Acute unilateral carotid baroreceptor denervation.
The first report on baroreceptor denervation in humans appeared in the 1930s (Bucy, 1936). Unilateral section of the glossopharyngeal nerve in five patients with glossopharyngeal neuralgia produced a prompt and pronounced rise in blood pressure in four out of five patients, which lasted from 5 to 12 days. This phenomenon was recognized as an effect of disruption of ‘nervous impulses from the carotid sinus which have a reducing effect on blood pressure’. In 1956 a patient died from a fatal hypertensive crisis following unilateral carotid sinus denervation, which had been performed for the relief of recurrent syncope due to a hypersensitive carotid sinus syndrome (Ford, 1956).
Lability of blood pressure in the hours following unilateral carotid endarterectomy for symptomatic carotid stenosis has been attributed to carotid baroreflex dysfunction (Ille et al. 1995; Ejaz & Meschia, 1999). However, in the acute phase following carotid endarterectomy, baroreflex sensitivity has been reported to be increased, decreased or unaltered (Tyden et al. 1980; Hirschl et al. 1991; Landesberg et al. 1998). Apart from trauma to the carotid sinus, baroreceptors or to the carotid sinus nerve (Angell-James & Lumley, 1974), removal of an atherosclerotic plaque may have a beneficial effect on baroreflex function by means of changes in the mechanical properties of the carotid sinus arterial wall and re-integration of baroreceptor areas into circulatory regulation (Angell-James & Lumley, 1974). In addition, the effect of unilateral carotid endarterectomy depends on the compensatory ability of the contralateral baroreceptor integrity. This may be limited by atherosclerotic changes in the non-operated carotid artery, since in atherosclerosis distensibility of the carotid sinus vessel wall and sensitivity of baroreceptors are reduced (Sleight, 1976; Randall et al. 1976).
Although evidence for lateralization of certain human autonomic control functions has been published (Hilz et al. 2001), a differential effect of left- versus right-sided deafferentiation of carotid baroreceptors has not been reported.
Long-term effects of unilateral carotid baroreceptor denervation.
In a prospective study, the effects of unilateral carotid endartectomy on carotid sinus baroreflex function were measured in 25 patients (Dehn & Angell-James, 1987). Six months after surgery, no overall change in blood pressure was found. Baroreflex sensitivity decreased in 2, remained unchanged in 15 and increased in 8 patients. Thus, similar to the findings in the acute phase following surgery, the long-term effects on baroreflex function were heterogeneous among individuals.
In a retrospective study on the effects of unilateral carotid endarterectomy (Timmers et al. 2001a), at a median interval of 4.3 years after surgery, baroreflex sensitivity was significantly lower in endarterectomized patients than in patients with an untreated uni-/bilateral carotid stenosis and healthy controls. So in these patients an unfavourable effect on baroreflex sensitivity prevailed. Despite this, ambulatory blood pressure level and variability did not differ between groups.
Long-term effects of bilateral carotid baroreceptor denervation.
In 1993, chronic failure of the baroreflex due to bilateral carotid denervation was described as a separate clinical syndrome, characterized by a limited blood pressure buffering capacity against excessive rises or falls in response to emotional and physical stimuli (Robertson et al. 1993) (Fig. 2A). Symptoms and signs included headache, palpitations, diaphoresis and pale flushing. They bear a strong resemblance to those of a phaeochromocytoma. In baroreflex failure, desinhibition of central activation of efferent sympathetic pathways arises from the absence of tonic inhibitory baroreceptor input to the vasomotor centres of the brainstem (Robertson et al. 1993; Persson, 1996). Apart from volatile hypertension, which is most common, baroreflex failure has a broad spectrum of other clinical presentations including predominant hypotension, orthostatic tachycardia and intolerance and malignant vagotonia with severe bradycardia, depending on the extent of baroreceptor denervation and concomitant destruction of autonomic structures (Kochar et al. 1984; Jordan et al. 1997; Ketch et al. 2002). Centrally acting sympatholytic agents like clonidine may reduce the frequency and severity of the attacks (Robertson et al. 1993; Biaggioni et al. 1994; Ejaz & Meschia, 1999).
Figure 2. Blood pressure variability following carotid sinus baroreceptor denervation
A, 24 h ambulatory blood pressure profile during normal daily activities characterized by labile hyper- and hypotension in a patient with baroreflex failure due to radiotherapy of the neck for nasopharyngeal carcinoma (Timmers et al. 1999). Dotted lines indicate upper levels for diastolic (< 90 mmHg) and sytolic (< 140 mmHg) normotension. B, individual frequency histograms of blood pressure calculated from 5 h ambulatory beat-by-beat recordings in 12 healthy controls (bottom left) and 8 patients after bilateral carotid body tumour resection (bottom right). x-axis: MAP = mean arterial pressure, y-axis: frequency of MAP level as percentage of total number of frequencies. Carotid body resected patients exhibit a broader distribution of MAP, indicating higher blood pressure variability. ‘Modal MAP’ refers to the MAP with the highest frequency during the individual blood pressure tracing.
