{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:47:44Z","timestamp":1791384464492,"version":"4.3.3"},"reference-count":26,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["JP22K07467"],"award-info":[{"award-number":["JP22K07467"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Ivabradine reduces heart rate by inhibiting the \u201cfunny current\u201d expressed on the sinoatrial node and improves mortality and morbidity in patients with systolic heart failure and sinus tachycardia. The funny current is known to be expressed also on the atrioventricular node according to experimental studies. However, the impact of ivabradine on PR interval remained unknown. Methods: Patients with a left ventricular ejection fraction of less than 50% who received 1 month of ivabradine were screened. Electrocardiographic and echocardiographic data, particularly concerning heart rate, the PR interval, and trans-mitral flow pattern, were collected at baseline and 1-month follow-up. The primary endpoint was defined as the composite of cardiovascular death and hospital readmission for worsening heart failure following ivabradine administration. Results: In the cohort of 29 enrolled patients (median age: 66 years, 62% male), the median baseline heart rate was 86 beats per minute and the median PR interval was 168 milliseconds. Following ivabradine administration, a significant decrease of 20 beats per minute in the heart rate and a significant increase of 24 milliseconds in the PR interval were observed. The truncated interval of the A-wave, detected in the trans-mitral flow, consistently demonstrated a negative correlation with the PR interval both before and after the administration of ivabradine. During a median of 1.8 years of follow-up, six patients reached the primary endpoint. A combination of heart rate reduction and PR prolongation following ivabradine administration, both of which were independent factors associated with the primary endpoint (p &lt; 0.05 for both), was associated with greater freedom from the primary endpoint compared with either\/neither of them (p = 0.002). Conclusions: Ivabradine seems to prolong PR interval, which is a novel surrogate marker of favorable clinical outcomes in patients with systolic heart failure. This effect may be associated with the dynamics of the trans-mitral flow pattern, in conjunction with heart rate and the PR interval. Clinical implications of PR interval-guided ivabradine therapy remains the future concern.<\/jats:p>","DOI":"10.3390\/jcm13020510","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T11:37:18Z","timestamp":1705405038000},"page":"510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["PR Interval as a Novel Therapeutic Target of Ivabradine Therapy\u2014Prognostic Impact of Ivabradine-Induced PR Prolongation in Heart Failure Patients"],"prefix":"10.3390","volume":"13","author":[{"given":"Riona","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-7637","authenticated-orcid":false,"given":"Teruhiko","family":"Imamura","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2703-2523","authenticated-orcid":false,"given":"Toshihide","family":"Izumida","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Kinugawa","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S0140-6736(10)61198-1","article-title":"Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study","volume":"376","author":"Swedberg","year":"2010","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4924","DOI":"10.3390\/molecules17054924","article-title":"The biological effects of ivabradine in cardiovascular disease","volume":"17","author":"Speranza","year":"2012","journal-title":"Molecules"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1016\/j.hrthm.2013.08.007","article-title":"Inhibition of I(f) in the atrioventricular node as a mechanism for dronedarone\u2019s reduction in ventricular rate during atrial fibrillation","volume":"10","author":"Verrier","year":"2013","journal-title":"Heart Rhythm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ijcard.2016.09.044","article-title":"Ivabradine reduced ventricular rate in patients with non-paroxysmal atrial fibrillation","volume":"224","author":"Wongcharoen","year":"2016","journal-title":"Int. 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