Heart-brain interactions in cardiac arrhythmias: Role of the autonomic nervous system

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The autonomic nervous system plays an important role in the genesis of ventricular arrhythmias and sudden cardiac death. Evidence is substantial for a neural component in sudden cardiac death. Sympathetic nerve sprouting and regional myocardial hyperinnervation following myocardial injury promote cardiac arrhythmia and sudden cardiac death through several potential mechanisms. Modulating autonomic tone is a potential method to reduce the risk of ventricular arrhythmias. Thoracic spinal cord stimulation is showing promise as a treatment for refractory angina. In addition, spinal cord stimulation has protected against ventricular tachycardia/ventricular fibrillation in animal models of postinfarction heart failure.



The autonomic nervous system has an important role in the genesis, maintenance, and interruption of ventricular arrhythmias.1 In most instances, sympathetic activation precipitates or enhances ventricular arrhythmias, whereas vagal tone suppresses their occurrence.2,3 Therefore, modulating autonomic tone has been proposed as a method to potentially suppress ventricular arrhythmias.4

An important mechanism underlying the development of ventricular arrhythmias is electrophysiologic heterogeneity. Electrical heterogeneity predisposes to the development of reentrant arrhythmias and other types of arrhythmias.5


Sympathetic nerve fibers are located subepicardially and travel along the routes of the major coronary arteries. In contrast, the vagus nerve is subendocardial in its location after it crosses the atrioventricular groove. A lesion of the heart produced by infarct or fibrosis can result in denervation of otherwise normal myocardium by interruption of neural axons traveling through the lesion. A defect in sympathetic function following myocardial infarction (MI) has been demonstrated in both animals and humans as measured by iodine-123-metaiodobenzylguanidine (MIBG) and C-11 hydroxyephedrine.6

Reduced uptake of MIBG in the inferior wall has recently been observed in patients with idiopathic ventricular fibrillation as compared with controls. Although no difference in survival could be detected between the two groups, patients with reduced uptake of MIBG had an increased incidence of ventricular tachyarrhythmias compared with those who did not have such a defect.7

Similar observations of sympathetic dysfunction have been made in a variety of animal models and humans with heart failure, coronary disease, and ventricular tachycardia in the absence of structural heart disease. In such instances, the speculation is that sympathetic heterogeneity may produce electrical heterogeneity and spur the development of ventricular arrhythmias. The arrhythmic mechanism is probably more complex than this description, however, because the response to sympathetic inhibition using beta-blockers is not uniform.

Evidence of nerve sprouting

Using a growth-associated protein antibody that marks axonal growth, nerve sprouting has been demonstrated in mice in areas of denervation following MI.8 Similarly, using growth-associated protein 43 staining, researchers have demonstrated nerve sprouting in the right atrial free wall, right atrial isthmus, and right ventricle in dogs after radiofrequency catheter ablation.9

Neural component in ventricular arrhythmias

Sympathetic hypersensitivity has been shown in areas of denervation, which may be related in part to nerve sprouting. Other sympathetic and electrical phenomena following myocardial injury include an upregulation of nerve growth factor, a heterogeneous distribution of sympathetic innervation, and electrical heterogeneity with areas of denervation, hyperinnervation, and normal nerve density.

Two discoveries by Chen and colleagues are perhaps most noteworthy. One is that nerve growth factor infusion and stellate ganglion stimulation following MI increase nerve density and ventricular arrhythmias, with increased burst frequency discharge of the stellate ganglion prior to the onset of ventricular tachycardia/ventricular fibrillation (VT/VF) in dogs.8 More recently, they have shown that infusion of nerve growth factor into the stellate ganglion prolongs the QT interval and prolongs ventricular arrhythmias.10

A relationship has been established between the hyperinnervation that occurs following myocardial injury and ventricular arrhythmias. Using immunocytochemical staining in explanted native hearts of transplant recipients, Chen and colleagues demonstrated colocalization of Schwann cells, sympathetic nerves, and nerve axons, as well as regional cardiac hyperinnervation, with the most abundant nerve sprouting in the areas bordering myocardial injury and normal myocardium.8 In addition, they demonstrated positive tyrosine hydroxylase staining of cardiac nerves in areas around coronary arteries in patients with coronary disease and idiopathic dilated nonischemic cardiomyopathy. At the origin of ventricular tachycardia (prior to transplant), nerve sprouting was shown by staining for S100 protein and tyrosine hydroxylase. The authors hypothesized that nerve sprouting may give rise to ventricular arrhythmia and sudden cardiac death, in which MI results in nerve injury, followed by sympathetic nerve sprouting and regional myocardial hyperinnervation.10

A link with circadian variations in QT interval length?

The observation that nerve growth factor infused into the left stellate ganglion prolongs the QT interval and prolongs ventricular arrhythmias, resulting in an inordinate risk of sudden death, is fascinating in the context of recent findings of a circadian variation in duration of the QT interval. In measuring QT intervals in 3,700 men without ventricular arrhythmias, we found that the QT interval peaked in winter (between October and January), with a 6-msec difference between the longest and shortest QT intervals.11 This increase in the QT interval in winter coincides with an increase in the incidence of sudden death, which occurs in many regions of the world regardless of climate. Whether or not this increase in sudden death in winter is related to a longer QT interval is supposition, but the potential interaction deserves further exploration. A similar surge in sudden death in winter was observed in patients who were eligible for an implantable cardioverter-defibrillator (ICD) but did not receive one, as opposed to those who did receive an ICD, which suggests that the mechanism responsible for the increase in sudden death in winter is a ventricular tachyarrhythmia that can be prevented by an ICD.12

How sympathetic hyperinnervation promotes cardiac arrhythmias is speculative, but increased density of sympathetic nerve endings could promote the release of sympathetic neurotransmitters during sympathetic excitation. The autonomic remodeling is associated with heterogeneous electrical remodeling of cardiomyocytes, resulting in prolongation of action potentials in hyperinnervated regions. Further, acute release of sympathetic neurotransmitters probably accentuates the heterogeneity of excitability and refractoriness, likely contributing to arrhythmia susceptibility.5

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