Mechanisms Underlying the Formation and Dynamics of Subcellular Calcium Alternans in the Intact Rat Heart

Abstract

Optical mapping of intact cardiac tissue reveals that, in some cases, intracellular calcium (Ca) release can alternate from one beat to the next in a large-small-large sequence, also referred to as Ca transient (CaT) alternans. CaT alternans can also become spatially phase-mismatched within a single cell, when one part of the cell alternates in a large-small-large sequence, whereas a different part alternates in a small-large-small sequence, a phenomenon known as subcellular discordant alternans. The mechanisms for the formation and spatiotemporal evolution of these phase-mismatched patterns are not known. We used confocal Ca imaging to measure CaT alternans at the sarcomeric level within individual myocytes in the intact rat heart. After a sudden change in cycle length (CL), 2 distinct spatial patterns of CaT alternans emerge. CaTs can form spatially phase-mismatched alternans patterns after the first few beats following the change in CL. The phase mismatch persists for many beats, after which it gradually becomes phase matched via the movement of nodes, which are junctures between phase-mismatched cell regions. In other examples, phase-matched alternans gradually become phase-mismatched, via the formation and movement of nodes. In these examples, we observed large beat-to-beat variations in the cell activation times, despite constant CL pacing. Using computer simulations, we explored the underlying mechanisms for these dynamical phenomena. Our results show how heterogeneity at the sarcomeric level, in conjunction with the dynamics of Ca cycling and membrane voltage, can lead to complex spatiotemporal phenomena within myocytes of the intact heart.