Abstract

Cardiovascular diseases including hypertension, arrhythmias, and heart failure are the leading causes of morbidity and mortality in the world. The autonomic nervous system regulates the electrical and mechanical function of the heart, and its dysfunction plays an important role in the pathophysiology of cardiovascular diseases, representing an emerging target for therapeutic intervention. However, fundamental gaps in our knowledge regarding autonomic control of the heart in health and the adverse remodeling that occurs in disease have impeded the development of neuromodulation therapies. The cardiac ANS consists of neurons located from the level of the brain to that of the heart itself. At the organ level, the intrinsic cardiac nervous system, a distributed network of ganglia and interconnecting nerves, serves as the final common pathway for the integration of neural inputs to the heart. Despite the importance of the ICNS, the impact of acute and chronic stress on the function of this neural network is not well-characterized. Therefore, we investigated the acute effects of premature ventricular contractions and the chronic remodeling induced by myocardial infarction on the ICNS by obtaining in vivo neuronal recordings from beating hearts. Both PVCs and MI affect a critical population of neurons within the ICNS—local circuit neurons. Given that they receive a convergence of afferent and efferent inputs and have intra- and interganglionic projections, local circuit neurons integrate information and coordinate regional cardiac function. Further, MI results in the formation of a neural sensory border zone, characterized by diminished afferent signals from the infarct and preserved signals from border and remote regions of the heart. These neural effects may underlie, at least in part, the mechanical dyssynchrony, electrical instability, and reflex activation of the ANS noted with PVCs and after MI. In addition, we demonstrated that the evoked cardiac response to vagus nerve stimulation, a neuromodulation therapy being evaluated for cardiac conditions, represents the dynamic interplay between afferent and efferent vagal fibers and reflex responses of the ANS. In conclusion, a better understanding of autonomic regulation of the heart will lead to the development of rationale neuroscience-based therapies for cardiovascular diseases.