{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:25:22Z","timestamp":1790735122796,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The potential benefit of heart rate reduction (HRR), independent of \u03b2-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416\u2009+\u2009hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg\/kg\/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure\u2013volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca++ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell\u2013derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH\/PAB rats. RV systolic-elastance (control, 121\u2009\u00b1\u2009116; MCT, 49\u2009\u00b1\u200936 vs. MCT+IVA, 120\u2009\u00b1\u200954; PAB, 70\u2009\u00b1\u200920 vs. PAB+IVA, 168\u2009\u00b1\u200976; SUHX, 86\u2009\u00b1\u200956 vs. SUHX\u2009+IVA, 218\u2009\u00b1\u2009111; all P\u2009&amp;lt;\u20090.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6\u2009\u00b1\u20091%; MCT, 13.4\u2009\u00b1\u20096.5 vs. MCT+IVA, 6.7\u2009\u00b1\u20092.6%; PAB, 11.4\u2009\u00b1\u20094.5 vs. PAB+IVA, 6.4\u2009\u00b1\u20095.1%; SUHX, 10\u2009\u00b1\u20094.6 vs. SUHX+IVA, 3.9\u2009\u00b1\u20092.2%; all P\u2009&amp;lt;\u20090.001) were improved by IVA versus controls. IVA had a dose\u2013response effect on induced pluripotent stem cell\u2013derived cardiomyocytes beat rate by delaying Ca++ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of \u03b2-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.<\/jats:p>","DOI":"10.1165\/rcmb.2019-0317oc","type":"journal-article","created":{"date-parts":[[2020,9,11]],"date-time":"2020-09-11T15:46:13Z","timestamp":1599839173000},"page":"843-855","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":20,"title":["Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension"],"prefix":"10.1093","volume":"63","author":[{"given":"Ryo","family":"Ishii","sequence":"first","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Okumura","sequence":"additional","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Akazawa","sequence":"additional","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manpreet","family":"Malhi","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Ebata","sequence":"additional","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Sun","sequence":"additional","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Fujioka","sequence":"additional","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Kato","sequence":"additional","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osami","family":"Honjo","sequence":"additional","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Golam","family":"Kabir","sequence":"additional","affiliation":[{"name":"The Keenan Research Center for Biomedical Research of St. Michael\u2019s Hospital, Toronto, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang M.","family":"Kuebler","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Connelly","sequence":"additional","affiliation":[{"name":"The Keenan Research Center for Biomedical Research of St. Michael\u2019s Hospital, Toronto, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason T.","family":"Maynes","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark K.","family":"Friedberg","sequence":"additional","affiliation":[{"name":"The Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"key":"2026021100444606400_bib1","doi-asserted-by":"crossref","first-page":"1801889","DOI":"10.1183\/13993003.01889-2018","article-title":"Risk stratification and medical therapy of pulmonary arterial hypertension","volume":"53","author":"Gali\u00e8","year":"2019","journal-title":"Eur Respir J"},{"key":"2026021100444606400_bib2","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1093\/cvr\/cvx148","article-title":"Treatment strategies for the right heart in pulmonary hypertension","volume":"113","author":"Westerhof","year":"2017","journal-title":"Cardiovasc Res"},{"key":"2026021100444606400_bib3","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jacc.2016.10.047","article-title":"The relationship between the right ventricle and its load in pulmonary hypertension","volume":"69","author":"Vonk Noordegraaf","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"2026021100444606400_bib4","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1164\/rccm.201003-0335OC","article-title":"Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats","volume":"182","author":"Bogaard","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021100444606400_bib5","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1152\/physiolgenomics.00166.2012","article-title":"Chronic carvedilol treatment partially reverses the right ventricular failure transcriptional profile in experimental pulmonary hypertension","volume":"45","author":"Drake","year":"2013","journal-title":"Physiol Genomics"},{"key":"2026021100444606400_bib6","doi-asserted-by":"crossref","first-page":"95240","DOI":"10.1172\/jci.insight.95240","article-title":"Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlled trial","volume":"2","author":"Farha","year":"2017","journal-title":"JCI Insight"},{"key":"2026021100444606400_bib7","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1183\/13993003.01032-2015","article-title":"2015 esc\/ers guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the european society of cardiology (esc) and the european respiratory society (ers). 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