{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T09:46:26Z","timestamp":1791798386012,"version":"4.3.4"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"abstract":"\n BACKGROUND:<\/jats:title>\n \n Type 2 long-QT syndrome results from\n KCNH2<\/jats:italic>\n -encoded Kv11.1 loss-of-function, but whether secondary inward-current dysfunction amplifies dysfunction remains unclear.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n We characterized sodium (\n SCN5A<\/jats:italic>\n , I\n Na<\/jats:sub>\n ) and L-type calcium channel (\n CACNA1C<\/jats:italic>\n , I\n Ca<\/jats:sub>\n ) function in KCNH2-G604S and variant-corrected isogenic control induced pluripotent stem cell\u2013derived cardiomyocytes (iPSC-CMs). Whole-cell patch-clamp measured action potential duration at 90% repolarization (APD90), and potassium (I\n Kr<\/jats:sub>\n ), sodium (I\n Na<\/jats:sub>\n ), and calcium (I\n Ca, L<\/jats:sub>\n ) currents. Fluo-4 imaging quantified calcium transients. A modified Kernik-Clancy iPSC-CM model incorporated experimentally measured persistent I\n Na,L<\/jats:sub>\n and I\n Ca,L<\/jats:sub>\n fractions and simulated isolated and combined current defects.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n KCNH2-G604S caused severe I\n Kr<\/jats:sub>\n loss-of-function (72.5% reduction). APD90 was prolonged in G604S-iPSC-CMs (765\u00b158 ms) compared with isogenic controls (368\u00b137 ms;\n P<\/jats:italic>\n <0.005), with early afterdepolarizations in 50% of G604S cells. Nifedipine, verapamil, and mexiletine successfully shortened APD90 and abolished early afterdepolarizations. Compared with isogenic control, I\n Na,L<\/jats:sub>\n (0.60\u00b10.1% versus 0.26\u00b10.06%;\n P<\/jats:italic>\n <0.01), persistent I\n Ca,L<\/jats:sub>\n (2.88\u00b10.55% versus 1.26\u00b10.35%;\n P<\/jats:italic>\n <0.05), and calcium transient decay times (\n P<\/jats:italic>\n <0.0001) were greater in G604S iPSC-CMs. Increased persistent I\n Ca,L<\/jats:sub>\n was phenocopied by E-4031 in isogenic controls and reduced by nifedipine in G604S iPSC-CMs. In silico modeling revealed that the I\n Kr<\/jats:sub>\n defect alone prolonged APD90 to only 620 ms. The addition of the observed I\n Na,L<\/jats:sub>\n defect had a small additive effect (+20 ms); however, incorporating persistent I\n Ca,L<\/jats:sub>\n synergistically extended APD90 to 758 ms, replicating the experimental phenotype. Flux dynamics analysis indicated that this persistent Ca\n 2+<\/jats:sup>\n entry suppresses the forward-mode sodium-calcium exchanger, forcing a compensatory reliance on sarcoplasmic-endoplasmic reticulum Ca-ATPase that primes for calcium instability.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n \n The KCNH2-G604S variant drives a severe multihit phenotype via primary I\n Kr<\/jats:sub>\n loss-of-function and secondary state-dependent gain-of-function in persistent I\n Ca,L<\/jats:sub>\n . These comprehensive validations demonstrate that the remodeled persistent I\n Ca,L<\/jats:sub>\n acts as the essential amplifier driving extreme action potential duration prolongation and Ca\n 2+<\/jats:sup>\n mishandling.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circep.126.014919","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T09:00:11Z","timestamp":1791795611000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Multichannel Dysfunction Associated With a Dominant-Negative\n KCNH2<\/i>\n Missense Variant, p.G604S, Results in Action Potential Duration Prolongation and Early Afterdepolarizations in a Patient-Specific, Reengineered Cardiomyocyte Model of Type 2 Long-QT Syndrome"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-2515","authenticated-orcid":true,"given":"Trung","family":"Huynh","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (T.H., D.Y., W.Z., D.J.T., R.G., J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0619-7070","authenticated-orcid":true,"given":"Dan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (T.H., D.Y., W.Z., D.J.T., R.G., J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7182-8147","authenticated-orcid":true,"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (T.H., D.Y., W.Z., D.J.T., R.G., J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4554-2244","authenticated-orcid":true,"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (T.H., D.Y., W.Z., D.J.T., R.G., J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5756-7417","authenticated-orcid":true,"given":"Ramin","family":"Garmany","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (T.H., D.Y., W.Z., D.J.T., R.G., J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5871-0265","authenticated-orcid":true,"given":"John R.","family":"Giudicessi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (T.H., D.Y., W.Z., D.J.T., R.G., J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic (J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-3333","authenticated-orcid":true,"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (T.H., D.Y., W.Z., D.J.T., R.G., J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic (J.R.G., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (M.J.A.), Mayo Clinic, Rochester, 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