Abstract P128: Inhomogeneous Upregulation of Sodium Channel Nav1.5 and Its Role in Discordant T Wave and Mechanical Alternans in Left Ventricular Hypertrophy
Objectives: Left ventricular hypertrophy (LVH) is associated with T wave alternans (TWA) that often heralds the development of malignant ventricular arrhythmias. Previous studies have shown that LVH results in an increase in late sodium current (INa-L). The purpose of this study was to examine ventricular transmural expression of the sodium channel Nav1.5 and its role in TWA and mechanical alternans in LVH.
Methods & Results: The renovascular hypertension model was used to induce LVH in rabbits. Expression of Nav1.5 in both left ventricular epicardium (Epi) and endocardium (Endo) was determined by reverse transcription-polymerase chain reaction. Transmembrane action potentials were simultaneously recorded from Epi and Endo together with a transmural ECG and isometric contraction force (ICF) in the arterially perfused left ventricular wedges. Interestingly, LVH resulted in inhomogeneous upregulation of Nav1.5 across the left ventricular wall: Nav1.5 mRNA increased in Endo by 63±13% from controls (n=6, p<0.01) but by only 13±11% (n=6, p=0.26) in Epi. In the left ventricular wedge preparations, discordant TWA and mechanical alternans, i.e. that a beat with longer QT and a larger T wave was associated with weaker ICF, occurred spontaneously in 8 of 31 LVH rabbits vs. 0 of 25 in controls at BCLs of 2000 to 4000 ms (p<0.01). A more marked beat to beat change in action potential duration (APD) in Endo than Epi resulted in an alternated change in transmural dispersion of repolarization that manifested as TWA on the ECG. ATX-II (a sodium channel enhancer) at 1 nM induced discordant TWA and mechanical alternans in LVH rabbits that did not exhibit spontaneous TWA (5 of 7 vs 0 of 5 in controls, p<0.01). Ranolazine at 10 to 30 μM abolished all TWA and mechanical alternans induced by ATX-II. During TWA and mechanical alternans, early after depolarizations could occur in Endo in the beat with longer APD and weaker ICF, leading to R-on-T extrasystoles capable of initiating torsade de pointes.
Conclusions: LVH results in a more marked increase in Nav1.5 mRNA level in endocardium than epicardium. This may contribute to a larger beat to beat change in endocardial APD, leading to discordant TWA and mechanical alternans that precipitate triggered arrhythmias.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).