Figure 2. Defective Ca²⁺ handling in failing hearts due to sympathetic overactivity.

Chronic activity of the sympathetic nervous system leads to phosphorylation of the β-AR, activation of β-AR kinase, and desensitization of β-ARs. The LTCC is also phosphorylated, and NCX expression is upregulated. An important contributor to impaired Ca²⁺ handling in HF is PKA hyperphosphorylation of RyR2. This leads to a higher sensitivity to Ca²⁺-induced Ca²⁺ release at low cytoplasmic Ca²⁺ concentrations, resulting in increased RyR2 open probability at low Ca²⁺ concentrations and a diastolic SR Ca²⁺ leak. The long-term effect of the diastolic Ca²⁺ leak is depletion of SR Ca²⁺ stores. SERCA2a expression and activity are decreased in HF, which is linked to phospholamban hypophosphorylation. In contrast, NCX expression and activity are upregulated in HF. Arrows indicate increased or decreased expression or activity in HF.