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Mitochondrial dysfunction and redox signaling in atrial tachyarrhythmia

Researchers at the University Hospital of Magdeburg (Germany) have discovered that atrial tachycardia is associated with mitochondrial dysfunction and oxidative stress followed by the activation of the NF-kB signalling pathway with induction of NF-kB target gene expression in atrial tissue. Their study will appear in the May 08 issue of Experimental Biology and Medicine. Multiple tachycardia-associated factors appear to contribute to this response, which all are directly or indirectly linked to oxidative stress. Accordingly, blockade of the angiotensin II type 1 receptor, inhibition of L-type calcium channels, inhibition of NADPH oxidase, applications of antioxidants, and inhibition of NF-B activation were all found to abolish or decrease the tachycardia-dependent changes in the atrial tissue.

The interdisciplinary research team, led by Uwe Lendeckel, a professor of Experimental Internal Medicine and Andreas Goette, Deputy Chief of Cardiology, designed the study to determine the influence of tachyarrhythmia on endocardial dysfunction (called endocardial remodelling) and to decipher the molecular mechanism(s) that translate pathologically increased heart rates into myocardial/endocardial dysfunction. Endocardial dysfunction appears as a well recognised risk factor for thromboembolic events in patients with atrial fibrillation (AF). Therefore, the underlying pathophysiology of endocardial remodelling is of clinical importance.

The facts that equal results were observed in ex vivo atrial tissue from patients with AF and in ex vivo rapidly paced tissue samples from patients with sinus rhythm (SR), together with the observation that verapamil most potently prevented oxidative stress and associated signalling pathway activation, led us to conclude that the elevated frequency per se and concomitant Ca2+-overload precede and induce mitochondrial dysfunction and oxidative stress in AF said Lendeckel. Goette added Our results have several clinical implications. Atrial ischemia produces an increase in cellular calcium load and oxidative stress in the atria. Thereby, atrial ischemia provides a specific substrate for AF. Recent experimental and clinical data showed that calcium channel blockers have a specific efficacy to prevent AF in this specific situation. Thus, our data provide more information about the potential pathophysiologic mechanism explaining why calcium channel blockers are effective and useful to attenuate atrial cellular remodelling especially under conditions of increased cellular calcium load and oxidative stress. The authors say the use of ex vivo human atrial tissue from patients with and without AF as well as the rapid pacing of atrial tissue slices to mimic AF ex vivo is a valuable approach to identify molecular and cellular effects that are solely due to the AF excluding the effects of concomitant cardiac diseases.

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine said Professor Lendeckel, Professor Goette and colleagues have demonstrated that inward calcium current via L-type calcium channels contributes to oxidative stress and increased expression of oxidative stress markers and adhesion molecules during cardiac tachyarrhythmia.. He further stated These observations are important to the understanding of the molecular mechanisms by which calcium overload and resulting mitochondrial dysfunction and resulting oxidative stress impact atrial remodelling during atrial fibrillation.


Contact: Dr. Uwe Lendeckel
Society for Experimental Biology and Medicine

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