Ca Channel Distribution in T-Tubules and Ca Alternans in Cardiac Myocytes

Abstract

In cardiac myocytes, the elementary Ca cycling events are Ca sparks, spatially discrete Ca release events due to random and collective openings of ryanodine receptor (RyR) channels clustered in close proximity to L-type Ca channels (LCCs), forming what are known as Ca release units (CRUs). A typical cardiac myocyte includes about 10,000 to 20,000 CRUs. It is well known that heart failure (HF) remodeling induces changes in whole cell currents and Ca cycling proteins that promote Ca alternans, manifested clinically as pulsus alternans. In addition to electrical remodeling, HF also induces structural remodeling of t-tubules that alters the spatial distribution of CRUs in a myocyte, creating orphaned RyRs that are not associated with LCCs. An interesting question is whether such modifications in the spatial organization of LCCs have independent effects on Ca alternans, even if the whole cell LCC current remains unchanged. Here we address this question by studying the role of the spatial organization of LCCs in the genesis of Ca alternans in a 3D computer model of a ventricular myocyte containing a diffusively coupled network of 20,000 (100x20x10) CRUs. We show Ca alternans is strongly promoted by increasing nonuniformity in LCC distribution among CRUs (simulating T-tubule disruption/dysregulation), independent of changes in the whole cell Ca current. This observation may provide a mechanistic link between T-tubule disruption and Ca alternans observed in failing myocytes. More generally, our results indicate that subcellular details of ion channel distribution can have profound effects on global cellular function not captured by whole cell current measurements.