Abstract 5335: Discordant T Wave and Mechanical Alternans in Left Ventricular Hypertrophy: Role of Late Sodium Current
T wave alternans (TWA) heralds the onset of malignant ventricular arrhythmias in left ventricular hypertrophy (LVH) and failure. We tested whether enhanced late sodium current (INa-L) in LVH causes abnormal intracellular calcium handling, leading to TWA and mechanical alternans. Transmembrane action potentials were simultaneously recorded from epicardium (Epi) and endocardium (Endo) together with a transmural ECG and isometric contraction force (ICF) in the arterially perfused LV wedges from 28 LVH rabbits . INa-L was recorded in single isolated myocytes. Myocytes from LVH hearts had significantly larger INa-L (0.97 ± 0.05 pA/pF) than from control hearts (0.69 ± 0.04 pA/pF, n= 5, p<0.01) that could be inhibited by ranolazine (10μM). TWA and mechanical alternans spontaneously occurred in 5 of 28 LVH rabbits at BCLs of 2000 to 4000 ms (p<0.01, vs. 0 of 25 in controls). ATX-II (an INa-L enhancer) at 1 nM induced TWA in 4 of 6 LVH rabbits that did not exhibit spontaneous TWA (p<0.01, vs. 0 of 5 in control). Ranolazine at 10 to 30 μM abolished all TWA and mechanical alternans induced by ATX-II in LVH rabbits. Features of TWA and mechanical alternans in LVH were:
beat to beat change in action potential duration (APD) that was more marked in Endo than Epi;
longer APD with larger T wave amplitude was associated with weaker ICF (discordant); and
early afterdepolarizations (EADs) capable of initiating R-on-T ectopic beats developed in the endocardium during a beat with longer APD and weaker ICF.
LVH is associated with a marked increase of INa-L
enhanced INa-L is associated with abnormal intracellular calcium handling that leads to mechanical and T wave alternans.
This research has received full or partial funding support from the American Heart Association, AHA National Center.