What gets on the nerves of cardiac patients? Pathophysiological changes in cardiac innervation

The autonomic nervous system regulates cardiac function by balancing the actions of sympathetic and parasympathetic inputs to the heart. Intrinsic cardiac neurocircuits integrate these autonomic signals to fine‐tune cardiac control, and sensory feedback loops regulate autonomic transmission in the face of external stimuli. These interconnected neural systems allow the heart to adapt to constantly changing circumstances that range from simple fluctuations in body position to running a marathon. The cardiac reflexes that serve to maintain homeostasis in health are disrupted in many disease states. This is often characterized by increased sympathetic and decreased parasympathetic transmission. Studies of cardiovascular disease reveal remodelling of cardiac neurocircuits at several functional and anatomical levels. Central circuits change so that sympathetic pathways become hyperactive, while parasympathetic circuits exhibit decreased activity. Peripheral sensory nerves also become hyperactive in disease, which increases patients’ risk for poor cardiac outcomes. Injury and disease also alter the types of neurotransmitters and neuropeptides released by autonomic nerves in the heart, and can lead to regional hyperinnervation (increased nerve density) or denervation (decreased nerve density) of cardiac tissue. The mechanisms responsible for neural remodelling are not fully understood, but neurotrophins and inflammatory cytokines are likely involved. Areas of active investigation include the role of immune cells and inflammation in neural remodelling, as well as the role of glia in modulating peripheral neuronal activity. Our growing understanding of autonomic dysfunction in disease has facilitated development of new therapeutic strategies to improve health outcomes. figure legend A summary diagram illustrating the progression of autonomic dysfunction following cardiac injury or disease. Afferent neurotransmission is increased and may contribute to the pathological remodelling of efferent autonomic activity, which is generally characterized by sympathetic hyperactivity and withdrawal of parasympathetic tone. Cardiac injury and disease is also associated with systemic and tissue‐specific inflammation, altered neuropeptide and neurotransmitter production, and alterations in cardiac nerve density. Together, these changes in autonomic transmission exacerbate cardiac dysfunction in disease.