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Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The short\u2010term variability of beat\u2010to\u2010beat <jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content> interval (<jats:styled-content style=\"fixed-case\">STV<jats:sub>QT<\/jats:sub><\/jats:styled-content>), induced by dofetilide is a strong surrogate of <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>orsades de pointes liability. Involvement of autonomic modulation in STV<jats:sub>QT<\/jats:sub> was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Increase in <jats:styled-content style=\"fixed-case\">STV<jats:sub>QT<\/jats:sub><\/jats:styled-content> induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and <jats:styled-content style=\"fixed-case\">QT<\/jats:styled-content> interval high\u2010frequency (<jats:styled-content style=\"fixed-case\">HF<\/jats:styled-content>) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when <jats:styled-content style=\"fixed-case\">HF<\/jats:styled-content> oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate <jats:styled-content style=\"fixed-case\">HF<\/jats:styled-content> oscillations were found in dogs with other h<jats:styled-content style=\"fixed-case\">ERG<\/jats:styled-content> blockers described as causing <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>orsades de pointes in humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These results demonstrate for the first time that beat\u2010to\u2010beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous <jats:styled-content style=\"fixed-case\">HF<\/jats:styled-content> autonomic oscillations in heart rate. When combined with evidence of h<jats:styled-content style=\"fixed-case\">ERG<\/jats:styled-content>\u2010blocking properties, enhancement of endogenous <jats:styled-content style=\"fixed-case\">HF<\/jats:styled-content> oscillations in heart rate could constitute an earlier and more sensitive biomarker than <jats:styled-content style=\"fixed-case\">STV<jats:sub>QT<\/jats:sub><\/jats:styled-content> for <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>orsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13093","type":"journal-article","created":{"date-parts":[[2015,1,27]],"date-time":"2015-01-27T09:15:04Z","timestamp":1422350104000},"page":"2878-2891","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Short\u2010term variability in <scp>QT<\/scp> interval and ventricular arrhythmias induced by dofetilide 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