title: The link between carotid artery disease and ischemic stroke may be partially attributable to autonomic dysfunction and failure of cerebrovascular autoregulation triggered by Darwinian maladaptation of the carotid baroreceptors and chemoreceptors.
abstract: Carotid artery stenosis is generally thought to induce stroke by either compromising cerebral perfusion or inciting embolic phenomena. Carotid baroreceptors and chemoreceptors are vital adaptations for cerebrovascular autoregulation that can behave mal-adaptively in the setting of modern diseases such as atherosclerosis. We hypothesize that acute cerebrovascular events may be partially attributable to autonomic dysfunction and cerebrovascular autoregulatory failure secondary to carotid sensor maladaptations. Specifically, we propose that atherosclerotic disease at the carotid bifurcation can interfere with baroreceptor and chemoreceptor function by buffering against accurate detection of physical and chemical parameters. Misperceptions of hypoxia and hypotension can trigger sympathetic bias and autonomic dysfunction which perturb cerebrovascular autoregulation and vasomotor tone, thereby compromising cerebral perfusion. The preferential association of strokes with morning arousal, stress, acute physical activity, winter months, illness, and older age may relate to this phenomenon. Sympathetic bias promotes inflammation and coagulation, a link likely forged during prehistoric evolution when trauma represented a more significant factor in natural selection. In the setting of carotid sensor dysfunction, the resulting inflammation and coagulation can promote acute cardiovascular events. The ensuing cerebral ischemia can induce further derangement of cerebrovascular autoregulation and upregulate adrenergia, inflammation, and coagulation in a feed-forward manner. Inflammation and coagulation can also exacerbate carotid sensor dysfunction by iteratively worsening atherosclerosis. Angioplasty, stenting, and endarterectomy may inadvertently cause acute and chronic carotid sensor dysfunction through manipulation, material interposition, and balloon-induced baroreceptor injury. Acute strokes during these procedures may result from carotid sensor dysfunction rather than embolization. Carotid body and sinus electro-modulation and non-balloon atherectomy represent new methods to prevent or treat cerebrovascular events. Pharmacologic modulation of autonomic balance, such as adrenergic blockade, long presumed contraindicated due to risk of cerebral hypoperfusion, may counter-intuitively offer benefit during acute strokes. Novel diagnostic paradigms may include functional analysis of carotid sensors as well as measurement of the anatomic thickness of calcified and non-calcified plaque near the carotid body. Carotid sensor dysfunction may be a source of systemic sympathetic bias and autonomic dysfunction observed during aging and, by association, many of the ailments associated with senescence. Modulation of carotid sensors may yield pervasive health benefits beyond those found by treating cerebrovascular disease.
authors.affiliation: Department of Dermatology, Stanford University Medical Center, Palo Alto, CA 94301, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Doux
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Yun
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D001342:Autonomic Nervous System Diseases / Q000150:complications*; D002545:Brain Ischemia / Q000209:etiology*; D002340:Carotid Artery Diseases / Q000209:etiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002628:Chemoreceptor Cells / Q000293:injuries / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000150:complications; D011311:Pressoreceptors / Q000293:injuries / Q000502:physiology*; D014656:Vascular Surgical Procedures / Q000009:adverse effects