PQ segment and QRS complex within the heart of FTO deficient mice. The sympathetic nervous system is known to play an important role in arrhythmogenesis. Catecholamines can increase automaticity and induce triggered activity, thereby increasing arrhythmic risk. Importantly, in this study we provide evidence of increased vulnerability to stress-induced tachyarrhythmias in mice lacking the FTO gene. Of note, arrhythmogenesis was almost completely absent in wild-type mice. It is interesting that arrhythmia vulnerability in FTO deficient mice was induced by stress exposure, as arrhythmic events were only sporadically noted during baseline recordings, and clearly more pronounced in response to the restraint than the injection stress. Taken together these findings point to a close link between FTO deficiency and arrhythmia vulnerability, particularly in conditions of sustained stress exposure. Investigation of potential electrophysiological changes relevant to arrhythmogenesis in the heart of FTO deficient mice revealed that no changes occurred in ventricular excitability and refractoriness, suggesting that arrhythmia vulnerability may not be linked to cellular electrophysiological abnormalities. Noteworthy, these measures were obtained in anesthetized mice, and therefore we cannot exclude that sympathetic hyperactivity in FTO deficient mice may have affected cardiac excitability and/or refractoriness in the awake state. In addition, our data indicate that arrhythmogenesis was not correlated to accumulation of fibrotic tissue in the left ventricular myocardium. Our hypothesis is that exaggerated sympathetic stress response triggered abnormal automaticity in non-pacemaker tissue. We found in FTO deficient mice signs of cardiac hypertrophy, affecting both the right and the left ventricles. The specific morphological changes were not investigated here, but might reflect structural changes in the hypertrophied myocardium altering the ion channels operating during the early repolarization phase. This hypothesis was based on the observation that the duration of QTc interval was longer in FTO deficient mice. Therefore, we hypothesize a role of ventricular hypertrophy in altering ventricular repolarization to explain QTc lengthening in these mice. The QTc interval is also influenced by the autonomic nervous system: abnormal sympathetic modulation or vagal withdrawal directly induce altered ventricular repolarization, thus leading to prolongation of the QTc interval. Therefore, exaggerated cardiac sympathetic predominance in mice lacking the FTO gene could contribute directly to both ventricular hypertrophy and abnormal ventricular repolarization independent from blood pressure, conditions that might serve as a substrate for arrhythmias. Further studies are needed in order to elucidate the biophysical mechanisms and the cellular and subcellular bases of the reported arrhythmogenesis.