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

doi:10.1016/j.mehy.2005.03.016

Medical Hypotheses

Volume 66, Issue 1, 2006, Pages 176-181

https://doi.org/10.1016/j.mehy.2005.03.016 Get rights and content

Summary

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 maladaptively 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 electromodulation 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 counterintuitively 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.

Section snippets

Hypothesis

Carotid artery stenosis is generally thought to induce stroke by either compromising cerebral perfusion or inciting embolic phenomena. Baroreceptors and chemoreceptors situated in structures at the carotid bifurcation represent vital adaptations for cerebrovascular autoregulation. These sensors can behave maladaptively in the setting of modern diseases such as atherosclerosis, which can create sensor misregistration unanticipated by evolution. We hypothesize that acute cerebrovascular events

Stroke and carotid stenosis

Stroke is the third leading cause of death in the United States [1]. Each year, more than 700,000 strokes lead to 150,000 deaths [2]. Carotid artery disease is a major cause of ischemic stroke [3]. Internal carotid artery stenosis is responsible for approximately 30% of ischemic strokes [4]. The most common site of stenosis is the proximal portion of the internal carotid artery known as the carotid bulb [5].

In patients with carotid artery disease, the risk of stroke is directly related to the

Implications

Autonomic dysfunction constitutes a recognized response to decreased brain perfusion [30]. By interpreting existing clinical evidence within a new paradigm of baroreceptor and chemoreceptor function, we have reason to believe that it can also be invoked as a cause of ischemic events.

Numerous therapeutic implications for stroke are apparent from this model. The use of adrenergic antagonists in the setting of cerebral ischemia is currently minimal due to the fear of inducing a decrease in

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Cited by (24)

