The proarrhythmogenic role of autonomics and emerging neuromodulation approaches to prevent sudden death in cardiac ion channelopathies

Figure 1. Autonomous innervation of the heart: left (yellow): the cell bodies of the post-ganglionic sympathetic neurons are located in the ganglia adjacent to the cervical and thoracic spinal cord, which receive inputs from the dorsal root ganglia of the spinal cord and central nervous system. Their axons travel along the epicardial vascular structures of the heart and penetrate through into the myocardium. The highest density in innervation is located in the subepicardial structures in the atria and base of the ventricles and surrounding the specialized conduction system. There are distinct afferent and efferent parasympathetic and sympathetic neural projections. The afferent nerve endings have numerous functions including their roles as mechano-, chemo-, or nociceptors. Among others, this allows that the afferent sympathetic fibres can provide beat-to-beat information to the central nervous system.2 Right (green): parasympathetic neurons are preganglionic fibres arising from the left and right vagus nerve and synapsing with a dense multiplexed network of ganglia located in the epicardial fat pats. Post-ganglionic fibres cross the AV groove and are thought to then dive intramurally to…

Figure 2. Intraventricular and transmural activation and repolarization gradients: (A) cardiac activation sequence spreads rapidly through the Purkinje network from apex to base and from endo- to epicardium (white arrows). Due to shorter APDs, repolarization occurs earliest in the subepicardial layer causing repolarization to move in the opposite direction (black arrows). (B) Transmural ventricular AP configurations: the prominent phase 1 notch of epicardial and midmyocardial APs is attributed to a high density of I to channels. Subepicardial APs have a shorter phase 3 due to stronger I Ks currents, whereas the midmyocardial cells take longest to repolarize due to weaker I Ks but stronger late I Na and Na+–Ca2+ exchanger currents.13–15

Figure 3. Characteristic ECG pattern, action potential configurations, and key ion channel alterations associated with ion channel alterations. Proposed treatment as per ESC guidelines for the Managements of Patients with Ventricular Arrhythmias excluding ICD indications and lifestyle recommendations.

Figure 4. Overview of existing autonomic neuromodulation therapies as relevant for the treatment of cardiac arrhythmias: green arrow = vagus nerve and branches, yellow chain = paravertebral sympathetic chain. (A) Non-invasive auricular branch VNS stimulation (as described in Dumoulin et al.32). (B) Baroreceptor activation therapy. (C) Schematic representation of low level invasive vagus nerve stimulation. (D) Schematic representation of spinal cord stimulation (as described in Harned et al.33) (E) Renal sympathetic denervation (reprinted with permission of Medtronic). (F ) Ganglionated plexi ablation. (G) Cardiac sympathetic denervation.

Figure 5. Arrhythmogenesis in CPVT: proposed mechanism of the spontaneous calcium release of the mutant ryanodine receptor (in red, large ‘mushroom’ shaped homo-tetramer) under adrenergic stimulation are: [1 orange] an enhanced basal activity and increased Ca2+ sensitivity decreasing the amount of calcium required for RYR2 activation39,40; [2 purple] a disrupted interaction with the binding protein (FKBP), which stabilizes the receptor in its closed form under physiological circumstances, leads to untimely opening41; [3 green] a defective inter-domain folding and pathological interaction between certain domains, which result in high sensitivity of RyR2 channel agonists and decrease the threshold for activation42; and [4 blue] calcium overload in the sarcoplasmic reticulum (SR) has been associated with increased triggered activity even in absence of adrenergic drive (store overload induced Ca2+ release).43 The resulting inappropriate diastolic calcium release from the sarco-plasmatic reticulum causes intracellular calcium overload and delayed after-polarization (A) that result in triggered activity (B), most prominently in the more susceptible Purkinje cells than the ventricular…

Figure 6. Overview novel molecular and central nervous system targets. Left: central autonomic nervous system centres, key targets for cardiac neuromodulation highlighted in green (vagal) or orange (sympathetic) (adapted from Benarroch et al.158) Right: overview of novel molecular targets including (A) inhibitory and excitatory G-protein coupled receptors including the cardiac receptors of norepinephrine, acetylcholine, and other neuropeptides. (B) Metabolic targets including adiponectin released from adipocytes. (C) Sigma-1 receptors, ligand specific cellular signalling pathways are still under investigation, inhibition of sodium channel currents, and reduction in calcium leakages have been described as possible anti-arrhythmic mechanism via sigma-1 receptors. (D) Chemorepellents/attractants, e.g. Semaphorin3A suppressing sympathetic nerve sprouting in the heart.

Figure 7. Investigational neuromodulation techniques: left: (A) Schematic representation of deep brain stimulation with implantable stimulator. (B) Schematic representation of non-invasive transcranial magnetic stimulation (as described in Holvoet et al.179). (C) Schematic representation of transcutaneous magnetic stimulation of the left stellate ganglion (as described in Markman et al.180). Middle: (D) Optogenetics: commonly used opsins in neuroscience are channelrhodopsin activated by blue light facilitating combined sodium and calcium current causing depolarization of the cell, halorhodopsin activated by yellow light and allowing chlorid currents causing hyperpolarization and cell ‘silencing’, and bacteriorhodopsin a proton pump gated by green light. (E) Chemogenetics: genetically modified receptors that respond exclusively to specific ligands are generated and induced in a viral vector. Right: schematic illustration of possible delivery modalities of opto- or chemogenetical therapies over (i) direct stereotactic injection to central autonomic centres, (ii) stellate ganglion (as described in Goel et al.181), or (iii) directly intravenous.