TheIntrinsic cardiac nervous system (ICNS), also known as the heart's "little brain," is a complex network ofneurons andganglia embedded within theheart tissue that regulatescardiac function independently of thecentral nervous system. It modulatesheart rate,conduction, andcardiac contractility in response to local andexternal stimuli.^[1][2] It forms part of theautonomic nervous system.

The ICNS consists of clusters of neurons, or ganglia, primarily located in theatrial andventricular walls, with higher concentrations in thesinoatrial (SA) andatrioventricular (AV) nodes.^[1][3] These ganglia contain:^[1][4]

• Afferent neurons: Detect mechanical and chemical changes in the heart.
• Efferent neurons: Modulate cardiac muscle activity.
• Interneurons: Facilitate communication within the ICNS.
• The system is organized intoganglionated plexuses (ganglionated plexi organlionic plexi;GP), interconnected bynerve fibers, forming aneural network around the heart.^[5][6][7][8]

The distribution of ganglia varies across species, with largermammals (e.g., humans, dogs) having more extensive networks than smaller mammals (e.g., mice, rats).^[1]

Cholinergic neurons throughout the GPs project to all areas of the heart.^[9] The GP are embedded in theepicardial fat pads, consisting of only a fewneurons or as many as 400 neurons.^[8]

Post ganglionic neurons from the vagal nerve pathways are components of theLigament of Marshall, forming part of the "intrinsic" heart nervous system.^[10]

There are intrinsic plexi that form part of theautonomic nervous system (ANS),^[11] the best known intrinsic plexus being theenteric nervous system. The GP are part of the cardiac intrinsic ANS.^[12]

In humans, the ganglia are mostly associated with the posterior or superior aspect of the atria.^[13] The ganglia mediate at least some of the effects ofvagal nerve stimulation on thesinoatrial node, although don't seem to mediate atrioventricular node conduction.^[14]

The ICNS originates fromneural crest cells (NCCs) duringembryonic development:^[1]

• Sympathetic neurons arise from trunk NCCs migrating along thedorsal aorta.
• Parasympathetic neurons derive from vagal NCCs andnodoseplacodes.
• Key factors likebone morphogenetic proteins (BMPs),PHOX2B, andHAND2 guide differentiation.

The ICNS integrates sensory information from the heart and coordinates local reflexes.^[1] Key functions include:^[1][5]

• Heart rate regulation: Adjusts SA node activity in response to stretch or chemical signals.
• Conduction modulation: Influences AV node andPurkinje fiber activity for coordinated contraction.
• Cardioprotection: Responds toischemia or stress by alteringcardiac output.

The ICNS interacts with theautonomic nervous system (ANS), receiving input fromsympathetic andparasympathetic pathways, but can operate autonomously during disruptions, such as inheart transplants.^[1]

ICNS neurons releaseneurotransmitters likeacetylcholine,norepinephrine, andneuropeptides (e.g.,substance P,neuropeptide Y,vasoactive intestinal peptide (VIP)).^[1][15] These mediate local signaling and modulateion channels incardiac cells, affectingcardiac action potentials andcontractility. The system exhibits plasticity, adapting to chronic conditions likeheart failure orhypertension.^[1][16]

Vagus nerve stimulation has been shown to inhibit the activity of the GP, possibly through nerves that expressNav1.8 (a sodium channel subtype that is necessary for action potentials in these nerves),^[17] but combining GP ablation with pulonary vein isolation may be a superior option.^[18]

In animal models, cardiac overload leads to change in the electrophysiological properties of these neurons, leading to the suggestion that such changes might be relevant to the pathophysiology ofheart failure.^[19]

Dysfunction in the ICNS is implicated inarrhythmias (atrial fibrillation),sick sinus syndrome, heart failure, andsudden cardiac death. Its role indenervated hearts (e.g., post-transplant) highlights its capacity for independent function. Research explores ICNS-targeted therapies, such asneuromodulation, to treat cardiac disorders.^[1]

GP are spatially close to thepulmonary veins, so pulmonary vein isolation necessarily affects the GP.^[20][21] GP has been shown to be a contributor toatrial fibrillation (AFib), such that ablation of the GP has been a strategy for treatment of AFib.^[8] GP ablation alone has been shown to eliminate AFib in approximately three-quarter of AFib patients.^[8]

Ligation of theleft atrial appendage may reduce AFib by alteration of the GP.^[22]

The ICNS was first described in the 19th century throughhistological studies of cardiac tissue. Advances inelectrophysiology andimaging in the 20th century elucidated its functional role.^[1][23]

• Cardiac anatomy

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