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.