1.3. Carotid body – a unifying hypothesis?
While an array of triggers incite or initiate downstream consequences such as prolonged bed rest or an autoimmune neuropathy that result in the POTS phenotype (in a manner analogous to the swiss cheese model of accident causation), we submit that chronic intermittent hypoxia (CIH) experienced by the carotid body constitutes an integral part of at least one pathway to dysautonomia. The carotid body (CB) is the primary
peripheral chemoreceptor, responding primarily to hypoxia, and to a lesser extent hypercapnia, acidosis, and hypoperfusion (
Iturriaga, 2018;
Dempsey and Smith, 2014), the latter being of particular interest. It is the most perfused organ per gram weight in the body. CB activation by hypercapnia or hypoxia causes circulatory changes in addition to expected hyperpnea: blood pressure and heart rate rise due to sympathetic efferent neuronal activation of vascular beds (
Marshall, 1994). The adjacent carotid sinus contains
mechanoreceptors that sense acute blood pressure changes, giving rise to the afferent arm of the
baroreflex that increases heart rate, vascular SNA, and peripheral
vasoconstriction in response to decreased
venous return upon assumption of upright posture. Interactions between
chemoreflex and baroreflex are recognized (
Prabhakar et al., 2005) spawning the notion of a ventilatory baroreflex (
Stewart et al., 2011), but
current evidence indicates that interaction between baroreflex and chemoreflex occurs in the brainstem. The CB chemoreflex has the unique ability to activate sympathetic traffic to peripheral blood vessels and increase cardiac vagal activity simultaneously and said chemoreflex and baroreflex are inseparably linked in their control of SNA. The CB is not only a multi-modal sensor but sends nonspecific tonic input to the medullary, respiratory pattern-generating, neurons through multiple CNS pathways. Moreover, it is a key intercessor of vascular SNA via medullary tracts independent of the brainstem respiratory network (
Dempsey and Smith, 2014). Pathways involved in chemo- and baro-receptor coupling are unclear but baro-mediated
respiratory effects have been recorded in medullary rhythm-generating neurons, which sit very near barosensitive sympathetic premotor neurons regulating vasomotor tone (
McMullan and Pilowsky, 2010).
Recent research underscores the importance of CB involvement in common disorders where aberrant sympathetic nervous system activation plays a key role (
Iturriaga, 2018;
Paton et al., 2013).
The overarching stimulus in these conditions is CIH. This phenomenon is most evident in heart failure whereupon low cardiac output and reduced carotid chemoreceptor blood flow results in stagnant hypoxia of the carotid body (
Ding et al., 2011). Central hypovolemia is a cardinal feature of POTS: evidence supports excessive reduction of central blood volume in typical POTS patients when upright and we demonstrated that central blood volume is reduced in POTS (
Stewart et al., 2018a). This predisposes patients to hypoperfusion of tissues cephalad to the heart, causing stagnant hypoxia from reduced
carotid blood flow – a key step causing SNA activation (
Marshall, 1994;
Prabhakar et al., 2005) in the pathophysiologic cascade in POTS. Indeed, initial orthostatic hypotension is more frequent in POTS than in controls, affecting 50% of POTS patients, with a lower minimum blood pressure (
Stewart et al., 2020). Thereafter, hypocapnia and reduced cardiac output in POTS maintains low cerebral blood flow and low carotid blood flow even though BP has normalized by vasoconstriction. Individuals do not spend all their time in the upright position, and patients often learn to assume a horizontal posture to relieve symptoms, setting the stage for intermittent carotid body and sinus hypoperfusion. Symptom chronicity then develops from repeated, continual
sympathetic stimulation via prolonged CB excitation due to CIH. (
Fig. 2). Hyperventilation following brief hypoxic episodes interspersed with normoxia results in increased SNA that is sustained over an hour or more – so-called long-term facilitation (
Mitchell et al., 1985). There are several mechanisms which perpetuate this sympathetic activation following cessation of CB stimulation (
Iturriaga, 2018). Increased CB chemoreceptor sensitivity and central processing of the carotid body afferent inputs may both contribute to enhanced SNA (
Prabhakar et al., 2005). Enhanced CB discharge further augments SNA, which, along with reduction in baroreflex efficiency, impairs control of vasomotor tone (
Iturriaga, 2018). Repeated exposure to brief hypoxic episodes increases respiratory-sympathetic coupling (
Prabhakar et al., 2015), setting up a vicious cycle. Moreover, central adaptive responses also occur with CIH, e.g. persistently high, tonic hyperactivity of medullary neurons (
Guyenet et al., 2018).
