**1. Introduction**

Since its identification over one hundred years ago, atrial fibrillation has been shown to occur frequently in the general population and is now recognized as an important medi‐ cal problem in developed societies. Three major hypotheses to explain cardiac rhythm dis‐ orders like atrial fibrillation have been proposed during this time and one of these three, impulse reentry has become predominate. The two other explanations, designated as fo‐ cal source hypotheses, have been relegated to a secondary role in understanding arrhyth‐ mia. Despite widespread acceptance of the reentry hypothesis, however, current noninvasive anti-arrhythmic drugs based on this mechanism poorly prevent or reverse atrial fibrillation or other types of arrhythmia. One interpretation of this paradoxical clinical re‐ sult is that mechanisms other than reentry initiate arrhythmias like atrial fibrillation in re‐ al-life settings. As a consequence, current non-invasive therapeutics may neither target nor effectively suppress important but unrecognized non-reentrant mechanisms that pro‐ voke clinical arrhythmia. We have found that challenging isolated non-automatic left at‐ rial muscle, left ventricular papillary muscle, and perfused heart in sinus rhythm with an activator of the voltage-independent Orai calcium channels provokes high frequent tachy‐ cardia and fibrillation. Thus the Orais and related voltage-independent calcium channels may be unexpected sources of arrhythmia. This manuscript provides (a) a synopsis of the identification of atrial fibrillation as a clinical entity, (b) an overview of the development of the three current hypotheses for arrhythmia, and (c) our hypothesis that dysregulated voltage-independent calcium channels may be a fourth means to provoke electrical insta‐ bility in heart muscle.

© 2013 Wolkowicz et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
