Carotid Sinus as a Mechanotransducer of Shear Oscillation

Objective The carotid sinus is a region in the cardiovascular system where flow characteristics are transduced by the autonomic nervous apparatus to help maintain cardiovascular homeostasis. The objective of this study is therefore to determine whether the carotid sinus acts as a mechanotransducer of wall shear stress oscillation. Results By utilizing magnetic resonance angiograms of undiseased carotid bifurcations, computational fluid dynamic simulations of blood flow were constructed. Employing boundary conditions meant to emulate normal blood flow at rest, the oscillatory shear index (OSI) was tabulated and mapped. The areas of highest OSI were well-isolated in the regions of the carotid bifurcations generally considered to comprise the carotid sinus.


Introduction
The Endothelium as a Mechanotransducer Vascular endothelium is a dynamic system responsible for both local and systemic control of many functions involved in autonomic homeostasis. As the intermediary between the flow of blood and vascular walls, the endothelium has many functions [1] but perhaps the most significant one is transduction of hemodynamic information from the blood to the underlying vessel wall [2].
Particularly, the anatomy of the carotid sinus nerve (CSN), with extensive communications between the sympathetic and parasympathetic fibers along its course from the skull base to the dilated portion of the origin of the internal carotid artery just distal to the common carotid bifurcation, supports its role as a substrate for the complex mechanisms by which the body maintains cardiovascular homeostasis. From the earliest descriptions in the 1950's [4], the literature describes the "baroreceptor" role of the carotid sinus, as that is clinically measurable and thereby relevant. The importance of blood pressure control for so many fields in medicine means the complexities of blood pressure homeostasis remain a much studied area.

The Carotid Sinus as a Mechanotransducer of Shear Oscillation
The location of the CSN makes it well suited to transducing flow characteristics only possible in an area such as the carotid sinus -namely just distal to a bifurcation in an area above the heart at an immediate tributary just off the left ventricular outflow tract.
Flow at a bifurcation allows for breakup of the smooth laminar flow, and the eddies created result in shear forces that can be directed, and therefore detected, at the vessel wall. To do so at the base of the internal carotid is appropriate when considering the distribution of blood flow between the external and internal carotid arteries, as noted by Sato and colleagues [5]. They found that, compared to rest, the blood flow in the internal carotid remained somewhat close to baseline whereas in the external carotid blood flow increased proportionally with increased common carotid blood flow. This phenomenon of maintaining internal carotid flows at baseline levels even in the setting of doubling cardiac work, supports the role of the carotid sinus as part of the cardiovascular homeostatic apparatus.
Therefore, the aim of this study is to examine if normal blood flow present at the carotid sinus allows it to be suitable as a sampling site for transduction of shear stress oscillation.
Our hypothesis states that if the areas of increased shear stress oscillation in normal carotid bifurcations coincides with sites where the CSN is seen to enter the vessel wall of the internal carotid, then the carotid sinus may be acting as a mechanotransducer of wall shear oscillation.

Methods
In this study, numerical simulations of blood flow in normal human carotid bifurcations were carried out to evaluate the wall shear characteristics in the region where the CSN is noted to insert into the wall adventitia. The blood is assumed to be incompressible Newtonian fluid. The Virtual Flow Simulator (VFS) code [6] is employed to simulate the blood flow in the carotid bifurcation. In VFS the blood flow is governed by the following incompressible Navier-Stokes equation and continuity equation: [Formula could not be included here. It can be found in the "Formulas" supplemental file.
See there also for missing characters denoted below by *** This is formula 1] where *** the fluid density, *** is the blood velocity, *** is the time, *** is the pressure, *** is the dynamic viscosity. In the present work, *** , and *** . The geometry of the carotid is represented using the immersed boundary (IB) method [7]. The wall of the carotid is assumed to be rigid. In simulations the carotid geometry, which is discretized using triangular meshes, is obtained based on magnetic resonance angiograms performed on patients admitted to Stony Brook Medical Center who underwent scans as part of an institutional stroke imaging protocol. The angiograms images were reviewed and obtained after approval by the institutional review board. Eleven angiograms were randomly selected for review from scans performed over a three month period in 2018. These images were reviewed anonymously. The criteria for selection included 1) that the images had to be obtained utilizing the same imaging protocol on the same scanner, 2) the angiograms had to be free of disease or filling defects of any kind, 3) the images themselves had to be sufficiently free of motion artifact, and 4) the patients had to be adults, the images had to be of the right carotid bifurcation. Of these initial scans, six met the criteria (1 female, 5 males) and were processed to create the mesh for simulation. To process each scan, 3D-TOF MRA data was cropped from the region containing the bifurcation. The 3D data was reconstructed using open-source software 3D-Slicer 4.8.1 [8] (www.slicer.org) in order to create a volume rendering. This rendering was imported into a stereolithography (STL) file and then used to create the grid.

Discussion
Initiators and transducers of vascular endothelial have been studied extensively. The importance of vascular endothelial function for homeostasis in various organ systems cannot be overstated; it spans cardiac [9], pulmonary [10], renal [11], hepatic [12], and other functions. This pervasive significance of endothelial function cannot be achieved without its ability to transduce and transmit local flow information to the organs surrounding the blood vessel. The process starts with transduction of local mechanical blood flow data, particularly wall shear stress, or mechanotransduction [13]. These blood flow characteristics are then transmitted to the surrounding vessel wall and parenchyma by the cytoskeletal anatomy of the cells which transmits wall shear forces across cells as well as by plasma membrane proteins, mechanosensitive ion channels, and abluminal cell surface adhesions [1]. These, in turn, utilize G-protein, Mitogen, and other intracellular pathways to transmit this data to broadcast it to subsequent cells along a specific pathway meant to effect a particular function. In this way, the autonomic nervous system consolidates this data from various sites where blood flow information is transduced to create a cohesive homeostatic system optimizing functioning and blood flow across various organ systems.
The location and shape of the sinus and its nerve at the base of the internal carotid is unique for a number of reasons. The dilated segment at the base of the internal carotid allows for an area of "recirculation" [14]. This area of recirculation where the laminar flow Our study shows that the areas of highest OSI qualitatively correlate well to the areas where the CSN is understood to be located within the adventitia of the carotid bifurcation.
The lower values of OSI in the regions excluding the carotid sinus support the notion that the flow shear characteristics are unique to the sinus region. When framing the discussion of the physiology of the carotid sinus, it is referred to as a baroreceptor, in part, because blood pressures can be directly measured in the experimental setting. By recasting the understanding of the carotid sinus as a mechanotransducer of WSS, we as clinicians may be closer to understanding what the autonomic nervous system is directly measuring. This suggests the possibility that future studies can focus on measurable parameters known to alter the shear characteristics of blood flow. Anesthesiologists can include "endothelial function" in the list of end-organ function (along with cardiac, pulmonary, and renal functions) considered in the calculus of proper perioperative resuscitation. Therefore "normal" OSI, or some proxy thereof, may represent a clinical end-point against which we can consider fluid and blood management in the clinical setting when assessing cardiovascular homeostasis.

Limitations
The small sample size may contribute to a lack of generalizability of the hypothesis that the carotid sinus may be a mechanotransducer of flow shear oscillation. Furthermore, the gender distribution of the subjects in the study may suggest that the OSI may isolate the CSN region well in males but not necessarily in females. Also, since the vessel diameter in males is larger when compared to females, the effect on shear oscillation and the relative effects of viscosity on the region of recirculatory flow has to be considered.

Declarations
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Supplementary Files
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