Résumé
Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and self-care. Herein, we show that the ryanodine receptor type 2 (RyR2)/intracellular Ca2þ release channels in patients and mice with HF were remodeled and leaky in hippocampal neurons. RyR2 remodeling was caused by hyperadrenergic stress and activation of the transforming growth factor (TGF-b) pathway. Mice protected against RyR2 Ca 2þ leak (RyR2-S2808A) were prevented from CD associated with HF. The downstream effectors of leaky neuronal RyR2 included dysregulation of the SNARE pathway, which orchestrates neurotransmission, and activation of Ca2þ-dependent enzymes in the Tau pathway associated with Alzheimer’s disease. Fixing RyR2 Ca 2þ leak in neurons improved cognitive function in HF mice. Taken together, we propose that HF is a systemic illness characterized by cardiogenic dementia and cardiac and skeletal muscle dysfunction. Intracellular Ca 2þ leak is a common effector for all three components of HF.