Autonomic modulation of ventricular electrical activity: recent developments and clinical implications

Fig. 1. Simplified, schematic overview of the cardiac neuraxis. Neural control is effectuated through reflex loops at different levels of the cardiac neuraxis. ICNS intrinsic cardiac nervous system. Blue arrows: afferent nerves. Green arrows: parasympathetic nerves. Red arrows: sympathetic nerves. Purple arrows: ICNS reflex loop

Fig. 2. Schematic representation of the electrical effects of sympathetic stimulation under health conditions and in the setting of sympathoexcitation. Healthy: The binding of norepinephrine (NE) or epinephrine to the β-receptor results in cAMP-mediated activation of protein kinase A (PKA). Next, PKA phosphorylates the L-type calcium channel (LTCC), promoting the influx of calcium. Simultaneously, the calcium-induced calcium release from the sarcoplasmic reticulum (SR) is also enhanced by the phosphorylation of the ryanodine receptor (RYR). Simultaneously, phospholamban is also phosphorylated, which enhances the calcium re-uptake through the sarco/endoplasmic reticulum calcium ATPase (SERCA). Lastly, PKA also phosphorylates INa and IK,s, which accommodate the faster heart rate by increasing conduction velocity and shortening repolarization, respectively. Sympathoexcitation: At the cellular level, sympathetic excitation results in the same effects as under healthy conditions. However, the increased calcium influx through the LTCC and the increased SR calcium release (due to increased calcium loading) improve contractile force, but also predispose to the development of early (EAD) or…

Fig. 3. Schematic overview of neuromodulatory interventions that are currently being developed or are already clinically implemented. Interventions are divided into three groups based on their respective primary target for modulation. The first group of interventions modulates the intrinsic cardiac nervous system (ICNS) or the myocytes and includes pharmacological inhibition of sympathetic overdrive, ICNS disruption or glial modulation. Glial modulation has been studied in the ICNS and in the stellate ganglia and is therefore connected to both. The second group (consisting of cardiac sympathetic denervation, stellate ganglia block, thoracic epidural anesthesia and (auricular) vagal nerve stimulation) directly modulate cardiac efferent and thereby either decrease sympathetic outflow or increase parasympathetic tone. The arrows next to the (auricular branch of the) vagal nerve depict the presence of afferent and/or efferent nerves. Thoracic epidural anesthesia affects cardiac efferents and afferents to a comparable extent and is therefore placed at the border of the second and the third group. Lastly, the third group (including spinal cord stimulation, carotid sinus stimulation and renal…