Letter to the Editor: Ca2+/calmodulin-dependent protein kinase II in heart failure and the role of sodium-glucose-cotransporter 2 inhibitors

Table 1 Key downstream targets and pathological consequences of aberrant Ca²⁺/calmodulin-dependent protein kinase II activation in heart failure

Specific target	CaMKII action	Pathophysiological consequence
RyR2	Phosphorylates RyR2 at Ser2814, increasing its open probability	Increased sarcoplasmic reticulum calcium leak, elevated diastolic calcium spark frequency, leading to abnormal calcium transients and triggered arrhythmias
PLB	Phosphorylates PLB at Thr17, relieving its inhibition on SERCA2a	Initially compensatory enhanced calcium reuptake; chronic/over-activation synergizes with SERCA2a downregulation, resulting in reduced SR calcium load and diastolic dysfunction
LTCC	Phosphorylates LTCC at Thr1604, prolonging channel opening and slowing inactivation	Increased calcium influx, prolonged action potential duration, establishing the substrate for early afterdepolarizations; exacerbates calcium overload
Nav1.5	Phosphorylates Nav1.5 at Ser516/Thr594, enhancing the late sodium current	Induces intracellular sodium overload, indirectly worsens calcium overload and action potential prolongation, significantly increasing arrhythmia risk
NCX	Indirectly promotes NCX protein expression via upstream signals (e.g., oxidative stress)	Increases reverse-mode NCX activity, leading to calcium influx and overload, impairing electrophysiological stability
Ito	Reduces Ito current density and function through chronic downregulation and acute phosphorylation-dependent gating modulation	Impairs early repolarization, prolongs action potential duration, and compromises repolarization reserve
HDAC	Phosphorylates and activates class I HDACs (e.g., HDAC1, HDAC3), driving pathological gene reprogramming	Promotes myocardial hypertrophy, fibrosis, and pathological remodeling

CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; RyR2: Ryanodine receptor 2; SR: Sarcoplasmic reticulum; PLB: Phospholamban; SERCA2a: Sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a; LTCC: L-type calcium channel; Na_v1.5: Voltage-gated sodium channel type V 1.5; HDAC: Histone deacetylase; ROS: Reactive oxygen species; CaM: Ca²⁺/calmodulin; I_to: Transient outward potassium current; NCX: Na⁺/Ca²⁺ exchanger.