{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:02:07Z","timestamp":1787022127630,"version":"build-2736575974"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["18lm0203047h0001"],"award-info":[{"award-number":["18lm0203047h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Despite the advances in the treatment of cardiovascular diseases, effective treatment remains to be established to improve the quality of life and prognosis of patients with chronic coronary syndromes. This study was aimed to evaluate the effectiveness and safety of the low-intensity pulsed ultrasound (LIPUS) therapy, which we have developed as a novel non-invasive angiogenic therapy through upregulation of endothelial nitric oxide synthase (eNOS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>We conducted a randomized, double-blind, placebo-controlled (RCT) pilot trial of the LIPUS therapy for patients with refractory angina pectoris. The patients who received optimal medical therapy without indication of PCI or CABG due to the lack of graftability or complexity of coronary lesions were enrolled. They were randomly divided into the LIPUS treatment group (N = 31) and the placebo group (N = 25) in a 1:1 fashion. The LIPUS therapy was performed in a transthoracic manner for 20 min for 3 sections each (mitral, papillary muscle, and apex levels) under the conditions that we identified; frequency 1.875 MHz, intensity 0.25 MPa, and 32 cycles. The primary endpoint was weekly use of nitroglycerin. Secondary endpoints included stress myocardial perfusion imaging and others. The average weekly nitroglycerin use (times\/week) was decreased from 5.50 to 2.44 in the LIPUS group and from 5.94 to 2.83 in the placebo group. The changes in the average weekly nitroglycerin use were comparable; -3.06 (95% CI: -4.481 to -1.648) in the LIPUS group (P&lt;0.01) and -3.10 (95% CI: -4.848 to -1.356) in the placebo group (P&lt;0.01). No adverse effects were noted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In the present study, the LIPUS therapy did not further ameliorate chest pain as compared with optimal medications alone in patients with refractory angina pectoris. The present findings need to be confirmed in another trial with a large number of patients. (Registration ID: UMIN000012369).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0287714","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T19:13:16Z","timestamp":1687633996000},"page":"e0287714","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["A randomized, double-blind, placebo-controlled pilot trial of low-intensity pulsed ultrasound therapy for refractory angina pectoris"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3420-9999","authenticated-orcid":true,"given":"Tomohiko","family":"Shindo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Ogata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Kurosawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumiko","family":"Eguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Kagaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichiro","family":"Hanawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhi","family":"Hasebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Nishimiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shiroto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Okumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruo","family":"Noguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Ozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Daida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhisa","family":"Hagiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Masuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taishiro","family":"Chikamori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Fukumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4314-259X","authenticated-orcid":true,"given":"Kenichi","family":"Tsujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6567-1687","authenticated-orcid":true,"given":"Hiroshi","family":"Kanai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Yasuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7534-4826","authenticated-orcid":true,"given":"Hiroaki","family":"Shimokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"pone.0287714.ref001","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1001\/jama.2022.0358","article-title":"Diagnosis and treatment of acute coronary syndromes: A review","volume":"327","author":"DL Bhatt","year":"2022","journal-title":"JAMA"},{"key":"pone.0287714.ref002","first-page":"e368","article-title":"2021AHA\/ACC\/ASE\/CHEST\/SAEM\/SCCT\/ SCMR guideline for the evaluation and diagnosis of chest pain: executive summary: a report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"144","author":"M Gulati","year":"2021","journal-title":"Circulation"},{"key":"pone.0287714.ref003","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1056\/NEJMoa1915922","article-title":"ISCHEMIA Research Group. Initial invasive or conservative strategy for stable coronary disease","volume":"382","author":"DJ Maron","year":"2020","journal-title":"N Engl J Med"},{"key":"pone.0287714.ref004","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1056\/NEJMoa070829","article-title":"COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease","volume":"356","author":"WE Boden","year":"2007","journal-title":"N Engl J Med"},{"key":"pone.0287714.ref005","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0140-6736(17)32714-9","article-title":"ORBITA investigators. