The role of calcium homeostasis remodeling in inherited cardiac arrhythmia syndromes

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  Fig. 1. Proteins of cardiac excitation-contraction coupling associated with long QT syndrome or catecholaminergic polymorphic ventricular tachycardia, caused by pathogenic mutation. Proteins with mutations associated with long QT syndrome are colored red; proteins with mutations associated with CPVT are colored blue; proteins with mutations that can cause long QT syndrome or CPVT are colored purple. Kv7.1; KCNQ1 gene, α-subunit of IKs channel, mutations underlie LQT1. Kv11.1; KCNH2 gene, α-subunit of IKr channel, mutation underlies LQT2. Nav1.5; SCN5a gene, α-subunit of INa channel, mutations underlie LQT3. Ankyrin B; ANK2 gene, functions as an adaptor protein, mutations underlie LQT4. minK; KCNE1 gene, β-subunit of IKs channel, mutations underlie LQT5. MiRP1; KCNE2 gene, β-subunit of IKr channel, mutations underlie LQT6. Kir2.1; KCNJ2 gene, α-subunit of IK1 channel, mutations underlie LQT7. LTCC; CACNA1C gene, mutations in α-subunit of ICa,L channel underlie LQT8 (Timothy syndrome). Cav3; CAV3 gene, caveolin-3 protein is a component of caveolae that co-localizes with Nav1.5, mutations underlie LQT9. β4; SCN4B gene, β-subunit of INa channel, mutation underlies LQT10. AKAP9; AKAP9 gene,…

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  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 INa. 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…