Alternating Early Afterdepolarizations Underlying Bradycardia-Dependent Macroscopic T Wave and Discordant Mechanical Alternans

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 (I Na-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 I Na-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. I Na-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 I Na-L blocker ranolazine or mexiletine. Conclusions: LVH enhances I Na-L density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. I Na-L blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.