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial","volume":"391","author":"R Al-Lamee","year":"2018","journal-title":"Lancet"},{"key":"pone.0287714.ref006","doi-asserted-by":"crossref","first-page":"e104863","DOI":"10.1371\/journal.pone.0104863","article-title":"Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia","volume":"9","author":"K Hanawa","year":"2014","journal-title":"PLoS One"},{"key":"pone.0287714.ref007","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.ultrasmedbio.2005.08.010","article-title":"Low-intensity ultrasound induces angiogenesis in rat hind-limb ischemia","volume":"32","author":"S Barzelai","year":"2006","journal-title":"Ultrasound Med Biol"},{"key":"pone.0287714.ref008","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1016\/j.ultrasmedbio.2007.05.007","article-title":"Ultrasound-induced angiogenic response in endothelial cells","volume":"33","author":"N Mizrahi","year":"2007","journal-title":"Ultrasound Med Biol"},{"key":"pone.0287714.ref009","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1126\/science.1065677","article-title":"Cell biology. Life without caveolae","volume":"293","author":"RG Parton","year":"2001","journal-title":"Science"},{"key":"pone.0287714.ref010","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nrm3512","article-title":"Caveolae as plasma membrane sensors, protectors and organizers","volume":"14","author":"RG Parton","year":"2013","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pone.0287714.ref011","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1161\/ATVBAHA.115.306477","article-title":"Low-intensity pulsed ultrasound enhances angiogenesis and ameliorates left ventricular dysfunction in a mouse model of acute myocardial infarction","volume":"36","author":"T Shindo","year":"2016","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"pone.0287714.ref012","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1152\/physrev.1995.75.3.519","article-title":"Flow-mediated endothelial mechanotransduction","volume":"75","author":"PF Davies","year":"1995","journal-title":"Physiol Rev"},{"key":"pone.0287714.ref013","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1172\/JCI27100","article-title":"Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels","volume":"116","author":"J Yu","year":"2006","journal-title":"J Clin Invest"},{"key":"pone.0287714.ref014","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3400\/avd.ra.20-00010","article-title":"Therapeutic angiogenesis with sound waves","volume":"13","author":"T Shindo","year":"2020","journal-title":"Ann Vasc Dis"},{"key":"pone.0287714.ref015","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/ca.20646","article-title":"Left ventricular anatomy: its nomenclature, segmentation, and planes of imaging","volume":"22","author":"JB Partridge","year":"2009","journal-title":"Clin Anat"},{"key":"pone.0287714.ref016","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1093\/eurheartj\/ehaa820","article-title":"Management of refractory angina: an update","volume":"42","author":"A Davies","year":"2021","journal-title":"Eur Heart J"},{"key":"pone.0287714.ref017","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1161\/01.CIR.103.24.2928","article-title":"Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial","volume":"103","author":"GJ Bech","year":"2001","journal-title":"Circulation"},{"key":"pone.0287714.ref018","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1097\/MCA.0000000000000648","article-title":"A randomized, triple-blind trial of cardiac shock-wave therapy on exercise tolerance and symptoms in patients with stable angina pectoris","volume":"29","author":"E Shkolnik","year":"2018","journal-title":"Coron Artery Dis"},{"key":"pone.0287714.ref019","doi-asserted-by":"crossref","first-page":"e0185555","DOI":"10.1371\/journal.pone.0185555","article-title":"Low-intensity pulsed ultrasound enhances angiogenesis and ameliorates contractile dysfunction of pressure-overloaded heart in mice","volume":"12","author":"T Ogata","year":"2017","journal-title":"PLoS One"},{"key":"pone.0287714.ref020","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1093\/cvr\/cvaa221","article-title":"Low-intensity pulsed ultrasound ameliorates cardiac diastolic dysfunction in mice -A possible novel therapy for HFpEF","volume":"117","author":"Y Monma","year":"2021","journal-title":"Cardiovasc Res"},{"key":"pone.0287714.ref021","article-title":"Beneficial effects of low-intensity pulsed ultrasound on right ventricular dysfunction in animal models","author":"T Nakata","year":"2022","journal-title":"JACC Basic Transl Sci"},{"key":"pone.0287714.ref022","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.brs.2018.05.012","article-title":"Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia\u2014Crucial roles of endothelial nitric oxide synthase","volume":"11","author":"K Eguchi","year":"2018","journal-title":"Brain Stimul"},{"key":"pone.0287714.ref023","doi-asserted-by":"crossref","first-page":"4958","DOI":"10.1038\/s41598-021-84473-6","article-title":"Low-intensity pulsed ultrasound therapy promotes recovery from stroke by enhancing angio-neurogenesis in mice in vivo","volume":"11","author":"S Ichijo","year":"2021","journal-title":"Sci Rep"},{"key":"pone.0287714.ref024","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1620\/tjem.2022.J078","article-title":"A pilot study of whole-brain low-intensity pulsed ultrasound therapy for early stage of Alzheimer\u2019s disease (LIPUS-AD): A randomized, double-blind, placebo-controlled trial","volume":"258","author":"H Shimokawa","year":"2022","journal-title":"Tohoku J Exp Med"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0287714","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T19:13:40Z","timestamp":1687634020000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0287714"}},"subtitle":[],"editor":[{"given":"Marc W.","family":"Merx","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,6,23]]},"references-count":24,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0287714","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,23]]}}}