Spark-induced sparks as a mechanism of intracellular calcium alternans in cardiac myocytes.
BACKGROUND
Intracellular calcium (Ca) alternans has been widely studied in cardiac myocytes and tissue, yet the underlying mechanism remains controversial.


OBJECTIVE
In this study, we used computational modeling and simulation to study how randomly occurring Ca sparks interact collectively to result in whole-cell Ca alternans.


RESULTS
We developed a spatially distributed intracellular Ca cycling model in which Ca release units (CRUs) are locally coupled by Ca diffusion throughout the myoplasm and sarcoplasmic reticulum (SR) network. Ca sparks occur randomly in the CRU network when periodically paced with a clamped voltage waveform, but Ca alternans develops as the pacing speeds up. Combining computational simulation with theoretical analysis, we show that Ca alternans emerges as a collective behavior of Ca sparks, determined by 3 critical properties of the CRU network from which Ca sparks arise: "randomness" (of Ca spark activation), "refractoriness" (of a CRU after a Ca spark), and "recruitment" (Ca sparks inducing Ca sparks in adjacent CRUs). We also show that the steep nonlinear relationship between fractional SR Ca release and SR Ca load arises naturally as a collective behavior of Ca sparks, and Ca alternans can occur even when SR Ca is held constant.


CONCLUSIONS
We present a general theory for the mechanisms of intracellular Ca alternans, which mechanistically links Ca sparks to whole-cell Ca alternans, and is applicable to Ca alternans in both physiological and pathophysiological conditions.
Rovetti
Robert
R
Department of Mathematics, Loyola Marymount University, Los Angeles, Calif., USA.
Cui
Xiaohua
X
Garfinkel
Alan
A
Weiss
James N
JN
Qu
Zhilin
Z
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D003198:Computer Simulation; D004058:Diffusion; D007700:Kinetics; D008390:Markov Chains; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D017711:Nonlinear Dynamics; D011336:Probability; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000502:physiology
D019831:Sodium-Calcium Exchanger; D002118:Calcium