Inhibition of cardiac potassium currents by oxidation-activated protein kinase A contributes to early afterdepolarizations in the heart.

Reactive oxygen species (ROS) have been shown to prolong cardiac action potential duration resulting in afterdepolarizations, the cellular basis of triggered arrhythmias. As previously shown, protein kinase A type I (PKA I) is readily activated by oxidation of its regulatory subunits. However, the relevance of this mechanism of activation for cardiac pathophysiology is still elusive. In this study, we investigated the effects of oxidation-activated PKA I on cardiac electrophysiology. Ventricular cardiomyocytes were isolated from redox-dead PKA-RI Cys17Ser knock-in (KI) and wild-type (WT) mice and exposed to H2O2 (200 µmol/L) or vehicle (Veh) solution. In WT myocytes, exposure to H2O2 significantly increased oxidation of the regulatory subunit I (RI) and thus its dimerization (threefold increase in PKA RI dimer). Whole cell current clamp and voltage clamp were used to measure cardiac action potentials (APs), transient outward potassium current (Ito) and inward rectifying potassium current (IK1), respectively. In WT myocytes, H2O2 exposure significantly prolonged AP duration due to significantly decreased Ito and IK1 resulting in frequent early afterdepolarizations (EADs). Preincubation with the PKA-specific inhibitor Rp-8-Br-cAMPS (10 µmol/L) completely abolished the H2O2-dependent decrease in Ito and IK1 in WT myocytes. Intriguingly, H2O2 exposure did not prolong AP duration, nor did it decrease Ito, and only slightly enhanced EAD frequency in KI myocytes. Treatment of WT and KI cardiomyocytes with the late INa inhibitor TTX (1 µmol/L) completely abolished EAD formation. Our results suggest that redox-activated PKA may be important for H2O2-dependent arrhythmias and could be important for the development of specific antiarrhythmic drugs.NEW & NOTEWORTHY Oxidation-activated PKA type I inhibits transient outward potassium current (Ito) and inward rectifying potassium current (IK1) and contributes to ROS-induced APD prolongation as well as generation of early afterdepolarizations in murine ventricular cardiomyocytes.

CaMKII and GLUT1 in heart failure and the role of gliflozins.

Empagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has been shown to reduce mortality and hospitalization for heart failure in diabetic patients in the EMPA-REG-OUTCOME trial (Zinman et al., 2015). Surprisingly, dapagliflozin, another SGLT2 inhibitor, exerted comparable effects on clinical endpoints even in the absence of diabetes mellitus (DAPA-HF trial) (McMurray et al., 2019). There is a myriad of suggested underlying mechanisms ranging from improved glycemic control and hemodynamic effects to altered myocardial metabolism, inflammation, neurohumoral activation and intracellular ion homeostasis. Here, we review the effects of gliflozins on cardiac electro-mechanical coupling with an emphasis on novel CaMKII-mediated pathways and on cardiac glucose and ketone metabolism in the failing heart. We focus on empagliflozin as it is the gliflozin with the most abundant experimental evidence for direct effects on the heart. Where useful, we aim to compare empagliflozin to other gliflozins. To facilitate understanding of empagliflozin-induced alterations, we first give a short summary of the pathophysiological role of CaMKII in heart failure, as well as cardiac changes of glucose and ketone body metabolism in the failing heart.