Caratterizzazione fenotipica e funzionale di un topo Knock-out condizionale e inducibile per il canale pacemaker HCN4

We report here that in an inducible and cardiac specific HCN4 adult knockout mouse model, ablation of HCN4 consistently leads to progressive development of severe bradycardia (~50% reduction of original rate) and AV block, eventually leading to heart arrest and death in ~5 days. In vitro analysis of SAN myocytes isolated from KO mice at the mean time of death revealed a strong reduction of both the If current (by ~70%) and of the spontaneous rate (by ~60%). In agreement with functional results, immunofluorescence and western blot analysis showed reduced expression of HCN4 protein in SAN tissue and cells. Our data show that cardiac HCN4 channels are essential for normal heart rhythm and survival of adult mice, and support the notion that dysfunctional HCN4 channels can be a direct cause of rhythm disorders.