Letter by Christ et al Regarding Article, “Angiotensin II Potentiates the Slow Component of Delayed Rectifier K+ Current via the AT1 Receptor in Guinea Pig Atrial Myocytes”
To the Editor:
Inhibitors of the renin-angiotensin system are generally accepted as first-line treatment of hypertension and heart failure. The underlying pathophysiological mechanism is reversal of vascular and myocardial remodeling. Zankov and colleagues1 hypothesize that the renin-angiotensin system could also play a role in the genesis of arrhythmias by acutely affecting the repolarization process. They show that in guinea pig atria, nanomolar concentrations of angiotensin II (Ang II) strongly increase the slowly activating delayed rectifier current IKs and therefore shorten action potential duration (APD). These findings are extrapolated to humans, and APD shortening by Ang II is suggested to facilitate and perpetuate atrial fibrillation (AF).
We disagree with this conclusion for several reasons. In human atria, the contribution of IKs to repolarization is expected to be less dominant than in the guinea pig because the IKs can only be detected in variable fractions of myocytes, ranging from 1 of 53 cells to 70%.2,3
Because human atrial myocytes exhibit additional repolarizing outward currents (Ito, IKur) that are absent in guinea pigs, IKs becomes less significant for determining APD. Activation of Ito and IKur during phase 1 repolarization pushes the plateau to a potential level below 0 mV.4 Because of the small and slow activation of IKs in this potential range, a significant contribution of IKs during the short lasting human atrial action potential is even less likely.
Electrical remodeling is defined as shortening in APD and loss of rate adaptation. If Ang II is directly involved in electrical remodeling by activating IKs, effective treatment of AF with angiotensin type 1 (AT1) receptor blockers such as candesartan should reverse electrical remodeling. However, in a dog model of AF, candesartan effectively reduced the duration of the AF episodes but did not reverse shortening of the atrial effective refractory period.5 Instead, the amelioration of AF by candesartan was associated with normalized intra-atrial conduction. The latter effect is explained by the antifibrotic action of AT1 blockers.
In conclusion, the impressive findings published Zankov et al demonstrate that Ang II increases IKs in guinea pig atrial myocytes. Nevertheless, great caution is mandatory with extrapolation to human pathophysiology. Whether AT1 receptors directly control repolarization in human atria remains to be elucidated.
Zankov DP, Omatsu-Kanbe M, Isono T, Toyoda F, Ding WG, Matsuura H, Horie M. Angiotensin II potentiates the slow component of delayed rectifier K+ current via the AT1 receptor in guinea pig atrial myocytes. Circulation. 2006; 113: 1278–1286.
Wang Z, Fermini B, Nattel S. Delayed rectifier outward current and repolarization in human atrial myocytes. Circ Res. 1993; 73: 276–285.
Wettwer E, Hála O, Christ T, Heubach JF, Dobrev D, Varro A, Ravens U. Role of Ikur in controlling action potential shape and contractility in the human atrium: influence of chronic fibrillation. Circulation. 2004; 110: 2299–2306.