Abstract 8799: Elevation of Polyamine Levels Contributes to the Down-regulation of Inward Rectifier Potassium Current and Arrhythmogenesis in Human Failing Heart
Down-regulation of cardiac inward rectifier K+ current (IK1) has been observed in the failing hearts of both experimental animals and humans. Reduction of IK1 may contribute to the action potential duration (APD)/QT prolongation and cardiac electric instability, which is believed to predispose the failing heart to life-threatening ventricular arrhythmias. Our previous studies demonstrated that IK1 was inhibited and modulated by endogenous polyamines. We tested the hypothesis that heart failure (HF) may be associated with an elevated polyamine level in failing myocytes, leading to a down-regulation of IK1 and increased abnormal electrical activities in failing myocytes. The IK1 and action potential (AP) were examined in isolated single myocytes of both failing and non-failing human hearts that received from heart transplantation and cadaveric heart donation. Intracellular polyamine concentrations of human ventricular tissue were measured using a high-performance liquid chromatography (HPLC) method. Interestingly, HF caused not only prominent action potential (APD) prolongation, but also shifting of the resting potential to a more positive potential in single myocytes. Early afterdepolarizations (EADs) were recorded in 12 of 16 myocytes isolated from 4 failing human hearts at a pacing cycle length of 4000 ms, whereas EADs were elicited in none of 16 cells isolated from 4 non-failing human hearts (p <0.01). The density of the IK1 was significantly decreased in myocytes of failing hearts compared with that in non-failing hearts at the voltage of −60 mV (2.4 ± 0.33 pA/pF in HF versus 3.97 ± 0.41 pA/pF in control, n=8 from 4 hearts, p <0.05). Moreover, intracellular polyamine (spermine) concentration was significantly increased in failing myocyte (6.7 ± 0.3 µg/mg DNA in HF versus 5.4 ± 0.1 µg/mg DNA in control, n=3 hearts, p <0.05). Furthermore, lowering polyamines levels significantly reduced the EADs incident in failing myocytes. In conclusion, our results demonstrated that HF is associated with a significant increase in the intracellular polyamine levels that may result in down-regulation of IK1, leading to genesis of EADs that play an important role in arrhythmogenesis of the failing hearts.
- © 2010 by American Heart Association, Inc.