{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:18:45Z","timestamp":1773299925866,"version":"3.50.1"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA remain unclear. We examined the cellular and ionic basis for macro-TWA in rabbits with left ventricular hypertrophy (LVH).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              The renovascular hypertension model was used to induce LVH in rabbits. Action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contractility in arterially perfused left ventricular wedges. Late sodium current (I\n              <jats:sub>Na-L<\/jats:sub>\n              ) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05, versus 0\/15 in controls) and were induced by an I\n              <jats:sub>Na-L<\/jats:sub>\n              enhancer ATX-II at 1 to 3 nM in additional 7. Macro-TWA and mechanical alternans occurred discordantly, that is, that longer QT interval and larger T wave were associated with weaker isometric contvractility. Alternating early afterdepolarizations in the endocardium caused macro-TWA in 12 of 15 LVH rabbits and, therefore, early afterdepolarization-dependent R-from-T extrasystoles and Torsades de Pointes always originated from the beats with longer QT and larger T wave during macro-TWA. I\n              <jats:sub>Na-L<\/jats:sub>\n              density was significantly larger in LVH myocytes than that of control myocytes. Macro-TWA, mechanical alternans, R-from-T extrasystoles, and Torsades de Pointes were all abolished by I\n              <jats:sub>Na-L<\/jats:sub>\n              blocker ranolazine or mexiletine.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              LVH enhances I\n              <jats:sub>Na-L<\/jats:sub>\n              density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. I\n              <jats:sub>Na-L<\/jats:sub>\n              blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.122.011453","type":"journal-article","created":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T19:43:10Z","timestamp":1672774990000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Alternating Early Afterdepolarizations Underlying Bradycardia-Dependent Macroscopic T Wave and Discordant Mechanical Alternans"],"prefix":"10.1161","volume":"16","author":[{"given":"Datun","family":"Qi","sequence":"first","affiliation":[{"name":"Zhengzhou University People\u2019s Hospital and Central China Fuwai Hospital, Zhengzhou, China (D.Q., C.G., G.-X.Y.)."},{"name":"Lankenau Institute for Medical Research, Wynnewood, PA (D.Q., X.-Q.Q., Y.G., J.W., W.Z., G.-X.Y.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7135-1033","authenticated-orcid":true,"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xinhua Hospital, Shanghai, China (W.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1350-8220","authenticated-orcid":true,"given":"Xiao-Qing","family":"Quan","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, Wynnewood, PA (D.Q., X.-Q.Q., Y.G., J.W., W.Z., G.-X.Y.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4215-2307","authenticated-orcid":true,"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, Wynnewood, PA (D.Q., X.-Q.Q., Y.G., J.W., W.Z., G.-X.Y.)."},{"name":"Henan University of Traditional Chinese Medicine, Zhengzhou, China (Y.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4286-7097","authenticated-orcid":true,"given":"Jianyong","family":"Wang","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, Wynnewood, PA (D.Q., X.-Q.Q., Y.G., J.W., W.Z., G.-X.Y.)."},{"name":"TEDA International Cardiovascular Hospital, Tianjin, China (J.W.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4284-1612","authenticated-orcid":true,"given":"Lily","family":"Guo","sequence":"additional","affiliation":[{"name":"New York University, NY (L.G.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenping","family":"Zhao","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, Wynnewood, PA (D.Q., X.-Q.Q., Y.G., J.W., W.Z., G.-X.Y.)."},{"name":"Affiliated Hospital of Hebei University, Baoding, China 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