Computational modelling of the intrinsic clock that rules the diurnal variation of cardiac ion channels

Disorders of the heart’s electrical system, including ventricular tachycardia, ventricular fibrillation, and atrial fibrillation are significant causes of death and disability. There is mounting evidence that fluctuations in cardiac electrophysiology during the day and night are in part dependent on the circadian clock, the heart's intrinsic diurnal rhythm, rather than merely behavioural and environmental adaptations. There are two kind of clocks that coexist and work together to regulate the heart. The master circadian clock placed in the suprachiasmatic nucleus, and the peripherical clock located directly in the heart. The heart’s intrinsic clock is formed by transcription-translation feedback loops that drive rhythmic changes in clock gene and protein expression with a periodicity of approximately 24 h. In the literature there aren’t models to describe the intrinsic clock and its influence on the rhythmic changes. In this thesis we simulated the behaviour of the clock genes and how they influence the regulation of specific ion channels, providing the first model of the intrinsic heart clock within a cellular electrophysiological model. Using this model, we showed how diurnal regulation of Kv11.1 channels underlying the rapid delayed rectifier potassium current regulated the APD over time, and we considered these variations as an indicator of potential arrhythmogenic risk. Ultimately, this study will help to better understand the dynamic regulation of cardiac electrophysiology instead of just evaluating acute or steady-state effects, potentially providing a better explanation of dynamic changes in arrhythmogenic risk, which might facilitate the identification of new therapeutic strategies.