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(Circulation. 2006;114:e565.)
© 2006 American Heart Association, Inc.

Correspondence

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"

Torsten Christ, MD; Erich Wettwer, PhD; Ursula Ravens, MD

Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany

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 I_Ks 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 I_Ks to repolarization is expected to be less dominant than in the guinea pig because the I_Ks 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 (I_to, I_Kur) that are absent in guinea pigs, I_Ks becomes less significant for determining APD. Activation of I_to and I_Kur during phase 1 repolarization pushes the plateau to a potential level below 0 mV.⁴ Because of the small and slow activation of I_Ks in this potential range, a significant contribution of I_Ks 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 I_Ks, 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 I_Ks 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.

	Acknowledgments

 
Disclosures

None.

	References

Top References

 

1. 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.[Abstract/Free Full Text]
   
2. Bertaso F, Sharpe CC, Hendry BM, James AF. Expression of voltage-gated K⁺ channels in human atrium. Basic Res Cardiol. 2002; 97: 424–433.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Wang Z, Fermini B, Nattel S. Delayed rectifier outward current and repolarization in human atrial myocytes. Circ Res. 1993; 73: 276–285.[Abstract/Free Full Text]
   
4. Wettwer E, Hála O, Christ T, Heubach JF, Dobrev D, Varro A, Ravens U. Role of I_kur in controlling action potential shape and contractility in the human atrium: influence of chronic fibrillation. Circulation. 2004; 110: 2299–2306.[Abstract/Free Full Text]
   
5. Kumagai K, Nakshima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003; 41: 2197–2204.[Abstract/Free Full Text]
   

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Circulation 2006 114: 1897. [Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Christ, T. Articles by Ravens, U. Search for Related Content PubMed PubMed Citation Articles by Christ, T. Articles by Ravens, U. Related Collections Arrythmias-basic studies Ion channels/membrane transport Related Article