A New Neuropathologic Mechanism of Blood pH Irregularities After Neck Trauma: Importance of Carotid Body−Glossopharyngeal Nerve Network Degeneration
2019, World Neurosurgery
Citation Excerpt :
In addition, according to Chang et al,24 the CB is stimulated by hypercapnia and low pH, in addition to hypoxia. Doux et al25 reported that CBs have vital functions in cerebrovascular and cardiorespiratory autoregulation and that CB dysfunction can result in cerebrovascular and cardiorespiratory autoregulation disorders. The CB initiates compensatory reflex adjustments to maintain homeostasis by monitoring blood characteristics (e.g., low PaO2) in the body.
We created a neck trauma model by injecting blood into the sheath of rabbits' carotid bodies (CBs). Then we determined the relationship between neuronal degeneration of the CB due to hemorrhage of this organ and its clinical effects such as blood pH and heart rhythm.
The present study included 24 adult male New Zealand rabbits. The animals were divided into 3 groups: control (n = 5); sham (0.5 mL saline injected into CBs; n = 5); and study (CB trauma model; n = 14). pH values and heart rhythms were recorded before the experiment to determine the values under normal conditions, and measurements were repeated thrice in the days following the experiment. The number of normal and degenerated neuron density of CBs was counted. The relationship between the blood pH values, heart rhythms, and degenerated neuron densities was analyzed.
Heart rhythms were 218 ± 20 in the control group, 197 ± 16 in the sham group (P = 0.09), and 167 ± 13 in the study group (P < 0.0005). pH values were 7.40 ± 0.041 in the control group, 7.321 ± 0.062 in the sham group (P = 0.203), and 7.23 ± 0.02 in study group (P < 0.0005). Degenerated neuron densities were 12 ± 4/mm³ in the control group, 430 ± 74/mm³ in the sham group (P < 0.005), and 7434 ± 810/mm³ in the study group (P < 0.0001).
A high degenerate neuron density in the CB can decrease blood pH and hearth rhythm after neck trauma, and there might be a close relationship between the number of degenerated neurons and clinical findings (such as heart rhythm and blood pH). This relationship suggests that injury to the glossopharyngeal nerve−CB network can cause acidosis by disturbing the breathing-circulating reflex and results in respiratory acidosis.
A New Determinant of Poor Outcome After Spontaneous Subarachnoid Hemorrhage: Blood pH and the Disruption of Glossopharyngeal Nerve–Carotid Body Network: First Experimental Study
2017, World Neurosurgery
The chemoreceptor network, consisting of the glossopharyngeal nerve and carotid body (GPN-CB), is essential for the regulation of blood pH. Its ischemic insults after subarachnoid hemorrhage (SAH), which may contribute to acidosis, have not been investigated.
Twenty-three hybrid rabbits were used. They were divided into 3 groups: 5 as a control group, 5 as a sham group, and the remaining 13 as the study group. Injections included 1 cm³ serum saline and 1 cm³ autolog arterial blood into the cisterna magna in the sham and study group, respectively. Blood pH values of all animals were recorded. After 2 weeks, animals were euthanized. The number of normal and degenerated neurons of the carotid bodies (CBs) was counted by stereologic methods and analyzed statistically.
Two of 13 rabbits died within the second week. The mean blood pH values were measured as 7.35 ± 0.07 in the control group (n = 5), 7.33 ± 0.06 in the sham group (n = 5), 7.29 ± 0.05 in rabbits with slight acidosis (n = 6), and 7.23 ± 0.02 in rabbits with prominent acidosis (n = 7). In the control group, the average normal neuronal density of the CBs was 6432 ± 790/mm³ and the degenerated neuron density was 11 ± 3/mm³, whereas the degenerated neuronal density in CBs was 35 ± 8/mm³ in the sham group and 1034 ± 112/mm³ in the slight acidosis–developed group (n = 6; P < 0.05). Conversely, degenerated neuron density of CBs was 2134 ± 251/mm³ in the prominent acidosis–developed animals (n = 7; P < 0.005). Interestingly, in the rabbits who died, the degenerated neuron density of the CB was 3160 ± 840/mm³.
An inverse relationship between neurodegeneration in the CB and pH values secondary to the disruption of the GPN-CB network after SAH was found, which may contribute to developing acidosis.
Systematic review and meta-analysis of postcarotid endarterectomy hypertension after eversion versus conventional carotid endarterectomy
2017, Journal of Vascular Surgery
Blood pressure (BP) instability after carotid endarterectomy (CEA) is a risk factor for cerebrovascular and cardiovascular complications. The role of the operative technique in the development of post-CEA hemodynamic instability is unclear. The primary goal of this study was to systematically review the literature to determine whether hypertension in the early postoperative period is dependent on the surgical technique used.
We searched MEDLINE, Cochrane CENTRAL, and Web of Science through June 2016 without restrictions to language or starting date. The interventions of interest were eversion CEA (E-CEA) compared with conventional CEA (C-CEA) with or without patch plasty. The primary outcome of interest was the incidence of postoperative need for vasodilator therapy because of hypertension in the early postoperative period, the duration of which was predefined in the individual studies. Secondary outcomes were the intergroup mean difference of the mean within-group changes of postoperative (24 hours) to baseline systolic BP, the incidence of hypotension requiring vasopressor therapy, and the rate of complications. The odds ratio (OR) of each binary outcome was pooled across studies with its 95% confidence interval (CI). For meta-analysis of continuous outcomes, the weighted mean differences with the corresponding 95% CIs were pooled. Strength of evidence of the outcomes was judged according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines.
We identified six studies, of which four were nonrandomized prospective and two retrospective with low to moderate risk of bias. In addition, results of a post hoc analyses of a randomized controlled trial were included, resulting in a total number of seven included studies. Duration of the postoperative study period ranged from 1 to 6 days. The meta-analysis of all studies regarding the primary outcome demonstrated increased rates of post-CEA hypertension after E-CEA (pooled OR, 2.75; 95% CI, 1.82-4.16; I² = 49.9%). The pooled weighted intergroup mean difference between the E-CEA and C-CEA effects on postoperative systolic BP was +12.92 mm Hg (95% CI, 8.06-17.78; I² = 93.6%; P < .0001). Hypotension was significantly higher in the C-CEA group (pooled OR, 11.37; 95% CI, 1.95-66.46; I² = 0%). There was no difference in postoperative complications including myocardial infarction, stroke, neck hematoma, or death. Strength of evidence contributing to the primary outcome as well as the hypotension outcome was graded as moderate and that contributing to the other secondary outcomes was graded as very low.
E-CEA increases the risk for post-CEA hypertension, whereas C-CEA is more often associated with hypotension, Careful BP monitoring at least in the early postoperative period after CEA is mandatory, especially when the eversion technique is used.
