Unilateral Carotid Body Resection in Resistant Hypertension

Summary Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.

F ound bilaterally at the bifurcation of the common carotid artery, the carotid bodies (CBs) are strategically located to ensure that adequate oxygen is supplied to the brain. With the highest blood flow per tissue weight of any organ (1), they are exquisitely sensitive to small alterations in blood oxygen, carbon dioxide, pH, and blood flow itself (2,3). Despite their small size, the CBs exert powerful reflex effects on the respiratory and cardiovascular system (4) that have been preserved through evolution and are deemed pivotal for survival (5), perhaps due to their defensive reflex role. This powerful afferent system normally remains quiescent at sea level in resting conditions, but during hypoxia, the CBs are activated, increasing ventilation, increasing sympathetic activity, inducing alkalosis, and contributing to periodic breathing during sleep (6,7).
In patients with hypertension, the CBs exhibit both hyper-reflexia and aberrant discharge; in sleep apnea, the activation of the CBs is, in part, responsible for the excessive sympathetic activity and hypertension associated with this condition (8). Moreover, the hypertension evoked in a rat model of sleep apnea (by chronic intermittent hypoxia), is reliant on afferent activity generated by the CBs (9), and patients with hypertension may have exaggerated peripheral chemoreflex sensitivity to hypoxia (10,11). Additionally, acute reversible inactivation of the CBs, with hyperoxia, caused a transient reduction in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in patients with hypertension (12). In rats with hypertension, severing the connection between the CBs and brain lowered both arterial pressure and sympathetic activity chronically (13). These data point toward the CBs as a therapeutic target to treat sympathetically mediated diseases (14). The global clinical problem and financial burden of hypertension continues to escalate (15), and 8% to 14% of the 1 billion patients with hypertension worldwide are drug resistant or intolerant (16). Therefore, new approaches for treating drug-resistant hypertension are justified, as are studies to identify the targets/ mechanisms driving hypertension. We describe the first prospective proof-of-concept, safety and feasibility study of unilateral (u) CB excision from a cohort of patients with drug-resistant hypertension.
We report, secondarily, on the proportion of these patients that showed a response in BP, the hypoxic ventilatory response (HVR), and MSNA.

Carotid Chemoreceptors and Human Hypertension
A U G U S T 2 0     Values are n/n (N) or mean AE SEM.

Carotid Chemoreceptors and Human Hypertension
A U G U S T 2 0 1 6 : 3 1 3 -2 4 over 5 to 20 min of quiet supine rest. Bursts were identified, and their frequency (Hz) and incidence (per 100 heart beats) were measured. Heart rate variability (HRV) was calculated using an add-on in Lab-Chart (AD Instruments) using spectral analysis conforming to previous guidelines (22) The spontaneous MSNA BRS was calculated using DBP and a similar calculation to that described previously (23).
SURGERY. The surgical removal of the CB was performed following the procedure described by Winter (24). Under either general or local anesthesia with sedation, an incision was made over the anterior aspect of the sternocleidomastoid muscle, one-third of the distance between the angle of the mandible and the clavicle, and over the region of the carotid bifurcation as identified via ultrasound/computed tomography angiography. The sternocleidomastoid muscle was retracted laterally along with the internal jugular vein to expose the carotid bifurcation. By gentle retraction of the external carotid artery (in some cases, the superior thyroid artery was cut to enhance retraction), the intercarotid septum was  Abbreviations as in Table 1.

