Output details

Mechanistic links between Na+ channel (SCN5A) mutations and impaired cardiac pacemaking in sick sinus syndrome

We created a state-of-the-art electrophysiologically and anatomically detailed model of the cardiac pacemaker, the sinus node. We used the model to dissect mechanisms of the sick sinus syndrome (SSS) - a potentially lethal cardiac condition where the pacemaking function is impaired. The mechanisms were linked with the underlying genetic mutations and vagal nerve activity. Vagal tone amplified the blocking effect of mutations on excitation waves generated by the pacemaker. Model predictions were confirmed in experiments. The study explains higher mortality in SSS patients at night, when vagal tone is greater - and hence, identified potential targets for therapeutic clinical interventions.