Sleep apnea and asymptomatic carotid stenosis: A complex interaction
2015, Chest
Citation Excerpt :
Because CSA is not exclusively associated with carotid stenosis, patients with concomitant diseases predisposing to CSA were excluded from the study. Because we excluded patients with high probability for CSA due to other reasons, CSA in our cohort may be considered as a functional consequence of the carotid stenosis.8,12 Even though our observational data do not allow us to address the underlying mechanisms of CSA in carotid stenosis, there are several facts supporting a potential link between CSA and carotid stenosis-mediated chemoreceptor dysfunction.
BACKGROUND: Carotid arteriosclerosis and sleep apnea are considered as independent risk factors for stroke. Whether sleep apnea mediates severity of carotid stenosis remains unclear. Sleep apnea comprises two pathophysiologic conditions: OSA and central sleep apnea (CSA). Although OSA results from upper airway occlusion, CSA reflects enhanced ventilatory drive mainly due to carotid chemoreceptor dysfunction.
METHODS: Ninety-six patients with asymptomatic extracranial carotid stenosis of ≥ 50% underwent polysomnography to (1) determine prevalence and severity of sleep apnea for different degrees of carotid stenosis and (2) analyze associations between OSA and CSA, carotid stenosis severity, and other arteriosclerotic risk factors.
RESULTS: Sleep apnea was present in 68.8% of patients with carotid stenosis. Prevalence and severity of sleep apnea increased with degree of stenosis (P≤ .05) because of a rise in CSA (P≤ .01) but not in OSA. Sleep apnea (OR, 3.8;P≤ .03) and arterial hypertension (OR, 4.1;P≤ .05) were associated with stenosis severity, whereas diabetes, smoking, dyslipidemia, BMI, age, and sex were not. Stenosis severity was related to CSA (P≤ .06) but not to OSA. In addition, CSA but not OSA showed a strong association with arterial hypertension (OR, 12.5;P≤ .02) and diabetes (OR, 4.5;P≤ .04).
CONCLUSIONS: Sleep apnea is highly prevalent in asymptomatic carotid stenosis. Further, it is associated with arteriosclerotic disease severity as well as presence of hypertension and diabetes. This vascular risk constellation seems to be more strongly connected with CSA than with OSA, possibly attributable to carotid chemoreceptor dysfunction. Because sleep apnea is well treatable, screening should be embedded in stroke prevention strategies.
Role of adenosine A2A receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control
2011, Toxicology and Applied Pharmacology
Citation Excerpt :
Remarkably, reported findings established critical modulatory roles for autonomic and adenosinergic profiles in cardiovascular pathophysiology. Impairment of autonomic and baroreflex modalities contributes to hypertension, coronary artery disease and ischemic stroke (Doux and Yun, 2006; Kougias et al., 2010). On the other hand, adenosine diminishes myocardial injury following myocardial infarction (Hodge et al., 1998) and A2A adenosine receptor activation guards against atherosclerosis (McPherson et al., 2001) prevents progression of atherosclerosis via upregulating proteins involved in reverse cholesterol transport and prevention of foam cell transformation (Reiss et al., 2004).
Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine–baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1–16 μg/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious rats; slopes of the curves were taken as measures of baroreflex sensitivity (BRS). Nicotine (25 and 100 μg/kg i.v.) dose-dependently reduced BRS_SNP in contrast to no effect on BRS_PE. BRS_SNP was also attenuated after intracisternal (i.c.) administration of nicotine. Similar reductions in BRS_SNP were observed in rats pretreated with atropine or propranolol. The combined treatment with nicotine and atropine produced additive inhibitory effects on BRS, an effect that was not demonstrated upon concurrent exposure to nicotine and propranolol. BRS_SNP was reduced in preparations treated with i.c. 8-phenyltheophylline (8-PT, nonselective adenosine receptor antagonist), 8-(3-Chlorostyryl) caffeine (CSC, A_2A antagonist), or VUF5574 (A₃ antagonist). In contrast, BRS_SNP was preserved after blockade of A₁ (DPCPX) or A_2B (alloxazine) receptors or inhibition of adenosine uptake by dipyridamole. CSC or 8-PT abrogated the BRS_SNP depressant effect of nicotine whereas other adenosinergic antagonists were without effect. Together, nicotine preferentially impairs reflex tachycardia via disruption of adenosine A_2A receptor-mediated facilitation of reflex cardiac sympathoexcitation. Clinically, the attenuation by nicotine of compensatory sympathoexcitation may be detrimental in conditions such as hypothalamic defense response, posture changes, and ventricular rhythms.
Hemodynamic changes in the posterior cerebral circulation triggered by insufficient sympathetic innervation - Cause of primary intracerebral hemorrhage?
2011, Medical Hypotheses
Citation Excerpt :
As a result, rupture of previously weakened arteries will happen. In sudden onset of high blood pressure sympathetic autoregulation has ability to respond to brief changes in blood pressure, and according to some studies enhance myogenic response to stretched arteries [1,4,16–20]. This is also suggesting that myogenic autoregulation may be partly under autonomic control.
Primary intracerebral hemorrhage (ICH) is caused by hypertensive disease of small penetrating blood vessels in the basal ganglia, brain stem and cerebellum. Those regions are supplied by arteries of the so-called posterior brain circulation with insufficient sympathetic innervation. We propose the following hypothesis: due to insufficient sympathetic innervation hemodynamic changes occur in the vascular bed of the posterior brain circulation serving as a key factor for arterial rupture. If autoregulation is insufficient to maintain normal cerebral blood flow, in abrupt rise in the blood pressure, the amount of blood is rising causing higher static pressure, and according to Laplace’s law higher pressure and larger radius leads to higher wall tension and subsequent rupture of arterial wall previously weakened by prolonged hypertension.

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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

Summary

Section snippets

Hypothesis

Stroke and carotid stenosis

Implications

Cardiol Clin

Neuroscience

Am J Hypertens

J Vasc Surg

Eur J Vasc Surg

Brain Res

Med Hypotheses

Med Hypotheses

Stroke trends in the WHO MONICA project

Stroke

Causes and severity of ischemic stroke in patients with internal carotid artery stenosis

JAMA

Early clinical differentiation of cerebral infarction from severe atherosclerotic stenosis and cardioembolism

Stroke

Infarcts of undetermined cause: the NINCDS Stroke Data Bank

Ann Neurol

The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators

N Engl J Med

Risk of stroke in the distribution of an asymptomatic carotid artery

Lancet

Vascular risks of asymptomatic carotid stenosis

Stroke

Outcome of asymptomatic patients with carotid disease. Asymptomatic cervical bruit study group

Neurology

Effect of carotid endarterectomy or stenting on impairment of dynamic cerebral autoregulation

Stroke