Abstract
Cardiomyocyte Na+ and Ca2+ mishandling, upregulated Ca2+/calmodulin-dependent kinase II (CaMKII), and increased reactive oxygen species (ROS) are characteristics of various heart diseases, including heart failure (HF), long QT (LQT) syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). These changes may form a vicious cycle of positive feedback to promote cardiac dysfunction and arrhythmias. In HF rabbit cardiomyocytes investigated in this study, the inhibition of CaMKII, late Na+ current (INaL), and leaky ryanodine receptors (RyRs) all attenuated the prolongation and increased short-term variability (STV) of action potential duration (APD), but in age-matched controls these inhibitors had no or minimal effects. In control cardiomyocytes, we enhanced RyR leak (by low [caffeine] plus isoproterenol mimicking CPVT) which markedly increased STV and delayed afterdepolarizations (DADs). These proarrhythmic changes were significantly attenuated by both CaMKII inhibition and mitochondrial ROS scavenging, with a slight synergy with INaL inhibition. Inducing LQT by elevating INaL (by Anemone toxin II, ATX-II) caused markedly prolonged APD, increased STV, and early afterdepolarizations (EADs). Those proarrhythmic ATX-II effects were largely attenuated by mitochondrial ROS scavenging, and partially reduced by inhibition of CaMKII and pathological leaky RyRs using dantrolene. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing LQT3 mutation SCN5A N406K, dantrolene significantly attenuated cell arrhythmias and APD prolongation. Targeting critical components of the Na+–Ca2+–CaMKII–ROS–INaL arrhythmogenic vicious cycle may exhibit important on-target and also trans-target effects (e.g., INaL and RyR inhibition can alter INaL-mediated LQT3 effects). Incorporating this vicious cycle into therapeutic strategies provides novel integrated insight for treating cardiac arrhythmias and diseases.
Highlights
Heart failure (HF) is characterized by cardiomyocyte Na+ and Ca2+ dysregulation including elevated intracellular [Na+] ([Na+]i) and late N a+ current (INaL), reduced sarcoplasmic reticulum (SR) Ca2+ uptake, and increased diastolic SR Ca2+ leak, Na+/Ca2+ exchange (NCX), and reactive oxygen species (ROS) that contribute to systolic dysfunction and arrhythmias [1, 2, 8, 27, 54]
Enhanced ryanodine receptors (RyRs) leak, calmodulin-dependent kinase II (CaMKII), and INaL all contribute to arrhythmogenic Action potentials (APs) changes in HF
The effects of direct INaL inhibition (GS-967) and CaMKII (AIP) on action potential duration (APD) and short-term variability (STV) could be expected because INaL and CaMKII activity are known to be elevated in HF, and CaMKII has been shown to directly enhance INaL [5, 27, 67]
Summary
Heart failure (HF) is characterized by cardiomyocyte Na+ and Ca2+ dysregulation including elevated intracellular [Na+] ([Na+]i) and late N a+ current (INaL), reduced sarcoplasmic reticulum (SR) Ca2+ uptake, and increased diastolic SR Ca2+ leak, Na+/Ca2+ exchange (NCX), and reactive oxygen species (ROS) that contribute to systolic dysfunction and arrhythmias [1, 2, 8, 27, 54]. A primary increase in SR C a2+ leak would promote CaMKII activation, which can promote INaL, prolong action potential duration (APD), increase [Na+]i, and ROS production that can further drive the cycle and amplify the functional impacts of initial insults at any given point
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