Treating cardiac dysrhythmias by targeting the neck: Off target or on the right track?

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The history of cardiology provides many examples of attempts to target cardiovascular pathophysiology by modulating the autonomic nervous system (ANS). The most widely used form of nonspecific and global autonomic modulation is beta‐receptor blockade. Beta‐blockers are proven to improve outcomes in patients with heart failure and myocardial infarction1 and prevent ventricular arrhythmias and sudden cardiac death.3 However, beta‐blockade is not perfect. It often is ineffective for the prevention of ventricular arrhythmias. Moreover, on occasion, excessive or nonspecific sympathetic blockade may not be helpful.4 In theory, targeted modulation of the ANS has the potential to restore autonomic balance in organs affected by autonomic dysfunction. Autonomic modulation has several potential and beneficial mechanisms, including sympathetic and parasympathetic effects via either the efferent and/or afferent limbs of each system. Examples of targeted autonomic modulation therapies for cardiovascular disorders include: (1) thoracolumbar sympathectomy and renal denervation for the treatment of hypertension6; (2) baroreceptor stimulation for the management of heart failure and hypertension7; (3) vagus nerve stimulation for the treatment of heart failure8; and (4) carotid body modulation for the treatment of heart failure and hypertension.9 Despite promising phase II studies for each of the aforementioned interventions, there are no conclusive phase III data to support their clinical use.
In the last several years the field of neuromodulation has increasingly focused on cardiac autonomics as a potential therapeutic target in the treatment of heart rhythm disorders. For example, in the case of atrial fibrillation, several approaches to modulate the ANS directly11 or indirectly via sensory input from the periphery13 are in continued development. Ventricular arrhythmia is one of the last (but not new) frontiers for neuromodulation. Ventricular arrhythmias are complex electrical phenomenon that can occur in patients with or without structural heart disease. Electrical storm (≥3 episodes of ventricular tachycardia or fibrillation in 24 hours) represents a particularly complicated and life‐threatening emergency. Electrical storm is more common than often appreciated, as recently shown in a meta‐analysis of 5,600 patients with implanted cardiac defibrillators, where 15% experienced electrical storm during 30‐month follow‐up.15 Not surprisingly, electrical storm is more common in secondary prevention patients and its occurrence is associated with a threefold increased risk of mortality.15 However, it is also notable that electrical storm carries a 2.5‐fold higher risk of death compared with isolated VT/VF episodes. This suggests that electrical storm is not just the frequent occurrence of ventricular arrhythmias in a 24‐hour window but is an indicator of severe cardiac dysfunction and global autonomic imbalance. Early therapeutic intervention is the key to successful management of electrical storm, given the close proximity of the arrhythmic event and its associated morbidity and mortality. In particular, recurrent VT/VF and ICD shocks can lead to systolic dysfunction, irreversible myocardial injury,17 downstream adrenergic activation, and further exacerbation of heart failure.19
Sympathetic activation is not only a result of ventricular arrhythmias but it often is an important cause/trigger of ventricular arrhythmias. The sympathetic nervous system communicates with the heart via efferent nerves to the heart and afferent nerves from the heart. Sympathetic efferent signaling induces changes in ventricular electrophysiology (even in normal hearts) by lowering the activation threshold20 and increasing automaticity of ventricular myocytes.22 The stellate ganglia are cervical autonomic ganglia containing a disproportionally high number of efferent and afferent fibers to and from the heart. There is mounting evidence to suggest that stellate ganglia play a central role in the regulation of the sympathetic tone in patients with cardiomyopathy and ventricular arrhythmias. For example, the stellate ganglia seem to contribute to neural remodeling when afferent nerves from the heart sense cardiac damage.
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