Fig. 10

Proposed pathogenetic processes. Model of how augmented HCN4 expression in the myocardium may contribute to pathological remodeling. HCN4 upregulation mediates diastolic Na⁺ influx into the cell, leading to a rise of [Na⁺]_i. Ca²⁺ homeostasis is tightly linked to Na⁺ regulation via the NCX activity. Under physiological conditions NCX primarily operates in (forward) Na⁺ -in/ Ca²⁺ -out mode, reducing diastolic [Ca²⁺]_i. High [Na⁺]_i gives rise to a shift of the NCX equilibrium towards ‘reverse mode’ thereby leading to increased [Ca²⁺]_i. Changed cytoplasmic Ca²⁺ cycling, in turn, interferes with SR calcium uptake resulting in increased SR Ca²⁺ stores, driven by augmented phosphorylation of PLN. Sarcoplasmic Ca²⁺ overload causes afterdepolarizations (ADs) and cardiac arrhythmogenesis, and high diastolic [Ca2⁺]_i activates µ-calpain Ca²⁺-sensor- and caspase-3-related apoptosis leading to adverse remodeling. Brown arrows indicate regulation of protein expression; green arrows denote changes of ion concentration