Figure 2. Atrial ectopy. Molecular pathways promoting Ca²⁺-mediated ectopy.

Increased sarcoplasmic reticulum (SR) Ca²⁺ leak and spontaneous SR Ca²⁺-release events (SCaEs) primarily result from dysfunction of the cardiac ryanodine receptor type-2 (RyR2) channel or SR Ca²⁺-overload. RyR2 dysfunction is promoted by increased RyR2 expression, hyperphosphorylation (e.g., due to increased Ca²⁺/calmodulin-dependent protein kinase-II, CaMKII, activity or improper targeting of protein phosphatase-1, PP1), or RyR2 oxidation due to increased reactive oxygen species (ROS). ROS mediated NLRP3 inflammasome activation amplifies the Ca²⁺-handling abnormalities and activates caspase-1 (Casp-1) which increases interleukin (IL)-1β generation and the formation of gasdermin-D-derived plasmamembrane-pores, allowing the release of IL-1β out of the cell, spreading inflammatory signaling. SR Ca²⁺-overload is promoted by increased activity of the SR Ca²⁺-ATPase-2a (SERCA2a) or elevated intracellular Na⁺, reducing Ca²⁺-extrusion via the Na⁺/Ca²⁺ exchanger type-1 (NCX1). SR Ca²⁺ overload also promotes L-type Ca²⁺-current (I_Ca,L)-dependent triggered Ca²⁺ waves (TCW). SCaEs and TCW activate a transient-inward current mediated by NCX (I_NCX) resulting in DADs or EADs, depending on their timing relative to the atrial action potential. DADs and EADs can promoted atrial ectopy, as well as reentry through increased heterogeneity of excitability and repolarization. Abbreviations: GSDM-D, N-terminal Gasdermin-D fragment; I-1, inhibitor-1 of PP1; JNK2, c-Jun N-terminal kinases-2; NLRP3, NACHT, LRR and PYD domains-containing protein 3; PLB, phospholamban; SLN, sarcolipin.