Fig. 2.

Comparison of proarrhythmic changes in action potentials and Ca²⁺ homeostasis in HF, CPVT, and LQTS 2 and 3 ventricular myocytes. a Schematic of action potentials, Ca²⁺ transients, and changes in intra-SR Ca²⁺ in a healthy human ventricular myocyte under β-adrenergic stimulation. Grey dashed lines indicate minimum and maximum Ca²⁺ levels reached in healthy myocytes. b In HF, APD is prolonged due to decrease in K⁺ currents and increase in late I_Na. Ca²⁺-dependent EADs/DADs underlie arrhythmogenesis under β-adrenergic stimulation. Enhanced sensitivity of RyR2 to intra-SR [Ca²⁺] due to increased phosphorylation and oxidation of the channel leads to termination of systolic Ca²⁺ release at reduced intra-SR [Ca²⁺]. Faster RyR2-mediated SR Ca²⁺ leak and reduced refractoriness of RyR2 also contributes to the enhanced propensity for proarrhythmic spontaneous Ca²⁺ release. Enhanced NCX1 activity, depressed SERCa activity and SR Ca²⁺ leak underlie reduced intra-SR [Ca²⁺] and diminished Ca²⁺ transient amplitude. Loss of dyadic contacts between T-tubular LTCCs and jSR RyR2s impedes Ca²⁺ transient rise. c Under β-adrenergic stimulation, CPVT myocytes exhibit spontaneous Ca²⁺ release via defective RyR2 complexes, leading to reduced Ca²⁺ transient amplitude and reduced intra-SR [Ca²⁺]. Posttranslational remodeling, mitochondrial dysfunction, and subcellular structural remodeling contribute to the hyperactivity of RyR2 caused by CPVT-associated mutations. Proarrhythmic activity of RyR2 drives NCX1 activity, causing a depolarizing inward current and DADs. Uncoupling of LTCCs and RyR2s due to dyad remodeling may increase Ca²⁺ transient rise time and reduce LTCC Ca²⁺-dependent inactivation which can result in longer APD. d In LQT2, loss-of-function mutation in KCNH2 reduces outward I_Kr and prolongs APD during β-adrenergic stimulation. SR Ca²⁺ leak is accelerated due to hyperphosphorylation of RyR2. SERCa-mediated SR Ca²⁺ uptake is accelerated at baseline due to PLB phosphorylation. Enhanced activity of hyperphosphorylated RyR2s contributes to a reduction of SR [Ca²⁺], Ca²⁺ transients amplitude, and arrhythmogenic EADs under β-adrenergic stimulation. e In LQT3, gain-of-function mutation in SCN5A increases inward late I_Na and prolongs APD. Arrhythmogenic activity occurs at rest, in the absence of β-adrenergic stimulation. Longer APD increases LTCC-mediated Ca²⁺ influx. Na⁺/Ca²⁺ overload and increased activity of SERCa due to PLB phosphorylation underlies increase in SR Ca²⁺ content, Ca²⁺ transient amplitude, and spontaneous RyR2-mediated Ca²⁺ release thereby EADs at slow rates