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Vagus nerve stimulation (VNS) is known to reduce the heart rate, and hence may be a non-pharmacological alternative for the management of persistent sinus tachycardia. To precisely regulate the heart rate using VNS, closed-loop control strategies are needed. Therefore, in this work, we developed two closed-loop VNS strategies using an in-silico model of the cardiovascular system. Both strategies employ a proportional-integral controller that operates on the current amplitude. While one control strategy continuously delivers stimulation pulses to the vagus nerve, the other applies bursts of stimuli in synchronization with the cardiac cycle. Both were evaluated in Langendorff-perfused rabbit hearts (n\u2009=\u20096) with intact vagal innervation. The controller performance was quantified by rise time (T<jats:sub>r<\/jats:sub>), steady-state error (SSE), and percentual overshoot amplitude (%OS). In the ex-vivo setting, the cardiac-synchronized variant resulted in T<jats:sub>r<\/jats:sub>\u2009=\u200910.7\u2009\u00b1\u20094.5\u00a0s, SSE\u2009=\u200912.7\u2009\u00b1\u20099.9\u00a0bpm and %OS\u2009=\u20095.1\u2009\u00b1\u20093.6% while continuous stimulation led to T<jats:sub>r<\/jats:sub>\u2009=\u200910.2\u2009\u00b1\u20095.6\u00a0s, SSE\u2009=\u200910\u2009\u00b1\u20096.7\u00a0bpm and %OS\u2009=\u20093.2\u2009\u00b1\u20091.9%. Overall, both strategies produced a satisfying and reproducible performance, highlighting their potential use in persistent sinus tachycardia.<\/jats:p>","DOI":"10.1038\/s41598-022-23407-2","type":"journal-article","created":{"date-parts":[[2022,11,5]],"date-time":"2022-11-05T11:03:00Z","timestamp":1667646180000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Closed-loop vagus nerve stimulation for heart rate control evaluated in the Langendorff-perfused rabbit heart"],"prefix":"10.1038","volume":"12","author":[{"given":"Max","family":"Haberbusch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Kronsteiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Margarethe","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Kiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno K.","family":"Podesser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Moscato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,5]]},"reference":[{"key":"23407_CR1","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/S0002-9343(02)01472-9","volume":"114","author":"E Umana","year":"2003","unstructured":"Umana, E., Solares, C. 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