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Long-term effects of bilateral baroreceptor denervation have been investigated in patients who had suffered from acute baroreflex failure following bilateral carotid body tumour resection (Smit et al. 2002). Ambulatory blood pressure level was found to remain slightly elevated as compared to pre-operative values. Overt hypertension, however, appears to be limited to the days and months following surgical carotid baroreceptor denervation, whereas episodic surges of hyper- as well as hypotension may persist for a longer period (Holton & Wood, 1965; Robertson et al. 1993; De Toma et al. 2000).
Retrospective studies were performed in patients who had undergone similar surgery, with a mean interval between the second (i.e. contralateral) operation and the study of 3.4 years (Timmers et al. 2003a). At the time of the study, at least 1 year after surgery, ambulatory blood pressure levels were normal in all patients. In the absence of chronic clinically overt baroreflex failure, vagal baroreflex sensitivity, calculated from the reflex changes in RR interval to phenylephrine injections (Smyth et al. 1969), was approximately 50 % lower in these patients than in healthy age-matched controls. The subnormal vagal baroreflex gain also emerged from minimal reciprocal heart rate changes during phase II blood pressure decrease and phase IV blood pressure overshoot during Valsalva's manoeuvre (Goldstein et al. 1982; Wieling & Karemaker, 1999). In addition, microneurography recording in a subgroup of five carotid body resected patients showed, that the baroreflex modulation of muscle sympathetic nerve activity (MSNA) was profoundly affected as well (Timmers et al. 2003b). These studies indicate that bilateral carotid sinus trauma causes permanent impairment of vagal as well as sympathetic baroreflex sensitivity. In these patients, the additional finding of an increased ambulatory blood pressure variability was explained by a lower baroreflex sensitivity (Fig. 2B). In hypertensives, baroreflex sensitivity has been shown to be negatively correlated with blood pressure variability (Mancia et al. 1986).
Chronic baroreflex failure has been reported as a late complication of radiotherapy of the neck (Robertson et al. 1983; Robertson et al. 1993; Timmers et al. 1999). Changes in carotid sinus baroreceptor function may be induced by irradiation damage to the carotid sinus and/or the glossopharyngeal nerves, although cranial nerve palsies are uncommon complications after radiotherapy to the neck (Cheng & Schultz, 1975). Alternatively, arterial baroreflex function may have been altered by structural changes of the internal carotid artery wall. Irradiation-induced atherosclerosis (Cheng et al. 1999) and fibrosis (Zidar et al. 1997) may result in a decreased distensibility of the carotid sinus and thereby may reduce stretch-induced afferent carotid sinus nerve activity (Angell-James, 1974).
The impact of neck irradiation for laryngeal or pharyngeal carcinoma on baroreflex function was retrospectively studied in 12 patients who had undergone bilateral radiation therapy for locally advanced laryngeal or pharyngeal cancer (Timmers et al. 2002). Irradiation fields included the carotid sinus area and the median interval between completion of radiotherapy and time of investigation was 3.3 years. Baroreflex sensitivity was 45 % lower in patients than in matched healthy controls. Ambulatory blood pressure variability was not different from matched control subjects. Although baroreflex sensitivity was decreased after neck irradiation, blood pressure buffering was unaffected.
In summary, labile hypertension due to baroreflex failure may arise from both uni- and bilateral carotid baroreceptor denervation. The incidence of this syndrome following carotid body tumour surgery, radiotherapy of the neck and carotid endarterectomy is low. Baroreflex dysfunction after unilateral denervation is usually mild and transient. In the long term following bilateral carotid denervation, the expression of baroreflex dysfunction is heterogeneous. Bilateral carotid denervation in humans does not elicit chronic hypertension, but in contrast to other investigated species, it causes a long-term increase of blood pressure variability. In humans, carotid baroreceptors are more important for dynamic than static blood pressure control. A chronic decrease in blood pressure buffering following carotid denervation suggests that humans have less potent compensatory mechanisms for loss of carotid baroreflex function than other investigated species. This may be due to our upright position, whereby tonic sympathoinhibitory influences from cardiac and pulmonary baroreceptors have become less than in quadruped species (Shade et al. 1991). As a consequence of a minor role for cardiac and pulmonary baroreceptors, loss of arterial baroreceptor function in humans may have a larger impact on blood pressure homeostasis.
Previous studies on the relative importance of carotid versus aortic baroreceptors in intact humans have yielded contrasting results. Experiments on selective (un)loading of aortic baroreceptors by simultaneous infusion of vasoactive substances and application of neck suction/pressure in order to maintain a stable carotid sinus transmural pressure, indicated that aortic baroreceptors are dominant in the baroreflex control of heart rate, with the carotid baroreceptors contributing only about 30 % (Mancia et al. 1977; Ferguson et al. 1985). In line with these observations, baroreflex control of heart rate is more importantly determined by the distensibility of the aortic arch than of the carotid sinus (Lenard et al. 2001). In contrast, combined neck suction/pressure with non-pharmacological (de)loading of aortic baroreceptors, indicate, that carotid baroreceptors are the principal contributors to baroreflex control of heart rate (Fadel et al. 2003). Our review of studies on iatrogenic denervation is in agreement with the latter study. These studies in intact humans should be interpreted with caution, however, since the baroreceptors respond to stretch and not pressure. The stimulus to be measured should be the diameter of the arteries and not blood pressure. Changes of dimensions of the baroreceptive arteries during the several interventions were not measured.