title: Integrating the theories of Darwin and Bernoulli: maladaptive baroreceptor network dysfunction may explain the pathogenesis of aortic aneurysms.
abstract: Current treatment options for aortic aneurysms are suboptimal and their pathogenic mechanisms remain unclear. We propose the existence of a coordinated multi-node baroreceptor network that measures pressures at all vascular bifurcations and enables system-wide hemodynamic coordination and vasomotor regulation, in accordance with the principle of Bernoulli. While the presence of baroreceptors at bifurcations remains unknown, behavior at the level of systems predicts their existence, possibly as glomus cell derivatives. We propose that pressure misregistration among sensor nodes at different vascular bifurcations can precipitate feed-forward dysfunctions that promote thrombosis, inflammation, and vasomotor dysregulation resulting in aneurysm formation. One example of this phenomenon is aortic aneurysm, which is currently attributed to focal anatomic defects. As plaque builds in the infrarenal aorta, the increased blood velocity through this segment can widen the difference between pressures sensed at the iliac and the renal artery bifurcations. Due to the Bernoulli effect, this change creates an incorrect impression of reduced dynamic pressure at the kidneys. The erroneous perception of hypovolemia can induce a pernicious cycle of maladaptive adrenergia and associated coagulation and thrombosis, particularly in the infrarenal aortic segment as the body attempts to normalize renal perfusion. Atherosclerosis can further exacerbate baroreceptor dysfunction by interfering with sensor biology in feed-forward fashion. Hypertension may be a consequence as well as a source of atherosclerosis and aneurysm. The described system may have evolved when trauma-related hypovolemia was a far more prevalent driver of natural selection but may be rendered maladaptive in the setting of modern stressors. Failure to address these factors may explain the suboptimal long-term outcomes with current surgical and endovascular treatments for aneurysms. Implications for other potential sensor networks including chemoreceptors and lymphoid tissues at bifurcating biologic branch-points such as vessels, airways, nerves, lymphatics, and ducts are discussed. Our framework may also provide a new basis for understanding thoracic aneurysm, renovascular dysfunctions, coronary artery disease, carotid artery disease, pulmonary embolism, portal hypertension, venous thrombosis, biliary disease, pancreatic disease, and neurologic disease. Novel treatment paradigms based on drugs or interconnected networks of devices that modulate sensors are envisioned. Improving the interface between sensors and their substrate information by techniques such as minimally traumatic atherectomy or thrombectomy may also restore appropriate sensor function. Lessons learned from bifurcation sensors and their potential maladaptations may generalize to other types of branching systems including botany, civil engineering, and Pitot tube aeronautics.
authors.affiliation: Palo Alto Institute, Palo Alto, CA, USA.
authors.forename: Buford R
authors.initials: BR
authors.lastname: Conley
authors.forename: John D
authors.initials: JD
authors.lastname: Doux
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Lee
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bazar
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Daniel
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Yun
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000209:etiology / Q000473:pathology*; D005075:Biological Evolution; D001794:Blood Pressure; D006801:Humans; D007249:Inflammation; D007700:Kinetics; D008962:Models, Theoretical; D011311:Pressoreceptors / Q000737:chemistry / Q000502:physiology*