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High-intensity vagus nerve stimulation therapy was shown to improve intrinsic heart rate recovery and left ventricular ejection fraction over a period of 1 year. Whether these beneficial effects are sustained across multiple years and are related to improved baroreceptor response was unknown.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>All patients (<jats:italic>n\u2009=\u2009<\/jats:italic>21) enrolled in the ANTHEM-HF clinical trial (NCT01823887, registered 4\/3\/2013) with 24\u00a0h ambulatory electrocardiograms at all time points and 54 normal subjects (PhysioNet database) were included. Intrinsic heart rate recovery, based on\u2009~\u20092000 spontaneous daily activity-induced heart rate acceleration\/deceleration events per patient, was analyzed at screening and after 12, 24, and 36\u00a0months of chronic vagus nerve stimulation therapy (10 or 5\u00a0Hz, 250\u00a0\u03bcs pulse width, 18% duty cycle, maximum tolerable current amplitude).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In response to chronic high-intensity vagus nerve stimulation (\u2265\u20092.0\u00a0mA), intrinsic heart rate recovery (all time points, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), heart rate turbulence slope, an indicator of baroreceptor reflex gain (all, <jats:italic>p<\/jats:italic>\u2009\u2264\u20090.02), and left ventricular ejection fraction (all, <jats:italic>p<\/jats:italic>\u2009\u2264\u20090.04) were improved over screening at 12, 24, and 36\u00a0months. Intrinsic heart rate recovery and heart rate turbulence slope were inversely correlated at both screening (<jats:italic>r<\/jats:italic>\u2009=\u20090.67, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.002) and 36\u00a0months (<jats:italic>r<\/jats:italic>\u2009=\u20090.78, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.005).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>This non-randomized study provides evidence of an association between improvement in intrinsic heart rate recovery and left ventricular ejection fraction during high-intensity vagus nerve stimulation for a period of\u2009\u2265\u20093\u00a0years. Correlated favorable effects on heart rate turbulence slope implicate enhanced baroreceptor function in response to chronic, continuously cyclic vagus nerve stimulation as a physiologic mechanism.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10286-021-00780-y","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:14:20Z","timestamp":1613693660000},"page":"453-462","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Chronic vagus nerve stimulation is associated with multi-year improvement in intrinsic heart rate recovery and left ventricular ejection fraction in ANTHEM-HF"],"prefix":"10.1007","volume":"31","author":[{"given":"Bruce D.","family":"Nearing","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imad","family":"Libbus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerrard M.","family":"Carlson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Badri","family":"Amurthur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce H.","family":"KenKnight","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard L.","family":"Verrier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,2,16]]},"reference":[{"key":"780_CR1","doi-asserted-by":"publisher","first-page":"e139","DOI":"10.1161\/CIR.0000000000000757","volume":"141","author":"Virani SS, Alonso A, Benjamin EJ, et al, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee","year":"2020","unstructured":"Virani SS, Alonso A, Benjamin EJ, et al, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee (2020) Heart disease and stroke statistics-2020 update: a report from the American Heart Association. 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Libbus, Carlson, and KenKnight and Mr. Amurther are employees of LivaNova USA. Drs. Verrier and Nearing have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"ANTHEM-HF complied with the Declaration of Helsinki. Local ethics committees at all sites approved the protocol. The present sub-study was conducted under a protocol approved by BIDMC\u2019s Institutional Review Board.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All patients provided written informed consent in local languages.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors approved this manuscript for publication.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Anonymized data not published within this article will be made available by request from any qualified investigator.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of data and material"}}]}}