Metabolic stress, reactive oxygen species, and arrhythmia

Abstract

Cardiac arrhythmias can cause sudden cardiac death (SCD) and add to the current heart failure (HF) health crisis. Nevertheless, the pathological processes underlying arrhythmias are unclear. Arrhythmic conditions are associated with systemic and cardiac oxidative stress caused by reactive oxygen species (ROS). In excitable cardiac cells, ROS regulate both cellular metabolism and ion homeostasis. Increasing evidence suggests that elevated cellular ROS can cause alterations of the cardiac sodium channel (Na(v)1.5), abnormal Ca(2+) handling, changes of mitochondrial function, and gap junction remodeling, leading to arrhythmogenesis. This review summarizes our knowledge of the mechanisms by which ROS may cause arrhythmias and discusses potential therapeutic strategies to prevent arrhythmias by targeting ROS and its consequences. This article is part of a Special Issue entitled "Local Signaling in Myocytes".

Figure 1

Schematic illustration of ROS-mediated ion channel alterations. ROS are generated from mitochondrial ETC electron leakage, NADPH oxidases, xanthine oxidase and NOS uncoupling in the heart. ROS induces functional and structural alteration of Na_v1.5 by both transcriptional and posttranslational mechanisms. Elevated ROS mediates SERCA inhibition, enhanced SR Ca²⁺ release from RyR, enhanced inward L-type Ca²⁺ current, and increased NCX activity to increase intracellular Ca²⁺ level. ROS-mediated CaMKII activation stimulates hyperphosphorylation of RyR, resulting SR Ca²⁺ leak. In mitochondria, stimulated ROS are release by the IMAC and the membrane permeability transition pore, causing K_ATP activation, the mitochondrial calcium uniporter activity, and NADH accumulation. This ROS-mediated network is likely to contribute to the pathogenesis of arrhythmias.

Figure 2

The effects of altering NAD(H) on arrhythmic risk in a mouse model of reduced Na⁺ current. Representative traces of MAPs from LV epicardium of (A) Langendorff-perfused SCN5A^+/− heart during standard pacing at BCL of 125 ms in the control condition. Vertical lines below the monophasic action potentials (MAPs) represent the times when electrical stimulations were delivered. (B) MAPs after 20 min of perfusion with 100 μmol/L [NAD⁺]_o. (C) Representative MAPs recorded during programmed electrical stimulation (PES) showing PES-induced ventricular tachycardia in SCN5A^+/− hearts under control condition. The final six paced beats at 125 BCL (S₁) were followed by an extra stimulus (S₂) delivered at a S₁-S₂ interval of 42 ms. PES induced a polymorphic ventricular tachycardia of frequency, 20-40 Hz, sustained for ≈19 seconds. (D) Representative trace of PES-induced MAP recording in same SCN5A^+/− heart after 20 min perfusion with 100 μM [NAD⁺]_o. S₂ stimuli delivered at a 35 ms S₁-S₂ interval produced a single MAP but failed to induce any arrhythmia. (Modified from reference [60])

Figure 3

The illustration of the effects of mitochondrial ROS induced by NADH on the I_Na. A proposed signaling pathway by which mutant GPD1-L and NADH downregulate Na_v1.5 by causing PKC activation and ROS overproduction from the mitochondrial ETC. ROS are released from the mitochondria by the IMAC, which is modulated by the mitochondrial benzodiazepine receptor. NAD⁺ inhibits mitochondrial ROS overproduction through PKA activation followed by the upregulation of Na_v1.5. (Modified from reference [16])