Role of late sodium current as a potential arrhythmogenic mechanism in the progression of pressure-induced heart disease

Abstract

Aims To determine the characteristics of the late Na current (INaL) and its arrhythmogenic potential in the progression of pressure-induced heart disease. Methods and Results Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the hearts developed isolated hypertrophy with preserved systolic contractility. In patch-clamp experiments both, INaL and the action potential duration (APD90) were unchanged. In contrast, after five weeks animals developed heart failure with prolonged APDs and the slowed INaL decay time which could be normalized by addition of the INaL inhibitor ranolazine (Ran) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Accordingly the APD90 could be significantly abbreviated by Ran, tetrodotoxin and the CaMKII inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) in myocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs. Moreover, the incidence of triggered activity was significantly increased in TAC myocytes and was largely prevented by Ran and AIP. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. Conclusion In pressure overload-induced heart failure a CaMKII-dependent augmentation of INaL plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot yet be found in early and still compensated hypertrophy. Inhibition of INaL and CaMKII exert potent antiarrhythmic effects and might therefore be of potential therapeutic interest.

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

“…Thus, the observed reduction in I Na at the LM of failing cardiomyocytes is likely predominantly caused by a decrease in Na V 1.5‐based channels, in particular those located at the crest. Increased late I Na is another key feature of HF and contributes to arrhythmogenesis 23. Interestingly, we observed location‐specific increased late openings of sodium channels at the crest of failing cardiomyocytes but not in the groove/T‐tubule region.…”

“…Apart from the cardiac sodium channel Na V 1.5, neuronal sodium channel isoforms (ie, Na V 1.1, Na V 1.3, and Na V 1.6) are also thought to populate the T tubules 29, 30, 31, 32. Studies on expression and function of neuronal sodium channel isoforms during HF have shown varied results, most likely because of variations in species (rat, rabbit, dog) and HF model (pressure and/or volume overload and embolizations) used, with the most consistent observation comprising an upregulation of Na V 1.1 5, 23, 33. However, we observed unaltered I Na gating properties at the LM of failing myocytes in addition to unchanged single‐channel conductance in both the crest and groove/T‐tubule microdomains, arguing against a change in neuronal sodium channel function.…”

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

“…34 Sodium ion influx via I Na,late also leads to APD prolongation. 12,13,16,35 When sufficient APD prolongation occurs, inward currents are able to recover from inactivation, become reactivated, and allow charge to enter the cell. If current entering the cell exceeds repolarizing K þ currents, an EAD can occur.…”

“…17,29,[43][44][45] The resulting calcium overload is thought to trigger intracellular Ca 2þ release from the sarco-endoplasmic reticulum (SR), leading to cytosolic Ca 2þ oscillations, automaticity, and triggered activity. 16,35,[46][47][48] Calcium overload and oscillatory activity are able to activate forward mode NCX. 49 This carries an inward positive current, also known as the transient inward current due to NCX stoichiometry…”

“…48,53 Furthermore, inhibition of I Na,late by ranolazine reduces the incidence of DADs and prevents triggered activity. 16,48,[53][54][55] Delayed afterdepolarizations have been observed in several types of cardiac tissue, including both atrial and ventricular myocytes, where they can lead to triggered activity and tachyarrhythmias. 56 The second mechanism of arrhythmia in the heart is abnormal conduction and includes conduction block and reentry.…”