Fig. 1.

Mechanisms of alternans and effects of β-adrenergic receptor (β-AR) stimulation. A: schematic representation of Ca²⁺ handling in ventricular cardiomyocytes, where Ca²⁺ influx via L-type Ca²⁺ current (I_CaL) triggers Ca²⁺ release from the sarcoplasmic reticulum (SR) via type 2 ryanodine receptors (RyR2). The Ca²⁺ then diffuses within the cell and is transported back to the SR via SERCA2a. Within the SR, two compartments are modeled: the junctional SR (JSR; the compartment containing RyR2s) and the network SR (NSR; containing SERCA2a). The predominant mechanisms of Ca²⁺ transient (CaT) alternans are based on RyR2 refractoriness (where the alternation of Ca²⁺ is driven by incomplete recovery from a sufficiently large release, inducing a small release only) or release-reuptake mismatch (where the alternans is due to reuptake insufficiency after a sufficiently large release). B: comparison of normalized CaT from the study of Gardner et al. (16) (left column) and our computational model (right column) under similar conditions. The experimental data come from mice, whereas the simulated traces are from a canine model, explaining the difference in duration and shape of CaTs. The heterozygous (HET)-sham trace is from myocardial infarction (MI)-free control mice; the knockout (KO)-sham trace is from MI-free mice with protein tyrosine phosphatase receptor-σ (PTPσ; an antireinnervation factor) knocked out, resulting in increased sympathetic innervation. The HET-MI trace is a trace from the denervated border zone (BZ), and the KO-MI trace is a trace from the hyperinnervated BZ. Hyperinnervation or simulated β-AR-stimulation with isoproterenol (ISO) abolished CaT alternans in the BZ.