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The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large\u2010scale clinical trials suggests that angiotensin <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We induced cardiac hypertrophy in wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) and angiotensin <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> type 1a receptor knockout (<jats:styled-content style=\"fixed-case\">AT1aR<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content>) mice by transverse aortic constriction (<jats:styled-content style=\"fixed-case\">TAC<\/jats:styled-content>). The susceptibility to ventricular tachycardia (<jats:styled-content style=\"fixed-case\">VT<\/jats:styled-content>) assessed in an <jats:italic>in vivo<\/jats:italic> electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of <jats:styled-content style=\"fixed-case\">AT<\/jats:styled-content>1<jats:styled-content style=\"fixed-case\">R<\/jats:styled-content> on the incidences of arrhythmias was also assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>As described previously, <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">AT1aR<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> mice with <jats:styled-content style=\"fixed-case\">TAC<\/jats:styled-content> developed cardiac hypertrophy to the same degree, but the incidence of <jats:styled-content style=\"fixed-case\">VT<\/jats:styled-content> was much lower in the latter. Moreover, although <jats:styled-content style=\"fixed-case\">TAC<\/jats:styled-content> induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in <jats:styled-content style=\"fixed-case\">AT1aR<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> mice. Acute pharmacological blockade of <jats:styled-content style=\"fixed-case\">AT1R<\/jats:styled-content> also reduced the incidence of arrhythmias.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our findings demonstrate that <jats:styled-content style=\"fixed-case\">AT1aR<\/jats:styled-content>\u2010mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12328","type":"journal-article","created":{"date-parts":[[2013,8,14]],"date-time":"2013-08-14T14:30:19Z","timestamp":1376490619000},"page":"1384-1395","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Angiotensin <scp>II<\/scp> type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy"],"prefix":"10.1111","volume":"170","author":[{"given":"Shinji","family":"Yasuno","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"},{"name":"EBM Research Center Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichiro","family":"Kuwahara","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chinatsu","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuaki","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Usami","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Kuwabara","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Ueshima","sequence":"additional","affiliation":[{"name":"EBM Research Center Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshio","family":"Nishikimi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuwa","family":"Nakao","sequence":"additional","affiliation":[{"name":"Department of Medicine and Clinical Science Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,11,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000072763.98069.B4"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(95)00563-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/eurheartj\/18.1.41","article-title":"Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. 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