Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy

Peter Hanna; Donald B. Hoover; Logan G. Kirkland; Elizabeth H. Smith; Megan D. Poston; Stanley G. Peirce; Chloe G. Garbe; Steven Cha; Shumpei Mori; Jaclyn A. Brennan; John Andrew Armour; Eric Rytkin; Igor R. Efimov; Olujimi A. Ajijola; Jeffrey L. Ardell; Kalyanam Shivkumar

doi:10.1002/ar.25686

Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy

Peter Hanna^*, Donald B. Hoover, Logan G. Kirkland, Elizabeth H. Smith, Megan D. Poston, Stanley G. Peirce, Chloe G. Garbe, Steven Cha, Shumpei Mori, Jaclyn A. Brennan, John Andrew Armour, Eric Rytkin, Igor R. Efimov, Olujimi A. Ajijola, Jeffrey L. Ardell, Kalyanam Shivkumar

^*Corresponding author for this work

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

Abstract

Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure-perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.

Original language	English (US)
Journal	Anatomical Record
DOIs	https://doi.org/10.1002/ar.25686
State	Accepted/In press - 2025

Funding

We thank Drs. Richard Shemin, Murray Kwon, and Abbas Ardehali of the UCLA Division of Cardiac Surgery for their assistance with tissue procurement. We thank the OneLegacy Foundation, Washington Regional Transplant Community, and Gift of Hope Organ and Tissue Donor Network in Chicago for the donor hearts. We are grateful to Anthony A. Smithson and Arvin Roque\u2010Verdeflor of the UCLA Translational Research Imaging Center (Department of Radiology) for their support in computed tomographic data acquisition. We appreciate Research Operations Manager Amiksha S. Gandhi for her dedication to support our projects. This work was made possible by support from NIH grants OT2OD023848 and P01 HL164311 and Leducq grant 23CVD04 to Kalyanam Shivkumar, NIH NRSA Postdoctoral Fellowship F32HL152609 and American Heart Association Career Development Award 23CDA1039446 to Peter Hanna, and the UCLA Amara Yad Project ( https://www.uclahealth.org/medical-services/heart/arrhythmia/about-us/amara-yad-project ).

Keywords

cardiac innervation
cardiomyopathy
cholinergic
immunohistochemistry
intrinsic cardiac nervous system
neuronal remodeling
noradrenergic

ASJC Scopus subject areas

Biotechnology
Anatomy
Histology
Ecology, Evolution, Behavior and Systematics

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10.1002/ar.25686

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Hanna, P., Hoover, D. B., Kirkland, L. G., Smith, E. H., Poston, M. D., Peirce, S. G., Garbe, C. G., Cha, S., Mori, S., Brennan, J. A., Armour, J. A., Rytkin, E., Efimov, I. R., Ajijola, O. A., Ardell, J. L., & Shivkumar, K. (Accepted/In press). Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy. Anatomical Record. https://doi.org/10.1002/ar.25686

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title = "Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy",

abstract = "Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure-perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.",

keywords = "cardiac innervation, cardiomyopathy, cholinergic, immunohistochemistry, intrinsic cardiac nervous system, neuronal remodeling, noradrenergic",

author = "Peter Hanna and Hoover, \{Donald B.\} and Kirkland, \{Logan G.\} and Smith, \{Elizabeth H.\} and Poston, \{Megan D.\} and Peirce, \{Stanley G.\} and Garbe, \{Chloe G.\} and Steven Cha and Shumpei Mori and Brennan, \{Jaclyn A.\} and Armour, \{John Andrew\} and Eric Rytkin and Efimov, \{Igor R.\} and Ajijola, \{Olujimi A.\} and Ardell, \{Jeffrey L.\} and Kalyanam Shivkumar",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.",

year = "2025",

doi = "10.1002/ar.25686",

language = "English (US)",

journal = "Anatomical Record",

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T1 - Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy

AU - Hanna, Peter

AU - Hoover, Donald B.

AU - Kirkland, Logan G.

AU - Smith, Elizabeth H.

AU - Poston, Megan D.

AU - Peirce, Stanley G.

AU - Garbe, Chloe G.

AU - Cha, Steven

AU - Mori, Shumpei

AU - Brennan, Jaclyn A.

AU - Armour, John Andrew

AU - Rytkin, Eric

AU - Efimov, Igor R.

AU - Ajijola, Olujimi A.

AU - Ardell, Jeffrey L.

AU - Shivkumar, Kalyanam

PY - 2025

Y1 - 2025

N2 - Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure-perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.

AB - Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure-perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.

KW - cardiac innervation

KW - cardiomyopathy

KW - cholinergic

KW - immunohistochemistry

KW - intrinsic cardiac nervous system

KW - neuronal remodeling

KW - noradrenergic

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JF - Anatomical Record

ER -

Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy

Abstract

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Keywords

ASJC Scopus subject areas

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