RESULTS
SAFETY. There were 2 serious adverse events consisting of prolonged hospitalization of patients with BP that was difficult to control. One of the events occurred shortly after the CB removal procedure, and this event was judged by the Clinical Events Committee (CEC) to be "possibly related" to the unilateral removal of the CB. In the other patient, multiple hospitalizations occurred for BP control before and after uCB removal, and the hospitalizations bore no consistent temporal relationship to the CB removal.
These hospitalizations were, therefore, judged by the CEC to be "unrelated" or "unlikely to be related" to the uCB.  Table 5), and although blood oxygen fell to lower minimal levels during desaturation episodes (from 87 AE 1% to 81 AE 1%; p < 0.05), there were no changes in the apnea-hypopnea index, apnea duration, baseline blood oxygen saturation, and average blood desaturation (Supplemental Table 5).   Table 2). We next determined if there was a proportion of patients that showed a reduction in BP and whether this correlated with any other measured variable.  Figure 3A). Night-time ASBP was also reduced at 3-month (À20 AE 4 mm Hg; p < 0.0243), 6-month (À16 AE 5 mm Hg; p < 0.047) and at 12-month follow-ups (À15 AE 6 mm Hg; although p ¼ 0.067) compared with screening ( Figure 3B) with 24-h ASBP following a similar time-course ( Figure 3C).
Comparing both day and night ASBP between responders and nonresponders, there were significant differences between patient groups at all time points However, compared with baseline, responders exhibited a decrease in total MSNA burst area/min at 3 months (À374 AE 102%$s/min; p ¼ 0.0137) and 6 months (À520 AE 135%$s/min; p ¼ 0.0296), but not at the 12-month follow-up (p ¼ 0.74) ( Figure 4C).
In contrast, total MSNA burst area/min compared with baseline did not change at any follow-up time in the nonresponders ( Figure 4C).  p ¼ 0.52) compared with baseline ( Figure 4D). There was no change in BRS relative to baseline in nonresponders at any time point ( Figure 4D) (p > 0.05).

CHARACTERISTIC DISTINCTIONS BETWEEN RESPONDERS
AND NONRESPONDERS. Before surgery and compared with nonresponders, responders had a higher hypoxic ventilatory response (p < 0.027) and faster ventilatory frequency (p < 0.025) ( Table 2) at baseline consistent with higher peripheral chemoreflex sensitivity and drive, respectively. Moreover, they consistently had the right carotid body removed.

DISCUSSION
The present first-in-man, proof-of-principle study was concerned with investigating the safety and feasibility of unilateral surgical resection of CB as a therapy in patients with drug-resistant hypertension. We found that this procedure was safe as As recently reviewed, CB resection (unilateral and bilateral) has been performed historically for the treatment of dyspnea in patients with asthma and chronic obstructive pulmonary disease (14). In 1 of these studies, a chronic reduction in BP was noted in patients who had hypertension, which was maintained for 6 months when the study ended; there was no BP change in the normotensive group (25).  data seen transiently using hyperoxia to inhibit CB afferent activity in humans with hypertension (12).
We also noted an improvement in MSNA BRS in the responder but not in the nonresponder patients, which could contribute mechanistically to the lowering of BP. This finding is consistent with the known antagonism between peripheral chemoreceptor and baroreflex function (10). baseline, and at 1-, 3-, 6-, and 12-month follow-ups (represented as change from screening). Two-way repeated measures analysis of variance was used (within groups *p < 0.05, **p < 0.01, ***p < 0.001; between groups †p < 0.05, † †p < 0.01, † † †p < 0.01). Abbreviations as in Figure 2.  Inflammation is also present in the CB of hypertensive rats (28) and may trigger release of cytokines, chemokines, and reactive oxygen species that could

FIGURE 4 Sympathetic Activity and its Baroreflex Control After uCB Resection
Representative raw muscle sympathetic nerve activity (MSNA) for a responder (A 1 ) and nonresponder (A 2 ) at baseline (left trace) and 6-month follow-up (right trace). (B) There was no difference in MSNA burst incidence between responders and nonresponders. However, MSNA area was reduced after uCB resection in the responders but not nonresponders (C), and spontaneous MSNA area baroreflex gain improved in responders but not in nonresponders (D). Two-way repeated measures analysis of variance was used (within groups *p < 0.05; between groups †p < 0.05); bursts/100HB ¼ bursts per 100 heart beats; other abbreviations as in Figure 2.

Carotid Chemoreceptors and Human Hypertension
A U G U S T 2 0  Carotid Chemoreceptors and Human Hypertension