Article

Integrating the theories of Darwin and Bernoulli: Maladaptive baroreceptor network dysfunction may explain the pathogenesis of aortic aneurysms

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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.

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... Only two studies have mentioned anatomical innervation of the aortic arch, dated 80 years ago [52,53]. Studies on baroreceptors in humans have been based so far on physiological approaches, with few of them related to the aortic arch [54][55][56][57][58][59][60][61][62][63]. However, such physiological studies determine baroreflex sensitivity only indirectly by recording electrocardiography and beat-to-beat blood pressure over time, calculating changes in heart rate in response to changes in arterial blood pressure. ...
... Consequently, they deliver only scant information about the baroreceptor nature or function for diagnostic or therapeutic purposes. These studies have shown that the calculated baroreceptor sensitivity is markedly affected by age [58,59] and is significantly diminished by patients with arterial hypertension [59], often due to stiffening of the larger elastic arteries, especially the aorta. Additional possible causes include vessel wall remodeling and inflammation. ...
... Consequently, they deliver only scant information about the baroreceptor nature or function for diagnostic or therapeutic purposes. These studies have shown that the calculated baroreceptor sensitivity is markedly affected by age [58,59] and is significantly diminished by patients with arterial hypertension [59], often due to stiffening of the larger elastic arteries, especially the aorta. Additional possible causes include vessel wall remodeling and inflammation. ...
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Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms [6] Shah PK. Inflammation, metalloproteinases, and increased proteolysis: an emerging pathophysiological paradigm in aortic aneurysm
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  • Jk Lee
  • Jm Shipley
Pyo R, Lee JK, Shipley JM, et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest 2000;105:1641–9. [6] Shah PK. Inflammation, metalloproteinases, and increased proteolysis: an emerging pathophysiological paradigm in aortic aneurysm. Circulation 1997;96:2115–7.
Clinical practice. Small abdom-inal aortic aneurysms
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Powell JT, Greenhalgh RM. Clinical practice. Small abdom-inal aortic aneurysms. N Engl J Med 2003;348(19): 1895–1901.
Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms
  • R Pyo
  • Jk Lee
  • Jm Shipley
Pyo R, Lee JK, Shipley JM, et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest 2000;105:1641-9.
Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms
  • Pyo