Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation

OBJECTIVES The purpose of this study was to determine whether atrial expres sion of the extracellular signal-regulated kinases Erk1/Erk2 and of the ang iotensin-converting enzyme (ACE) is altered in patients with atrial fibrill ation (AF). BACKGROUND Recent studies have demonstrated that atrial fibrosis can provid e a pathophysiologic substrate for AF. However, the molecular mechanisms re sponsible for the development of atrial fibrosis are unclear. METHODS Atrial tissue samples of 43 patients undergoing open heart surgery were examined. Seventeen patients had chronic persistent AF (greater than o r equal to 6 months; CAF), 8 patients had paroxysmal AF (PAF) and 18 patien ts had no history of AF. Erk expression was analyzed at the mRNA (quantitat ive reverse transcription polymerase chain reaction), the protein (immunobl ot techniques) and atrial tissue (immunohistochemistry) levels. Erk-activat ing kinases (MEK1/2) and ACE were analyzed by immunoblot techniques. RESULTS Increased amounts of Erk2-mRNA were found in patients with CAF (75 +/- 20 U vs. sinus rhythm: 31 +/- 25 U; p < 0.05). Activated Erk1/Erk2 and MEK1/2 were increased to more than 150% in patients with AF compared to pat ients with sinus rhythm. No differences between CAF and PAF were found. The expression of ACE was three-fold increased during CAF. Amounts of activate d Erk1/Erk2 were reduced in patients treated with ACE inhibitors. Patients with AF showed an increased expression of Erk1/Erk2 in interstitial cells a nd marked atrial fibrosis. CONCLUSIONS An ACE-dependent increase in the amo unts of activated Erk1/Erk2 in atrial interstitial cells may contribute as a molecular mechanism for the development of atrial fibrosis in patients wi th AF. These findings may have important impact on the treatment of AF. (C) 2000 by the American College of Cardiology.