{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:43:43Z","timestamp":1792514623606,"version":"4.5.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T00:00:00Z","timestamp":1611360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL030077"],"award-info":[{"award-number":["R01-HL030077"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01-HL141084"],"award-info":[{"award-number":["P01-HL141084"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL142282"],"award-info":[{"award-number":["R01-HL142282"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F32-HL144017"],"award-info":[{"award-number":["F32-HL144017"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Diabetic hyperglycaemia is associated with increased arrhythmia risk. We aimed to investigate whether hyperglycaemia alone can be accountable for arrhythmias or whether it requires the presence of additional pathological factors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Action potentials (APs) and arrhythmogenic spontaneous diastolic activities were measured in isolated murine ventricular, rabbit atrial, and ventricular myocytes acutely exposed to high glucose. Acute hyperglycaemia increased the short-term variability (STV) of action potential duration (APD), enhanced delayed afterdepolarizations, and the inducibility of APD alternans during tachypacing in both murine and rabbit atrial and ventricular myocytes. Hyperglycaemia also prolonged APD in mice and rabbit atrial cells but not in rabbit ventricular myocytes. However, rabbit ventricular APD was more strongly depressed by block of late Na+ current (INaL) during hyperglycaemia, consistent with elevated INaL in hyperglycaemia. All the above proarrhythmic glucose effects were Ca2+-dependent and abolished by CaMKII inhibition. Importantly, when the repolarization reserve was reduced by pharmacological inhibition of K+ channels (either Ito, IKr, IKs, or IK1) or hypokalaemia, acute hyperglycaemia further prolonged APD and further increased STV and alternans in rabbit ventricular myocytes. Likewise, when rabbit ventricular myocytes were pretreated with isoproterenol or angiotensin II, hyperglycaemia significantly prolonged APD, increased STV and promoted alternans. Moreover, acute hyperglycaemia markedly prolonged APD and further enhanced STV in failing rabbit ventricular myocytes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We conclude that even though hyperglycaemia alone can enhance cellular proarrhythmic mechanisms, a second hit which reduces the repolarization reserve or stimulates G protein-coupled receptor signalling greatly exacerbates cardiac arrhythmogenesis in diabetic hyperglycaemia.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvab006","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T14:07:45Z","timestamp":1610287665000},"page":"2781-2793","source":"Crossref","is-referenced-by-count":42,"title":["Two-hit mechanism of cardiac arrhythmias in diabetic hyperglycaemia: reduced repolarization reserve, neurohormonal stimulation, and heart failure exacerbate susceptibility"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3113-221X","authenticated-orcid":false,"given":"Bence","family":"Hegyi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4539-8222","authenticated-orcid":false,"given":"Christopher Y","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8874-4765","authenticated-orcid":false,"given":"Julie","family":"Bossuyt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2237-9483","authenticated-orcid":false,"given":"Donald M","family":"Bers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,23]]},"reference":[{"key":"2021121807435775100_cvab006-B1","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1073\/pnas.68.4.820","article-title":"Mutation and cancer: statistical study of retinoblastoma","volume":"68","author":"Knudson","year":"1971","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021121807435775100_cvab006-B2","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0092-8674(01)00243-4","article-title":"Molecular and cellular mechanisms of cardiac arrhythmias","volume":"104","author":"Keating","year":"2001","journal-title":"Cell"},{"key":"2021121807435775100_cvab006-B3","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1161\/CIRCRESAHA.116.304030","article-title":"Genetics of sudden cardiac death","volume":"116","author":"Bezzina","year":"2015","journal-title":"Circ Res"},{"key":"2021121807435775100_cvab006-B4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/eurheartj\/ehz486","article-title":"2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD","volume":"41","author":"Cosentino","year":"2020","journal-title":"Eur Heart J"},{"key":"2021121807435775100_cvab006-B5","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1093\/eurheartj\/ehi376","article-title":"Diabetes, glucose level, and risk of sudden cardiac death","volume":"26","author":"Jouven","year":"2005","journal-title":"Eur Heart J"},{"key":"2021121807435775100_cvab006-B6","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1001\/jama.1979.03290450033020","article-title":"Diabetes and cardiovascular disease. 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