Intrinsic cardiac nervous system

The Intrinsic cardiac nervous system (ICNS), also known as the heart's "little brain," is a complex network of neurons and ganglia embedded within the heart tissue that regulates cardiac function independently of the central nervous system. It modulates heart rate, conduction, and cardiac contractility in response to local and external stimuli.^[1][2]

Anatomy

The ICNS consists of clusters of neurons, or ganglia, primarily located in the atrial and ventricular walls, with higher concentrations in the sinoatrial (SA) and atrioventricular (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 into ganglionated plexuses, interconnected by nerve fibers, forming a neural network around the heart.^[5][6][7]

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

Development

The ICNS originates from neural crest cells (NCCs) during embryonic development:^[1]

• Sympathetic neurons arise from trunk NCCs migrating along the dorsal aorta.
• Parasympathetic neurons derive from vagal NCCs and nodose placodes.
• Key factors like bone morphogenetic proteins (BMPs), PHOX2B, and HAND2 guide differentiation.

Function

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 and Purkinje fiber activity for coordinated contraction.
• Cardioprotection: Responds to ischemia or stress by altering cardiac output.

The ICNS interacts with the autonomic nervous system (ANS), receiving input from sympathetic and parasympathetic pathways, but can operate autonomously during disruptions, such as in heart transplants.^[1]

Physiology

ICNS neurons release neurotransmitters like acetylcholine, norepinephrine, and neuropeptides (e.g., substance P, neuropeptide Y, vasoactive intestinal peptide (VIP)).^[1][8] These mediate local signaling and modulate ion channels in cardiac cells, affecting cardiac action potentials and contractility. The system exhibits plasticity, adapting to chronic conditions like heart failure or hypertension.^[1][9]

Clinical significance

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

History

The ICNS was first described in the 19th century through histological studies of cardiac tissue. Advances in electrophysiology and imaging in the 20th century elucidated its functional role.^[1][10]