The Intrinsic Cardiac Nervous System: From Pathophysiology to Therapeutic Implications

Abstract

The cardiac autonomic nervous system (CANS) plays a pivotal role in cardiac homeostasis as well as in cardiac pathology. The first level of cardiac autonomic control, the intrinsic cardiac nervous system (ICNS), is located within the epicardial fat pads and is physically organized in ganglionated plexi (GPs). The ICNS system does not only contain parasympathetic cardiac efferent neurons, as long believed, but also afferent neurons and local circuit neurons. Thanks to its high degree of connectivity, combined with neuronal plasticity and memory capacity, the ICNS allows for a beat-to-beat control of all cardiac functions and responses as well as integration with extracardiac and higher centers for longer-term cardiovascular reflexes. The present review provides a detailed overview of the current knowledge of the bidirectional connection between the ICNS and the most studied cardiac pathologies/conditions (myocardial infarction, heart failure, arrhythmias and heart transplant) and the potential therapeutic implications. Indeed, GP modulation with efferent activity inhibition, differently achieved, has been studied for atrial fibrillation and functional bradyarrhythmias, while GP modulation with efferent activity stimulation has been evaluated for myocardial infarction, heart failure and ventricular arrhythmias. Electrical therapy has the unique potential to allow for both kinds of ICNS modulation while preserving the anatomical integrity of the system.

Keywords: cardiac autonomic nervous system; cardioneuroablation; ganglionated plexi ablation; intrinsic cardiac nervous system; neuromodulation.

Figure 1

Cardiac nervous system functional and anatomical organization in humans. Blue: afferent nervous system with its ganglia and the peripheral receptors: nodose ganglia and C7-T4 dorsal root ganglia (DRG). Green: parasympathetic efferent nervous system. Red: sympathetic efferent nervous system. Purple: local circuit neurons (or interneurons). All the afferent and efferent structures except for the autonomic nuclei in the central nervous system are bilateral, although mostly represented as unilateral for simplicity. Cardiac afferent fibers traveling across the paravertebral sympathetic ganglia (usually referred to as cardiac sympathetic afferent fibers) directly reach the DRG without having synapses before. Created with Biorender.

Figure 2

Anatomy of the intrinsic cardiac nervous system. On the left is the anterosuperior view, on the right is the posteroinferior view. The intrinsic cardiac nervous system includes all kinds of neurons, namely sensory neurons, motor neurons and local circuit neurons (or interneurons), and therefore all the basic constituents of neural circuits. These neurons are located within the ganglionated plexi (GPs) that are found in distinct areas of the heart. As extensively described in the text, GP exerts preferential, but not exclusive, influence over specific regions. For instance, the right atrial GP (RAGP, recently renominated superior paraseptatal GP or SPSGP) primarily controls sinoatrial nodal function, while the posteromedial left atrial GP (PMLGP, recently renominated inferior paraseptal GP or IPSGP) primarily controls atrioventricular nodal function. CMVGP: craniomedial ventricular GP, CS: coronary sinus, DAGP: dorsal atrial GP, LA: left atrium, LAGP: left atrial GP, IPSGP: inferior postero-septal GP, PA: pulmonary artery, RA: right atrium, RVGP: right ventricular GP, PMLGP: left atrial GP, SPSGP: superior postero-septal GP, SVC: superior vena cava. Created with Biorender.