Mechanisms of SR calcium release in healthy and failing human hearts

Normal heart contraction and rhythm relies on the proper flow of calcium ions (Ca²⁺) into cardiac cells and between their intracellular organelles, and any disruption can lead to arrhythmia and sudden cardiac death. Electrical excitation of the surface membrane activates voltage-dependent L-type Ca²⁺ channels to open and allow Ca²⁺ to enter the cytoplasm. The subsequent increase in cytoplasmic Ca²⁺ concentration activates calcium release channels (RyR2) located at specialised Ca²⁺ release sites in the sarcoplasmic reticulum (SR), which serves as an intracellular Ca²⁺ store. Animal models have provided valuable insights into how intracellular Ca²⁺ transport mechanisms are altered in human heart failure. The aim of this review is to examine how Ca²⁺ release sites are remodelled in heart failure and how this affects intracellular Ca²⁺ transport with an emphasis on Ca²⁺ release mechanisms in the SR. Current knowledge on how heart failure alters the regulation of RyR2 by Ca²⁺ and Mg²⁺ and how these mechanisms control the activity of RyR2 in the confines of the Ca²⁺ release sites is reviewed.