The normal functioning of our hearts is maintained by the brain via an intricate network of nerves. As an added layer of safety, the heart has its own ‘little brain’, called the intracardiac nervous system (ICN) to monitor and correct any local disturbances in communication. The ICN is essential in supporting heart health and can even protect cardiac muscle during a heart attack. But it’s not clear how exactly the ICN carries out these roles, because the organization of the neurons that make up the ICN are poorly understood.
In a groundbreaking study published in iScience on May 26th, researchers at Thomas Jefferson University, in Philadelphia, Pennsylvania, and their collaborators have been able to answer these questions in unprecedented detail.
“The ICN represents a big void in our understanding that falls between neurology and cardiology,” said co-senior author James Schwaber, PhD, director of the Daniel Baugh Institute for Functional Genomics and Computational Biology (DBI) and co-senior author of the study. “Our goal was to bridge that gap by providing an anatomical framework of the ICN and a foundation to understand its role in heart health.”
“The only other organ for which such a detailed high-resolution 3D map exists is the brain,” said co-senior author Raj Vadigepalli, PhD, Professor of Pathology, Cell Biology and Anatomy. “In effect, what we have created is the first comprehensive roadmap of the heart’s nervous system that can be referenced by other researchers for a range of questions about the function, physiology, and connectivity of different neurons in the ICN.”
The study drew on technologies and expertise from different research groups (from Jefferson and University of Central Florida) and industry partners (Strateos and MBF Bioscience), eventually creating a dual-approach pipeline. One approach involved a novel imaging technique called Knife-Edge Scanning Microscopy (KSEM) that allowed the researchers to build a precise 3D model of the entire rodent heart; it is the first use of this technology for cardiac research. The second approach used a technique called laser capture microdissection to sample single neurons for gene expression analysis, as well as to precisely map their individual positions within the 3D structure of the heart.
The 3D map revealed hitherto unknown complexity of the ICN. The researchers found that the neurons that make up the ICN are found in a coherent band of clusters on the base (top) of the heart, where the heart’s veins and arteries enter and leave, but also extend down the length of the left atrium on the back of the heart. They are positioned close to certain key heart structures like the sinoatrial node.
When comparing male and female rat hearts, the researchers also found sex-specific differences in the way neurons were organized, both spatially and by their gene expression.
This project is part of a NIH research program called Stimulating Peripheral Activity to Relieve Conditions (SPARC), which aims to promote development of therapeutic devices that modulate electrical activity in nerves to improve organ function. “Around thirty years ago, there were studies showing peripheral nerves like the vagus nerve were critical for the health of organs like the heart and stimulating them could even remediate disease,” explained Dr. Schwaber. “But those studies were not able to tell us what amount, frequency and location of stimulation is beneficial or harmful.”
“Now that we know where neurons are located in relation to heart structures, we can ask questions like — does stimulating in one location, or even selectively stimulating specific neurons make a difference?” said Dr. Vadigepalli.
The researchers are delighted that the pipeline they created is now being used by other groups in the SPARC research program.
“Eventually the hope is to create a 3D map for the human heart, both in health and disease,” says Dr. Schwaber. “We’ve created the foundation for an endless possibility of future studies.”
- Achanta S, Gorky J, Leung C, et al. A comprehensive integrated anatomical and molecular atlas of rodent intrinsic cardiac nervous system. [published online ahead of print, 2020 May 23]. iScience. 2020;101140. doi:10.1016/j.isci.2020.101140