Alternating Early Afterdepolarizations Underlying Bradycardia-Dependent Macroscopic T Wave and Discordant Mechanical Alternans. (3rd January 2023)

• Record Type: Journal Article
• Authors: Qi, Datun; Li, Wei; Quan, Xiao-Qing; Gao, Yuan; Wang, Jianyong; Guo, Lily; Zhao, Wenping; Liu, Tong; Gao, Chuanyu; Yan, Gan-Xin
• Is Part Of: Circulation. Volume 16:Number 1(2023)
• Page Start: e011453
• Publication Date: 2023-01-03
• Subjects: early afterdepolarization -- late sodium current -- left ventricular hypertrophy -- Torsades de Pointes -- T wave alternans; Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.128
• DOI: 10.1161/CIRCEP.122.011453
• Languages: English
• ISSNs: 1941-3149

Abstract

Abstract : Background: 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). Methods: 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 (INa-L ) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique. Results: Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits ( P <0.05, versus 0/15 in controls) and were induced by an INa-L 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. INa-L 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 INa-L blocker ranolazine or mexiletine. Conclusions: LVH enhances INa-L density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. INa-L blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.