR22","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/nrg3747","volume":"15","author":"WH Wei","year":"2014","unstructured":"Wei WH, Hemani G, Haley CS. Detecting epistasis in human complex traits. Nat Rev Genet. 2014;15:722\u201333.","journal-title":"Nat Rev Genet"},{"key":"214_CR23","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/s41576-019-0127-1","volume":"20","author":"V Tam","year":"2019","unstructured":"Tam V, Patel N, Turcotte M, Bosse Y, Pare\u0301 G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20:467\u201384.","journal-title":"Nat Rev Genet"},{"key":"214_CR24","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1152\/physiolgenomics.00004.2015","volume":"47","author":"PB Munroe","year":"2015","unstructured":"Munroe PB, Tinker A. Genome-wide association studies and contribution to cardiovascular physiology. Physiol Genomics. 2015;47:365\u201375.","journal-title":"Physiol Genomics"},{"key":"214_CR25","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/ajh\/hpx154","volume":"31","author":"SM Herrmann","year":"2018","unstructured":"Herrmann SM, Textor SC. Current concepts in the treatment of renovascular hypertension. Am J Hypertens. 2018;31:139\u201349.","journal-title":"Am J Hypertens"},{"key":"214_CR26","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/S2213-8587(17)30135-3","volume":"5","author":"TA Williams","year":"2017","unstructured":"Williams TA, Lenders JWM, Mulatero P, Burrello J, Rottenkolber M, Adolf C, et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol. 2017;5:689\u201399.","journal-title":"Lancet Diabetes Endocrinol"},{"key":"214_CR27","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1136\/bmj.2.5816.729","volume":"2","author":"JJ Brown","year":"1972","unstructured":"Brown JJ, Davies DL, Ferriss JB, Fraser R, Haywood E, Lever AF, et al. Comparison of surgery and prolonged spironolactone therapy in patients with hypertension, aldosterone excess, and low plasma renin. Br Med J. 1972;2:729\u201334.","journal-title":"Br Med J"},{"key":"214_CR28","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.amjmed.2008.09.038","volume":"122","author":"DS Wald","year":"2009","unstructured":"Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290\u2013300.","journal-title":"Am J Med"},{"key":"214_CR29","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1038\/hr.2013.142","volume":"37","author":"H Takagi","year":"2014","unstructured":"Takagi H, Mizuno Y, Niwa M, Goto SN, Umemoto T. A meta-analysis of randomized controlled trials of azilsartan therapy for blood pressure reduction. Hypertens Res. 2014;37:432\u20137.","journal-title":"Hypertens Res"},{"key":"214_CR30","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1053\/j.ajkd.2018.10.012","volume":"73","author":"R Iatrino","year":"2019","unstructured":"Iatrino R, Lanzani C, Bignami E, Casamassima N, Citterio L, Meroni R, et al. Lanosterol synthase genetic variants, endogenous ouabain, and both acute and chronic kidney injury. Am J Kidney Dis. 2019;73:504\u201312.","journal-title":"Am J Kidney Dis"},{"key":"214_CR31","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1124\/jpet.114.217133","volume":"351","author":"M Ferrandi","year":"2014","unstructured":"Ferrandi M, Molinari I, Rastaldi MP, Ferrari P, Bianchi G, Manunta P. Rostafuroxin protects from podocyte injury and proteinuria induced by adducin genetic variants and ouabain. J Pharmacol Exp Ther. 2014;351:278\u201387.","journal-title":"J Pharmacol Exp Ther"},{"key":"214_CR32","doi-asserted-by":"publisher","first-page":"E1728","DOI":"10.3390\/ijms17101728","volume":"17","author":"L Villa","year":"2016","unstructured":"Villa L, Buono R, Ferrandi M, Molinari I, Benigni F, Bettiga A, et al. Ouabain contributes to kidney damage in a rat model of renal ischemia-reperfusion injury. Int J Mol Sci. 2016;17:E1728.","journal-title":"Int J Mol Sci"},{"key":"214_CR33","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/j.jash.2016.10.009","volume":"10","author":"M Wilhelm","year":"2016","unstructured":"Wilhelm M, Winkler A, Rief W, Doering BK. Effect of placebo groups on blood pressure in hypertension: a meta-analysis of beta-blocker trials. J Am Soc Hypertens. 2016;10:917\u201329.","journal-title":"J Am Soc Hypertens"},{"key":"214_CR34","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1126\/science.aaf5406","volume":"352","author":"SN Goodman","year":"2016","unstructured":"Goodman SN. STATISTICS. Aligning statistical and scientific reasoning. Science. 2016;352:1180\u20131.","journal-title":"Science"},{"key":"214_CR35","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/d41586-018-01023-3","volume":"553","author":"MR Munafo\u0300","year":"2018","unstructured":"Munafo\u0300 MR, Davey Smith G. Robust research needs many lines of evidence. Nature. 2018;553:399\u2013401.","journal-title":"Nature"},{"key":"214_CR36","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1001\/jama.2015.18359","volume":"315","author":"TA Kotchen","year":"2016","unstructured":"Kotchen TA, Cowley AW Jr, Liang M. Ushering hypertension into a new era of precision medicine. JAMA. 2016;315:343\u20134.","journal-title":"JAMA"}],"container-title":["The Pharmacogenomics Journal"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41397-021-00214-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41397-021-00214-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41397-021-00214-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T21:00:38Z","timestamp":1684616438000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41397-021-00214-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,1]]},"references-count":36,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["214"],"URL":"https:\/\/doi.org\/10.1038\/s41397-021-00214-y","relation":{},"ISSN":["1470-269X","1473-1150"],"issn-type":[{"value":"1470-269X","type":"print"},{"value":"1473-1150","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,1]]},"assertion":[{"value":"29 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"GB, as it may be seen from the introduction and discussion, this study is the last of a long series aimed at detecting a target \u201ccausal\u201d molecular mechanism(s) of hypertension amenable to be \u201ccorrected\u201d by a small molecule in patients. To this end, GB was employee of the Universit\u00e0 Vita Salute San Raffaele, Milano, Italy and consultant of pharmaceutical companies, that changed over time (Prassis RostaQuo Sigma Tau, Settimo M.se-Pomezia Italy; CVie Therapeutics, Taipei; Windtree Therapeutics, Warrington, USA), receiving a salary from the former and a consultancy fee from the latter, this being well known to both parties. In 2016, as Emeritus Professor, to comply with some local regulations, GB changed his position from consultant to employee at CVie Therapeutics first and then at Windtree; at present, he is consultant at Windtree. PF was consultant of CVie Therapeutics, Taipei, Taiwan first, and then of Windtree Therapeutics, Warrington, PA, USA. MF was an employee of Windtree Therapeutics, Warrington, PA, USA. SC received personal fees from Windtree Therapeutics, Warrington, USA. LFL was employee of CVie Therapeutics Taipei Taiwan. XL was CEO of CVie therapeutics Taipei Taiwan. CVie Therapeutics and Windree Therapeutics paid research grants for this study to the Institutions of GAS, NG, RB, CEC, TDW, KLW, PM, LC, DC, JAS, and CL have no conflicts of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All studies were approved by the local ethics committees and all participants provided written informed consent.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical statement"}}]}}