Novel Ca²⁺ wave mechanisms in cardiac myocytes revealed by multiscale Ca²⁺ release model

Integrating cellular sarcoplasmic reticulum (SR) Ca²⁺ release with the known Ca²⁺ activation properties of RyR2s remains challenging. The sharp increase in SR Ca²⁺ permeability above a threshold SR luminal [Ca²⁺] is not reflected in RyR2 kinetics from single-channel studies. Additionally, the current paradigm that global Ca²⁺ release (Ca²⁺ waves) arises from interacting local events (Ca²⁺ sparks) faces a key issue that these events rarely activate neighboring sites. We present a multiscale model that reproduces Ca²⁺ sparks and waves in skinned ventricular myocytes using experimentally validated RyR2 kinetics. The model spans spatial domains from 10⁻⁸ to 10⁻⁴ m and timescales from 10⁻⁶ to 10 s. Ca²⁺ release sites are distributed in cubic voxels (0.25-µm sides) informed by super-resolution micrographs. We use parallel computing to calculate Ca²⁺ transport, diffusion, and buffering. Substantial increases in SR Ca²⁺ release occur, and Ca²⁺ waves initiate when Ca²⁺ sparks become prolonged above a threshold SR [Ca²⁺]. These prolonged events (Ca²⁺ embers) are much more likely than Ca²⁺ sparks to activate release from neighboring sites and accumulate increases in cytoplasmic [Ca²⁺] along with an associated fall in Ca²⁺ buffering power. This primes the cytoplasm for Ca²⁺-induced Ca²⁺ release (CICR) that produces Ca²⁺ waves. Thus, Ca²⁺ ember formation and CICR are both essential for initiation and propagation of Ca²⁺ waves. Cell architecture, along with the differential effects of RyR2 opening and closing rates, collectively determines the SR [Ca²⁺] threshold for Ca²⁺ embers, waves, and the phenomenon of store overload–induced Ca²⁺ release.