UCLA

Dysfunction of the autonomic nervous system has been implicated in the progression of most cardiovascular disorders, including congestive heart failure, myocardial infarction, and ventricular arrhythmias. Central to cardiovascular disease progression are the tenets of reflexive sympathoexcitation and reduced parasympathetic tone; indeed, beta blockade and inhibition of the renin-angiotensin-aldosterone system are the mainstays of medical treatment for most cardiovascular disorders. In Yucatan minipigs, myocardial infarction (MI) led to substantial impairments in left ventricular mechanical function and high susceptibility to ventricular tachycardia and fibrillation. At the tissue level, MI promoted anisotropic electrical conduction, while also leading to greater repolarization heterogeneity and steep repolarization gradients at the border-zone. Myocytes from MI animals exhibited myofibril disarray and a high degree of myocytolysis, a characteristic finding in autopsy specimens of patients with sudden cardiac death. Moreover, extracardiac neural remodeling of the stellate ganglia, the principal efferent sympathetic input to the heart, included greater neuropeptide Y expression, cholinergic transdifferentiation, and a high degree of satellite glial cell activation. Similarly, the thoracic dorsal root ganglia, which serve as the primary source of general visceral afferent fibers to the heart, demonstrated high levels of neuronal nitric oxide synthase expression as well as activation of glial cells. In healthy minipigs, sympathetic afferent and efferent block reduced the effects of sympatho-activation by blunting interstitial norepinephrine release in the left ventricular myocardium. In minipigs with MI, chronic vagal nerve stimulation substantially improved cardiac mechanical function and reduced ventricular arrhythmias following MI, partly by stabilizing activation and repolarization in the border-zone. Finally, MI-associated extracardiac neural remodeling, particularly glial activation in the stellate and dorsal root ganglia, was mitigated by chronic VNS. In conclusion, this work suggests that restoration of parasympathetic function, whether pharmacologically or through neuromodulation, is an attractive therapeutic strategy for post-MI cardiac dysfunction. Furthermore, an improved understanding of cardiac autonomic dysfunction may lead to rationale, neuroscientifically-inspired approaches to treat cardiovascular disease.