LETTER TO THE EDITOR
Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease
Andreas Goette, MD
University Hospital Magdeburg, Department of Internal Medicine, Division of Cardiology, Leipzigerstr. 44, 39120 Magdeburg, Germany
Uwe Lendeckel, PhD
andreas.goette{at}medizin.uni-magdeburg.de
Atrial fibrillation (AF) causes various changes in atrial electrophysiology and morphology (1). Recently, an increased activity of the atrial angiotensin II (AngII) system was found in patients with AF and concomitant structural heart disease (SHD) (1–3). This corresponds to an increased amount of atrial fibrous tissue. The initial trigger for activation of the AngII system typically is the underlying ventricular disease and not AF per se (1).
Boldt et al. (4) tried to analyze the expression of AngII receptors type 1 (AT1) and 2 (AT2) in patients with and without mitral valve disease (MVD). The investigators claim that AT1 is upregulated in fibrillating left atria, whereas AT2 remains unchanged. These findings are contrary to results from our group (3).
How can these differences be explained? When dealing with receptor expression in humans, defining "controls" is an important issue. This is especially true when determining the real impact of the arrhythmia on angiotensin II receptor (AT) regulation, because concomitant heart diseases dramatically influence AngII levels. Boldt et al. (4) performed a pooled analysis using 74 left atrial tissue samples from patients with AF; 15 patients served as "matched" controls. Their analysis revealed, however, no differences at all in receptor expression between comparable patient groups with MVD ± chronic AF (cAF). Furthermore, patients with MVD and cAF are not different compared to patients with SHD in sinus rhythm (Fig. 5 in Boldt et al. [4]). The only difference, using an unpooled analysis, was between patients in SR (plus SHD) and patients with lone AF (Fig. 5 in Boldt et al. [4]). What does this mean for the pathophysiology of AF? As multiple studies clearly showed, the pathophysiology of lone AF is not equal to AF in the presence of MVD; neither is paroxysmal AF comparable to cAF (1).
A stunning finding of Boldt et al. (4) is the lack of substantial expression of AT1 in patients with SR (Fig. 2 of Boldt et al. [4]), known to be abundantly expressed by all cardiac cell types. Moreover, AT2 expression appears from that figure to be about 10x compared to AT1. Remarkably, both receptor subtypes have the same protein size (52 kDa). The investigators claim to support their findings by immunohistologic analysis, which locates sites of expression rather than allowing quantification.
A direct comparison between left and right atrial tissue was not performed in a single patient. In sum, it remains unclear whether the described differences in AT expression are solely due to the presence or absence of AF or to the impact of present coronary artery/valve diseases.
What can we learn about receptor expression in AF? Expression patterns are clearly time-dependent and, as observed for other signaling pathways, differences exist between right and left atria. In patients with long-lasting AF (average 47 months in our study) a reversal of AT1/AT2 expression may occur similar to ventricular receptor levels during heart failure, which is also characterized by extensive ventricular fibrosis (5). Sustained increase of peptide hormone levels often down-regulates their receptor (5). Down-regulation of AT1 may indeed follow an initial phase of up-regulation. Thus, our previous results do "fit into the pathophysiology." However, the time course of receptor expression has not yet been analyzed.
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References
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- Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415:219–226[CrossRef][Medline]
- Goette A, Staack T, Arndt M, et al. Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol. 2000;35:1669–1677[Abstract/Free Full Text]
- Goette A, Arndt M, Röcken C, et al. Regulation of angiotensin II receptor subtypes during atrial fibrillation in humans. Circulation. 2000;101:2678–2681[Abstract/Free Full Text]
- Boldt A, Wetzel U, Weigl J, et al. Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease. J Am Coll Cardiol. 2003;42:1785–1792[Abstract/Free Full Text]
- Asano K, Dutcher DL, Port JD, et al. Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium. Circulation. 1997;95:1193–1200[Abstract/Free Full Text]
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