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Cardiac microcurrent therapy delivers a low-intensity, nondepolarizing direct current across the myocardium and has been proposed to modulate fibrosis, inflammation, and remodeling in heart failure with reduced ejection fraction. In Cardiac Microcurrent I (New York Heart Association III nonischemic heart failure with reduced ejection fraction), left ventricular ejection fraction increased by 12.6% at 6 months, 6-minute walk distance improved by 191 m, and 8 of 10 patients improved to New York Heart Association I within 2 weeks. In the randomized Cardiac Microcurrent II trial, patients showed further improvements, including a 5.1% increase in left ventricular ejection fraction, a reduction in New York Heart Association class (up to 69%), and a 38 m increase in 6-minute walk distance. However, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels did not show a consistent corresponding reduction. In vitro, microcurrent altered the myofibroblast phenotype and reduced the expression of transforming growth factor-\u03b21, collagen, \u03b1-smooth muscle actin, and fibronectin. Transcriptomics revealed downregulation of inflammatory and immune pathways, while cardiomyocytes from spontaneously hypertensive rats exhibited enhanced survival and stress resistance. This review combines early clinical observations and preclinical findings to examine potential mechanisms of action and bioelectrical effects of cardiac microcurrent therapy. Given the limited clinical evidence and largely in vitro nature of the data, the current mechanistic findings should be considered preliminary. We highlight key knowledge gaps and propose future studies to define molecular mechanisms, discover biomarkers, analyze key signaling pathways, and evaluate clinical outcomes in adequately powered, sham-controlled trials, which could further validate this therapeutic approach.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.126.014407","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:00:18Z","timestamp":1787130018000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Microcurrent Therapy in Cardiac Repair: Bridging Mechanistic Biology and Clinical Evidence"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2936-1702","authenticated-orcid":true,"given":"Jesus Eduardo","family":"Rame","sequence":"first","affiliation":[{"name":"Bruce and Robbi Toll Heart and Vascular Institute, Thomas Jefferson University, Philadelphia, PA (J.E.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4129-0804","authenticated-orcid":true,"given":"Dipthi","family":"Bachamanda Somesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6471-1483","authenticated-orcid":true,"given":"David","family":"Lanfear","sequence":"additional","affiliation":[{"name":"Henry Ford Cardiovascular Medicine, Royal Oak, MI (D.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8671-7007","authenticated-orcid":true,"given":"Marat","family":"Fudim","sequence":"additional","affiliation":[{"name":"Duke University, Durham, NC (M.F.)."},{"name":"Duke Clinical Research Institute, Durham, NC (M.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1223-327X","authenticated-orcid":true,"given":"Stavros","family":"Drakos","sequence":"additional","affiliation":[{"name":"Cardiovascular, Renal &amp; Metabolism Center, University of Utah School of Medicine, Salt Lake City (S.D.)."},{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City (S.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-2466","authenticated-orcid":true,"given":"Daniel","family":"Burkhoff","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Foundation, New York City, NY (D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0000-0356","authenticated-orcid":true,"given":"Rob S.","family":"MacLeod","sequence":"additional","affiliation":[{"name":"Scientific Computing and Imaging Institute (R.S.M.L.), University of Utah, Salt Lake City."},{"name":"Department of Biomedical Engineering (R.S.M.L.), University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7683-4720","authenticated-orcid":true,"given":"Javed","family":"Butler","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Mississippi Medical Center, Jackson (J.B.)."},{"name":"Baylor Scott and White Research Institute, Dallas, TX (J.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5986-6528","authenticated-orcid":true,"given":"Arantxa","family":"Gonz\u00e1lez Miqueo","sequence":"additional","affiliation":[{"name":"Centre for Applied Medical Research (CIMA), Department of Cardiology and Cardiac Surgery, Cl\u00ednica Universidad de Navarra, Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, Spain (A.G.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5195-7096","authenticated-orcid":true,"given":"Faouzi","family":"Kallel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0805-8683","authenticated-orcid":true,"given":"Stefan D.","family":"Anker","sequence":"additional","affiliation":[{"name":"Department of Cardiology (CVK) of German Heart Center Charit\u00e9, Charit\u00e9, Berlin, Germany (S.D.A.)."},{"name":"German Center for Cardiovascular Research (DZHK) Partner Site Berlin, Charit\u00e9 Universit\u00e4tsmedizin, Berlin, Germany (S.D.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2010.10.008"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0b013e3182116e39"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.retram.2016.09.003"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2018.01.013"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2012.158"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00777"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1349-6"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2026.117795"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/jce.16222"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13242"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.CLIM.2006.04.299"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1097\/MAT.0000000000001537"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0166-2236(97)01101-6"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00020.2004"},{"key":"e_1_3_3_16_2","unstructured":"Wang ET Zhao M. 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