CaMKII-dependent late Na⁺current increases electrical dispersion and arrhythmia in ischemia-reperfusion

Abstract

The mechanisms underlying Ca/calmodulin-dependent protein kinase II (CaMKII)-induced arrhythmias in ischemia-reperfusion (I/R) are not fully understood. We tested the hypothesis that CaMKII increases late Na current ( I) via phosphorylation of Na1.5 at Ser during I/R, thereby increasing arrhythmia susceptibility. To test our hypothesis, we studied isolated, Langendorff-perfused hearts from wild-type (WT) mice and mice expressing Na channel variants Na1.5-Ser571E (S571E) and Na1.5-Ser571A (S571A). WT hearts showed a significant increase in the levels of phosphorylated CaMKII and Na1.5 at Ser [p-Na1.5(S571)] after 15 min of global ischemia (just before the onset of reperfusion). Optical mapping experiments revealed an increase in action potential duration (APD) and APD dispersion without changes in conduction velocity during I/R in WT and S571E compared with S571A hearts. At the same time, WT and S571E hearts showed an increase in spontaneous arrhythmia events (e.g., premature ventricular contractions) and an increase in the inducibility of reentrant arrhythmias during reperfusion. Pretreatment of WT hearts with the Na channel blocker mexiletine (10 μM) normalized APD dispersion and reduced arrhythmia susceptibility during I/R. We conclude that CaMKII-dependent phosphorylation of Na1.5 is a crucial driver for increased I arrhythmia triggers, and substrate during I/R. Selective targeting of this CaMKII-dependent pathway may have therapeutic potential for reducing arrhythmias in the setting of I/R. NEW & NOTEWORTHY Ca/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of Na1.5 at Ser leads to a prolongation of action potential duration (APD), increased APD dispersion, and increased arrhythmia susceptibility after ischemia-reperfusion in isolated mouse hearts. Genetic ablation of the CaMKII-dependent phosphorylation site Ser on Na1.5 or low-dose mexiletine (to inhibit late Na current) reduced APD dispersion, arrhythmia triggers, and ventricular tachycardia inducibility.

Apelin increases atrial conduction velocity, refractoriness, and prevents inducibility of atrial fibrillation

“…Consistent with findings of previous studies in both atrial ( 24 ) and ventricular myocytes ( 21 , 23 ), we found that exposing left atrial myocytes to apelin increased the maximal I Na conduction in association with a reversible hyperpolarizing shift in steady-state sodium channel activation combined with AP prolongation. This latter finding can help explain the ability of apelin to increase atrial refractoriness and prolong APDs, as reported previously ( 40 , 41 )), actions which are expected to reduce arrhythmia vulnerability ( 42 ).…”

Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients

“…A recent study reported that CaMKIId activation contributes to diastolic Na þ and Ca 2þ overload and impaired diastolic function. 29 Indeed, our western blot analysis showed that CaMKIId autophosphorylation was significantly up-regulated by 308 ± 42% in HCM iPSC-CMs compared with Ctrl iPSC-CMs, which was partially suppressed by I Ca or I NaL blockers ( Figure 6B). To confirm the role of CaMKIId in DD, we sought to over-express (OE) the constitutivelyactive form of CaMKIId T287D in Ctrl iPSC-CMs, and to knockdown (KD) CaMKIId in HCM iPSC-CMs (Supplementary material online, Figure S10A-C).…”

βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function

“…Optical mapping of ex vivo heart preparations. Optical mapping techniques were used to measure the electrical impulse propagation in the anterior portion of the isolated heart, as described (39). Briefly, hearts were perfused with oxygenated Tyrode's solution (at 37°C and pH of 7.4) via the aorta using a rolling pump at 2 mL/min.…”