Abstract 16014: The Role of IKr in Transmural Repolarization Abnormalities in Human Heart Failure
Heart failure (HF) claims around 250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. Action potential (AP) prolongation is a hallmark change of the failing myocardium and may promote arrhythmias. Potassium channel dysregulation may contribute to AP duration (APD) changes. To investigate the role of the potassium current, IKr, in repolarization abnormalities during HF, we optically mapped coronary-perfused left ventricular (LV) free wall from non-failing (n=5) and failing (n=5) human hearts. The LV wedge preparation was used to examine transmural APD80s, and optical mapping was performed before and after addition of the IKr-blocking drug, E-4031 (1 µM). Results are reported in the order of endo-, mid-, and epicardium unless stated otherwise. For non-failing hearts, average APD80 values recorded at a 1000 ms cycle length are (in ms) 432.6±46.5, 403.6±64.0, and 394.0±75.2 without E-4031 and 751.3±218.7, 697.4±218.6, and 656.3±152.4 with E-4031. For failing hearts, average APD80 values are (in ms) 468.6±37.0, 449.8±43.1, and 449.0±44.3 without E-4031 and 549.8±156.7, 545.6±130.7, and 556.6±149.0 with E-4031. The delta APD80s (calculated as [(APD80E-4031/APD80Control)-1]*100) are greater for non-failing hearts (73.5±46.7, 73.0±48.8, and 67.6±27.2) than for failing hearts (16.9±30.0, 20.5±20.6, and 23.1±22.3) with endo- and midmyocardial values approaching (p=0.052 and p=0.057, respectively) and epicardial values achieving statistical significance (p=0.035). We then assessed Kv11.1 protein expression levels in non-failing and failing human hearts using Western blot. We found a trend toward decreased Kv11.1 hERG1a isoform expression in failing (0.59±0.37 for epi- and 0.64±0.18 for endocardium) compared to non-failing hearts (1.09±0.43 for epi- and 0.88±0.47 for endocardium, p=0.07 and p=0.30), but we saw a trend toward increased Kv11.1 hERG1b expression in failing (1.39±0.88 for epi- and 1.48±0.88 for endocardium) compared to non-failing (0.99±0.33 for epi- and 0.95±0.36 for endocardium, p=0.32 and p=0.21) hearts. These results suggest that reduced functional expression of IKr may be involved in arrhythmogenic remodeling of transmural APDs during human HF.
- © 2011 by American Heart Association, Inc.