**10. Conclusions**

four possibilities we are now investigating.

Atrial (*and ventricular*) arrhythmias are disturbances in electrical activity that disrupt the regular, rhythmic contraction of the upper (*or lower*) heart chambers. These electrical insta‐ bilities arise from normal or dysfunctional heart muscle, from the heart specialized conduc‐ tion system or from the 'muscular sleeves' of major supraventricular vessels. Because arrhythmia is recorded as abnormal electrical activity and since experimental faradic stimu‐ lation can initiate arrhythmia, it is viewed as having a purely electrical origin. Indeed the dominant explanations for arrhythmia hypothesize it originates from (a) changes in the elec‐ trical properties of heart muscle that alter electrical impulse conduction, (b) changes in the properties of the voltage-dependent ion channels responsible for normal electrical activity which alter impulse conduction, (c) changes in the myocytic milieu that permit normal volt‐ age-dependent ion channels to spontaneously generate electrical impulses or (d) changes in myocyte calcium homeostasis that alter heart resting membrane potential or otherwise indi‐ rectly enhance muscle excitability.

During the past fifty years, however, it has become clear that all cells contain a staggering array of interrelated signaling pathways and processes which regulate normal and 'abnor‐ mal' cell functions. Like all other cells, heart cells, too, express voltage-independent calcium signaling pathways which underlie cardiac processes like inotropy and diseases like hyper‐ trophy or atherosclerosis. The three earlier hypotheses for arrhythmia noted above ignore the importance of voltage-independent cell signaling in heart ectopy. That is, they assume that voltage-independent cell signaling does not influence cardiac voltage-dependent ion channels or affect arrhythmia. One corollary of this dominant electrocentric view of arrhyth‐ mia is that the fundamental biophysical properties of voltage-dependent ion channels meas‐ ured in normal muscle are the only properties these proteins can evince, that these ion channels are essentially immutable activities. However, clinical and experimental data sug‐ gest that one or more signaling events greatly influence the electrical properties of heart muscle and somehow increase its ability to generate ectopic electrical impulses.

Our data demonstrate that a recognized activator of the voltage-independent Orai calcium channels provokes persistent or paroxysmal tachycardia at rates of up to 12Hz in non-auto‐ matic rat left atrial or left ventricular papillary muscles. This activator also induces a reversi‐ ble type of fibrillation in intact perfused rat hearts. These data lead to the hypothesis outlined here that calcium entry through voltage-independent ion channels, specifically through the Orai channels, and/or calcium signaling events downstream of these channels elicit ectopic electrical activity in atrial (*and ventricular*) muscle. This hypothesis implies that a wide range of extracellular and intracellular signals may disrupt heart muscle electrical stability through their actions on voltage-independent calcium homeostasis that enhance voltage-independent calcium channel activity. This hypothesis provides a framework for fu‐ ture experimental tests of whether voltage-independent calcium signaling related to auto‐ nomic activity, to stress or to calcium store filling state are key molecular sources for arrhythmia. Importantly, our data to be published elsewhere indicate that dysregulated voltage-independent calcium signaling alter the fundamental characteristics of voltage-de‐ pendent ion channels, transforming them from non-automatic activities that require an ex‐ ternal depolarizing influence to automatic activities that spontaneously depolarize heart muscle. If rigorously validated, this fourth putative arrhythmogenic mechanism would sat‐ isfy the 'focal source' hypothesis for arrhythmia.
