Chronic intermittent hypoxia (CIH), is a well-established model for sleep apnea and is a major risk factor for various cardiovascular diseases (CVDs). Autonomic imbalance, particularly sympathetic overactivity and parasympathetic withdrawal, has emerged as a pivotal contributor for CIH-induced cardiovascular diseases (including hypertension, arrhythmia, baroreflex impairment and heart failure). Despite understanding the functional alterations linked to CIH, the potential structural remodeling of cardiac sympathetic innervation remains unclear. Understanding the sympathetic neuroanatomical structural changes associated with CIH will give insights into the functional alterations associated with CIH-induced CVDs and facilitate development of effective therapeutic approaches.
Previously, together with collaborators, the research team led by Dr. Zixi Jack Cheng provided a map for sympathetic innervation in the heart atria in healthy conditions. In their new study published today in the Journal of Physiology, they extended their work utilizing a 3D scaffold mapping tool from the NIH SPARC program to determine the distribution of cardiac sympathetic innervation remodeling following CIH exposure. To accomplish this work, Dr. Cheng led his team (including the co-first authors Drs. Ariege Bizanti and Yuanyuan Zhang; University of Central Florida), as well as Dr. David Gozal at University of Missouri, and Dr. Julian F.R. Paton at University of Auckland. SPARC Data and Resource Center members Drs. Peter Hunter, Dr. Richard Christie, Maci Heal and Dr. Susan Tappan further collaborated with the international research team to spatially fit a common coordinate framework cardiac model with the data.
“The SPARC organ scaffolds provide a common coordinate system for registering multiple data sets into an anatomically accurate spatial framework. Jack Cheng’s lab uses the mouse heart scaffold to visualize the spatial relationships between sympathetic and parasympathetic innervation of the left and right atria. These spatial data can then be used in physiological modelling of autonomic regulation of myocardial function in health and disease.”
Peter Hunter, Distinguished Professor and founder of the Auckland Bioengineering Institute at the University of Auckland
For example, in this new study, they integrated the traced data in normal and CIH conditions onto the 3D heart scaffold to visualize the remodeling of autonomic innervation of the atria in a more intuitive way (Figure 1). The 3D mapping undertaken in this study serves as a valuable tool to deepen our understanding of the neuroanatomical pathophysiology underlying CIH-induced autonomic remodeling.
The findings uncovered significant remodeling of sympathetic innervation in the atria induced by CIH, manifesting as increased regional innervation density and number of axon branching points. Thus, this work underscores a significant correlation between the structural alterations in sympathetic innervation of the heart induced by CIH and the established functional changes (including hypertension, atrial fibrillation and heart failure), ultimately contributing to CIH-induced cardiovascular diseases. The current study supports the hypothesis that CIH triggers autonomic imbalance, partly mediated by structural remodeling of cardiac innervation. Furthermore, the anatomical techniques and methodologies applied in this study offer an anatomical foundation that can be extrapolated to explore numerous other pathological conditions leading to autonomic dysfunction. Read more about the experiment here
Figure 1: Extensive mapping of innervation of the left and right atrium on the 3D heart scaffold. Axon innervation in the entire atria was digitally traced (yellow). Through the smooth fitting of corresponding parts of the anatomical scaffold to annotated features of the atrium with SPARC scaffold software, an optimal fit for all data set in room air (RA, left) and chronic intermittent hypoxia (CIH, right) conditions is achieved.
